4097 lines
224 KiB
Plaintext
4097 lines
224 KiB
Plaintext
Subject: PiHKAL: The Chemical Story. File 1 of 6
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This is part 1 of 6 of the second half of PiHKAL: A Chemical Love
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Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos
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or misprints in this file; further, because of ASCII limitations,
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many of the typographical symbols in the original book could not be
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properly represented in these files.
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If you are seriously interested in the chemistry contained in these
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files, you should order a copy of the book PiHKAL. The book may be
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purchased for $22.95 ($18.95 + $4.00 postage and handling) from
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Transform Press, Box 13675, Berkeley, CA 94701. California residents
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please add $1.38 State sales tax.
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At the present time, restrictive laws are in force in the United
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States and it is very difficult for researchers to abide by the
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regulations which govern efforts to obtain legal approval to do work
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with these compounds in human beings.... No one who is lacking legal
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authorization should attempt the synthesis of any of the compounds
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described in these files, with the intent to give them to man. To do
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so is to risk legal action which might lead to the tragic ruination of
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a life. It should also be noted that any person anywhere who
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experiments on himself, or on another human being, with any of the
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drugs described herin, without being familiar with that drug's action
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and aware of the physical and/or mental disturbance or harm it might
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cause, is acting irresponsibly and immorally, whether or not he is
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doing so within the bounds of the law.
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A SHORT INDEX TO THE PHENETHYLAMINES
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This short index to the phenethylamines lists the 179 entries that
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follow in alphebetical order. The abbreviation PEA is for
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phenethylamine, and A is for amphetamine. The long index includes all
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synonyms and is in Appendix A.
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Code Compact chemical name
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1 AEM a-Ethyl-3,4,5-trimethoxy-PEA
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2 AL 4-Allyloxy-3,5-dimethoxy-PEA
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3 ALEPH 4-Methylthio-2,5-dimethoxy-A
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4 ALEPH-2 4-Ethylthio-2,5-dimethoxy-A
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5 ALEPH-4 4-Isopropylthio-2,5-dimethoxy-A
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6 ALEPH-6 4-Phenylthio-2,5-dimethoxy-A
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7 ALEPH-7 4-Propylthio-2,5-dimethoxy-A
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8 ARIADNE 2,5-Dimethoxy-a-ethyl-4-methyl-PEA
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9 ASB 3,4-Diethoxy-5-methoxy-PEA
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10 B 4-Butoxy-3,5-dimethoxy-PEA
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11 BEATRICE 2,5-Dimethoxy-4,N-dimethyl-A
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12 BIS-TOM 2,5-Bismethylthio-4-methyl-A
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13 BOB 4-Bromo-2,5,'-trimethoxy-PEA
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14 BOD 2,5,'-Trimethoxy-4-methyl-PEA
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15 BOH '-Methoxy-3,4-methylenedioxy-PEA
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16 BOHD 2,5-Dimethoxy-'-hydroxy-4-methyl-PEA
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17 BOM 3,4,5,'-Tetramethoxy-PEA
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18 4-Br-3,5-DMA 4-Bromo-3,5-dimethoxy-A
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19 2-Br-4,5-MDA 2-Bromo-4,5-methylenedioxy-A
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20 2C-B 4-Bromo-2,5-dimethoxy-PEA
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21 3C-BZ 4-Benzyloxy-3,5-dimethoxy-A
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22 2C-C 4-Chloro-2,5-dimethoxy-PEA
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23 2C-D 4-Methyl-2,5-dimethoxy-PEA
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24 2C-E 4-Ethyl-2,5-dimethoxy-PEA
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25 3C-E 4-Ethoxy-3,5-dimethoxy-A
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26 2C-F 4-Fluoro-2,5-dimethoxy-PEA
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27 2C-G 3,4-Dimethyl-2,5-dimethoxy-PEA
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28 2C-G-3 3,4-Trimethylene-2,5-dimethoxy-PEA
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29 2C-G-4 3,4-Tetramethylene-2,5-dimethoxy-PEA
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30 2C-G-5 3,4-Norbornyl-2,5-dimethoxy-PEA
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31 2C-G-N 1,4-Dimethoxynaphthyl-2-ethylamine
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32 2C-H 2,5-Dimethoxy-PEA
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33 2C-I 4-Iodo-2,5-dimethoxy-PEA
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34 2C-N 4-Nitro-2,5-dimethoxy-PEA
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35 2C-O-4 4-Isopropoxy-2,5-dimethoxy-PEA
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36 2C-P 4-Propyl-2,5-dimethoxy-PEA
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37 CPM 4-Cyclopropylmethoxy-3,5-dimethoxy-PEA
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38 2C-SE 4-Methylseleno-2,5-dimethoxy-PEA
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39 2C-T 4-Methylthio-2,5-dimethoxy-PEA
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40 2C-T-2 4-Ethylthio-2,5-dimethoxy-PEA
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41 2C-T-4 4-Isopropylthio-2,5-dimethoxy-PEA
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42 Y-2C-T-4 4-Isopropylthio-2,6-dimethoxy-PEA
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43 2C-T-7 4-Propylthio-2,5-dimethoxy-PEA
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44 2C-T-8 4-Cyclopropylmethylthio-2,5-dimethoxy-PEA
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45 2C-T-9 4-(t)-Butylthio-2,5-dimethoxy-PEA
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46 2C-T-13 4-(2-Methoxyethylthio-2,5-dimethoxy-PEA
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47 2C-T-15 4-Cyclopropylthio-2,5-dimethoxy-PEA
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48 2C-T-17 4-(s)-Butylthio-2,5-dimethoxy-PEA
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49 2C-T-21 4-(2-Fluoroethylthio)-2,5-dimethoxy-PEA
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50 4-D 4-Trideuteromethyl-3,5-dimethoxy-PEA
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51 '-D ','-Dideutero-3,4,5-trimethoxy-PEA
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52 DESOXY 4-Me-3,5-Dimethoxy-PEA
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53 2,4-DMA 2,4-Dimethoxy-A
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54 2,5-DMA 2,5-Dimethoxy-A
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55 3,4-DMA 3,4-Dimethoxy-A
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56 DMCPA 2-(2,5-Dimethoxy-4-methylphenyl)-
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cyclopropylamine
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57 DME 3,4-Dimethoxy-'-hydroxy-PEA
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58 DMMDA 2,5-Dimethoxy-3,4-methylenedioxy-A
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59 DMMDA-2 2,3-Dimethoxy-4,5-methylenedioxy-A
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60 DMPEA 3,4-Dimethoxy-PEA
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61 DOAM 4-Amyl-2,5-dimethoxy-A
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62 DOB 4-Bromo-2,5-dimethoxy-A
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63 DOBU 4-Butyl-2,5-dimethoxy-A
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64 DOC 4-Chloro-2,5-dimethoxy-A
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65 DOEF 4-(2-Fluoroethyl)-2,5-dimethoxy-A
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66 DOET 4-Ethyl-2,5-dimethoxy-A
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67 DOI 4-Iodo-2,5-dimethoxy-A
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68 DOM 4-Methyl-2,5-dimethoxy-A
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69 Y-DOM 4-Methyl-2,6-dimethoxy-A
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70 DON 4-Nitro-2,5-dimethoxy-A
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71 DOPR 4-Propyl-2,5-dimethoxy-A
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72 E 4-Ethoxy-3,5-dimethoxy-PEA
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73 EEE 2,4,5-Triethoxy-A
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74 EEM 2,4-Diethoxy-5-methoxy-A
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75 EME 2,5-Diethoxy-4-methoxy-A
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76 EMM 2-Ethoxy-4,5-dimethoxy-A
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77 ETHYL-J N,a-diethyl-3,4-methylenedioxy-PEA
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78 ETHYL-K N-Ethyl-a-propyl-3,4-methylenedioxy-PEA
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79 F-2 Benzofuran-2-methyl-5-methoxy-6-
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(2-aminopropane)
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80 F-22 Benzofuran-2,2-dimethyl-5-methoxy-6-
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(2-aminopropane)
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81 FLEA N-Hydroxy-N-methyl-3,4-methylenedioxy-A
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82 G-3 3,4-Trimethylene-2,5-dimethoxy-A
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83 G-4 3,4-Tetramethylene-2,5-dimethoxy-A
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84 G-5 3,4-Norbornyl-2,5-dimethoxy-A
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85 GANESHA 3,4-Dimethyl-2,5-dimethoxy-A
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86 G-N 1,4-Dimethoxynaphthyl-2-isopropylamine
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87 HOT-2 2,5-Dimethoxy-N-hydroxy-4-ethylthio-PEA
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88 HOT-7 2,5-Dimethoxy-N-hydroxy-4-(n)-propylthio-PEA
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89 HOT-17 2,5-Dimethoxy-N-hydroxy-4-(s)-butylthio-PEA
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90 IDNNA 2,5-Dimethoxy-N,N-dimethyl-4-iodo-A
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91 IM 2,3,4-Trimethoxy-PEA
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92 IP 3,5-Dimethoxy-4-isopropoxy-PEA
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93 IRIS 5-Ethoxy-2-methoxy-4-methyl-A
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94 J a-Ethyl-3,4-methylenedioxy-PEA
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95 LOPHOPHINE 3-Methoxy-4,5-methylenedioxy-PEA
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96 M 3,4,5-Trimethoxy-PEA
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97 4-MA 4-Methoxy-A
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98 MADAM-6 2,N-Dimethyl-4,5-methylenedioxy-A
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99 MAL 3,5-Dimethoxy-4-methallyloxy-PEA
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100 MDA 3,4-Methylenedioxy-A
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101 MDAL N-Allyl-3,4-methylenedioxy-A
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102 MDBU N-Butyl-3,4-methylenedioxy-A
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103 MDBZ N-Benzyl-3,4-methylenedioxy-A
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104 MDCPM N-Cyclopropylmethyl-3,4-methylenedioxy-A
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105 MDDM N,N-Dimethyl-3,4-methylenedioxy-A
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106 MDE N-Ethyl-3,4-methylenedioxy-A
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107 MDHOET N-(2-Hydroxyethyl)-3,4-methylenedioxy-A
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108 MDIP N-Isopropyl-3,4-methylenedioxy-A
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109 MDMA N-Methyl-3,4-methylenedioxy-A
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110 MDMC N-Methyl-3,4-ethylenedioxy-A
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111 MDMEO N-Methoxy-3,4-methylenedioxy-A
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112 MDMEOET N-(2-Methoxyethyl)-3,4-methylenedioxy-A
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113 MDMP a,a,N-Trimethyl-3,4-methylenedioxy-PEA
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114 MDOH N-Hydroxy-3,4-methylenedioxy-A
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115 MDPEA 3,4-Methylenedioxy-PEA
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116 MDPH a,a-Dimethyl-3,4-methylenedioxy-PEA
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117 MDPL N-Propargyl-3,4-methylenedioxy-A
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118 MDPR N-Propyl-3,4-methylenedioxy-A
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119 ME 3,4-Dimethoxy-5-ethoxy-PEA
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120 MEDA 3,4-Ethylenedioxy-5-methoxy-A
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121 MEE 2-Methoxy-4,5-diethoxy-A
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122 MEM 2,5-Dimethoxy-4-ethoxy-A
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123 MEPEA 3-Methoxy-4-ethoxy-PEA
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124 META-DOB 5-Bromo-2,4-dimethoxy-A
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125 META-DOT 5-Methylthio-2,4-dimethoxy-A
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126 METHYL-DMA N-Methyl-2,5-dimethoxy-A
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127 METHYL-DOB 4-Bromo-2,5-dimethoxy-N-methyl-A
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128 METHYL-J N-Methyl-a-ethyl-3,4-methylenedioxy-PEA
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129 METHYL-K N-Methyl-a-propyl-3,4-methylenedioxy-PEA
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130 METHYL-MA N-Methyl-4-methoxy-A
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131 METHYL-MMDA-2 N-Methyl-2-methoxy-4,5-
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methylenedioxy-A
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132 MMDA 3-Methoxy-4,5-methylenedioxy-A
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133 MMDA-2 2-Methoxy-4,5-methylenedioxy-A
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134 MMDA-3a 2-Methoxy-3,4-methylenedioxy-A
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135 MMDA-3b 4-Methoxy-2,3-methylenedioxy-A
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136 MME 2,4-Dimethoxy-5-ethoxy-A
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137 MP 3,4-Dimethoxy-5-propoxy-PEA
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138 MPM 2,5-Dimethoxy-4-propoxy-A
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139 ORTHO-DOT 2-Methylthio-4,5-dimethoxy-A
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140 P 3,5-Dimethoxy-4-propoxy-PEA
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141 PE 3,5-Dimethoxy-4-phenethyloxy-PEA
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142 PEA PEA
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143 PROPYNYL 4-Propynyloxy-3,5-dimethoxy-PEA
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144 SB 3,5-Diethoxy-4-methoxy-PEA
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145 TA 2,3,4,5-Tetramethoxy-A
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146 3-TASB 4-Ethoxy-3-ethylthio-5-methoxy-PEA
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147 4-TASB 3-Ethoxy-4-ethylthio-5-methoxy-PEA
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148 5-TASB 3,4-Diethoxy-5-methylthio-PEA
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149 TB 4-Thiobutoxy-3,5-dimethoxy-PEA
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150 3-TE 4-Ethoxy-5-methoxy-3-methylthio-PEA
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151 4-TE 3,5-Dimethoxy-4-ethylthio-PEA
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152 2-TIM 2-Methylthio-3,4-dimethoxy-PEA
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153 3-TIM 3-Methylthio-2,4-dimethoxy-PEA
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154 4-TIM 4-Methylthio-2,3-dimethoxy-PEA
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155 3-TM 3-Methylthio-4,5-dimethoxy-PEA
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156 4-TM 4-Methylthio-3,5-dimethoxy-PEA
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157 TMA 3,4,5-Trimethoxy-A
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158 TMA-2 2,4,5-Trimethoxy-A
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159 TMA-3 2,3,4-Trimethoxy-A
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160 TMA-4 2,3,5-Trimethoxy-A
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161 TMA-5 2,3,6-Trimethoxy-A
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162 TMA-6 2,4,6-Trimethoxy-A
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163 3-TME 4,5-Dimethoxy-3-ethylthio-PEA
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164 4-TME 3-Ethoxy-5-methoxy-4-methylthio-PEA
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165 5-TME 3-Ethoxy-4-methoxy-5-methylthio-PEA
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166 2T-MMDA-3a 2-Methylthio-3,4-methylenedioxy-A
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167 4T-MMDA-2 4,5-Thiomethyleneoxy-2-methoxy-A
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168 TMPEA 2,4,5-Trimethoxy-PEA
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169 2-TOET 4-Ethyl-5-methoxy-2-methylthio-A
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170 5-TOET 4-Ethyl-2-methoxy-5-methylthio-A
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171 2-TOM 5-Methoxy-4-methyl-2-methylthio-A
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172 5-TOM 2-Methoxy-4-methyl-5-methylthio-A
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173 TOMSO 2-Methoxy-4-methyl-5-methylsulfinyl-A
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174 TP 4-Propylthio-3,5-dimethoxy-PEA
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175 TRIS 3,4,5-Triethoxy-PEA
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176 3-TSB 3-Ethoxy-5-ethylthio-4-methoxy-PEA
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177 4-TSB 3,5-Diethoxy-4-methylthio-PEA
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178 3-T-TRIS 4,5-Diethoxy-3-ethylthio-PEA
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179 4-T-TRIS 3,5-Diethoxy-4-ethylthio-PEA
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PHENETHYLAMINES
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#1 AEM; a-ETHYLMESCALINE; 2-AMINO-1-(3,4,5-TRIMETHOXYPHENYL)BUTANE; 1-(3,4,5-TRIMETHOXYPHENYL)-2-AMINOBUTANE
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SYNTHESIS: To a solution of 45 g 3,4,5-trimethoxybenzaldehyde in 1.2 L
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IPA, there was added 125 g nitropropane and 67.5 g t-butylammonium
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acetate and the reaction mixture was held at reflux for 16 h. This
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was poured into 6 L H2O, and extracted with 2x250 mL hexane. The
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pooled extracts were stripped of solvent under vacuum giving a residue
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that slowly set to a crystalline mass. On filtering, there was
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obtained 9.4 g of a crude yellow product which, on recrystallization
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from hexane provided 8.7 g of slightly sticky bright yellow crystals
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of 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1, with a mp of 71-73 !C.
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A second recrystallization from hexane gave fine yellow crystals with
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a mp of 72-73 !C. Attempts at the preparation of this nitrostyrene by
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the more conventional methods with ammonium acetate in acetic acid led
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either to the formation of a white product C23H30N2O8 which was
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composed of a molecule of the nitrostyrene, one of the benzaldehyde
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itself, and a molecule of ammonia, or to 3,4,5-trimethoxybenzonitrile,
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from reaction with the decomposition products of nitropropane.
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A stirred suspension of 5.9 g LAH in 310 mL anhydrous Et2O was held at
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a gentle reflux in an inert atmosphere. A solution of 8.5 g
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2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1 in 125 mL Et2O is added
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drop-wise over the course of 0.5 h. The reaction was maintained at
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reflux for 6 h, then cooled, and the excess hydride destroyed by the
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cautious addition of 300 mL 1.8 N H2SO4. The phases were separated,
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and the aqueous phase brought to a pH of 6 by the addition of a
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saturated Na2CO3 solution. The neutral solution was brought to a
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boil, and clarified by filtration through paper. To the hot filtrate
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there was added a solution of 8.9 g picric acid in 100 mL boiling
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EtOH. The mixture was stirred and cooled, with the formation of a
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heavy yellow crystalline mass. After standing in the ice tub for
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several hours the mixture was filtered, providing 8.0 g of the picrate
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salt with a mp of 176-181 !C from H2O. A solution of this salt in 300
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mL boiling H2O was treated with 60 mL concentrated HCl. On cooling,
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there was a deposition of picric acid, which was removed by
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filtration. The aqueous filtrate was washed with 3x50 mL
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nitrobenzene, then with 3x50 mL Et2O. The pH was brought above 9 by
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the addition of aqueous NaOH, and the filtrate was extracted with
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3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave
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a nearly colorless oil, which was dissolved in 300 mL anhydrous Et2O
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and saturated with hydrogen chloride gas. The white crystals of
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2-amino-1-(3,4,5-trimethoxyphenyl)butane hydrochloride (AEM) were
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removed by filtration, Et2Owashed, and air dried. They weighed 4.72
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g.
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DOSAGE: greater than 220 mg.
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DURATION: unknown.
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EXTENSIONS AND COMMENTARY: The extension of the two-carbon chain of
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mescaline by alpha-methylation to the three carbon chain of TMA
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approximately doubled the potency of the compound. And it was felt to
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be a completely logical possibility that, by extending it one more
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carbon atom, to the four carbon chain of alpha-ethyl-mescaline, it
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might double again. And following that logical progression, the
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doubling of potency with each additional carbon atom, the factor would
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be 2 to the 7th power by the alpha-octyl (or 256x that of mescaline,
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or a milligram as active dose) and with a side chain of a 70-carbon
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alkyl group (alpha-heptacontylmescaline) it would take just a single
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molecule to be intoxicating. This was rich fantasy stuff. As an
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active compound, just where would it go in the brain? With an
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80-carbon side-chain, would one-thousandth of a single molecule be
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enough for a person? Or might a single molecule intoxicate a thousand
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people? And how long a chain on the alpha-position might be
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sufficient that, by merely writing down the structure on a piece of
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paper, you would get high? Maybe just conceiving the structure in
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your mind would do it. That is, after all, the way of homeopathy.
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Maybe it was just as well that this added two-carbon side-chain with
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lowered activity was already enough to disprove the doubling pattern.
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But by the time this non-activity had been learned, the alpha series
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had already been pushed out quite aways. The machinery of making the
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appropriate nitroalkane was straightforward, by reaction of the alkyl
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halide with nitrous acid, and separating the unwanted nitrite ester
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from the wanted nitroalkane by fractional distillation. The
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nitrostyrenes all formed reasonably although often in terrible yields,
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and reduced reasonably, and all formed crystalline picrates for
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isolation and crystalline hydrochloride salts for pharmacological
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manipulation. But since the first of these, AEM, was not active,
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there was no enthusiasm for tasting anything higher. This family was
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never published; why publish presumably inactive and thus
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uninteresting material? The Table presents the properties of the
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precursor nitrostyrenes, and the product picrate and hydrochloride
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salts, at least whatever information I can still find after thirty
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years:
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TABLE. Physical Properties of the a-Alkylmescaline Homologues and
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their Precursor Nitrostyrenes
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Code Name NS mp !C picrate mp !C HCl mp !C
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APM Alpha-propylmescaline 82-83 214-218
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ABM Alpha-butylmescaline 73-74 169-174 182-184
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AAM Alpha-amylmescaline 54-55 162-163 155-158
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AHM Alpha-hexylmescaline 51-52
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ASM* Alpha-heptylmescaline 43-44
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AOM Alpha-octylmescaline **
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ANM Alpha-nonylmescaline 46-47 ***
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AUM Alpha-undecylmescaline ***
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* S is for septyl, to distinguish heptyl from hexyl. **Never
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made, as no nonylbromide could be located to make the needed
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nitrononane. ***The synthesis got as far as the nitrostyrene stage
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when the inactivity of AEM was determined, and the project was
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dropped.
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#2 AL; 4-ALLYLOXY-3,5-DIMETHOXYPHENETHYLAMINE;
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3,5-DIMETHOXY-4-ALLYLOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
|
|
its preparation), 100 mg decyltriethylammonium iodide, and 13.6 g
|
|
allyl iodide in 50 mL anhydrous acetone was treated with 6.9 g finely
|
|
powdered anhydrous K2CO3 and held at reflux for 16 h. The color
|
|
changed from a near-black to a light yellow. The mixture was
|
|
filtered, the solids washed with acetone, and the solvent from the
|
|
combined filtrate and washes removed under vacuum. The residue was
|
|
suspended in acidified H2O, and extracted with 3x100 mL CH2Cl2. The
|
|
pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl
|
|
(which lightened the color of the extract) and then stripped of
|
|
solvent under vacuum giving 12.4 g of an amber-colored oil. This was
|
|
distilled at 125-137 !C at 0.1 mm/Hg to yield 5.7 g of
|
|
3,5-dimethoxy-4-allyloxyphenylacetonitrile as a yellow oil. Anal.
|
|
(C13H15NO3S) C,H.
|
|
|
|
A suspension of 4.0 g LAH in 150 mL anhydrous THF under N2 was cooled
|
|
to 0 !C and vigorously stirred. There was added, dropwise, 2.8 mL
|
|
100% H2SO4, followed by 5.5 g
|
|
3,5-dimethoxy-4-allyloxyphenylacetonitrile in 10 mL anhydrous THF.
|
|
The reaction mixture was stirred at 0 !C for a few min, then brought
|
|
to a reflux on the steam bath for 30 min. After cooling back to room
|
|
temperature, there was added sufficient IPA to destroy the excess
|
|
hydride, followed by sufficient 10% NaOH to form granular solids.
|
|
These were removed by filtration, and washed with 20 mL IPA. The
|
|
filtrate and washes were stripped of solvent under vacuum andthe
|
|
residue added to 100 mL dilute H2SO4. This was washed with 2x50 mL
|
|
CH2Cl2, made basic with aqueous NaOH, and extracted with 2x75 mL
|
|
CH2Cl2. These extracts were pooled, the solvent removed under vacuum,
|
|
and the residue distilled at 110-120 !C at 0.4 mm/Hg to give 4.9 g of
|
|
a colorless oil. This was dissolved in 15 mL IPA, neutralized with
|
|
concentrated HCl (55 drops required), and diluted with 50 mL Et2O.
|
|
The product was removed by filtration, washed with Et2O, and air dried
|
|
to give 4.9 g of 3,5-dimethoxy-4-allyloxyphenethylamine hydrochloride
|
|
(AL) as white crystals.
|
|
|
|
DOSAGE: 20 - 35 mg.
|
|
|
|
DURATION: 8 - 12 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 24 mg) I first became aware of something
|
|
in about 10 minutes, a pleasant increase in energy. By 20 minutes it
|
|
was getting pronounced and was a nice, smooth development. During the
|
|
next hour positive and negative feelings developed simultaneously.
|
|
Following a suggestion, I ate a bit of food even though I had not been
|
|
hungry, and to my surprise all the negative feelings dropped away. I
|
|
felt free to join the others wherever they were at. I moved into the
|
|
creative, free-flowing kind of repertoire which I dearly love, and
|
|
found everything enormously funny. Much of the laughter was so deep
|
|
that I felt it working through buried depressions inside me and
|
|
freeing me. From this point on, the experience was most enjoyable.
|
|
The experience was characterized by clear-headedness and an abundance
|
|
of energy which kept on throughout the day and evening. At one point
|
|
I went out back and strolled along to find a place to worship. I had
|
|
a profound sense of the Presence and great love and gratitude for the
|
|
place, the people, and the activities taking place. The come-down
|
|
from the experience was very gradual and smooth. Food tasted
|
|
wonderful. I went to bed late, and quite ready for bed, although the
|
|
energy was still running. However, sleep was not long in coming.
|
|
|
|
(with 24 mg) The onset was extremely gradual and graceful, with the
|
|
first alert that one could really sense at about 50 minutes. This was
|
|
succeeded by a slow gentle climb to the peak at one hour and fifteen
|
|
minutes. The experience itself left all of the sensory modalities
|
|
functional; speech was cogent and rather fluid. In fact, there was an
|
|
unusual ease of free association. All throughout the session, the
|
|
talk was high in spirits and somehow indicative of an inner
|
|
excitement. Affect was entirely pleasant, but not exalting nor
|
|
conducive to insight or to problem solving. There were no
|
|
requirements for withdrawal into the self. The material seemed wholly
|
|
social in nature. No visual, auditory or olfactory sharpening was in
|
|
evidence. The plateau for this material seemed unusually long. I was
|
|
unable to sleep for several hours, and took 25 mg Librium before sleep
|
|
arrived. The next day was a lethargic and slow one, with the inner
|
|
feeling that the effects had not worn off until the middle of the day
|
|
following ingestion.
|
|
|
|
(with 35 mg) I was a distinct +1 in 35 minutes and a +2 by the end of
|
|
the hour. My head congestion in no way cleared up, absolving the
|
|
material from having that particular virtue. The entire experience
|
|
was somewhat dissociated Q I could not connect with my feelings.
|
|
Although my mind remained clear, there was a hangover feeling at the
|
|
end of the experiment.
|
|
|
|
EXTENSIONS AND COMMENTARY: This compound was first explored in Prague
|
|
by Leminger. He provided only the synthetic details and the statement
|
|
that it was the most active compound that he had studied, with
|
|
activity at 20 milligrams, with perceptual changes, color enhancement,
|
|
and difficult dreams during sleep that night. Some effects persisted
|
|
for more than 12 hours. Dosages above 35 milligrams remain
|
|
unexplored.
|
|
|
|
As AL is one of the most potent 3,4,5-trisubstituted phenethylamines
|
|
yet described, and since the corresponding amphetamines are of yet
|
|
greater potency, it would be a good guess that
|
|
4-allyloxy-3,5-dimethoxyamphetamine (3C-AL) would be an interesting
|
|
compound to explore. It could be made from syringaldehyde in reaction
|
|
with allyl iodide, followed by the formation of a nitrostyrene with
|
|
nitroethane, followed by reduction with aluminum hydride. It is, as
|
|
of the present time, both unsynthesized and unexplored.
|
|
|
|
|
|
|
|
#3 ALEPH; DOT; PARA-DOT; 2,5-DIMETHOXY-4-METHYLTHIOAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 2.3 g
|
|
2,5-dimethoxy-4-(methylthio)benzaldehyde (see under 2C-T for its
|
|
synthesis) in 7.5 mL nitroethane was treated with 0.45 g anhydrous
|
|
ammonium acetate and heated on the steam bath for 6 h. The excess
|
|
solvent/reagent was removed under vacuum leaving a mass of orange
|
|
crystals as residue. These were ground up under 10 mL MeOH,
|
|
col-lected by filtration, washed with a little MeOH, and air dried to
|
|
provide 2.6 g crude
|
|
1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene. After
|
|
recrystallization from 140 mL boiling MeOH, filtering and drying there
|
|
was in hand 1.8 g of bright orange crystals with a mp of 137-138 !C.
|
|
Anal. (C12H15NO4S) C,H,N,S.
|
|
|
|
A suspension of 1.4 g LAH in 10 mL anhydrous Et2O and 40 mL anhydrous
|
|
THF was put under an inert atmosphere and, with good stirring, brought
|
|
up to a gentle reflux. A solution of 1.8 g
|
|
1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene in 30 mL anhydrous
|
|
THF was added dropwise at a rate that maintained the reflux. Heating
|
|
and stirring were maintained for an additional 7 h, then the reaction
|
|
mixture was allowed to return to room temperature. There was added
|
|
1.6 mL H2O (dissolved in a little THF), followed by 1.6 mL 15% NaOH,
|
|
and finally another 4.8 mL H2O. Stirring was continued until all the
|
|
curdy solids had turned white. The reaction mixture was filtered, and
|
|
the filter cake washed with THF. The filtrate and the washings were
|
|
combined, and the solvent removed under vacuum. The residue was 1.3 g
|
|
of a colorless oil that solidified. Its mp of 90-93 !C was improved
|
|
slightly to 91-93 !C with recrystallization from hexane. The product
|
|
was dissolved in 25 mL warm IPA, neutralized with concentrated HCl
|
|
(0.57 mL required) and then diluted with 100 mL anhydrous Et2O. After
|
|
a moment's delay, the white crystalline product appeared. It was
|
|
removed by filtration, washed with Et2O, and air dried to provide 1.2
|
|
g 2,5-dimethoxy-4-methylthioamphetamine hydrochloride (ALEPH) with a
|
|
mp of 200-201 !C. Recrystallization from IPA gave an analytical
|
|
sample with a mp of 204-205 !C. Anal. (C12H20ClNO2S) C,H; N: calcd,
|
|
5.04; found, 5.52.
|
|
|
|
DOSAGE: 5 - 10 mg.
|
|
|
|
DURATION: 6 - 8 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 5 mg) The initial hints of action were
|
|
physical Q warming of first the legs, and then a comfortable warmth
|
|
spread over the entire body. Intense intellectual stimulation, one
|
|
that inspired the scribbling of some 14 pages of handwritten notes.
|
|
Which is a pretty good record for an experience that is almost
|
|
entirely non-verbal. The afterglow was benign and rich in empathy for
|
|
everything. And by the sixth hour I was quite hungry.
|
|
|
|
(with 10 mg) There was a rapid shift of frame of reference that made
|
|
simple tasks such as reading and tuning the radio quite alien. I
|
|
happened to catch the eyes of Pretty Baby, the cat, at the same moment
|
|
she looked at me, and she turned and fled. I am able to interact with
|
|
people on the telephone quite well but mechanical things, such as
|
|
arranging flowers or alphabetizing names, are beyond me. Driving
|
|
would be impossible.
|
|
|
|
EXTENSIONS AND COMMENTARY: This specific compound is probably the
|
|
first sulfur-containing phenethylamine to have been evaluated as a
|
|
potentially active CNS stimulant or psychedelic. It was a complete,
|
|
total, absolute unknown. The first trials were made at the
|
|
sub-microgram level, specifically at 0.25 micrograms, at 11:30 AM on
|
|
September 3, 1975. Part of this extreme precaution was due to the
|
|
uniqueness of a new heteroatom in a phenethylamine system. But part
|
|
was due to the strange manic excitement that occurred at the time of
|
|
the isolation and characterizing of the final product in the
|
|
laboratory. Although it was certainly all placebo response, I was
|
|
jumpy and unable to stay in the lab for more than a few minutes at a
|
|
time. Maybe dust in the air? Maybe some skin contact with the free
|
|
base? Now, I know there was nothing, but the possibility of
|
|
extraordinary potency was real, and I did indeed wash everything down
|
|
anyway. In fact, it took a total of 18 trials to work the
|
|
experimental dosage up to as much as a single milligram. In
|
|
retrospect, overly cautious. But retrospection, as they say, is
|
|
cheap.
|
|
|
|
The 5 milligram experiment, briefly quoted from above, is the stuff of
|
|
Chapter 14 of this book, important in that it gives an interesting
|
|
example of some thought processes associated with psychedelic
|
|
intoxication, ego-inflation, and what might be thought of as bits of
|
|
mania. As is always the case with peak experiences that happen to be
|
|
catalyzed by drugs, this extraordinary event could not be duplicated.
|
|
At 7 milligrams there was an uneventful +1, and some 10 milligrams was
|
|
needed to generate a full +3 experience. The first clue of the
|
|
erratic nature of the Aleph family came from an independent assay by a
|
|
colleague of mine, one who was very familiar with such states of
|
|
consciousness, but for whom this was not a time for peak experiences.
|
|
At 10 milligrams he told me that he had had only mild effects which he
|
|
found relatively uninteresting.
|
|
|
|
As it stands, ALEPH remains relatively unexplored. Its two positional
|
|
isomers are entered here as ORTHO-DOT and META-DOT. Three higher
|
|
homologues have been more thoroughly looked at, and the generic name
|
|
ALEPH (the first letter of the Hebrew alphabet) was given this group
|
|
on the basis that they might have extraordinary properties in common.
|
|
But the real treasure came in the exploring of the 2-carbon
|
|
homologues, the compounds that make up the 2C-T family. Here, there
|
|
proved to be much less uncertainty as to reasonable dosages, and much
|
|
more richness in the subjective nature of the experience.
|
|
|
|
|
|
|
|
#4 ALEPH-2; 2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 2.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde
|
|
(see under 2C-T-2 for its synthesis) in 12 mL nitroethane was treated
|
|
with 0.4 g anhydrous ammonium acetate and heated on the steam bath for
|
|
3 h. All volatiles were removed under vacuum, leaving a residue that
|
|
set up as brilliant red crystals. These were mechanically removed
|
|
from the evaporation flask, blown free of nitroethane vapor, and
|
|
recrystallized from boiling EtOH, producing 1.8 g pale orange
|
|
crystals, with a mp of 110-112 !C. Recrystallization from 20 mL
|
|
boiling IPA gave, after filtering and air drying, 1.70 g light orange
|
|
crystals of 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene with a
|
|
mp of 112-113 !C.
|
|
|
|
A suspension of 1.2 g LAH in 75 mL anhydrous THF was put under an
|
|
inert atmosphere and, with good stirring, brought up to a gentle
|
|
reflux. A solution of 1.5 g
|
|
1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene in 20 mL anhydrous
|
|
THF was added dropwise. Heating and stirring were maintained for an
|
|
additional 24 h, and then the reaction mixture was allowed to come
|
|
back to room temperature with stirring. There was added 1.4 mL H2O
|
|
(dissolved in a little THF), followed by 1.4 mL 15% NaOH and finally
|
|
another 4.2 mL H2O. Stirring was continued until all the curdy solids
|
|
had turned white. The reaction mixture was filtered, and the filter
|
|
cake washed with THF. The filtrate and the washings were combined,
|
|
and the solvent removed under vacuum. The residue was 1.1 g of a pale
|
|
amber oil. This was dissolved in 6 mL IPA, neutralized with
|
|
concentrated HCl (about 8 drops were required) and then diluted with
|
|
150 mL anhydrous Et2O. The slightly cloudy solution was stirred for a
|
|
couple of min, then there was the formation of a heavy white
|
|
crystalline mass. This was removed by filtration, washed with Et2O,
|
|
and air dried to provide 1.1 g 2,5-dimethoxy-4-ethylthioamphetamine
|
|
hydrochloride (ALEPH-2) with a mp of 128-130 !C with decomposition.
|
|
|
|
DOSAGE: 4 - 8 mg
|
|
|
|
DURATION: 8 - 16 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 4 mg) There was a warm feeling in the
|
|
total body and a light pressure in the head that changed with time
|
|
into the feeling of a balloon without any anatomical definition. The
|
|
usual color perception was not very much increased, and my vision was
|
|
not sharpened as it was with DOM. Rather, I noticed waves of
|
|
movement, very smooth and not too busy. Both my tactile perception
|
|
and auditory acuity were enhanced. The main effect for me was,
|
|
paradoxically, an easier handling of the outer world. None of the
|
|
jitters of amphetamine. The body feeling is good, healthy, and I am
|
|
at peace with the body-mind dualism. These are pretty much personal
|
|
comments Q I will write up the pharmacological points later.
|
|
|
|
(with 5 mg) This turned out to be a day of extraordinary visuals and
|
|
interpretations. About two hours into it, I felt that the effects
|
|
were still climbing, but there was a marvelous onset of visual
|
|
distortions and illusions, right at the edge of hallucination. The
|
|
logs in the fireplace were in continuous motion. The notepaper I was
|
|
writing on seemed to scrunch and deform under the pressure of the pen.
|
|
Nothing would stay still; everything was always moving. There was a
|
|
phase of unabated inflation. The intensity was noticeably dropping at
|
|
the five hour point and I observed considerable residual shakes and a
|
|
muscular tremor. Even towards midnight there was some
|
|
tooth-rubbiness, but I was able to get a somewhat fretful though
|
|
adequate sleep.
|
|
|
|
(with 5 mg) I was exposed to a number of new environments and it was
|
|
difficult to completely separate the experience into what was seen
|
|
differently and what was seen for the first time. The Santa Cruz
|
|
Mystery Spot should have been bizarre but it was simply hokey. And
|
|
yet the boardwalk that should have been depressing was totally
|
|
magical. The day was unworldly and I ended up with considerable
|
|
muscular weakness. All in all, I handled it well, but I probably
|
|
wonUt do it again.
|
|
|
|
(with 7 mg) An amazing unification of visual hallucination seen only
|
|
in the very fine detail of something, and what must be considered
|
|
retinal hallucination. There is no one-to-one correspondence between
|
|
the many retinal cells of the high-resolution part of the eye. Thus,
|
|
the mind can pick and choose, sometimes from the right eye, and
|
|
sometimes from the left. And so a small curve or bump can become
|
|
whatever you wish. For a moment. And then it chooses again, but
|
|
differently. Is all of our perceived world as subjective as this?S
|
|
|
|
(with 8 mg) Extreme intoxication, but almost no visual phenomena.
|
|
Even well into the evening, I know I absolutely could not drive. Why?
|
|
I donUt know, since this experiment, at least, seemed to be quite free
|
|
of strange colors and wiggly lines and streaks of light. It's that I
|
|
donUt trust that the reality I see is the same reality that the other
|
|
driver might see. I am very much the center of the world about me,
|
|
and I donUt think I could trust anyone else to fully respect my
|
|
reality.
|
|
|
|
EXTENSIONS AND COMMENTARY: As with ALEPH itself, and in most ways with
|
|
the entire ALEPH family, there is no predictability of the
|
|
dose/response relationship. One person had expressed his psychic
|
|
isolation by taking and maintaining a fetal position in relative
|
|
hibernation for several hours and with substantial amnesia; this at a
|
|
four milligram dose. Yet another person, at fully twice this amount,
|
|
was aware of a slight light-headedness that could in no way be
|
|
measured as more than a bare threshold. But by the time this erratic
|
|
nature had become apparent, the ALEPHS had been assigned and made, up
|
|
to and including ALEPH-7.
|
|
|
|
ALEPH-3 was intended to be the methallylthio compound,
|
|
2,5-dimethoxy-4-('-methallylthio)amphetamine. The thioether
|
|
(2,5-dimethoxyphenyl '-methallyl sulfide) was easily made from
|
|
2,5-dimethoxythiophenol (see 2C-T-2 for its preparation) with 3.4 g
|
|
dissolved in a solution of 1.7 g KOH in 25 mL boiling EtOH, and 2.72 g
|
|
methallyl chloride, heated 1 h on the steam bath, poured into 250 mL
|
|
H2O, extracted with 3x100 mL CH2Cl2, and solvent removal yielding 4.4
|
|
g of the sulfide as an amber oil. An effort to convert this to
|
|
2,5-dimethoxy-4-('-methallylthio)benzaldehyde (7.2 g POCl3, 6.7 g
|
|
N-methylformanilide, 4.2 g of the crude sulfide from above, 15 min
|
|
heating on the steam bath, H2O hydrolysis, hexane extraction of the
|
|
residues from a CH2Cl2 extraction) produced 3.1 g of a
|
|
peppermint-smelling oil that distilled at 140-160 !C at 0.3 mm/Hg and
|
|
which did indeed have an aldehyde group present (by proton NMR) but
|
|
the rest of the spectrum was a mess, and the project was abandoned.
|
|
|
|
Several years later, this entire project was reinitiated, and the
|
|
aldehyde was obtained as a yellow crystal, but again it was not
|
|
pursued. At that time, the earlier try had been totally forgotten,
|
|
and a brand new ALEPH- (or 2C-T-) number had been assigned; i.e., 20.
|
|
Thus, the corresponding phenethylamine
|
|
(2,5-dimethoxy-4-('-methallylthio)phenethylamine), had it ever been
|
|
made, which it was not, would have been called either 2C-T-3 or
|
|
2C-T-20, and the amphetamine homologue would probably have been
|
|
ALEPH-20.
|
|
|
|
A closely related 2C-T-X compound was also started quite a while later
|
|
Q this was the allylthio homologue of the methallyl material 2C-T-3 or
|
|
2C-T-20. Its place in the flow of things is evident from its
|
|
numbering, 2C-T-16. A mixture of 2,5-dimethoxythiophenol and KOH and
|
|
allyl chloride in MeOH gave 2,5-dimethoxyphenyl allyl sulfide as a
|
|
white oil which boiled at 110-125 !C at 0.25 mm/Hg. This, with POCl3
|
|
and N-methylformanilide provided
|
|
2,5-dimethoxy-4-(allylthio)benzaldehyde which distilled at 140-160 !C
|
|
at 0.4 mm/Hg and could be recrystallized from MeOH as a pale yellow
|
|
solid. Reaction of this aldehyde in nitroethane in the presence of
|
|
ammonium acetate (steam bath for 2.5 h) provided
|
|
2,5-dimethoxy-4-allylthio-'-nitrostyrene as red crystals from
|
|
acetonitrile. Its mp was 114-115 !C. Anal. (C13H15NO4S) C,H. This
|
|
has not yet been reduced to the final amine,
|
|
2,5-dimethoxy-4-allylthiophenethylamine, 2C-T-16. The corresponding
|
|
amphetamine would be, of course, ALEPH-16.
|
|
|
|
ALEPH-5 was to be the cyclohexylthio analogue
|
|
(2,5-dimethoxy-4-cyclohexylthioamphetamine). The thioether
|
|
(2,5-dimethoxyphenyl cyclohexyl sulfide) was successfully made from
|
|
1.7 g 85% KOH pellets in 25 mL hot EtOH, 3.4 g 2,5-dimethoxythiophenol
|
|
(again, see under 2C-T-2 for its preparation), and 4.9 g cyclohexyl
|
|
bromide, 3 h on the steam bath, into 500 mL H2O, extraction with 3x100
|
|
mL CH2Cl2, washing the extracts with 5% NaOH, and evaporation to yield
|
|
5.2 g of an amber oil. The aldehyde, (made from 6.1 g POCl3 and 5.4 g
|
|
N-methylformanilide, heated until claret colored, then treated with
|
|
5.0 g of the above crude thioether, heating for 20 min on the steam
|
|
bath, into 300 mL H2O, and over-night stirring) was obtained as 3.1 g
|
|
of a flesh-colored solid that was clearly neither pure nor completely
|
|
correct. Repeated partitioning with organic solvents and cooling and
|
|
scratching the residues finally provided a pale orange crystal (1.3 g,
|
|
mp 88-93 !C) which, after twice recrystallizing from MeOH, gave 0.4 g
|
|
of pale yellow crystals with a mp 95-96 !C and a textbook perfect NMR
|
|
in CDCl3 (CHO, 1H (s) 10.41; ArH 2H (s) 6.93, 7.31; OCH3, 6H, (2s) at
|
|
3.88 and 3.92; CH, 1H br. at 3.34; and (CH2)5 10H br. at 1.20-2.34).
|
|
The nitrostyrene was prepared from 200 mg of the above aldehyde in 1.2
|
|
mL nitroethane and 0.1 g ammonium acetate overnight on the steam bath,
|
|
the solvent removed to give an orange oil that spontaneously
|
|
crystallized after a few monthsU standing. This was never
|
|
characterized, but sits there on the shelf to be reduced to ALEPH-5
|
|
some inspired day. The two-carbon homo-logue of this
|
|
(2,5-dimethoxy-4-cyclohexylthiophenethylamine) will someday be called
|
|
2C-T-5 (if it is ever made).
|
|
|
|
The remaining members of this family, ALEPH-4, ALEPH-6, and ALEPH-7
|
|
have actually been prepared and they have all been entered here in
|
|
Book II, under their own names.
|
|
|
|
|
|
|
|
#5 ALEPH-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 2.0 g
|
|
2,5-dimethoxy-4-((i)-propylthio)benzaldehyde (see under 2C-T-4 for its
|
|
synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous
|
|
ammonium acetate and heated on the steam bath for 12 h, then allowed
|
|
to stir for another 12 h at room temperature. The excess
|
|
solvent/reagent was removed under vacuum leaving a residue as a heavy
|
|
deep orange two-phase oily mass. This was brought into one phase with
|
|
2 mL MeOH and then, with continued stirring, everything spontaneously
|
|
crystallized. This product was removed by filtration and, after
|
|
washing sparingly with cold MeOH and air drying, yielded 2.0 g of
|
|
1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene as orange
|
|
crystals with a mp of 96-98 !C. After recrystallization from 15 mL
|
|
boiling 95% EtOH, filtering and air drying to constant weight, there
|
|
was obtained 1.6 g of orange crystals with a mp of 99-100 !C.
|
|
|
|
A suspension of 1.0 g LAH in 100 mL warm THF was stirred under a N2
|
|
atmosphere and heated to a gentle reflux. To this there was added,
|
|
dropwise, a solution of 1.2 g
|
|
1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene in 20 mL
|
|
anhydrous THF. This mixture was held at reflux for 1 day, then
|
|
stirred at room temperature for 2 days. There was then added, slowly
|
|
and with caution, 1 mL of H2O, followed by 1 mL of 15% NaOH, and
|
|
finally by another 3 mL of H2O. Stirring was continued until the
|
|
reaction mixture became white and granular, then all solids were
|
|
removed by filtration and the filter cake was washed with additional
|
|
THF. The filtrate and washings were combined, and the solvent removed
|
|
under vacuum to give 1.1 g of residue which was an almost white oil.
|
|
This was dissolved in 6 mL IPA, neutralized with concentrated HCl (10
|
|
drops were required) and then diluted with 200 mL anhydrous Et2O. The
|
|
resulting slightly turbid solution was clarified by filtration through
|
|
a sintered glass filter, and the clear and slightly yellow filtrate
|
|
was allowed to stand. A fine white crystalline product slowly
|
|
separated over the next few h. This product,
|
|
2,5-dimethoxy-4-(i)-propylthioamphetamine hydrochloride (ALEPH-4) was
|
|
removed by filtration, and after washing with Et2O and air drying,
|
|
weighed 0.5 g and had a mp of 146-147 !C, with prior sintering at 144
|
|
!C.
|
|
|
|
DOSAGE: 7 - 12 mg.
|
|
|
|
DURATION: 12 - 20 h
|
|
|
|
QUALITATIVE COMMENTS: (with 7 mg) Things started off going downhill,
|
|
initially negative with tension and depression, but as the momentum
|
|
developed, so did the positive effect. My discomfort continued to
|
|
develop, but I was struck by the visual beauty of the trees and the
|
|
small stream that flowed off the mountain. My experience continued to
|
|
grow, simultaneously, in both the negative and the positive direction.
|
|
Physically I was uncomfortable and found my breathing difficult, but I
|
|
acknowledged a rapture in the very act of breathing. All moved over
|
|
to the plus side with time, and the evening was gorgeous. I have
|
|
never seen the sky so beautiful. The only flaw was when I choked on
|
|
some lemonade and it seemed to me I almost drowned. I have been
|
|
extremely conscious of eating, drinking and swallowing ever since. I
|
|
barely slept the whole night and awoke extremely tired. I felt that
|
|
the experience continued for many days, and I feel that it is one of
|
|
the most profound and deep learning experiences I have had. I will
|
|
try it again, but will block out more time for it.
|
|
|
|
(with 8 mg) There was without question a plus two, but none of the
|
|
edges of unreality that are part of LSD. The sounds that are just
|
|
outside of my hearing are intriguing, and distract me from the
|
|
eyes-closed imagery that is just barely possible with music while
|
|
lying down. But, going outside, there were no obvious sources of the
|
|
sounds that I heard. Could I drive? I suspect so. I took a shower
|
|
and did just that Q I drove to San Francisco without incident, and
|
|
walked amongst the many strange faces on the downtown streets.
|
|
|
|
(with 12 mg) The experience was very intense but completely under
|
|
control except for a twenty minute period right in the middle of it.
|
|
I had to get away from everything, from everyone. There was a sense
|
|
of being surrounded and moved in upon that was suffocating. I was
|
|
weighed down with everything Q physical, psychic, emotional. My
|
|
clothes had to come off, my hair had to be released, my shoes went, I
|
|
needed to move away from where I was, to somewhere else, to some new
|
|
place, any new place, with the hope that my other old place wouldnUt
|
|
follow me. Pretty soon I found I was myself, I could breathe again,
|
|
and I was OK. Rather sheepishly, I dressed and rejoined the group.
|
|
The rest of the day was spectacular, but those few minutes were scary.
|
|
What if I couldnUt have escaped?S
|
|
|
|
EXTENSIONS AND COMMENTARY: Again, there are hints and suggestions of
|
|
complexities. These, and several other reports, suggest some sensory
|
|
confusion, and interpretive aspects that are to some extent
|
|
threatening. There is an underlying suggestion of body toxicity. I
|
|
know of no experiment that exceeded 12 milligrams and I would not be
|
|
able to predict what might come forth at higher dosages. I personally
|
|
choose not to try them.
|
|
|
|
|
|
|
|
#6 ALEPH-6 2,5-DIMETHOXY-4-PHENYLTHIOAMPHETAMINE
|
|
|
|
SYNTHESIS: To a 300 mL three-neck round-bottom flask set up with a
|
|
magnetic stirrer and protected with a N2 atmosphere, there was added
|
|
75 mL hexane, 3.5 g tetramethylethylenediamine, and 4.2 g
|
|
p-dimethoxybenzene. The reaction mixture was cooled to 0 !C with an
|
|
external ice bath, and there was then added 19 mL of 1.6 M
|
|
butyllithium in hexane. With stirring, the reaction was brought up to
|
|
room temperature, and there were produced loose, creamy solids. There
|
|
was then added, as a solid and portionwise, 6.6 g diphenyldisulfide
|
|
which resulted in an exothermic reaction and the production of a
|
|
nearly clear solution. After stirring an additional 10 min, the
|
|
reaction was quenched in 500 mL of dilute NaOH. The hexane phase was
|
|
separated, and the aqueous phase extracted with 4x100 mL CH2Cl2 The
|
|
organic extracts were combined, washed with dilute HCl and the
|
|
solvents were removed under vacuum to provide 6.0 g of
|
|
2,5-dimethoxyphenyl phenyl sulfide as an impure amber oil. A small
|
|
sample was saved for microanalysis and NMR, and the re-mainder
|
|
converted to the corresponding benzaldehyde.
|
|
|
|
A mixture of 6.1 g POCl3 and 5.4 g N-methylformanilide was heated for
|
|
3 min on the steam bath, and then added to the remainder of the
|
|
above-described 2,5-dimethoxyphenyl phenyl sulfide. The reaction
|
|
became immediately a deep red and, after heating on the steam bath for
|
|
0.5 h, was dumped into a large quantity of H2O, producing a granular
|
|
brown solid. This was removed by filtration, and washed sparingly
|
|
with cold MeOH (the washes were saved). The resulting pale yellow
|
|
solids were recrystallized from 20 mL boiling absolute EtOH providing,
|
|
after cooling, filtration and air drying, 4.4 g of extremely pale
|
|
yellow crystals of 2,5-dimethoxy-4-(phenylthio)benzaldehyde. This had
|
|
a mp of 119-119.5 !C. All washes and mother liquors were combined,
|
|
flooded with H2O and extracted with CH2Cl2. This solvent was removed
|
|
under vacuum, and the residue (a viscous oil) was dissolved in a
|
|
little EtOH which, on cooling in dry ice, gave 1.2 g of a second crop
|
|
of the aldehyde, mp 117-119 !C. Recrystallization from 5 mL 95% EtOH
|
|
gave an additional 0.4 g product with a mp of 118-119 !C. This mp was
|
|
not improved by recry-stallization from cyclohexane. The NMR specrum
|
|
was excellent, with OCH3 singlets (3H) at 3.45 and 3.80 ppm; ArH
|
|
singlets at 6.28 and 7.26 ppm, the C6H5 as a broad peak centered at
|
|
7.50, and the CHO proton at 10.37 ppm.
|
|
|
|
A solution of 4.4 g 2,5-dimethoxy-4-(phenylthio)benzaldehyde in 32 mL
|
|
nitroethane was treated with 0.8 g anhydrous ammonium acetate and
|
|
heated on the steam bath for 21 h. The excess solvent/reagent was
|
|
removed under vacuum, leaving a dark red oil as residue. After much
|
|
diddling and fiddling around, this set up as a crystalline mass.
|
|
These solids were ground under 20 mL cold MeOH and filtered, providing
|
|
5.3 g of the crude nitrostyrene as an orange crystalline residue
|
|
product after air-drying. This was ground up under 10 mL MeOH, the
|
|
insolubles collected by filtration, washed with a little MeOH, and air
|
|
dried to provide 5.3 g crude
|
|
1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene as yellow
|
|
crystals, with a mp of 100-102 !C (with prior sintering at about 98
|
|
!C). This was recrystallized from 50 mL boiling 95% EtOH. After
|
|
cooling in an ice bath, it was filtered, washed with EtOH, and air
|
|
drying provided gold-yellow crystals with a mp of 105-106 !C. The
|
|
proton NMR was excellent (in CDCl3).
|
|
|
|
A suspension of 2.0 g LAH in 100 mL refluxing THF, under an inert
|
|
atmosphere and with good stirring, was treated with a solution of 3.5
|
|
g 1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene in 20 mL
|
|
anhydrous THF added dropwise at a rate that maintained the reflux.
|
|
Heating and stirring were maintained for an additional 36 h, and then
|
|
the reaction mixture was stirred at room temperature for an additional
|
|
24 h. There was added 2.0 mL H2O (dissolved in a little THF),
|
|
followed by 2.0 mL 15% NaOH, and finally another 6.0 mL H2O. Stirring
|
|
was continued until all formed solids had turned white. The reaction
|
|
mixture was filtered, and the filter cake washed with THF. The
|
|
filtrate and the washings were combined and the solvent removed under
|
|
vacuum. The residue was 2.8 g of an oil that quite obviously
|
|
contained some H2O. This was dissolved in 400 mL CH2Cl2, washed first
|
|
with dilute NaOH and then with 4x150 mL 1N HCl. The organic phase was
|
|
stripped of solvent under vacuum, yielding a pale amber oil that
|
|
crystallized. This was ground first under Et2O, giving 3.4 g of a
|
|
yellow solid. This was then ground under 10 mL of acetone, yielding
|
|
2.4 g of a white crystalline solid that darkened at 170 !C, sintered
|
|
at 187 !C and had a mp of 191-193 !C. This was dissolved in 20 mL hot
|
|
95% EtOH, and diluted with 40 mL Et2O to provide a clear solution
|
|
which, after a minute's scratching with a glass rod, deposited
|
|
2,5-dimethoxy-4-phenylthioamphetamine hydrochloride (ALEPH-6) as white
|
|
solids. After filtration and air drying, the weight was 1.8 g, with a
|
|
mp of 194-195 !C. The dilute HCl washes, after being made basic with
|
|
aqueous NaOH and extraction with CH2Cl2 gave a trivial quantity of
|
|
additional product.
|
|
|
|
DOSAGE: greater than 40 mg.
|
|
|
|
DURATION: probably long.
|
|
|
|
QUALITATIVE COMMENTS: (with 30 mg) I had an alert at the one hour
|
|
point, and in another hour there was a clear 1+. There was a not well
|
|
defined, gentle un-worldliness. And it was still there quite
|
|
unchanged twelve hours later. In a group I find that all voices about
|
|
me are of equal intensity and equal importance. But this is not at
|
|
all distracting. This will be a long lived thing for sure.
|
|
|
|
(with 40 mg) I am into a subtle but real effect, no more than one
|
|
plus, but real. I feel primed, but nothing more. It is not
|
|
interfering with work, maybe even helping with it. After another hour
|
|
of static one-plusness I decided to use it as a primer to LSD, using
|
|
the usual 60 microgram quantity that is standard for primer studies.
|
|
The combination showed definite synergism, with a rapid show of the
|
|
LSD effects (within fifteen minutes) and an almost three plus effect.
|
|
This is most unusual for the usual 60 microgram challenge amount. An
|
|
absolutely delightful intoxication that had sufficiently descended
|
|
towards baseline that I accepted a ride to a party that evening in
|
|
Marin County to attend a poetry reading. There I felt myself at
|
|
baseline and accepted (unusual for me) a little marijuana. And with
|
|
the utmost quiet and delicacy, a rather incredible change of state
|
|
took place. The most memorable event was the awareness of a clarinet
|
|
playing somewhere, and the sneaky sounds from it actually coming along
|
|
the carpet out of the dining room and into the hallway and through the
|
|
door and into the room where I was, and all of them gathering at my
|
|
feet like docile kittens waiting for me to acknowledge them. I did,
|
|
non-verbally, and I was amazed at the many additional follow-up sounds
|
|
that came from the same clarinet along the same twisty path along the
|
|
floor and through the door and into my space, over what seemed to be
|
|
the next million hours. I ended up with a marvelous collection of
|
|
notes and phrases at my feet, and I felt somehow honored. My speech
|
|
sounded OK to me, but I knew that it would be odd to the ears of
|
|
others, so I kept quiet. A final measure of the weirdness of the
|
|
ALEPH-6/LSD/Pot combination was the viewing of the Larkspur ferry at
|
|
its dock, abandoned for the evening and with no one aboard it, and
|
|
with all that clean, dry sleeping space going to waste with so many
|
|
people sleeping on the streets these days. Once home, I slept soundly
|
|
and for a long while. Incredible experience.
|
|
|
|
EXTENSIONS AND COMMENTARY: In a sense, this compound was a
|
|
disappointment. The beauty of putting a whole new ring into an active
|
|
structure is that it provides a marvelous vehicle for introducing new
|
|
substituents in new arrangements. Had Aleph-6 been a cleanly active
|
|
and potent compound, then the new phenyl group could have been made
|
|
electronegative to varying degrees (with methoxy substitution for
|
|
example) or electropositive to varying degrees (with trifluoromethyls
|
|
or nitros) and this fine-tuning could have been extremely rewarding.
|
|
|
|
But this material had the earmarks of one of those forever threshold
|
|
things. The 40 milligram experiment was hopelessly compromised, and
|
|
nothing higher was ever scheduled or tried. The two-carbon homologue,
|
|
2,5-dimethoxy-4-phenylthiophenethylamine, or 2C-T-6, has never even
|
|
been synthesized, let alone assayed.
|
|
|
|
|
|
|
|
#7 ALEPH-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 2.6 g
|
|
2,5-dimethoxy-4-((n)-propylthio)benzaldehyde (see under 2C-T-7 for its
|
|
synthesis) in 20 mL nitroethane and 0.5 g anhydrous ammonium acetate
|
|
was heated on the steam bath overnight. The excess solvent/reagent
|
|
was removed under vacuum leaving an orange oil as a residue that
|
|
cry-stallized spontaneously. This crude product was recrystallized
|
|
from 20 mL boiling MeOH to give, after cooling, filtering, and air
|
|
drying, 2.4 g of
|
|
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene as orange
|
|
crystals. Its mp was 83-84 !C with prior sintering at 81 !C.
|
|
|
|
A suspension of 1.5 g LAH in 150 mL of warm anhydrous THF was stirred
|
|
under an inert atmosphere and brought up to a gentle reflux. A
|
|
solution of 2.3 g
|
|
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene in 25 mL
|
|
anhydrous THF was added dropwise at a rate that maintained the reflux.
|
|
Heating and stirring were continued for 2 days, and then the reaction
|
|
mixture was allowed to stir at room temperature for an additional 2
|
|
days. There was added 1.5 mL H2O (dissolved in 10 mL THF), followed
|
|
by 1.5 mL 15% NaOH, and finally another 4.5 mL H2O. Stirring was
|
|
continued until all the curdy solids had turned white. The reaction
|
|
mixture was filtered, and the filter cake washed with slightly wet
|
|
THF. The filtrate and the washings were combined, and the solvent
|
|
removed under vacuum. The residue was about 2 mL of an amber colored
|
|
oil that was dissolved in 200 mL CH2Cl2. This solution was washed
|
|
with first dilute NaOH, and then with saturated brine. Removal of the
|
|
solvent gave a pale amber oil that was dissolved in 10 mL IPA,
|
|
neutralized with about 14 drops of concentrated HCl, and diluted with
|
|
200 mL anhydrous Et2O. The clear solution was decanted from a little
|
|
gritty material, and then set aside to allow the formation of
|
|
2,5-dimethoxy-4-(n)-propylthioamphetamine hydrochloride (ALEPH-7) as
|
|
fine white crystals. After filtration and air drying, there was
|
|
obtained 1.8 g of an off-white powder.
|
|
|
|
DOSAGE: 4 - 7 mg.
|
|
|
|
DURATION: 15 - 30 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 4 mg) At the second hour I had a
|
|
paraesthetic twinge or two (all pins and needles), and then felt quite
|
|
relaxed, quite willing to let this play itself out. In the evening my
|
|
ears still feel 'popped' and there is a little bit of physical
|
|
awareness. There is not much fun with this. The night following, I
|
|
was unable to sleep and only dozed slightly, but I seemed to be OK the
|
|
next day.
|
|
|
|
(with 6 mg) The alert was felt within a half hour, and then nothing
|
|
more. Then, over the next two hours, there was the evolution of an
|
|
extremely neutral state. I danced wildly to a record of Keith
|
|
Jarrett, but somehow didnUt care for his style. I fell apart
|
|
emotionally, with tears and a feeling of total loss of everything.
|
|
Everything was visible to me only in some strange wide-angle lens
|
|
viewing. I went for a walk, a waste of time. I tried classical
|
|
music, but only jazz was acceptable. It was a couple of days before I
|
|
lost the residual strangeness feeling. Never again.
|
|
|
|
(with 7 mg) I did this alone, and in retrospect I wish I had not.
|
|
Somewhere between the hours 2 and 3, I got to a full +++, and I was
|
|
concerned that I saw the effects still developing. Where would it go
|
|
now? There was no reality loss as with LSD, no shakes or shimmers,
|
|
but an intense and profound +++ of something characterized only by the
|
|
absence of extremes. And I am frightened because this is still
|
|
deepening. A couple of calls to friends were not successful, but I
|
|
found an ally in the Palo Alto area, and I told him I was coming to
|
|
visit. My greater than one hour drive there was okay only because I
|
|
had programmed every move ahead of time. In retrospect, to drive was
|
|
completely stupid, and I certainly will never do it again, under any
|
|
circumstances. But, there I was. I knew which lane I would be on, on
|
|
the S.F. Bay Bridge, at every moment of my travels. The middle lane
|
|
through the tunnel. The second from the left when descending into San
|
|
Francisco. The white lane-marker stripes were zipping up past my
|
|
lateral field of vision as I drove, those that were to my right zipped
|
|
past my right eye, those to the left past my left eye. Like disturbed
|
|
fruit flies leaving an over-ripe peach. But, as everything had been
|
|
preprogrammed, there were no surprises. I made it successfully, and
|
|
my baby-sitting friend probed, with a blend of curiosity, love, and
|
|
envy, my uncaring state. And in the course of the next couple of
|
|
hours, this state evolved into a friendly, familiar place. I was
|
|
still fully +++, but now for the first time I was at peace with it. A
|
|
fruit salad tasted heavenly. By midnight I was able to doze lightly,
|
|
and the next day I was sure that there were some residual effects.
|
|
The second evening's sleep repaired everything. The neutralness was
|
|
something new to me. I donUt like not caring. Was this the RBethS
|
|
state of the strange twenty minutes seen by SL in the ALEPH-4
|
|
experience?S
|
|
|
|
(with 7 mg) Strange, pleasant, unexciting, long-lasting. The induced
|
|
state was characterized by: clear unintoxicated central field of
|
|
vision, concentration but with the periphery sensed as being filled
|
|
with a kind of strangeness, and also something sensed inside, at the
|
|
back of the head. A feeling of something waiting to erupt, which
|
|
never does. I had a faint touch of amusement, yet no part of the
|
|
experience had the depth or richness of other compounds. No tremors.
|
|
Slight visuals, but only when looked for. Hunger not present, but
|
|
food tasted fine when eaten. Mildly pleasant but one would not take
|
|
it again unless bored stiff.
|
|
|
|
EXTENSIONS AND COMMENTARY: This drug was the first definition of the
|
|
term, Beth state.
|
|
|
|
There is something of the Fournier Transform in any and all drug
|
|
experiments. A psychedelic drug experience is a complex combination
|
|
of many signals going all at the same time. Something like the sound
|
|
of an oboe playing the notes of the A-major scale. There are events
|
|
that occur in sequence, such as the initial A, followed by B, followed
|
|
by C-sharp and on and on. That is the chronology of the experience,
|
|
and it can be written down as a series of perceived phenomena. The
|
|
notes of the scale. Black quarter notes, with flags at the tops of
|
|
their staffs, going up the page of music.
|
|
|
|
But within each of these single events, during the sounding of the
|
|
note RA,S for example, there is a complex combination of harmonics
|
|
being produced at the same time, including all components from the
|
|
fundamental oscillation on up through all harmonics into the
|
|
inaudible. This mixture defines the played instrument as being an
|
|
oboe. Each component may be shared by many instruments, but the
|
|
particular combination is the unique signature of the oboe.
|
|
|
|
This analogy applies precisely to the study of psychedelic drugs and
|
|
their actions. Each drug has a chronology of effect, like the notes
|
|
of the A-major scale. But there are many components of a drugUs
|
|
action, like the harmonics from the fundamental to the inaudible
|
|
which, taken in concert, defines the drug. With musical instruments,
|
|
these components can be shown as sine waves on an oscilloscope. One
|
|
component, 22%, was a sine wave at a frequency of 1205 cycles, and a
|
|
phase angle of +55!. But in psychopharmacology? There is no psychic
|
|
oscillo-scope. There are no easily defined and measured harmonics or
|
|
phase angles. Certainly, any eventual definition of a drug will
|
|
require some such dissection into components each of which makes some
|
|
contribution to the complex whole. The mental process may some day be
|
|
defined by a particular combination of these components. And one of
|
|
them is this Beth state. It is a state of uncaring, of anhe-donia,
|
|
and of emotionlessness.
|
|
|
|
Many drugs have a touch of this Beth state, ALEPH-7 more than most.
|
|
If a sufficient alphabet of effects (I am using the Alephs, Beths,
|
|
Gimels, and Daleths of the Hebrew as token starters only) were to be
|
|
accumulated and defined, the actions of new materials might someday be
|
|
more exactly documented. Could depression, euphoria, and
|
|
disinhibition for example, all be eventually seen as being made up of
|
|
their component parts, each contributing in some measured way to the
|
|
sum, to the human experience? The psychologists of the world would be
|
|
ecstatic. And drugs such as ALEPH-7 might be useful in helping to
|
|
define one of these parts.
|
|
|
|
|
|
|
|
#8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE;
|
|
1-(2,5-DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE;
|
|
2,5-DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE
|
|
|
|
SYNTHESIS: In 50 mL of benzene there was dissolved 31.6 g
|
|
2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its
|
|
preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine. This
|
|
solution was held at reflux in a Dean Stark apparatus for 24 h,
|
|
effectively removing the water of reaction. Upon cooling, there was
|
|
deposited 19.6 g of 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
|
|
as brilliant orange crystals. The mp, after recrystallization from
|
|
MeOH, was 114-115 !C and a second recrystallization increased the mp
|
|
another 2 !C. Anal. (C13H17NO4) C,H,N.
|
|
|
|
A suspension of 12.5 g LAH in 600 mL anhydrous THF was stirred
|
|
magnetically, and brought up to a reflux. To this there was added,
|
|
dropwise, 15.0 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
|
|
dissolved in 150 mL THF. Refluxing was continued for 15 h and, after
|
|
cooling, the excess hydride was decomposed by the addition of 12.5 mL
|
|
H2O. The inorganic salts were made loose and granular by the addition
|
|
of 12.5 mL 15% NaOH followed by an additional 37.5 mL H2O. These
|
|
solids were removed by filtration, and the filter cake was washed with
|
|
THF. The combined filtrate and washings were stripped of solvent
|
|
under vacuum. The residue was dissolved in anhydrous Et2O, and
|
|
treated with hydrogen chloride gas, yielding
|
|
1-(2,5-dimethoxy-4-methylphenyl)-2-aminobutane hydrochloride (ARIADNE)
|
|
as white crystals which, after recrystallization from IPA, weighed
|
|
11.4 g and had a mp of 232.5-234.5 !C. Anal. (C13H22ClNO2) C,H,N,Cl.
|
|
The racemic mixture was resolved into its optical isomers by the
|
|
formation of salts with (+)-2'-nitrotartranilic acid (to give the RSS
|
|
isomer) or with (+)-2'-chlorotartranilic acid (to give the RRS
|
|
isomer). The RRS isomer can also be prepared by the reductive
|
|
amination of 1-(2,5-dimethoxy-4-methylphenyl)-2-butanone (from the
|
|
above nitrostyrene and elemental iron) with (+)-a-methyl benzylamine
|
|
followed by the hydrogenolysis of the benzyl group.
|
|
|
|
DOSAGE: as psychedelic, unknown.
|
|
|
|
DURATION: short.
|
|
|
|
QUALITATIVE COMMENTS: (with 12 mg) I believe that my mood has
|
|
distinctly improved, and my sleep that evening was excellent. This is
|
|
physically benign.
|
|
|
|
(with 32 mg) There was some sort of threshold that lasted for a
|
|
couple of hours.
|
|
|
|
(with 25 mg of the RRS isomer) There is the alert of a psychedelic,
|
|
with none of the rest of the package. Perhaps a bit of paranoia. And
|
|
by the fifth hour everything is largely gone.
|
|
|
|
EXTENSIONS AND COMMENTARY: How does one discover a new drug for a
|
|
malady that does not exist in experimental animals? Drugs that
|
|
interfere with sleep, or with appetite, or with some infecting
|
|
bacterium, are naturals for animal screening, in that animals sleep,
|
|
eat, and can be easily infected. But there are lots of syndromes that
|
|
involve a state of mind, and these are uniquely human. Many of the
|
|
psychopharmacological anti-this or anti-that agents address ailments
|
|
such as anxiety, psychosis, paranoia, or depression, which are only
|
|
known in man. So how does one discover a new drug in areas such as
|
|
these? If one has in hand a drug that is known to be effective in one
|
|
of these human ailments, an animal assay can be set up to give some
|
|
measurable response to that specific drug, or a biochemical property
|
|
can be rationalized as being related to a mechanism of action. And
|
|
with the known drug as a calibration, and restricting your search to
|
|
structurally related compounds, you can find structural relatives that
|
|
give the same responses.
|
|
|
|
But how does one find a new class? One way is to kind of stumble into
|
|
it as a side-line of human experimentation with new psychedelics. But
|
|
it is really difficult to pick up the clues as to what will be a good
|
|
anti-depressant if you are not depressed. This compound, to which I
|
|
had given the name of ARIADNE as the first of my ten Rclassic ladiesS
|
|
(IUll say more about them later), was not really a stimulant of any
|
|
kind, certainly it was not a psychedelic, and yet there was something
|
|
there. It had been explored rather extensively as a potential
|
|
psychotherapeutic ally by a friend of mine. He said that there seemed
|
|
to be some value in a few of his patients who had some underlying
|
|
depression, but not much of anything with the others. So, I decided
|
|
to call it an anti-depressant. I had mentioned some of this history
|
|
one time when I was giving an address at a conference on the East
|
|
Coast, and my host (who happened to be the research director at a
|
|
large pharmaceutical house) asked if I would send him a sample. His
|
|
company did many animal tests, one of which showed that it was not
|
|
hallucinogenic (a cat whose tail erected dramatically with DOM did
|
|
nothing with ARIADNE) and another that showed re-motivation (some old
|
|
maze-running monkeys who had decided not to run any more mazes changed
|
|
their minds with ARIADNE).
|
|
|
|
So patents were obtained for the RRS isomer, the more effective
|
|
isomer, covering its use for such things as the restoring of
|
|
motivation in senile geriatric patients. And a tradename of
|
|
Dimoxamine was assigned it, despite several voices that held out for
|
|
Ariadnamine. But it didnUt have what was needed to make it all the
|
|
way to the commercial market
|
|
|
|
Many, many analogues of ARIADNE have been made, and for a variety of
|
|
reasons. In the industrial world there is research backup carried
|
|
out, not only for the discovery of new things, but also for patent
|
|
protection of old things. Several dozen analogues of ARIADNE have
|
|
been made and pharmacologically evaluated, and some of them have been
|
|
put into the published literature. The major points of variation have
|
|
been two: keep the 4-position methyl group intact, and make the
|
|
variations on the alpha-carbon (propyl, butyl, dimethyl, phenyl,
|
|
benzyl, phenethyl, etc. Q an extensive etc.) or: keep the
|
|
alpha-position ethyl group intact and make the variations on the
|
|
4-position (chloro, iodo, methylthio, carboxy, etc. Q again, an
|
|
extensive etc.).
|
|
|
|
Some of these analogues I had made, and sent in for animal screening.
|
|
The high potency of DOB suggested the bromo-counterpart of ARIADNE.
|
|
The making of this entailed the proteo counterpart,
|
|
1-(2,5-dimethoxyphenyl)-2-aminobutane. Reaction of
|
|
2,5-dimethoxybenzaldehyde with nitropropane in benzene in a Dean Stark
|
|
apparatus with cyclohexylamine as a catalyst produced
|
|
1-(2,5-dimethoxyphenyl)-2-nitrobutene, which crystallized as orange
|
|
crystals from MeOH with a mp of 47-47.5 !C. Anal. (C12H15NO4) C,H,N.
|
|
This was reduced to the amine 1-(2,5-dimethoxyphenyl)-2-aminobutane
|
|
with LAH in ether, and this gave a hydrochloride salt with a mp of
|
|
172-174 !C after recrystallization from acetonitrile. The free base
|
|
of this compound was brominated in acetic acid to give
|
|
1-(2,5-dimethoxy-4-bromophenyl)-2-aminobutane which yielded a white
|
|
hydrochloride salt with a mp of 204-206 !C following recrystallization
|
|
from IPA. The isomeric non-brominated analogue,
|
|
1-(3,4-dimethoxyphenyl)-2-aminobutane was made and explored by the
|
|
Chemical Warfare group at Edgewood Arsenal; its code number is
|
|
EA-1322.
|
|
|
|
Several of the alpha-ethyl analogues of ARIADNE were N,N-dialkylated,
|
|
and were target compounds for halogenation with radio-iodine or
|
|
radio-fluorine, for evaluation as potential brain blood-flow
|
|
indicators. In these studies. all examples followed a common flow
|
|
diagram. The reaction of the appropriate benzaldehyde and
|
|
nitropropane, using N,N-dimethylethylenediamine as a catalyst and
|
|
following recrystallization from MeOH, gave the corresponding
|
|
1-aromatic-2-nitro-1-butene (the nitrostyrene) which, by reduction
|
|
with elemental iron, gave the corresponding 2-butanone (which was
|
|
distilled at about 0.3 mm/Hg). This led, by reductive amination with
|
|
dimethylamine hydrochloride and sodium cyanoborohydride, to the
|
|
corresponding N,N-dimethyl product which was distilled at about 0.3
|
|
mm/Hg and which, in no case, either formed a solid HCl salt or reacted
|
|
with carbon dioxide from the air. From 2,4-dimethoxybenzaldehyde, the
|
|
nitrostyrene appeared as yellow crystals, the ketone as a white oil,
|
|
and the product N,N-dimethyl-1-(2,4-dimethoxyphenyl)-2-aminobutane as
|
|
a white oil. From 2,5-dimethoxybenzaldehyde, the nitrostyrene formed
|
|
bright yellow crystal, the ketone was an off-white oil, and the
|
|
product N,N-dimethyl-1-(2,5-dimethoxyphenyl)-2-aminobutane was a white
|
|
oil. From 3,5-dimethoxybenzaldehyde, the nitrostyrene formed pale
|
|
yellow crystals that discolored on exposure to the light, the ketone
|
|
was an off-white clear oil, and the product
|
|
N,N-dimethyl-1-(3,5-dimethoxyphenyl)-2-aminobutane was a white oil.
|
|
From 2,6-dimethoxybenzaldehyde, the nitrostyrene was obtained as
|
|
orange crystals, and was not pursued further.
|
|
|
|
A number of ARIADNE analogues have been made, or at least started,
|
|
purely to serve as probes into whatever new areas of
|
|
psychopharmacological activity might be uncovered. One of these is a
|
|
HOT compound, and one is a TOM compound, and a couple of them are the
|
|
pseudo (or near-pseudo) orientations. The HOT analogue was made from
|
|
the nitrostyrene precursor to ARIADNE itself, reduced not with LAH or
|
|
AH (which would give the primary amine), but rather with sodium
|
|
borohydride and borane dimethylsulfide. The product,
|
|
1-(2,5-dimethoxy-4-methylphenyl)-N-hydroxy-2-aminobutane
|
|
hydrochloride, was a white crystalline material. The 5-TOM analogue
|
|
got as far as the nitrostyrene. This was made from
|
|
2-methoxy-4-methyl-5-(methylthio)benzaldehyde (see under the 5-TOM
|
|
recipe for its preparation) and nitropropane in acetic acid, and gave
|
|
bright yellow crystals. The true pseudo-analogue is the
|
|
2,4,6-trimethoxy material based on TMA-6, which is the RrealS
|
|
pseudo-TMA-2. The nitrostyrene from 2,4,6-trimethoxybenzaldehyde and
|
|
nitropropane crystallized from MeOH/CH3CN as fine yellow crystals, and
|
|
this was reduced with AH in cold THF to
|
|
1-(2,4,6-trimethoxyphenyl)-2-aminobutane which was a bright, white
|
|
powder.
|
|
|
|
And the near-pseudo analogue?
|
|
|
|
First, what is near-pseudo? I have explained already that the
|
|
RnormalS world of substitution patterns is the 2,4,5. Everyone knows
|
|
that that is the most potent pattern. But, the 2,4,6 is in many ways
|
|
equipotent, and has been named the pseudo-stuff. The Rreal,S or
|
|
RtrueS pseudo-stuff. So what is the RnearS pseudo-stuff? I am
|
|
willing to bet that the rather easily obtained 2,3,6-trisubstitution
|
|
pattern, and the much more difficult to obtain 2,3,5-substitution
|
|
pattern, will produce treasures every bit as unexpected and remarkable
|
|
as either the 2,4,5- or the 2,4,6- counterparts. These are neither
|
|
RrealS nor Rpseudo,S but something else, and I will find a name for
|
|
them when the time comes, something weird from the Greek alphabet.
|
|
And this will double again the range of possible exploration. The
|
|
TMA-5 analogue mentioned came from 2,3,6-trimethoxybenzaldehyde and
|
|
nitropropane using cyclohexylamine as a catalyst (yellow-orange
|
|
solids) which was reduced to the amine with AH. This hydrochloride
|
|
salt is an air-stable white powder. All of these materials remain
|
|
unexplored.
|
|
|
|
Somewhere in the wealth of compounds implicit in the many structural
|
|
variables possible (the normal versus the pseudo versus the
|
|
near-pseudo patterns, coupled with the wide variety of promising
|
|
substituents that can be placed on the 4-position, together with the
|
|
availability of the the unexplored members of the Ten Classic Ladies
|
|
harem), it would seem inescapable that interesting compounds will
|
|
emerge.
|
|
|
|
Just what is this all about the ten RClassic Ladies?S In the chemical
|
|
struc-ture of DOM, there is a total of nineteen hydrogen atoms. Some
|
|
of these are indis-tinguishable from others, such as the three
|
|
hydrogen atoms on a methyl group. But there are exactly ten RtypesS
|
|
of hydrogen atoms present. And, not having much, if any, intuition as
|
|
to just why DOM was so powerful a psychedelic, I decided to
|
|
systematically replace each of the ten unique hydrogens, one at a time
|
|
of course, with a methyl group. And I planned to give the resulting
|
|
materials the names of famous ladies, alphabetically, as you walk
|
|
around the molecule.
|
|
|
|
ARIADNE was the first of these, the methyl for a hydrogen atom on the
|
|
methyl group of the amphetamine chain. It was Ariadne who gave the
|
|
long piece of thread to Theseus to guide him through the mazes of the
|
|
Labyrinth so he could escape after killing the Minotaur. The record
|
|
is fuzzy as to whether, after the successful killing, she went with
|
|
him, or let him go on alone. A methyl group on the nitrogen atom
|
|
produced BEATRICE. There is the legendary Beatrijs of the Dutch
|
|
religious literature of the 14th century, and there is the Beatrice
|
|
from Beatrice and Benedict (of Berlioz fame). But the one I had in
|
|
mind was the lady from Florence whom Dante immortalized in the Divina
|
|
Commedia, and she is entered under her own name in this footnote.
|
|
Replacing the alpha-hydrogen of DOM with a methyl group would give the
|
|
phentermine analogue which is named CHARMIAN. You may be thinking of
|
|
Cleopatra's favorite attendant, but I was thinking of the sweet wife
|
|
of a very dear friend of mine, a lady who has been in a state of
|
|
gentle schizophrenia for some forty years now. The MDA analogue of
|
|
CHARMIAN has been described in this foornote under the code name of
|
|
MDPH. CHARMIAN, herself, has been synthesized and is of very much
|
|
reduced potency in animals, as compared to DOM. It has not been tried
|
|
in man as far as I know.
|
|
|
|
The two beta-hydrogen atoms of DOM are distinct in that, upon being
|
|
replaced with methyl groups, one would produce a threo-isomer, and the
|
|
other an erythro-isomer. I have named them DAPHNE (who escaped from
|
|
Apollo by becoming a laurel tree which was, incidentally, named for
|
|
her) and ELVIRA (who might not be too well known classically, but
|
|
whose name has been attached to Mozart's 21st piano concerto as its
|
|
slow movement was used as theme music for the movie Elvira Madigan).
|
|
I donUt know if either of this pair has been made Q I started and got
|
|
as far as the cis-trans mixture of adducts betweeen nitroethane and
|
|
2,5-dimethoxy-4-methylacetophenone. Whoever finally makes them gets
|
|
to assign the names. I had made and tested the corresponding
|
|
homologues of DMMDA that correspond to these two ladies.
|
|
|
|
And there are five positions (2,3,4,5 and 6) around the aromatic ring,
|
|
each of which either carries a hydrogen atom or a methyl group that
|
|
has a hydrogen atom. There is the 2-methoxy group which can become a
|
|
2-ethoxy group to produce a compound called FLORENCE. Her name is the
|
|
English translation of the Italian Firenze, a city that, although
|
|
having a female name, has always seemed thoroughly masculine to me.
|
|
There is the 3-hydrogen atom which can become a 3-methyl group to
|
|
produce a compound called GANESHA. This is a fine elephant-headed
|
|
Indian God who is the symbol of worldly wisdom and also has been seen
|
|
as the creator of obstacles. Here I really blew it; the Classic Lady
|
|
turned out to be a Classic Gentle-man; not even the name is feminine.
|
|
There is the 4-methyl group which can become a 4-ethyl group to
|
|
produce a compound called HECATE who presided over magic arts and
|
|
spells. There is the 5-methoxy group which can become a 5-ethoxy
|
|
group to produce a compound called IRIS, who is the Goddess of the
|
|
rainbow. And there is the 6-hydrogen atom which can become a 6-methyl
|
|
group to produce a compound called JUNO, who is pretty much a ladyUs
|
|
lady, or should I say a woman's woman.
|
|
|
|
GANESHA, 2,5-dimethoxy-3,4-dimethylamphetamine has been made, and has
|
|
proven to be an extraordinary starting point for a large series of
|
|
potent phenethylamines and amphetamines which are described in this
|
|
book. HECATE was given a synonym early in this process, and is now
|
|
known as DOET (2,5-dimethoxy-4-ethylamphetamine). IRIS has also been
|
|
entered under her name, and the other ethoxy homologue, FLORENCE,
|
|
would be easily made based on the preparation of the phenethylamine
|
|
analogue, 2CD-2ETO. Perhaps it has already been made somehow,
|
|
somewhere, as I have noted that I have claimed its citrate salt as a
|
|
new compound in a British patent. And, finally, JUNO
|
|
(3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from
|
|
2,5-dimethoxy-m-xylene, which was reacted with POCl3 and
|
|
N-methylformanilide to the benzaldehyde, mp 53-54 !C, and to the
|
|
nitrostyrene with nitroethane, mp 73-74 !C from cyclohexane, and to
|
|
the final amine hydrochloride with LAH in THF). Rather amazingly, I
|
|
have had JUNO on the shelf for almost 14 years and have not yet gotten
|
|
around to tasting it.
|
|
|
|
|
|
|
|
#9 ASB; ASYMBESCALINE; 3,4-DIETHOXY-5-METHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: To a solution of 32 g of 5-bromobourbonal in 150 mL DMF
|
|
there was added 31 g ethyl iodide and 32 g of finely ground 85% KOH
|
|
pellets. There was the formation of a purple color and a heavy
|
|
precipitate. On gradual heating to reflux, the color faded to a pale
|
|
yellow and the precipitate dissolved over the course of 1 h. The
|
|
heating was continued for an additional 1 h. The reaction mixture was
|
|
added to 1 L H2O, and extracted with 2x150 mL of petroleum ether. The
|
|
extracts were pooled, washed with 2x200 mL 5% NaOH and finally with
|
|
H2O. After drying over anhydrous K2CO3 the solvents were removed
|
|
under vacuum to yield 36 g of crude 3-bromo-4,5-diethoxybenzaldehyde
|
|
as an amber liquid. This was used without purification for the
|
|
following step. Distillation at 105-115 !C at 0.3 mm/Hg provided a
|
|
white sample which did not crystallize. Anal. (C11H13BrO3 ) C,H.
|
|
|
|
A mixture of 36 g 3-bromo-4,5-diethoxybenzaldehyde and 17 mL
|
|
cyclohexylamine was heated with an open flame until it appeared to be
|
|
free of H2O. The residue was put under a vacuum (0.4 mm/Hg) and
|
|
distilled at 135-145 !C, yielding 42 g
|
|
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine as a viscous light
|
|
greenish oil. This slowly set to a crystalline glass with a mp of
|
|
60-61 !C. Recrystallization from hexane gave a white crystalline
|
|
product without any improvement in the mp. Anal. (C17H24BrNO2) C,H.
|
|
This is a chemical intermediate to a number of active bases, taking
|
|
advantage of the available bromine atom. This can be exchanged with a
|
|
sulfur atom (leading to 5-TASB and 3-T-TRIS) or with an oxygen atom as
|
|
described below.
|
|
|
|
A solution of 18 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine in
|
|
250 mL anhydrous Et2O was placed in an atmosphere of He, stirred
|
|
magnetically, and cooled with an external dry ice/acetone bath. Then
|
|
36 mL of a 1.5 M solution of butyllithium in hexane was added over 2
|
|
min, producing a clear yellow solution. This was stirred for 10 min.
|
|
There was then added 30 mL of butyl borate at one time, the stirring
|
|
continued for 5 min. The stirred solution was allowed to return to
|
|
room temperature. There was added 150 mL of saturated aqueous
|
|
ammonium sulfate. The Et2O layer was separated, and the aqueous phase
|
|
extracted with another 75 mL Et2O. The combined organic phases were
|
|
evaporated under vacuum. The residue was dissolved in 100 mL MeOH,
|
|
diluted with 20 mL H2O, and then treated with 15 mL 35% H2O2 added
|
|
over the course of 2 min. This mildly exothermic reaction was allowed
|
|
to stir for 15 min, then added to 500 mL H2O. This was extracted with
|
|
2x100 mL CH2Cl2 and the solvent removed under vacuum. The residue was
|
|
suspended in 150 mL dilute HCl and heated on the steam bath for 0.5 h.
|
|
Stirring was continued until the reaction was again at room
|
|
temperature, then it was extracted with 2x75 mL CH2Cl2. These
|
|
extracts were pooled and extracted with 3x100 mL dilute aqueous KOH.
|
|
The aqueous extracts were washed with CH2Cl2, reacidified with HCl,
|
|
and reextracted with 2x75 mL CH2Cl2. These extracts were pooled, and
|
|
the solvent removed under vacuum to yield a brown residue. This was
|
|
distilled at 107-127 !C at 0.4 mm/Hg to yield 8.3 g of
|
|
3,4-diethoxy-5-hydroxybenzaldehyde as an oil that set to a tan solid.
|
|
Recrystallization from cyclohexane gave a white product with a mp of
|
|
70.5-71.5 !C. Anal. (C11H14O4) C,H.
|
|
|
|
A solution of 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde and 3.0 g
|
|
KOH in 75 mL EtOH was treated with 5 mL methyl iodide and stirred at
|
|
room temperature for 5 days. The reaction mixture was added to 400 mL
|
|
H2O and extracted with 2x50 mL CH2Cl2. The extracts were pooled,
|
|
washed with 2x150 mL dilute NaOH, and the solvent removed under
|
|
vacuum. The residual oil was distilled at 95-110 !C at 0.3 mm/Hg to
|
|
yield 8.2 g of 3,4-diethoxy-5-methoxybenzaldehyde as a pale yellow
|
|
liquid. This product was a crystalline solid below 20 !C but melted
|
|
upon coming to room temperature. It was analyzed, and used in further
|
|
reactions as an oil. Anal. (C12H16O4) C,H.
|
|
|
|
To a solution of 6.4 g 3,4-diethoxy-5-methoxybenzaldehyde in 40 mL
|
|
nitromethane there was added about 0.5 g anhydrous ammonium acetate,
|
|
and this was held at reflux for 1 h. The excess solvent/reagent was
|
|
removed under vacuum, producing a red oil which set up to crystals.
|
|
These were recrystallized from 40 mL boiling MeOH to yield 3.0 g of
|
|
3,4-diethoxy-5-methoxy-'-nitrostyrene as yellow plates, with a mp of
|
|
89-90 !C. Anal. (C13H17NO5) C,H.
|
|
|
|
A solution of 3.0 g LAH in 150 mL anhydrous THF under He was cooled to
|
|
0 !C and vigorously stirred. There was added, dropwise, 2.1 mL of
|
|
100% H2SO4, followed by the dropwise addition of a solution of 3.5 g
|
|
3,4-diethoxy-5-methoxy-'-nitrostyrene in 30 mL anhydrous THF, over the
|
|
course of 10 min. The addition was exothermic. The mixture was held
|
|
at reflux on the steam bath for 30 min. After cooling again, the
|
|
excess hydride was destroyed with IPA, followed by the addition of 10%
|
|
NaOH sufficient to covert the aluminum oxide to a white, granular
|
|
form. This was removed by filtration, the filter cake washed with
|
|
IPA, the mother liquor and filtrates combined, and the solvents
|
|
removed under vacuum to provide a yellow oil. This residue was added
|
|
to 100 mL dilute H2SO4 producing a cloudy suspension and some yellow
|
|
insoluble gum. This was washed with 2x75 mL CH2Cl2. The aqueous
|
|
phase was made basic with 25% NaOH, and extracted with 2x75 mL CH2Cl2.
|
|
The solvent was removed from these pooled extracts and the residue
|
|
distilled at 110-135 !C at 0.4 mm/Hg to provide 2.0 g of a colorless
|
|
liquid. This was dissolved in 7 mL IPA, neutralized with about 40
|
|
drops of concentrated HCl, followed by 50 mL anhydrous Et2O with
|
|
stirring. The initially clear solution spontaneously deposited a
|
|
white crystalline solid. This was diluted with an additional 30 mL
|
|
Et2O, let stand for 1 h, and the solids removed by filtration. After
|
|
Et2O washing, the product was air-dried to yield 1.25 g of
|
|
3,4-diethoxy-5-methoxyphenethylamine hydrochloride (ASB) with a mp of
|
|
142-143 !C. Anal. (C13H22ClNO3) C,H.
|
|
|
|
DOSAGE: 200 - 280 mg.
|
|
|
|
DURATION: 10 - 15 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 240 mg) There was a pleasant and easy
|
|
flow of day-dreaming thoughts, quite friendly and somewhat erotic.
|
|
There was a gentle down-drift to my starting baseline mental status by
|
|
about midnight (I started at 9:00 AM). I never quite made it to a
|
|
+++, and rather regretted it.
|
|
|
|
(with 280 mg) The plateau of effect was evident by hour two, but I
|
|
found the experience lacking the visual and interpretive richness that
|
|
I had hoped for. Sleep was very fitful after the effects had largely
|
|
dropped Q it was hard to simply lie back and relax my guard Q and even
|
|
while being up and about the next day I felt a residual plus one.
|
|
Over all, there were few if any of the open interactions of 2C-B or
|
|
LSD. Some negative side seemed to be present.
|
|
|
|
(with 280 mg) The entire session was, in a sort of way, like being in
|
|
a corridor outside the lighted halls where a beautiful mescaline
|
|
experience is taking place, sensing the light from behind a grey door,
|
|
and not being able to find my way in from the dusky underside
|
|
passageways. This is sort of a gentle sister of mescaline, but with a
|
|
tendency to emphasize (for me, at this time) the negative, the sad,
|
|
the struggling. Sleep was impossible before the fifteenth hour. When
|
|
I tried, I got visions of moonlight in the desert, with figures around
|
|
me which were the vampire-werewolf aspect of the soul, green colored
|
|
and evil. I had to sit quietly in the living room and wait patiently
|
|
until they settled back to wherever they belonged and stopped trying
|
|
to take over the scene. During the peak of the experience, my pulse
|
|
was thready, somewhat slowed, and uneven. There was a faint feeling
|
|
of physical weirdness.
|
|
|
|
EXTENSIONS AND COMMENTARY: This specific amine was a target for a
|
|
single study in cats many years ago, in Holland, using material
|
|
obtained from Hoffman La Roche in Basel. Their findings are hard to
|
|
evaluate, in that 200 milligrams was injected into a 3.75 kilogram cat
|
|
(53 mg/Kg), or about twice the dosage that they used in their studies
|
|
with metaescaline. Within 5 minutes there were indications of
|
|
catatonia, and within a half hour the animal was unable to walk. This
|
|
condition persisted for two days, at which time the animal died.
|
|
Although this dose was many times that used in man, perhaps hints of
|
|
the physical unease and long action are there to be gleaned. The
|
|
consensus from over a half dozen experiments is that there is not
|
|
enough value to be had to offset the body load experienced.
|
|
|
|
A comment is needed on the strange name asymbescaline! In the
|
|
marvelous world of chemical nomenclature, bi- (or di-) usually means
|
|
two of something, and tri- and tetra- quite reasonably mean three and
|
|
four of something. But occasionally there can be an ambiguity with bi
|
|
(or tri or tetra) in that bi some-thing-or-other might be two
|
|
something-or-others hooked together or it might be two things hooked
|
|
onto a something-or-other. So, the former is called bi- and the
|
|
latter is called bis-. This compound is not two escalines hooked
|
|
together (bi-escaline) but is only one of them with two ethyl groups
|
|
attached (bis-escaline or bescaline). And since there are two ways
|
|
that this can be done (either symmetrically or asymmetrically) the
|
|
symmetric one is called symbescaline (or SB for short) and this one is
|
|
called asymbescaline (or ASB for short). To complete the terminology
|
|
lecture, the term tri- becomes tris- (the name given for the drug with
|
|
all three ethoxy groups present in place of the methoxys of mescaline)
|
|
and the term tetra- mutates into the rather incredible tetrakis-!
|
|
|
|
|
|
|
|
#10 B; BUSCALINE; 4-(n)-BUTOXY-3,5-DIMETHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
|
|
preparation), 100 mg decyltriethylammonium iodide, and 11 g n-butyl
|
|
bromide in 50 mL anhydrous acetone was treated with 6.9 g finely
|
|
powdered anhydrous K2CO3 and held at reflux for 10 h. An additional 6
|
|
g of n-butyl bromide was added to the mixture, and the refluxing
|
|
continued for another 48 h. The mixture was filtered, the solids
|
|
washed with acetone, and the solvent from the combined filtrate and
|
|
washes removed under vacuum. The residue was suspended in acidified
|
|
H2O, and extracted with 3x175 mL CH2Cl2. The pooled extracts were
|
|
washed with 2x50 mL 5% NaOH, once with dilute HCl, and then stripped
|
|
of solvent under vacuum giving 13.2 g of a deep yellow oil. This was
|
|
distilled at 132-145 !C at 0.2 mm/Hg to yield 5.0 g of
|
|
4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile as a pale yellow oil
|
|
which set up to crystals spontaneously. The mp was 42-43 !C. Anal.
|
|
(C14H19NO3) C H N.
|
|
|
|
A solution of AH was prepared by the cautious addition of 0.67 mL of
|
|
100% H2SO4 to 25 mL of 1.0 M LAH in THF, which was being vigorously
|
|
stirred under He at ice bath temperature. A total of 4.9 g of
|
|
4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile was added as a solid
|
|
over the course of 10 min. Stirring was continued for another 5 min,
|
|
then the reaction mixture was brought to reflux on the steam bath for
|
|
another 45 min. After cooling again to room temperature, IPA was
|
|
added to destroy the excess hydride (about 5 mL) followed by 10 mL of
|
|
15% NaOH which was sufficient to make the aluminum salts loose, white,
|
|
and filterable. The reaction mixture was filtered, the filter cake
|
|
washed with IPA, and the mother liquor and washes combined and the
|
|
solvent removed under vacuum to yield an amber oil. This residue was
|
|
treated with dilute H2SO4 which generated copious solids. Heating
|
|
this suspension effected solution, and after cooling, all was washed
|
|
with 3x50 mL CH2Cl2. The aqueous phase was made basic with aqueous
|
|
NaOH, and the product extracted with 2x100 mL CH2Cl2. The extracts
|
|
were evaporated to a residue under vacuum, and this was distilled at
|
|
128-138 !C at 0.5 mm/Hg yielding 3.8 g of a colorless oil. This was
|
|
dissolved in 40 mL IPA, neutralized with concentrated HCl (about 55
|
|
drops required) and, with vigorous stirring, 80 mL of anhydrous Et2O
|
|
was added which produced fine white plates. After standing for
|
|
several h, the product was filtered, washed with 20% IPA in Et2O, and
|
|
finally with Et2O. Air drying yielded 3.9 g of
|
|
4-(n)-butyloxy-3,5-dimethoxyphenethylamine hydrochloride (B) with a mp
|
|
of 152-153 !C. An analytical sample melted at 155-157 !C. Anal.
|
|
(C14H24ClNO3) C,H,N.
|
|
|
|
DOSAGE: greater than 150 mg.
|
|
|
|
DURATION: several hours.
|
|
|
|
QUALITATIVE COMMENTS: (with 120 mg) There is a strange taste, not
|
|
really bitter, it does not linger. The slight change of baseline has
|
|
certainly disappeared by the eighth hour. No noticeable changes in
|
|
either the visual or the auditory area.
|
|
|
|
(with 150 mg) Throughout the experiment it was my impression that
|
|
whatever effects were being felt, they were more in body than mind.
|
|
The body load never mellowed out, as it would have with mescaline,
|
|
after the first hour or two. Mental effects didnUt develop in any
|
|
interesting way. I was aware of brief heart arrhythmia. Tummy was
|
|
uncomfortable, off and on, and there was light diarrhea. Even as late
|
|
as the fifth hour, my feet were cold, and the whole thing left me with
|
|
a slightly uncomfortable, 'Why did I bother?' feeling.
|
|
|
|
EXTENSIONS AND COMMENTARY: There is a jingle heard occasionally in
|
|
chemical circles, concerning the homologues of methyl. It goes,
|
|
RThere's ethyl and propyl, but butyl is futile.S And to a large
|
|
measure this is true with the 4-position homologues of mescaline.
|
|
This butyl compound, B or Buscaline, had originally been patented in
|
|
England in 1930 without any physical or pharmacological description,
|
|
and the few physical studies that had involved it (lipophilic this and
|
|
serotonin that) suggested that it was less active than mescaline.
|
|
|
|
In principle, the 5-, the 6-, the 7- and the on-up homologues might be
|
|
called amylescaline (possibly pentescaline?), hexescaline,
|
|
heptescaline (possibly septescaline), and God-knows-what-scaline.
|
|
They would certainly be easily makeable, but there would be little
|
|
value that could be anticipated from nibbling them. In keeping with
|
|
the name B (for butoxy), these would be known as A (for amyloxy, as
|
|
the use of a P could confuse pentoxy with propoxy), as H (for
|
|
hexyloxy, but careful; this letter has been used occasionally for
|
|
DMPEA, which is Homopiperonylamine), and as S (the H for heptyloxy has
|
|
been consumed by the hexyloxy, so let's shift from the Greek hepta to
|
|
the Latin septum for the number seven). It seems most likely that the
|
|
toxic symptoms that might well come along with these phenethylamines
|
|
would discourage the use of the dosage needed to affect the higher
|
|
centers of the brain. The same generally negative feeling applies to
|
|
the amphetamine counterparts 3C-B, 3C-A, 3C-H and 3C-S.
|
|
|
|
A brief reiteration of the 2C-3C nomenclature, to avoid a possible
|
|
misunderstanding. The drug 2C-B is so named in that it is the
|
|
two-carbon chain analogue of the three-carbon chain compound DOB. The
|
|
drug 3C-B is so named because it is the three-carbon chain analogue of
|
|
the two-carbon chain compound Buscaline, or more simply, B. There is
|
|
no logical connection whatsoever, either structural or
|
|
pharmacological, between 2C-B and 3C-B.
|
|
|
|
|
|
|
|
#11 BEATRICE; N-METHYL-DOM; 2,5-DIMETHOXY-4,N-DIMETHYLAMPHETAMINE
|
|
|
|
SYNTHESIS: A fused sample of 5.0 g of white, crystalline free base
|
|
2,5-dimethoxy-4-methylamphetamine, DOM, was treated with 10 mL ethyl
|
|
formate, and held at reflux on the steam bath for several h. Removal
|
|
of the solvent gave 5.5 g of a white solid, which could be
|
|
recrystallized from 15 mL MeOH to give 3.8 g of fine white crystals of
|
|
2,5-dimethoxy-N-formyl-4-methylamphetamine. An analytical sample from
|
|
ethyl formate gave granular white crystals.
|
|
|
|
To a stirred suspension of 4.0 g LAH in 250 mL anhydrous Et2O at
|
|
reflux and under an inert atmosphere, there was added, by the shunted
|
|
Soxhlet technique, 4.2 g of 2,5-dimethoxy-N-formyl-4-methylamphetamine
|
|
as rapidly as its solubility in hot Et2O would allow. The mixture was
|
|
held at reflux for 24 h and then stirred at room temperature for
|
|
several additional days. The excess hydride was destroyed with the
|
|
addition of dilute H2SO4 (20 g in 500 mL water) followed by the
|
|
additional dilute H2SO4 needed to effect a clear solution. The Et2O
|
|
was separated, and the aqueous phase extracted with 100 mL Et2O and
|
|
then with 2x250 mL CH2Cl2. Following the addition of 100 g potassium
|
|
sodium tartrate, the mixture was made basic with 25% NaOH. The clear
|
|
aqueous phase was extracted with 3x250 mL CH2Cl2 These extracts were
|
|
pooled, and the solvent removed under vacuum. The residual amber oil
|
|
was dissolved in 400 mL anhydrous Et2O, and saturated with hydrogen
|
|
chloride gas. The white crystals that formed were removed by
|
|
filtration, washed with Et2O, and air dried to constant weight. There
|
|
was obtained 4.2 g of product with a mp of 131.5-133.5 !C. This
|
|
product was recrys-tallized from 175 mL boiling ethyl acetate to give
|
|
3.5 g 2,5-dimethoxy-4,N-di-methylamphetamine hydrochloride (BEATRICE)
|
|
as pale pink crystals with a mp of 136-137 !C. A sample obtained from
|
|
a preparation that employed the methyl sulfate methylation of the
|
|
benzaldehyde adduct of DOM had a mp of 125-126 !C and presented a
|
|
different infra-red spectrum. It was, following recrystallization
|
|
from ethyl acetate, identical to the higher melting form in all
|
|
respects.
|
|
|
|
DOSAGE: above 30 mg.
|
|
|
|
DURATION: 6 - 10 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 20 mg) There was a gentle and demanding
|
|
rise from the one to the three hour point that put me into an
|
|
extremely open, erotic, and responsive place. I had to find a
|
|
familiar spot to orient myself, and the kitchen served that need. As
|
|
the experience went on, it showed more and more of a stimulant
|
|
response, with tremor, restlessness, and a bit of trouble sleeping.
|
|
But there was no anorexia! An OK experience.
|
|
|
|
(with 30 mg) There is a real physical aspect to this, and I am not
|
|
completely happy with it. There is diarrhea, and I am restless, and
|
|
continuously aware of the fact that my body has had an impact from
|
|
something. The last few hours were spent in talking, and I found
|
|
myself still awake some 24 hours after the start of the experiment.
|
|
The mental was not up there to a +++, and yet the physical disruption
|
|
was all that I might care to weather, and exceeds any mental reward.
|
|
When I did sleep, my dreams were OK, but not rich. Why go higher?S
|
|
|
|
EXTENSIONS AND COMMENTARY: This is another example of the N-methyl
|
|
homologues of the psychedelics. None of them seem to produce stuff of
|
|
elegance. It is clear that the adding of an N-methyl group onto DOM
|
|
certainly cuts down the activity by a factor of ten-fold, and even
|
|
then results in something that is not completely good. Three
|
|
milligrams of DOM is a winner, but even ten times this, thirty
|
|
milligrams of N-methyl-DOM, is somewhat fuzzy. In the rabbit
|
|
hyperthermia studies, this compound was some 25 times less active than
|
|
DOM, so even animal tests say this is way down there in value. This
|
|
particular measure suggests that the active level in man might be 75
|
|
milligrams. Well, maybe, but I am not at all comfortable in trying it
|
|
at that level. In fact I do not intend to explore this any further
|
|
whatsoever, unless there is a compelling reason, and I see no such
|
|
reason. For the moment, let us leave this one to others, who might be
|
|
more adventurous but less discriminating.
|
|
|
|
In browsing through my notes I discovered that I had made another
|
|
N-substitution product of DOM. Efforts to fuse free-base DOM with the
|
|
ethyl cyclopropane carboxylate failed, but the reaction between it and
|
|
the acid chloride in pyridine gave the corresponding amide, with a mp
|
|
of 156-157 !C from MeOH. Anal. (C16H23NO3) C,H,N. This reduced
|
|
smoothly to the corresponding amine,
|
|
N-cyclopropyl-2,5-dimethoxy-4-methylamphetamine which formed a
|
|
hydrochloride salt melting at 153-156 !C. I canUt remember the
|
|
reasoning that led to this line of synthesis, but it must not have
|
|
been too exciting, as I never tasted the stuff.
|
|
|
|
|
|
|
|
#12 BIS-TOM; 4-METHYL-2,5-bis-(METHYLTHIO)AMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum
|
|
ether was magnetically stirred under a He atmosphere. To this there
|
|
was added 50 mL of a 1.6 M hexane solution of butyllithium, and the
|
|
exothermic reaction, which produced a granular precipitate, was
|
|
allowed to stir for 12 h. The mixture was cooled to 0 !C and there
|
|
was then added 7.5 g dimethyldisulfide. There was a heavy precipitate
|
|
formed, which tended to become lighter as the addition of the
|
|
disulfide neared completion. After 20 min additional stirring, the
|
|
reaction mixture was poured into H2O that contained some HCl. The
|
|
phases were separated and the aqueous phase extracted with 50 mL Et2O.
|
|
The organic phase and extract were combined, washed with dilute NaOH,
|
|
and then with H2O. After drying over anhydrous K2CO3, the solvent was
|
|
removed under vacuum and the residue distilled to give a fraction that
|
|
boiled at 75-85 !C at 0.3 mm/Hg and weighed 5.3 g. This was about 80%
|
|
pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be
|
|
the monothiomethyl analogues. A completely pure product was best
|
|
obtained by a different, but considerably longer, procedure. This is
|
|
given here only in outline. The phenolic OH group of
|
|
3-methyl-4-(methylthio)phenol was converted to an SH group by the
|
|
thermal rearrangement of the N,N-dimethylthioncarbamate. The impure
|
|
thiophenol was liberated from the product N,N-dimethylthiolcarbamate
|
|
with NaOH treatment. The separation of the phenol/thiophenol mixture
|
|
was achieved by a H2O2 oxidation to produce the intermediate
|
|
3-methyl-4-methylthiophenyldisulfide. This was isolated as a white
|
|
crystalline solid from MeOH, with a mp of 78-79 !C. Anal. (C16H18S4)
|
|
C,H. It was reduced with zinc in acetic acid, and the resulting
|
|
thiophenol (a water-white liquid which was both spectroscopically and
|
|
microanalytically correct) was methylated with methyl iodide and KOH
|
|
in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free
|
|
of any contaminating mono-sulfur analogues.
|
|
|
|
A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic
|
|
acid was treated with a crystal of iodine followed by the addition of
|
|
3.5 g elemental bromine. This mixture was heated on the steam bath
|
|
for 1 h, which largely discharged the color and produced a copious
|
|
evolution of HBr. Cooling in an ice bath produced solids that were
|
|
removed by filtration. Recrystallization from IPA gave 1.9 g of
|
|
2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with
|
|
a mp of 133-134 !C. Anal. (C9H11BrS2) C,H. An alternate synthesis of
|
|
this intermediate was achieved from 1,4-dibromobenzene which was
|
|
converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp
|
|
of 83.5-84.5 !C) with sodium methylmercaptide in
|
|
hexamethylphosphoramide. This was dibrominated to
|
|
2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white
|
|
platelets from hexane melting at 195-199 !C). This, in Et2O solution,
|
|
reacted with BuLi to replace one of the bromine atoms with lithium,
|
|
and subsequent treatment with methyl iodide gave
|
|
2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to
|
|
the above material (by TLC and IR) but with a broader mp range.
|
|
|
|
A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL
|
|
anhydrous Et2O, stirred magnetically and under a He atmosphere, was
|
|
treated with 10 mL of a 1.6 M solution of butyllithium in hexane.
|
|
After stirring for 10 min there was added 2.5 mL N-methylformanilide
|
|
which led to an exothermic reaction. After another 10 min stirring,
|
|
the reaction mixture was added to 100 mL dilute HCl, the phases were
|
|
separated, and the aqueous phase extracted with 2x50 mL Et2O. The
|
|
combined organic phase and extracts were dried over anhydrous K2CO3,
|
|
and the solvent removed under vacuum. The partially solid residue was
|
|
distilled at 140-150 !C at 0.2 mm/Hg to give a crystalline fraction
|
|
that, after recrystallization from 15 mL boiling IPA gave
|
|
2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid
|
|
which weighed 1.1 g and had a mp of 107-109 !C. An analytical sample
|
|
from MeOH melted at 110-111 !C with an excellent IR and NMR. Anal.
|
|
(C10H12OS2) C,H. An alternate synthesis of this aldehyde employs the
|
|
2,5-bis-(methylthio)toluene described above. A CH2Cl2 solution of
|
|
this substituted toluene containing dichloromethyl methyl ether was
|
|
treated with anhydrous AlCl3, and the usual workup gave a distilled
|
|
fraction that spontaneously crystallized to the desired aldehyde but
|
|
in an overall yield of only 11% of theory.
|
|
|
|
To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15
|
|
mL nitroethane there was added 0.15 g anhydrous ammonium acetate and
|
|
the mixture was heated on the steam bath for 1 h. The excess solvent
|
|
was removed under vacuum and the residue was dissolved in 10 mL
|
|
boiling MeOH. This solution was decanted from a little insoluble
|
|
residue, and allowed to cool to ice bath temperature yielding, after
|
|
filtering and drying to constant weight, 0.55 g of
|
|
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as
|
|
pumpkin-colored crystals with a mp of 90-91 !C. This was not improved
|
|
by recrystallization from EtOH. Anal. (C12H15NO2S2) C,H.
|
|
|
|
A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an
|
|
inert atmosphere, cooled to 0 !C with an external ice bath, and
|
|
treated with 0.42 mL 100% H2SO4, added dropwise. A solution of 0.5 g
|
|
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL
|
|
anhydrous THF was added over the course of 5 min, and the reaction
|
|
mixture held at reflux for 30 min on the steam bath. After cooling
|
|
again to ice temperature, the excess hydride was destroyed by the
|
|
addition of IPA and the inorganics were converted to a loose, white
|
|
filterable form by the addition of 1.5 mL 5% NaOH. These solids were
|
|
removed by filtration and the filter cake was washed with 2x50 mL IPA.
|
|
The combined filtrate and washings were stripped of solvent under
|
|
vacuum to give a residue that was a flocculant solid. This was
|
|
suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the
|
|
combined organics extracted with 2x50 mL dilute H3PO4. The aqueous
|
|
extracts were made basic, and the product removed by extraction with
|
|
2x75 mL CH2Cl2. After removal of the solvent under vacuum, the
|
|
residue was distilled at 126-142 !C at 0.2 mm/Hg to give 0.2 g of
|
|
product which crystallized in the receiver. This was dissolved in 1.5
|
|
mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted
|
|
with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2
|
|
g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM)
|
|
as white crystals with a mp of 228-229 !C. Anal. (C12H20ClNS2) C,H.
|
|
|
|
DOSAGE: greater than 160 mg.
|
|
|
|
DURATION: unknown.
|
|
|
|
QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something
|
|
in the latter part of the afternoon. A suggestion of darting,
|
|
physically (when going to sleep), but nothing at the mental level.
|
|
This is as high as I will go.
|
|
|
|
EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept
|
|
that BIS-TOM is not an active compound. The replacement of the
|
|
2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped
|
|
the potency by a factor of 15x, and the replacement of the 5-position
|
|
oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a
|
|
factor of about 10x. It would be a logical calculation that the
|
|
replacement of both oxygen atoms with sulfur might drop the potency by
|
|
a factor of 150x. So, with DOM being active at maybe 5 milligrams, a
|
|
logical prediction of the active level of BIS-TOM would be 750
|
|
milligrams. And maybe this would be the right level, but with the
|
|
hints of neurological disturbance that seemed to be there at 160 mg,
|
|
there was no desire to go up by a factor of five again. The rewards
|
|
would simply not be worth the risks.
|
|
|
|
The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate
|
|
aldehyde above, first by reaction with nitromethane to give the
|
|
nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 !C.
|
|
Anal. (C11H13NO2S2) C,H. This was reduced with AH to give
|
|
2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as
|
|
ivory-colored crystals with a mp of 273-277 !C.
|
|
|
|
Although there are many interesting psychedelic drugs with sulfur
|
|
atoms in them (the TOMUs, the TOETUs, the ALEPH's and all of the
|
|
2C-TUs), there just arenUt many that contain two sulfur atoms.
|
|
BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably
|
|
also fail, as the phenethylamines are rarely more potent than the
|
|
corresponding amphetamines. This leaves 2C-T-14 as the remaining
|
|
hope, and its synthesis is still underway.
|
|
|
|
|
|
|
|
#13 BOB; '-METHOXY-2C-B; 4-BROMO-2,5-'-TRIMETHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: To a vigorously stirred suspension of 2.1 g
|
|
4-bromo-2,5-dimethoxy-'-nitrostyrene [from
|
|
4-bromo-2,5-dimethoxybenzaldehyde and nitromethane in acetic acid with
|
|
ammonium acetate as a catalyst, mp 157-158 !C, anal. (C10H10BrNO4)
|
|
C,H] in 20 mL anhydrous MeOH, there was added a solution of sodium
|
|
methoxide in MeOH (generated from 0.5 g metallic sodium in 20 mL
|
|
anhydrous MeOH). After a few min there was added 10 mL acetic acid
|
|
(no solids formed) followed by the slow addition of 50 mL of H2O. A
|
|
cream-colored solid was produced, which was removed by filtration and
|
|
washed well with H2O. After air drying the product,
|
|
1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane, weighed 2.0
|
|
g. An analytical sample from MeOH was off-white in color and had a mp
|
|
of 119-120 !C. Anal. (C11H14BrNO5) C,H.
|
|
|
|
A solution of LAH (15 mL of 1 M solution in THF) was diluted with an
|
|
equal volume of anhydrous THF, and cooled (under He) to 0 !C with an
|
|
external ice bath. With good stirring there was added 0.38 mL 100%
|
|
H2SO4 dropwise, to minimize charring. This was followed by the
|
|
addition of 1.0 g
|
|
1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane as a solid
|
|
over the course of 5 min. After an hour of stirring at 0 !C, the
|
|
temperature was brought up to a gentle reflux on the steam bath for 30
|
|
min. There was no vigorous exothermic reaction seen, unlike that with
|
|
the syntheses of BOD, BOH and BOM. The reaction mixture was cooled
|
|
again to 0 !C, and the excess hydride was destroyed by the cautious
|
|
addition of IPA. This was followed by sufficent dilute aqueous NaOH
|
|
to give a white granular character to the oxides, and to assure that
|
|
the reaction mixture was basic. The reaction mixture was filtered,
|
|
and the filter cake washed first with THF fol-lowed by IPA. The
|
|
combined filtrate and washings were stripped of solvent under vacuum
|
|
and dissolved in dilute H2SO4, with the apparent generation of yellow
|
|
solids. This was washed with 2x50 mL CH2Cl2, and the aqueous phase
|
|
made basic with NaOH. This was extracted with 2x50 mL CH2Cl2, and the
|
|
pooled extracts were stripped of solvent under vacuum. The residue
|
|
was distilled at 130-150 !C at 0.2 mm/Hg to give 0.2 g of product as a
|
|
clear white oil. This fraction was dissolved in 10 mL IPA, and
|
|
neutralized with 4 drops concentrated HCl. The addition of 30 mL
|
|
anhydrous Et2O allowed the formation of
|
|
4-bromo-2,5,'-trimethoxyphenethylamine hydrochloride (BOB) as a fine
|
|
white crystalline product. This was removed by filtration, washed
|
|
with Et2O, and air dried. There was obtained 0.1 g white crystals
|
|
with a mp of 187-188 !C. Anal. (C11H17BrClNO3) C,H.
|
|
|
|
DOSAGE: 10 - 20 mg.
|
|
|
|
DURATION: 10 - 20 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 10 mg) I donUt know if it was me this
|
|
day, or if it was the chemical, but I got into a granddaddy of a
|
|
paranoid, sociopathic snit, without feeling and without emotion. I
|
|
was indifferent to everything. Later on, there was some improvement,
|
|
with body tingling (good, IUm pretty sure) and a sense of awareness
|
|
(good, I guess) but I still canceled my evening dinner company. All
|
|
in all, pretty negative.
|
|
|
|
(with 10 mg) I had to get away and into myself, so I weeded in the
|
|
vegetable garden for almost an hour. Then I lay down in the bedroom,
|
|
and enjoyed a magnificent vegetable garden, in Southern France, in my
|
|
mind's eye. An extraordinary zucchini. And the weeds had all been
|
|
magically pulled. In another couple of hours a neurological
|
|
over-stimulation became apparent, and I spent the rest of the day
|
|
defending myself. In the evening, I took 100 milligrams phenobarbital
|
|
which seemed to smooth things just enough. Too bad. Nice material,
|
|
otherwise.
|
|
|
|
(with 15 mg) The erotic was lustful, but at the critical moment of
|
|
orgasm, the question of neurological stability became quite apparent.
|
|
Does one really let go? Everything seemed a bit irritable. The
|
|
tinnitus was quite bad, but the excitement of the rich altered place I
|
|
was in was certainly worth it all. Through the rest of the day, I
|
|
became aware of how tired I was, and how much I wanted to sleep, and
|
|
yet how scared I was to give myself over to sleep. Could I trust the
|
|
body to its own devices without me as an overseeing caretaker? LetUs
|
|
risk it. I slept. The next day there was a memory of this turmoil.
|
|
Clearly the first part of the experience might have been hard to
|
|
define, but it was quite positive. But the last part makes it not
|
|
really worth while.
|
|
|
|
EXTENSIONS AND COMMENTARY: This compound, BOB, is the most potent of
|
|
the BOX series. And yet, as with all of the members of this family,
|
|
there are overtones of physical concern, and of some worry as to the
|
|
integrity of the body. There may well be a separation of activity
|
|
with the two optical isomers, but there is not a tremendous push to
|
|
explore this particular family much further. They canUt all be
|
|
winners, I guess. What would be the activities of compounds with a
|
|
sulfur instead of an oxygen at the beta-oxygen position? What would
|
|
be the nature of action if there were an alpha-methyl group, making
|
|
all of these into amphetamine derivatives? Or what about both a
|
|
sulfur and a methyl group? And what about the isomers that are
|
|
intrinsic to all of this, the threo- and the erythro- and the RDUsS
|
|
and the RLUsS? All this is terra incognita, and must someday be
|
|
looked into. It is chemically simple, and pharmacologically
|
|
provocative. Someone, somewhere, someday, answer these questions!
|
|
|
|
|
|
|
|
#14 BOD; '-METHOXY-2C-D; 4-METHYL-2,5,'-TRIMETHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 39.6 g
|
|
1-(2,5-dimethoxy-4-methylphenyl)-2-nitrostyrene (see recipe for 2C-D
|
|
for its preparation) in 300 mL warm MeOH was prepared. Separately, a
|
|
solution of 9 g elemental sodium in 150 mL MeOH was also prepared.
|
|
This sodium methoxide solution was added to the well-stirred
|
|
nitrostyrene solution, which resulted in a dramatic loss of color.
|
|
There was then added 75 mL acetic acid, and all was poured into 2 L
|
|
H2O. This was extracted with 3x100 mL CH2Cl2. The pooled extracts
|
|
were stripped of solvent, and the 35 g of residue was treated with 5
|
|
mL MeOH, allowed to stand for a short while, decanted from some
|
|
insoluble residue, and the separated clear solution kept at 0 !C
|
|
overnight. There was the deposition of a yellow crystalline product
|
|
which, after removal by filtration and air drying, weighed 9.7 g.
|
|
Recrystallization from 25 mL MeOH gave, after filtering and drying,
|
|
8.4 g of canary-yellow crystals of
|
|
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane with a mp of
|
|
78-79 !C. Evaporation of the mother liquors from the filtration of
|
|
the first crop yielded 3.8 g of additional product which, upon
|
|
recrystallization from 11 mL MeOH, provided another 2.7 g with a mp of
|
|
77-78 !C. Further workup of the mother liquors yielded only impure
|
|
starting nitrostyrene.
|
|
|
|
A solution of LAH (96 mL of 1 M solution in THF) was cooled, under He,
|
|
to 0 !C with an external ice bath. With good stirring there was added
|
|
2.4 mL 100% H2SO4 dropwise, to minimize charring. This was followed
|
|
by the addition of 10.8 g
|
|
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane. There was
|
|
immediate discoloration. After the addition was complete, the
|
|
reaction mixture was held at reflux on the steam bath for 2 h. After
|
|
cooling again, the excess hydride was destroyed with 4 mL IPA and the
|
|
reaction mixture made basic with 15% NaOH. The insoluble inorganic
|
|
salts were removed by filtration, and the filter cake was washed first
|
|
with THF, and then with IPA. The bright yellow filtrate and washes
|
|
were pooled and stripped of solvent under vacuum, yielding 14 g of a
|
|
yellow oil. This was suspended in 1 L dilute H2SO4 to give an ugly,
|
|
cloudy, yellow-orange mess. Extraction with 3x75 mL CH2Cl2 removed
|
|
much of the color, and the remaining aqueous phase was made basic with
|
|
25% NaOH, and extracted with 3x75 mL CH2Cl2. Evaporation of the
|
|
solvent under vacuum gave 9 g of a pale amber oil which was distilled
|
|
at 115-130 !C at 0.4 mm/Hg. The water-white distillate was dissolved
|
|
in 15 mL IPA, neutralized with concentrated HCl, and then diluted with
|
|
70 mL anhydrous Et2O. After a few min, white crystals formed, and
|
|
these were removed by filtration and Et2O washed. When air-dried to
|
|
constant weight, 4.49 g brilliant white crystals of
|
|
4-methyl-2,5,'-trimethoxyphenethylamine hydrochloride (BOD) with a mp
|
|
of 171-172 !C with decomposition, were obtained. The mother liquors
|
|
on standing deposited 0.66 g additional crystals which were impure and
|
|
were discarded. Anal. (C12H20ClNO3) C,H.
|
|
|
|
DOSAGE: 15 - 25 mg.
|
|
|
|
DURATION: 8 - 16 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 20 mg) There were some very pleasant
|
|
visuals starting at 2-2.5 hours and continuing to 4-5 hours after the
|
|
beginning of the experiment. Open eye visuals seem to come on after
|
|
staring at particular areas, such as the living room ceiling or at
|
|
trees. The surroundings tended to move slightly. There was no
|
|
flowing of the images at all. When looking at the pine trees, the
|
|
needles appeared crystal clear and sharply defined, with strong
|
|
contrasts. Though the mental effect is difficult to define, I am not
|
|
sure it was all that great. I did become tired of the effect (along
|
|
with the confusion) after 8 hours, and was quite happy to note that it
|
|
did taper off in the early evening. I am not particularly sure I
|
|
would want to try this material again.
|
|
|
|
(with 20 mg) For the first three or so hours, the beauty of the
|
|
experience was marred by a strange discomfort. There was some
|
|
queasiness, and I felt a sluggishness of mind. Then I began moving in
|
|
and out of a pleasant place, and finally the discomfort completely
|
|
dissolved and the experience turned full on. Height of beauty, visual
|
|
perception. Lights below are amazing. Outside, marvelous sense of
|
|
Presence. There is not an elation, as often with other materials, but
|
|
a strong, even powerful sense of goodness, inner strength, solidity.
|
|
|
|
(with 25 mg) This was quite quick. The onset of the experience was
|
|
apparent within a half hour, and we were both at +++ within the hour.
|
|
Body load minimal. There was very little visual, compared with some
|
|
materials. Very interesting eyes-closed, but not continually Q just
|
|
now and then an intense vision might flash. Very benign and friendly
|
|
and pleasant and good-humored feeling. Superb for conversation and
|
|
conceptualization.
|
|
|
|
(with 25 mg) The body load was quite noticeable for everyone. But
|
|
the general state of mind was excellent; everyone was extremely
|
|
relaxed and funny. Puns, insults, delightful amusement. Not very
|
|
much insight work possible. Juices were needed and tolerated well,
|
|
but no one was particularly hungry. Sleep was difficult for most
|
|
people, not deep and not too refreshing. Excellent material, but body
|
|
price a bit too much for the mental effects. Pleasant, and I wouldnUt
|
|
hesitate to take it again, but nothing very memorable except the
|
|
tremendous humor and laughter, which was truly delightful.
|
|
|
|
EXTENSIONS AND COMMENTARY: This compound, BOD, was the first
|
|
exploratory member of a new family of phenethylamines. This family is
|
|
called the BOX series because an oxygen atom has been put on the
|
|
benzylic carbon (the Rbenzyl-oxyS or RBOS) of each of several well
|
|
studied drugs with recognized substituent patterns on the aromatic
|
|
ring. The RXS would be RD,S as used here with BOD, making reference
|
|
to 2C-D, it would be a RBS in BOB making reference to 2C-B, etc.
|
|
Actually the original thought was to make the ROS into an ROMS for
|
|
methoxy, as this would allow more versatility in the naming of things
|
|
such as ethoxys (ROES) or hydroxys (ROHS), but the methoxylated 2C-B
|
|
analogue would have come out as BOMB, so the idea was dropped.
|
|
|
|
Actually, the concept of naming of drugs with some acronym that is
|
|
pronounceable has led into some interesting byways. Some examples
|
|
have been unintended. I have heard DOM pronounced RdomeS and DOET
|
|
pronounced as Rdo it.S And elsewhere I have mentioned the embarrassing
|
|
occasions where the TOM and TOET families were pronounced Rthe toms
|
|
and twats.S Some examples have had names that have been contractions
|
|
of popular names, such as XTC for ecstasy. And there are instances
|
|
where a name might be proposed simply to irritate the newspaper
|
|
people. An early street suggestion for PCP was FUK, and a current
|
|
name for free-base methamphetamine is SNOT. And marijuana is fondly
|
|
called SHIT by its aficionados. The final RAS on government groups
|
|
such as the CIA or the DEA or the FDA is strongly reminscent of the
|
|
final RAS which stands for amphetamine in things such as TMA and MDMA.
|
|
Might there someday be a drug such as
|
|
4-cyclopropylmethyl-N-isopropylamphetamine (CIA), or
|
|
3,5-dimethoxy-4-ethylamphetamine (DEA)? It has just occurred to me
|
|
that there is already a 4-fluoro-2,5-dimethoxyamphetamine (FDA), but I
|
|
have already named it DOF. If all drugs were known only by publicly
|
|
embarrassing names, there might be less publicity given them by the
|
|
press.
|
|
|
|
Back to the commentary on BOD. The rationale for this inclusion of a
|
|
beta-oxygen atom into the structure of a phenethylamine is based
|
|
directly on the chemistry that occurs naturally in the brain. The
|
|
phenethylamine neurotransmitter, dopamine, is converted both in the
|
|
brain and in the body to the equally important transmitter
|
|
norepinephrine by just this sort of transformation. There is the
|
|
enzymatic addition of an oxygen atom to the RbenzylicS position of
|
|
dopamine. And identical chemistry goes on with tyramine in a number
|
|
of plants and animals, with a similar addition of oxygen to form
|
|
octopamine, so-named for its discovered presence in the salivary
|
|
glands of Octopus vulgaris. In the first explorations in the BOX
|
|
series, this oxygen was intentionally blocked with a methyl group, to
|
|
ease its entry into the brain, and increase the possibilities of its
|
|
being active as a psychedelic. As mentioned above, the RDS in BOD
|
|
follows from its ring orientation pattern being the same as that of
|
|
2C-D (and this, originally from the mimicking of the pattern of DOM).
|
|
All of these D- compounds have the 2,5-dimethoxy-4-methyl
|
|
ring-substitution pattern.
|
|
|
|
An interesting complication is also part of this structure package.
|
|
The added methoxy group (or hydroxy group, see recipe for BOHD) also
|
|
adds a new asymmetric center, allowing for the eventual separation of
|
|
the material into two optical isomers. And at such time as the
|
|
corresponding amphetamine homologues might be made and studied, the
|
|
presence of yet another chiral center (under the alpha-methyl group)
|
|
will demand that there be actually two racemic compounds synthesized,
|
|
and a total of four isomers to contend with, if really careful and
|
|
thorough work is to be done.
|
|
|
|
A parallel chemistry to all of this follows the addition of sodium
|
|
ethoxide (rather than sodium methoxide) to the nitrostyrene. The
|
|
final product, then, is the ethoxy homologue
|
|
2,5-dimethoxy-'-ethoxy-4-methylphenethylamine, or BOED. It is down in
|
|
human potency by a factor of three, with a normal dosage being 70-75
|
|
milligrams. It has a ten hour duration, and is both anorexic and
|
|
diuretic. There have been no visual effects or insights reported, but
|
|
rather simply a highly intoxicated state.
|
|
|
|
Two synonyms, two definitions, and an expression of admiration. The
|
|
word norepinephrine is synonymous with noradrenalin, and the word
|
|
epinephrine is synonymous with adrenalin. The distinctions are that
|
|
the first in each case is American and the second British. And the
|
|
term RchiralS indicates a potential asymmetry in a molecule that would
|
|
allow eventual separation into two optical isomers. The term
|
|
RracemicS refers to a mixture of these two isomers which has not yet
|
|
been separated into the individual components. A racemic mixture is
|
|
called a racemate and, from the point of view of the human animal
|
|
(which is completely asymmetric), must be considered as a mixture of
|
|
two structurally identical but optically mirror-image isomers, which
|
|
can be potentially separated and which will certainly have different
|
|
pharmacologies. And the admiration? This is directed to the explorer
|
|
who ventured close enough to an octopus to locate its salivary glands
|
|
and to discover a phenethylamine there!
|
|
|
|
|
|
|
|
#15 BOH; '-METHOXY-3,4-METHYLENEDIOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: To a solution of 30 g piperonal in 100 mL acetic acid there
|
|
was added 20 mL nitromethane and 10 mL cyclohexylamine. After heating
|
|
on the steam bath for 1.5 h, the reaction mixture started to
|
|
crystallize. The mixture was cooled in an ice bath, and the heavy
|
|
mass of deposited crystals removed by filtration and washed with 20 mL
|
|
acetic acid. All was supended in 100 mL warm MeOH, cooled again, and
|
|
filtered to give 24.5 g of 3,4-methylenedioxy-'-nitrostyrene as
|
|
canary-yellow crystals, with a mp of 158-160 !C. Reduction of this
|
|
compound with LAH gives rise to MDPEA, which is a separate entry with
|
|
a recipe of its own.
|
|
|
|
To a vigorously stirred suspension of 20 g 3,4-methylenedioxy-'-nitro
|
|
-styrene in 100 mL anhydrous MeOH there was added a freshly prepared
|
|
solution of 5.5 g elemental sodium in 100 mL MeOH. The nitrostyrene
|
|
goes into solution over the course of 5 min. There was then added,
|
|
first, 50 mL acetic acid with the stirring continued for an additional
|
|
1 min. There was then added 300 mL H2O. An oil separated and was
|
|
extracted into 200 mL CH2Cl2. The organic extract was washed with 500
|
|
mL dilute aqueous NaHCO3, followed by 500 mL H2O. Removal of the
|
|
solvent gave a residue that was distilled at 128-145 !C at 0.4 mm/Hg,
|
|
providing 16.6 g of a yellow viscous liquid which slowly crystallized.
|
|
An analytical sample was recrystallized from four volumes of MeOH to
|
|
give 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane as bright
|
|
yellow crystals with a mp of 58-59 !C. Anal. (C10H11NO5) C,H.
|
|
|
|
A solution of LAH (100 mL of 1 M solution in THF) was cooled, under
|
|
He, to 0 !C with an external ice bath. With good stirring there was
|
|
added 2.5 mL 100% H2SO4 dropwise, to minimize charring. This was
|
|
followed by the addition of 12 g
|
|
1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane over the course
|
|
of 2 min. There was an immediate loss of color. After a few minutes
|
|
further stirring, the temperature was brought up to a reflux with a
|
|
heating mantle. There was a gentle gas evolution for a few min,
|
|
followed by an exothermic reaction that exceeded the capacity of the
|
|
condenser. Once the reaction had subsided, the unreacted hydride was
|
|
destroyed with a minimum of IPA, and 15% NaOH was added to convert the
|
|
inorganics to a loose white filterable mass. The reaction mixture was
|
|
filtered, and the filter cake washed thoroughly with THF. The
|
|
combined filtrate and washes were stripped of solvent under vacuum,
|
|
providing an orange oil. This was dissolved in 400 mL dilute H2SO4,
|
|
which was washed with 3x75 mL CH2Cl2. After making the aqueous phase
|
|
basic, it was extracted with 2x100 mL CH2Cl2. The pooled extracts
|
|
were stripped of solvent under vacuum, and the residue distilled at
|
|
103-112 !C at 0.5 mm/Hg. There was obtained 2.5 g of a colorless,
|
|
viscous oil which was dissolved in 25 mL IPA, neutralized with 45
|
|
drops of concentrated HCl, and finally diluted with 30 mL anhydrous
|
|
Et2O. There was thus formed
|
|
'-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (BOH) as a
|
|
fine white crystalline product. The mp was 105-106.5 !C, with
|
|
bubbling and darkening. The mp properties proved to be inconsistent,
|
|
as the salt was a hydrate. Recrystallization from CH3CN, or simply
|
|
heating to 100 !C in toluene, converted the salt to an anhydrous form,
|
|
with mp of 152-153 !C. Anal. (C10H14ClNO3) C,H.
|
|
|
|
DOSAGE: 80 - 120 mg.
|
|
|
|
DURATION: 6 - 8 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 90 mg) Distinct body awareness in an
|
|
hour. The threshold is mostly physical. Faint sense of inside
|
|
warmth, skin prickling, cold feet, loose bowels, anorexia. By the
|
|
fifth hour, I was on the downslope, and in retrospect I found it good
|
|
humored but not insightful.
|
|
|
|
(with 100 mg) There was a vague nausea, and a chilling of the feet.
|
|
It reached a real plus two, with dilated pupils and quite a thirst.
|
|
How can one describe the state? There were no visuals, and I was not
|
|
even stoned. I was just very turned on. And I was completely back to
|
|
baseline by hour number six.
|
|
|
|
EXTENSIONS AND COMMENTARY: There are several reports of a nice, mild
|
|
mood enhancement in the 20-40 milligram dosage area, but searches for
|
|
psychedelic effects at higher levels gave a strange mix of some sort
|
|
of an altered state along with bodily discomfort. The BOH name for
|
|
this member of the BOX family follows the convention discussed in the
|
|
BOD recipe Q with RHS for homopiperonylamine, the simplest of the
|
|
muni-metro family, q.v. The demethylated homologue of BOH is BOHH,
|
|
and is the methylenedioxy analogue of norepinephrine. It might well
|
|
hydrolytically open up in the body to provide this neurotransmitter,
|
|
and serve as some sort of transmitter in its own right. It is
|
|
discussed under DME.
|
|
|
|
Maybe there is something to the concept that when you imitate a
|
|
neurotransmitter too closely, you get a hybrid gemisch of activity.
|
|
The term Rpro-drugS is used to identify a compound that may not be
|
|
intrinsically active, but one which metabolizes in the body to provide
|
|
an active drug. I feel the term should have been pre-drug, but
|
|
pro-drug was the word that caught on. BOH may well act in the body as
|
|
a pro-drug to norepinephrine, but with the temporary blocking of the
|
|
polar functions with ether groups, it can gain access to the brain.
|
|
And once there, it can be stripped of these shields and play a direct
|
|
neurological role. I uncovered a very similar analogy in the
|
|
tryptamine world some years ago. Just as norepinephrine is a
|
|
neurotransmitter, so is serotonin. And I found that by putting an
|
|
O-ether on the indolic phenol (to hide its polarity) and an
|
|
alpha-methyl group next to the primary amine (to protect it from
|
|
metabolic deaminase), it became an extremely potent, and most complex,
|
|
psychedelic. This was the compound alpha,O-dimethylserotonin, or
|
|
a,O-DMS. There is an uncanny analogy between this tryptamine and the
|
|
phenethylamine BOH.
|
|
|
|
Somehow the quiet voice deep inside me says, donUt use too much, too
|
|
quickly. Maybe one of the optical isomers is the body thing, and the
|
|
other isomer is the mind thing. So far, only the racemic mixture has
|
|
been tasted, to the best of my knowledge.
|
|
|
|
|
|
|
|
#16 BOHD; 2,5-DIMETHOXY-'-HYDROXY-4-METHYLPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 0.4 g
|
|
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane (see
|
|
preparation in the recipe for BOD) in 3.0 mL acetic acid was heated to
|
|
100 !C on a steam bath. There was added 1.0 g powdered zinc, followed
|
|
by additional acetic acid as needed to maintain smooth stirring.
|
|
After 0.5 h there was added 1.0 mL concentrated HCl and, following an
|
|
additional few minutes heating, the reaction mixture was poured into
|
|
300 mL H2O. After washing the aqueous phase with 3x75 mL CH2Cl2, the
|
|
mixture was made basic with 25% NaOH, and extracted with 3x50 mL
|
|
CH2Cl2. Removal of the solvent and distillation of the residue at
|
|
130-140 !C 0.25 mm/Hg gave an oil that, on dissolving in IPA,
|
|
neutralization with concentrated HCl, and the addition of anhydrous
|
|
Et2O, gave beautiful white crystals of
|
|
2,5-dimethoxy-'-hydroxy-4-methylphenethylamine hydrochloride (BOHD).
|
|
The yield was 0.2 g, and the mp was 180-181 !C. The infrared spectrum
|
|
was that of an amine salt with a strong OH group present. Anal.
|
|
(C11H18ClNO3) C,H.
|
|
|
|
DOSAGE: greater than 50 mg.
|
|
|
|
DURATION: unknown.
|
|
|
|
QUALITATIVE COMMENTS: (with 50 mg) At about the two hour point, there
|
|
was a precipitous drop of blood pressure (from 120/72 to 84/68)
|
|
although the pulse stayed steady at 60. This trend had been apparent
|
|
in earlier trials, and was being watched carefully. No further tests
|
|
are planned.
|
|
|
|
EXTENSIONS AND COMMENTARY: The usual method of making
|
|
beta-ethanolamine such as this is through the reduction of the
|
|
cyanohydrin of the corresponding benzaldehyde and, in fact, that
|
|
method is described in the recipe for DME. This above procedure was
|
|
actually part of an exploration of different agents that might be used
|
|
in the reduction of the intermediate nitroalkane. This product was
|
|
the unexpected result of trying zinc.
|
|
|
|
Why the potent cardiovascular effect seen by this compound? There are
|
|
a couple of points that might argue for some adrenolytic toxicity.
|
|
This material is a beta-ethanolamine and, with maybe one or two
|
|
exceptions, clinically used beta-receptor blockers are
|
|
beta-ethanolamines. In fact, a few of these so-called beta-blockers
|
|
actually have two methoxy groups on the aromatic rings, also a
|
|
property of BOHD. The antidiabetic drug Butaxamine (BW 64-9 in the
|
|
code of Burroughs Wellcome) is identical to BOHD except that the
|
|
4-methyl group is on the alpha-carbon instead, and there is a tertiary
|
|
butyl group on the nitrogen atom. Another point involves the
|
|
proximity of the beta-hydroxy group and the methoxyl oxygen atom in
|
|
the 2-position of the ring. There is going to be a strong
|
|
hydrogen-bonding with this orientation, with the formation of a stable
|
|
six-membered ring. This might help obscure the hydrophilic nature of
|
|
the free hydroxyl group and allow the compound to pass into the brain
|
|
easily. If this group is masked by an easily removed group such as an
|
|
acetate ester, one gets the compound
|
|
beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is
|
|
similar to BOHD as a hypotensive.
|
|
|
|
The code-naming procedure used here (and elsewhere here in Book II)
|
|
is: (1) to use RBOS as the alert to there being an oxygen on the
|
|
benzyl carbon of a phenethylamine (it is a benzyl alcohol); (2) if
|
|
there is just one more letter (a third and last letter) it will
|
|
identify the 2C-X parent from which it has been derived [RBS comes
|
|
from 2C-B, RDS comes from 2C-D, RHS comes from homopiperonylamine
|
|
(MDPEA) rather than from 2C-H, RMS comes from mescaline, and in every
|
|
case the beta-substituent is a methoxy group]; and (3) if there are
|
|
four letters, then the fourth letter is as above, and the third letter
|
|
(the next to last letter) is the substituent on that benzylic oxygen.
|
|
With a three letter code, the substituent is a methyl group, an RHS
|
|
for a third letter of four makes it a hydroxyl group, and an RAS for
|
|
the third letter is an acetyl group, and an RES is for an ethyl group.
|
|
A similar sort of cryptographic music was composed by Du Pont in their
|
|
three-number codes for the Freons. The first number was one less than
|
|
the number of carbons in the molecule, the second number was one more
|
|
than the number of hydrogens in the molecule, the third number was the
|
|
exact number of fluorines in the molecule, and the rest of the bonds
|
|
were filled with chlorines, Thus Freon 11 (really Freon 011) was
|
|
trichlorofluoromethane and Freon 116 was hexafluoroethane.
|
|
|
|
Complex, yes. But both systems are completely straightforward, and
|
|
flexible for future creations. A few additional examples of similar
|
|
beta-ethanolamines are scattered throughout Book II and they have, in
|
|
general, proved to be uninteresting, at least as potential psychedelic
|
|
compounds.
|
|
|
|
|
|
|
|
#17 BOM; '-METHOXYMESCALINE; 3,4,5,'-TETRAMETHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: To a vigorously stirred suspension of 9.0 g
|
|
'-nitro-3,4,5-trimethoxystyrene (see under the recipe for M for the
|
|
preparation of this intermediate) in 50 mL anhydrous MeOH there was
|
|
added a solution obtained from the addition of 2.0 g metallic sodium
|
|
to 50 mL anhydrous MeOH. The bright orange color faded to a light
|
|
cream as the nitrostyrene went into solution. After 3 min there was
|
|
added 30 mL acetic acid, which produced white solids, and this was
|
|
followed by further dilution with 150 mL H2O. The formed solids were
|
|
removed by filtration, washed well with H2O, and recrystallized from
|
|
150 mL boiling MeOH. After removal of the product by filtration and
|
|
air drying to constant weight, there was obtained 6.9 g of
|
|
1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane as fine,
|
|
cream-colored crystals. The mp was 143-144 !C, and the Rf by TLC
|
|
(silica-gel plates and CH2Cl2 as moving phase) was identical to that
|
|
of the starting aldehyde. Anal. (C12H17NO6) C,H.
|
|
|
|
A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
|
|
to 0 !C with an external ice bath. With good stirring there was added
|
|
1.25 mL 100% H2SO4 dropwise, to minimize charring. This was followed
|
|
by the addition of 6 g of solid
|
|
1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane over the course of
|
|
2 min. There was some gas evolution. After 5 min additional
|
|
stirring, the temperature was brought up to a reflux with a heating
|
|
mantle. There was a gentle gas evolution for a few minutes, followed
|
|
by an exothermic reaction with vigorous gas evolution. Once
|
|
everything had settled down, the reaction mixture was held at reflux
|
|
temperature for an additional 2 h. The excess hydride was destroyed
|
|
by the addition of IPA and 15% NaOH was added to convert the inorganic
|
|
salts to a loose white filterable mass. The reaction mixture was
|
|
filtered, and the filter cake washed thoroughly with THF. The
|
|
combined filtrate and washes were stripped of solvent under vacuum
|
|
which provided a red-brown liquid. This was dissolved in dilute H2SO4
|
|
and washed with 3x75 mL CH2Cl2. After making the aqueous phase basic
|
|
with NaOH, it was extracted with 2x100 mL CH2Cl2. The pooled extracts
|
|
were stripped of solvent under vacuum, and the colorless residue
|
|
distilled at 120-150 !C at 0.3 mm/Hg. There was obtained 2.8 g of a
|
|
colorless oil which was dissolved in 30 mL IPA and neutralized with
|
|
concentrated HCl, allowing the spontaneous formation of the
|
|
hydrochloride salt. This was diluted with 75 mL anhydrous Et2O,
|
|
yielding 2.8 g 3,4,5,'-tetramethoxyphenethylamine hydrochloride (BOM)
|
|
as a white crystalline product. This had a mp of 198.5-199.5 !C.
|
|
Anal. (C12H20ClNO4) C,H.
|
|
|
|
DOSAGE: greater than 200 mg.
|
|
|
|
DURATION: unknown.
|
|
|
|
EXTENSIONS AND COMMENTARY: There are some indicators of central
|
|
activity with assays involving both the 120 milligram and the 180
|
|
milligram levels, but nothing that can be rated as over a plus one.
|
|
It can be seen with the two active members of the BOX series (BOD and
|
|
BOB) that the potency is about equal to, or a little more (up to a
|
|
factor of maybe x2), than the analogue without the methoxyl group on
|
|
the aliphatic chain. If this formula were to hold in the relationship
|
|
between mescaline and BOM, the active level might well be in the
|
|
200-400 milligram range. But at the moment, it remains unknown.
|
|
|
|
Again, the name of the compound (BOM) is from the RBO-S prefix of this
|
|
family (from benzyl + oxy), plus the RMS of mescaline (which has
|
|
provided the ring substitution pattern).
|
|
|
|
|
|
|
|
#18 4-BR-3,5-DMA; 3,5-DIMETHOXY-4-BROMOAMPHETAMINE
|
|
|
|
SYNTHESIS: The starting material 3,5-dimethoxy-4-bromobenzoic acid
|
|
(made from the commercially available resorcinol by the action of
|
|
methyl sulfate) was a white crystalline solid from aqueous EtOH with a
|
|
mp of 248-250 !C. Reaction with thionyl chloride produced
|
|
3,5-dimethoxy-4-bromobenzoyl chloride which was used as the crude
|
|
solid product, mp 124-128 !C. This was reduced with tri-O-(t)-butoxy
|
|
lithium aluminum hydride to produce 3,5-dimethoxy-4-bromobenzaldehyde
|
|
which was recrystallized from aqueous MeOH and had a mp of 112-114 !C.
|
|
Anal. (C9H9BrO3) C,H. This aldehyde, with nitroethane and anhydrous
|
|
ammonium acetate in acetic acid, was converted to the nitrostyrene
|
|
1-(3,5-dimethoxy-4-bromophenyl)-2-nitropropene, with a mp of 121-121.5
|
|
!C. Anal. (C11H12BrNO4) C,H,N. This was reduced at low temperature
|
|
with just one equivalent of LAH, to minimize reductive removal of the
|
|
bromine atom. The product 3,5-dimethoxy-4-bromoamphetamine
|
|
hydrochloride (4-BR-3,5-DMA) was isolated in a 37% yield and had a mp
|
|
of 221-222 !C. Anal. (C11H17BrClNO2) C,H,N.
|
|
|
|
DOSAGE: 4 - 10 mg.
|
|
|
|
DURATION: 8 - 12 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 3 mg) This is certainly no placebo. At
|
|
about 2 hours I felt some analgesia and numbing in my extremities, but
|
|
if there were any sensory distortions, they were barely perceptible.
|
|
|
|
(with 6 mg) There is a very shallow threshold, no more.
|
|
|
|
(with 10 mg) I can certainly confirm the indications of anesthesia
|
|
that were hinted at. It was for me central in nature, however. I
|
|
could (this at three hours) pierce a skin pinch on my left arm with no
|
|
bother except for the emerging of the needle due to skin resistance.
|
|
There was little bleeding. And multiple needle prickings into the
|
|
thumb abductor were not felt. A quick plunge of the tip of my little
|
|
finger into boiling water elicited reflex response, but no residual
|
|
pain. Judgment was OK, so I stayed out of physical trouble, luckily!
|
|
The perhaps ++ was dropping in the fourth or fifth hour, and by the
|
|
tenth hour there were few effects still noted, except for some
|
|
teeth-rubbiness and a burning irritation at the pin-prick area, so
|
|
feeling is back. No sleep problems at just past midnight.
|
|
|
|
EXTENSIONS AND COMMENTARY: Here is a complex and, at the moment,
|
|
totally undefined drug. There were two independent reports of
|
|
analgesia, yet a thorough screen in experimental animals, conducted by
|
|
a major pharmaceutical house, failed to confirm any of it. A ++
|
|
report does not necessarily reflect a psychedelic effect, since this
|
|
quantitative measure of the level of activity represents the extent of
|
|
impairment of function, regardless of the nature of the drug producing
|
|
it. In other words, if you were experiencing the effects of a drug
|
|
that would in your judgment interfere with safe and good driving, this
|
|
would be a ++ whether your performance was being limited by a
|
|
psychedelic, a stimulant, a hypnotic or a narcotic. None of the
|
|
quantitative reports ever mentioned any sensory distortion (analgesia
|
|
is a loss, not a distortion) or visual effect. Perhaps 4-BR-3,5-DMA
|
|
showed its ++ as a narcotic. But then, the rats had said no.
|
|
|
|
|
|
|
|
#19 2-BR-4,5-MDA; 6-BR-MDA; 2-BROMO-4,5-METHYLENEDIOXYAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 3,4-methylenedioxyamphetamine (MDA) in acetic
|
|
acid was treated with elemental bromine, generating the hydrobromide
|
|
salt of 2-bromo-4,5-methylenedioxyamphetamine in a yield of 61% of
|
|
theory. The mp was 221-222 !C. Anal. (C10H13Br2NO2) C,H,Br.
|
|
|
|
DOSAGE: 350 mg.
|
|
|
|
DURATION: unknown.
|
|
|
|
EXTENSIONS AND COMMENTARY: Both the synthetic and the pharmacological
|
|
details for this compound are sparse. There has been only a single
|
|
report of the human activity of this drug in the literature, and the
|
|
statement has been offered that the effects are amphetamine-like. No
|
|
other qualitative comments have been made available, and neither I nor
|
|
anyone in my circle has tried it, personally. Someday, perhaps. But
|
|
at that high level, perhaps not.
|
|
|
|
|
|
|
|
#20 2C-B; 4-BROMO-2,5-DIMETHOXYPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 100 g of 2,5-dimethoxybenzaldehyde in 220 g
|
|
nitromethane was treated with 10 g anhydrous ammonium acetate, and
|
|
heated on a steam bath for 2.5 h with occasional swirling. The
|
|
deep-red reaction mixture was stripped of the excess nitromethane
|
|
under vacuum, and the residue crystallized spontaneously. This crude
|
|
nitrostyrene was purified by grinding under IPA, filtering, and
|
|
air-drying, to yield 85 g of 2,5-dimethoxy-'-nitrostyrene as a
|
|
yellow-orange product of adequate purity for the next step. Further
|
|
purification can be achieved by recrystallization from boiling IPA.
|
|
|
|
In a round-bottomed 2 L flask equipped with a magnetic stirrer and
|
|
placed under an inert atmosphere, there was added 750 mL anhydrous
|
|
THF, containing 30 g LAH. There was then added, in THF solution, 60 g
|
|
2,5-dimethoxy-'-nitrostyrene. The final solution was a dirty
|
|
yellow-brown color, and it was kept at reflux temperature for 24 h.
|
|
After cooling, the excess hydride was destroyed by the dropwise
|
|
addition of IPA. Then 30 mL 15% NaOH was added to convert the
|
|
inorganic solids to a filterable mass. The reaction mixture was
|
|
filtered and the filter cake washed first with THF and then with MeOH.
|
|
The combined mother liquors and washings were freed of solvent under
|
|
vacuum and the residue suspended in 1.5 L H2O. This was acidified
|
|
with HCl, washed with with 3x100 mL CH2Cl2, made strongly basic with
|
|
25% NaOH, and reextracted with 4x100 mL CH2Cl2. The pooled extracts
|
|
were stripped of solvent under vacuum, yielding 26 g of oily residue,
|
|
which was distilled at 120-130 !C at 0.5 mm/Hg to give 21 g of a white
|
|
oil, 2,5-dimethoxy-phenethylamine (2C-H) which picks up carbon dioxide
|
|
from the air very quickly.
|
|
|
|
To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine in 40
|
|
mL glacial acetic acid, there was added 22 g elemental bromine
|
|
dissolved in 40 mL acetic acid. After a couple of min, there was the
|
|
formation of solids and the simultaneous evolution of considerable
|
|
heat. The reaction mixture was allowed to return to room temperature,
|
|
filtered, and the solids washed sparingly with cold acetic acid. This
|
|
was the hydrobromide salt. There are many complicated salt forms,
|
|
both polymorphs and hydrates, that can make the isolation and
|
|
characterization of 2C-B treacherous. The happiest route is to form
|
|
the insoluble hydrochloride salt by way of the free base. The entire
|
|
mass of acetic acid-wet salt was dissolved in warm H2O, made basic to
|
|
at least pH 11 with 25% NaOH, and extracted with 3x100 mL CH2Cl2.
|
|
Removal of the solvent gave 33.7 g of residue which was distilled at
|
|
115-130 !C at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50
|
|
mL H2O containing 7.0 g acetic acid. This clear solution was vigorous
|
|
stirred, and treated with 20 mL concentrated HCl. There was an
|
|
immediate formation of the anhydrous salt of
|
|
2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B). This mass
|
|
of crystals was removed by filtration (it can be loosened considerably
|
|
by the addition of another 60 mL H2O), washed with a little H2O, and
|
|
then with several 50 mL portions of Et2O. When completely air-dry,
|
|
there was obtained 31.05 g of fine white needles, with a mp of 237-239
|
|
!C with decomposition. When there is too much H2O present at the time
|
|
of adding the final concentrated HCl, a hydrated form of 2C-B is
|
|
obtained. The hydrobromide salt melts at 214.5-215 !C. The acetate
|
|
salt was reported to have a mp of 208-209 !C.
|
|
|
|
DOSAGE: 12 - 24 mg.
|
|
|
|
DURATION: 4 - 8 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 16 mg) A day at the Stanford museum.
|
|
Things were visually rich, yet I felt that I was reasonably
|
|
inconspicuous. The Rodin sculptures were very personal and not
|
|
terribly subtle. I saw Escher things in the ceiling design, when I
|
|
decided to sit in a foyer somewhere and simply pretend to rest.
|
|
Walking back, the displays seen in the bark of the eucalyptus trees,
|
|
and the torment and fear (of others? of themselves?) in the faces of
|
|
those who were walking towards us, were as dramatic as anything I had
|
|
seen in the art galleries. Our appetites were enormous, and we went
|
|
to a smorgasbord that evening. A rich experience in every possible
|
|
way.
|
|
|
|
(with 20 mg) The drug effect first became known to me as a shift of
|
|
colors toward golden and rose tones. Pigments in the room became
|
|
intensified. Shapes became rounder, more organic. A sensation of
|
|
lightness and rivulets of warmth began seeping through my body.
|
|
Bright lights began pulsing and flashing behind my closed lids. I
|
|
began to perceive waves of energy flowing through all of us in unison.
|
|
I saw all of us as a gridwork of electrical energy beings, nodes on a
|
|
bright, pulsating network of light. Then the interior landscape
|
|
shifted into broader scenes. Daliesque vistas were patterned with
|
|
eyes of Horus, brocades of geometric design began shifting and
|
|
changing through radiant patterns of light. It was an artistUs
|
|
paradise Q representing virtually the full pantheon of the history of
|
|
art.
|
|
|
|
(with 20 mg) The room was cool, and for the first hour I felt cold
|
|
and chilled. That was the only mildly unpleasant part. We had been
|
|
hanging crystals earlier that day, and the visions I had were
|
|
dominated by prismatic light patterns. It was almost as if I became
|
|
the light. I saw kaleidoscopic forms Q similar to, but less intense
|
|
than, when on acid Q and organic forms like Georgia OUKeefe flowers,
|
|
blossoming and undulating. My body was flooded with orgasms Q
|
|
practically from just breathing. The lovemaking was phenomenal,
|
|
passionate, ecstatic, lyric, animal, loving, tender, sublime. The
|
|
music was voluptuous, almost three-dimensional. Sometimes the sound
|
|
seemed distorted to me, underwater like. This was especially so for
|
|
the less good recordings Q but I could choose to concentrate on the
|
|
beauty of the music or the inadequacy of the sound's quality, and
|
|
mostly chose to concentrate on the beauty.
|
|
|
|
(with 24 mg) I am totally into my body. I am aware of every muscle
|
|
and nerve in my body. The night is extraordinary Q moon full.
|
|
Unbelievably erotic, quiet and exquisite, almost unbearable. I cannot
|
|
begin to unravel the imagery that imposes itself during the finding of
|
|
an orgasm. Trying to understand physical/spiritual merging in nature
|
|
Q .
|
|
|
|
EXTENSIONS AND COMMENTARY: Four quotations were chosen arbitrarily
|
|
from literally hundreds that have worked their ways into the files.
|
|
The vast majority are positive, ranging from the colorful to the
|
|
ecstatic. But not all are. There are people who choose not to go
|
|
into the corporeal but, rather, prefer the out-of-body experience.
|
|
They express discomfort with 2C-B, and seem to lean more to the
|
|
Ketamine form of altered state, one which dissociates body from mind.
|
|
|
|
There have been reports of several overdoses that prove the intrinsic
|
|
safety of this compound. Prove is used here in the classic British
|
|
sense; i.e., to challenge. RThe proof of the pudding is in the
|
|
eating,S is not a verification of quality, but an inquiry into the
|
|
quality itself. (The French simplify all this by using two separate
|
|
verbs for prove.) One overdose was intentional, the other accidental.
|
|
|
|
(with 64 mg) I found only mild visual and emotional effects at the 20
|
|
milligram dose, so I took the remaining 44 milligrams. I was
|
|
propelled into something not of my choosing. Everything that was
|
|
alive was completely fearsome. I could look at a picture of a bush,
|
|
and it was just that, a picture, and it posed no threat to me. Then
|
|
my gaze moved to the right, and caught a bush growing outside the
|
|
window, and I was petrified. A life-form I could not understand, and
|
|
thus could not control. And I felt that my own life-form was not a
|
|
bit more controllable.S This was from the comments of a physician who
|
|
assured me that he saw no neurological concerns during this dramatic
|
|
and frightening experience.
|
|
|
|
(with 100 mg) I had weighed correctly. I had simply picked up the
|
|
wrong vial. And my death was to be a consequence of a totally stupid
|
|
mistake. I wanted to walk outside, but there was a swimming pool
|
|
there and I didnUt dare fall into it. A person may believe that he
|
|
has prepared himself for his own death, but when the moment comes, he
|
|
is completely alone, and totally unprepared. Why now? Why me? Two
|
|
hours later, I knew that I would live after all, and the experience
|
|
became really marvelous. But the moment of facing death is a unique
|
|
experience. In my case, I will some day meet it again, and I fear
|
|
that I will be no more comfortable with it then than I was just now.
|
|
This was from the comments of a psychologist who will, without doubt,
|
|
use psychedelics again in the future, as a probe into the unknown.
|
|
|
|
Many of the reports that have come in over the years have mentioned
|
|
the combination of MDMA and 2C-B. The most successful reports have
|
|
followed a program in which the two drugs are not used at the same
|
|
time, nor even too closely spaced. It appears that the optimum time
|
|
for the 2C-B is at, or just before, the final baseline recovery of the
|
|
MDMA. It is as if the mental and emotional discoveries can be
|
|
mobilized, and something done about them. This combination has
|
|
several enthusiastic advocates in the psychotherapy world, and should
|
|
be the basis of careful research when these materials become legal,
|
|
and accepted by the medical community.
|
|
|
|
A generalized spectrum of 2C-B action can be gleaned from the many
|
|
reports that have been written describing its effects. (1) There is a
|
|
steep dose response curve. Over the 12 to 24 milligram range, every 2
|
|
milligrams can make a profound increase or change of response.
|
|
Initially, one should go lightly, and increase the dosage in
|
|
subsequent trials by small increments. A commonly used term for a
|
|
level that produces a just perceptible effect is Rmuseum level.S This
|
|
is a slightly-over-threshold level which allows public activities
|
|
(such as viewing paintings in a museum or scenery watching as a
|
|
passenger in a car) to be entered into without attracting attention.
|
|
There can be considerable discomfort associated with being in the
|
|
public eye, with higher doses. (2) The 2C-B experience is one of the
|
|
shortest of any major psychedelic drug. Wherever you might be, hang
|
|
on. In an hour or so you will be approaching familiar territory
|
|
again. (3) If there is anything ever found to be an effective
|
|
aphrodisiac, it will probably be patterned after 2C-B in structure.
|
|
|
|
There are two RTweetiosS known that are related to 2C-B. (See recipe
|
|
#23 for the origin of this phrase.) The 2-EtO- homologue of 2C-B is
|
|
4-bromo-2-ethoxy-5-methoxyphenethylamine, or 2CB-2ETO. The
|
|
unbrominated benzaldehyde (2-ethoxy-5-methoxybenzaldehyde) had a
|
|
melting point of 47.5-48.5 !C, the unbrominated nitrostyrene
|
|
intermediate a melting point of 76-77 !C, and the final hydrochloride
|
|
a melting point of 185-186 !C. The hydrobromide salt had a melting
|
|
point of 168.5-169.5 !C. It seems that one gets about as much effect
|
|
as can be had, with a dosage of about 15 milligrams, and increases
|
|
above this, to 30 and to 50 milligrams merely prolong the activity
|
|
(from about 3 hours to perhaps 6 hours). At no dose was there an
|
|
intensity that in any way resembled that of 2C-B.
|
|
|
|
The 2,5-DiEtO- homologue of 2C-B is
|
|
4-bromo-2,5-diethoxyphenethylamine, or 2CB-2,5-DIETO. The
|
|
unbrominated impure benzaldehyde (2,5-diethoxybenzaldehyde) had a
|
|
melting point of about 57 !C, the unbrominated impure nitrostyrene
|
|
intermediate a melting point of about 60 !C, and the final
|
|
hydrochloride a melting point of 230-231 !C. The hydrobromide salt
|
|
had a melting point of 192-193 !C. At levels of 55 milligrams, there
|
|
was only a restless sleep, and strange dreams. The active level is
|
|
not yet known.
|
|
|
|
I have been told of some studies that have involved a positional
|
|
rearrangement analogue of 2C-B. This is
|
|
2-bromo-4,5-dimethoxyphenethylamine (or 6-BR-DMPEA). This would be
|
|
the product of the elemental bromination of DMPEA, and it has been
|
|
assayed as the hydrobromide salt. Apparently, the intravenous
|
|
injection of 60 milligrams gave a rapid rush, with intense visual
|
|
effects reported, largely yellow and black. Orally, there may be some
|
|
activity at the 400 to 500 milligram area, but the reports described
|
|
mainly sleep disturbance. This would suggest a stimulant component.
|
|
The N-methyl homologue of this rearranged compound was even less
|
|
active.
|
|
|
|
|
|
|
|
#21 3C-BZ; 4-BENZYLOXY-3,5-DIMETHOXYAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 268 g 2,6-dimethoxyphenol and 212 g allyl
|
|
bromide in 700 mL dry acetone was treated with 315 g anhydrous K2CO3
|
|
and held at reflux for 16 h. The solvent was removed under vacuum,
|
|
and the residue dissolved in H2O and extracted with 3x100 mL CH2Cl2.
|
|
The pooled extracts were washed with 5% NaOH, then with H2O, and the
|
|
solvent removed under vacuum. The residue, which weighed 245 g, was
|
|
stirred and heated in an oil bath to 230 !C at which point an
|
|
exothermic reaction set in. The heating was maintained at 230 !C for
|
|
0.5 h, and then the reaction mixture distilled. There was obtained a
|
|
total of 127 g of 5-allyl-1,3-dimethoxy-2-hydroxybenzene as a
|
|
colorless distillate, that was identical in all respects to natural
|
|
5-methoxyeugenol obtained from Oil of Nutmeg.
|
|
|
|
A solution containing 40.4 g 5-methoxyeugenol and 26.6 g benzyl
|
|
chloride in 65 mL EtOH was added, all at once, to a hot and well
|
|
stirred solution of 11.7 g KOH in 500 mL EtOH. The potassium salt of
|
|
the phenol crystallized out immediately. By maintaining reflux
|
|
conditions, this slowly redissolved, and was replaced by the steady
|
|
deposition of KCl. After 6 h, the reaction mixture was cooled, and
|
|
the solids removed by filtration. The filtrate was stripped of
|
|
solvent under vacuum to give 57 g of crude
|
|
5-allyl-2-benzyloxy-1,3-dimethoxybenzene. This was dissolved in a
|
|
solution of 60 g KOH in 80 mL EtOH and heated on the steam bath for 16
|
|
h. The reaction mixture was quenched in 500 mL H2O, and extracted
|
|
with 2x200 mL CH2Cl2. Removal of the solvent under vacuum gave 35.6 g
|
|
of crude 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene.
|
|
|
|
To a stirred, ice-cold solution of 33.6 g of the above impure
|
|
2-benzyloxy-1,3-dimethoxy-5-propenylbenzene and 13.6 g pyridine in 142
|
|
mL acetone, there was added 24.6 g tetranitromethane. After stirring
|
|
for 3 min, there was added a solution of 7.9 g KOH in 132 mL H2O,
|
|
followed by additional H2O. The oily phase that remained was H2O
|
|
washed, and then diluted with an equal volume of MeOH. This slowly
|
|
set up to yellow crystals, which were removed by filtration and washed
|
|
sparingly with MeOH. There was obtained 9.2 g
|
|
1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene with a mp of 84-85
|
|
!C. An analytical sample, from EtOH, had a mp of 86-87 !C.
|
|
|
|
To a refluxing suspension of 5.5 g LAH in 360 mL anhydrous
|
|
Et2O under an inert atmosphere, there was added 8.6 g
|
|
1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene by letting the
|
|
condensing Et2O leach out a saturated solution from a modified Soxhlet
|
|
condenser. The addition took 1.5 h and the refluxing was maintained
|
|
for an additional 4 h. After cooling, the excess hydride was
|
|
destroyed by the cautious addition of 330 mL of 1.5 N H2SO4. The
|
|
aqueous phase was heated up to 80 !C, filtered through paper to remove
|
|
a small amount of insoluble material, and treated with a solution of 8
|
|
g picric acid in 150 mL boiling EtOH. Cooling in the ice chest
|
|
overnight gave globs of the amine picrate, but no clear signs of
|
|
crystallization. These were washed with cold H2O, then dissolved in
|
|
5% NaOH to give a bright yellow solution. This was extracted with
|
|
3x150 mL CH2Cl2, the solvent removed under vacuum, the residue
|
|
dissolved in 300 mL anhydrous Et2O, freed from a little particulate
|
|
material by filtration through paper, and then saturated with hydrogen
|
|
chloride gas. There was thus obtained, after filtering, Et2O washing
|
|
and air drying, 2.5 g 4-benzyloxy-3,5-dimethoxyamphetamine
|
|
hydrochloride (3C-BZ) as a white solid with a mp of 161-164 !C.
|
|
|
|
DOSAGE: 25 - 200 mg.
|
|
|
|
DURATION: 18 - 24 h.
|
|
|
|
QUANTITATIVE COMMENTS: (with 25 mg) I went into an emotionally
|
|
brittle place, and for a while I was uncomfortable with childhood
|
|
reminiscences. The seeing of my family's Christmas tree in my mind
|
|
was almost too much. I cried.
|
|
|
|
(with 50 mg) The action is distinct Q wakeful Q alerting and wound
|
|
up. Hypnogogic imagery, and I could not sleep at night with my mind
|
|
doing many uncontrolled, tangential, busy things. I had fleeting
|
|
nausea early in the process.
|
|
|
|
(with 100 mg) I took this in two portions. Following 50 milligrams I
|
|
was aware of a slight light-headedness at a half-hour, but there was
|
|
little else. At 1 1/2 hours, I took the second 50 milligrams and the
|
|
augmentation of effects was noted in another half hour. The
|
|
experience quietly built up to about the fifth hour, with some erotic
|
|
fantasy and suggestions of changes in the visual field. I could not
|
|
sleep until the twelfth hour, and my dreams were wild and not too
|
|
friendly. There was no body threat from this, but I was not
|
|
completely baseline until the next day. I am not too keen to do this
|
|
again Q it lasts too long.
|
|
|
|
(with 100 mg) No effects.
|
|
|
|
(with 150 mg) This is in every way identical to 100 micrograms of
|
|
LSD.
|
|
|
|
(with 180 mg) I can compare this directly to TMA which was the
|
|
material I took last week. Many similarities, but this is
|
|
unquestionably more intense than the TMA was at 200 milligrams. It is
|
|
hard to separate the degree of impact that this drug has, from the
|
|
simple fact that it lasts forever, and I was getting physically tired
|
|
but I couldnUt sleep. There is some amphetamine-like component, more
|
|
than with TMA.
|
|
|
|
EXTENSIONS AND COMMENTARY: Two points are worthy of commentary; the
|
|
potency and the promise of 3C-BZ.
|
|
|
|
As to potency, there is such uncertainty as to the effective dose,
|
|
that it is for all intents and purposes impossible to predict just
|
|
what dose should be considered for a person's first time with this.
|
|
The choice of quotations was made with the intention of giving a
|
|
picture of this scatter. A total of ten subjects have explored this
|
|
compound, and the very broad range given above, 25 to 200 milligrams,
|
|
reflects the degree of variation that has been encountered.
|
|
|
|
Which is a shame, because the concept of a new ring such as is found
|
|
here on the 4-position would have allowed an extremely wide array of
|
|
substituents. Electron-rich things, electron-poor things, heavy
|
|
things, light things, and on and on. This could have been a location
|
|
of much variation, but it is a possibility that the uncertainties of
|
|
dosage might extrapolate to these novel ring substitutions as well.
|
|
Only a single variation was made, the 4-fluorobenzyl analogue. This
|
|
was prepared following exactly the procedure given here for 3C-BZ,
|
|
except for the replacement of benzyl chloride with 4-fluorobenzyl
|
|
chloride. The allyl intermediate was an oil, but the propenyl isomer
|
|
gave solids with a melting point of 59-60 !C from hexane. The
|
|
nitrostyrene was a yellow crystalline solid from methanol with a
|
|
melting point of 98-99 !C. The end product,
|
|
3,5-dimethoxy-4-(4-fluorobenzyloxy)amphetamine hydrochloride (3C-FBZ)
|
|
was a white solid with a melting point of 149-150 !C. It has been
|
|
assayed only up to 4 milligrams and there was absolutely no activity
|
|
of any kind observed at that level.
|
|
|
|
|
|
|
|
#22 2C-C; 2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE
|
|
|
|
SYNTHESIS: (from 2C-H) The free base of 2,5-dimethoxyphenethylamine
|
|
was generated from its salt (see recipe for 2C-H for the preparation
|
|
of this compound) by treating a solution of 16.2 g of the
|
|
hydrochloride salt in 300 mL H2O with aqueous NaOH, extraction with
|
|
3x75 mL CH2Cl2, and removal of the solvent from the pooled extracts
|
|
under vacuum. The colorless residue was dissolved in 75 mL glacial
|
|
acetic acid (the solids that initially formed redissolved completely)
|
|
and this was cooled to 0 !C with an external ice bath. With vigorous
|
|
stirring, there was added 4.0 mL of liquid chlorine, a little bit at a
|
|
time with a Pasteur pipette. The theoretical volume was 3.4 mL, but
|
|
some was lost in pipetting, some on contact with the 0 !C acetic acid,
|
|
and some was lost by chlorination of the acetic acid. The reaction
|
|
turned a dark amber color, was allowed to stir for an additional 10
|
|
min, then quenched with 400 mL H2O. This was washed with 3x100 mL
|
|
CH2Cl2 (which removed some of the color) then brought to neutrality
|
|
with dilute aqueous NaOH and treated with a small amount of sodium
|
|
dithionite which discharged most of the color (from deep brown to pale
|
|
yellow). The reaction was made strongly basic with aqueous KOH, and
|
|
extracted with 3x75 mL CH2Cl2. The pooled extracts were washed once
|
|
with H2O and the solvent was removed under vacuum leaving about 10 mL
|
|
of a deep amber oil as residue. This was dissolved in 75 mL IPA and
|
|
neutralized with concentrated HCl which allowed spontaneous
|
|
crystallization. These crystals were removed by filtration, washed
|
|
with an additional 20 mL IPA, and air-dried to constant weight. There
|
|
was thus obtained 4.2 g 2,5-dimethoxy-4-chlorophenethylamine
|
|
hydrochloride (2C-C) with a mp of 218-221 !C. Recrystallization from
|
|
IPA increased this to 220-222 !C. The position of chlorination on the
|
|
aromatic ring was verified by the presence of two para-protons in the
|
|
NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O solution of the
|
|
hydrochloride salt.
|
|
|
|
Synthesis from 2C-B. To a solution of 7.24 g
|
|
2,5-dimethoxy-4-bromophenethylamine (2C-B) and 4.5 g phthalic
|
|
anhydride in 100 mL anhydrous DMF there was added molecular sieves.
|
|
After 16 h reflux, the reaction mixture was cooled and the sieves
|
|
removed by filtration. The addition of a little CH2Cl2 prompted the
|
|
deposition of yellow crystals which were recrystallized from EtOH.
|
|
The resulting 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane
|
|
weighed 7.57 g and had a mp of 141-142 !C. Anal. (C18H16BrNO4)
|
|
C,H,N,Br.
|
|
|
|
A solution of 14.94 g of
|
|
1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g
|
|
cuprous chloride in 300 mL anhydrous DMF was heated for 5 h at reflux.
|
|
The cooled mixture was poured into 20 mL H2O that contained 13 g
|
|
hydrated ferric chloride and 3 mL concentrated HCl. The mixture was
|
|
maintained at about 70 !C for 20 min, and then extracted with CH2Cl2.
|
|
After washing the pooled organic extracts with dilute HCl and drying
|
|
with anhydrous MgSO4, the volatiles were removed under vacuum to
|
|
provide a solid residue. This was recrystallized from EtOH to provide
|
|
12.18 g of 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as
|
|
yellow needles that had a mp of 138-140 !C. Anal. (C18H16ClNO4)
|
|
C,H,N,Cl.
|
|
|
|
To 60 mL absolute EtOH there was added 12.2 g
|
|
1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of
|
|
100% hydrazine. The solution was held at reflux for 15 min. After
|
|
cooling, the cyclic hydrazone by-product was removed by filtration,
|
|
and the alcoholic mother liquors taken to dryness under vacuum. The
|
|
residue was distilled at 145-155 !C at 0.05 mm/Hg to give 5.16 g of a
|
|
clear, colorless oil. This was dissolved in anhydrous Et2O and
|
|
treated with hydrogen chloride gas, producing
|
|
2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white
|
|
crystals with a mp of 220-221 !C. Anal. (C10H15Cl2NO2) C,H,N.
|
|
|
|
DOSAGE: 20 - 40 mg.
|
|
|
|
DURATION: 4 - 8 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than 2C-B,
|
|
and there is a longer latency in coming on. It took an hour and a
|
|
half, or even two hours to get there. It had a slight metallic
|
|
overtone.
|
|
|
|
(with 24 mg) I was at a moderately high and thoroughly favorable
|
|
place, for several hours. It seemed to be a very sensual place, but
|
|
without too much in the way of visual distraction.
|
|
|
|
(with 40 mg) There were a lot of visuals Q something that I had noted
|
|
at lower levels. There seems to be less stimulation than with 2C-B,
|
|
and in some ways it is actually sedating. And yet I was up all night.
|
|
It was like a very intense form of relaxation.
|
|
|
|
EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50
|
|
milligrams which seems to increase yet further the intensity and the
|
|
duration. I have one report of an intravenous administration of 20
|
|
milligrams, and the response was described as overwhelming. The
|
|
effects peaked at about 5 minutes and lasted for perhaps 15 minutes.
|
|
|
|
The halogens represent a small group of atoms that are unique for a
|
|
couple of reasons. They are all located in a single column of the
|
|
periodic table, being monovalent and negative. That means that they
|
|
can be reasonably stable things when attached to an aromatic nucleus.
|
|
But, being monovalent, they cannot be modified or extended in any way.
|
|
Thus, they are kind of a dead end, at least as far as the 2C-X series
|
|
is considered. The heaviest, iodine, was explored as the
|
|
phen-ethylamine, as 2C-I, and as the amphetamine as DOI. These are
|
|
the most potent. The next lighter is bromine, where the
|
|
phenethylamine is 2C-B and the amphetamine is DOB. These two are a
|
|
bit less potent, and are by far the most broadly explored of all the
|
|
halides. Here, in the above recipe, we have the chlorine counterpart,
|
|
2C-C. There is also the corresponding amphetamine DOC. These are
|
|
less potent still, and much less explored. Why? Perhaps because
|
|
chlorine is a gas and troublesome to handle (bromine is a liquid, and
|
|
iodine is a solid). The fluorine analogue is yet harder to make, and
|
|
requires procedures that are indirect, because fluorine (the lightest
|
|
of all the halides) is not only a gas, but is dangerous to handle and
|
|
does not react in the usual halogen way. There will be mention made
|
|
of 2C-F, but DOF is still unexplored.
|
|
|
|
The treatment of the 2C-B phthalimide described above, with cuprous
|
|
cyanide rather than cuprous chloride, gave rise to the cyano analog
|
|
which, on hydrolysis with hydrazine, yielded
|
|
2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with
|
|
hot, strong base gave the corresponding acid,
|
|
2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of
|
|
either of these compounds has been made in the human animal, as far as
|
|
I know.
|
|
|
|
|
|
|
|
#23 2C-D; LE-25; 2,5-DIMETHOXY-4-METHYLPHENETHYLAMINE
|
|
|
|
SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was
|
|
added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g
|
|
dimethyl sulfate. After about 2 h, the reaction mixture was no longer
|
|
basic, and another 40 mL of the 25% NaOH was added. Even with
|
|
stirring for a few additional days, the reaction mixture remained
|
|
basic. It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2
|
|
and the pooled extracts stripped of solvent under vacuum. The
|
|
remaining 56.4 g of amber oil was distilled at about 70 !C at 0.5
|
|
mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The
|
|
aqueous residues, on acidification, provided a phenolic fraction that
|
|
distilled at 75-100 !C at 0.4 mm/Hg to give 5.8 g of a pale yellow
|
|
distillate that partially crystallized. These solids (with mp of
|
|
54-62 !C) were removed by filtration, and yielded 3.1 g of a solid
|
|
which was recrystallized from 50 mL hexane containing 5 mL toluene.
|
|
This gave 2.53 g of a white crystalline product with a mp of 66-68 !C.
|
|
A second recrystallization (from hexane) raised this mp to 71-72 !C.
|
|
The literature value given for the mp of 2-methyl-4-methoxyphenol is
|
|
70-71 !C. The literature value given for the mp of the isomeric
|
|
3-methyl-4-methoxyphenol is 44-46 !C. This phenol, on ethylation,
|
|
gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon
|
|
2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS.
|
|
|
|
A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated
|
|
for 10 min on the steam bath, and then there was added 30.4 g of
|
|
2,5-dimethoxytoluene. Heating was continued for 2.5 h, and the
|
|
viscous, black, ugly mess was poured into 600 mL of warm H2O and
|
|
stirred overnight. The resulting rubbery miniature-rabbit-droppings
|
|
product was removed by filtration and sucked as free of H2O as
|
|
possible. The 37.2 g of wet product was extracted on the steam-bath
|
|
with 4x100 mL portions of boiling hexane which, after decantation and
|
|
cooling, yielded a total of 15.3 g of yellow crystalline product.
|
|
This, upon recrystallization from 150 mL boiling hexane, gave pale
|
|
yellow crystals which, when air dried to constant weight, represented
|
|
8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 !C.
|
|
Anal. (C8H12O3) C,H,N. The Gattermann aldehyde synthesis gave a
|
|
better yield (60% of theory) but required the use of hydrogen cyanide
|
|
gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3
|
|
g malononitrile in absolute EtOH, treated with a drop of
|
|
triethylamine, was an orange crystalline product. A sample
|
|
recrystallized from EtOH gave a mp of 138.5-139 !C.
|
|
|
|
A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g
|
|
nitromethane was treated with 1.1 g anhydrous ammonium acetate and
|
|
heated for 50 min on the steam bath. Stripping off the excess
|
|
nitromethane under vacuum yielded orange crystals which weighed 12.2
|
|
g. These were recrystallized from 100 mL IPA providing yellow
|
|
crystals of 2,5-dimethoxy-4-methyl-'-nitrostyrene which weighed, when
|
|
dry, 7.70 g. The mp was 117-118 !C, and this was increased to 118-119
|
|
!C upon recrystallization from benzene/heptane 1:2.
|
|
|
|
To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under
|
|
an inert atmosphere, there was added 7.7 g
|
|
2,5-dimethoxy-4-methyl-'-nitrostyrene in 35 mL THF over the course of
|
|
0.5 h. This reaction mixture was held at reflux for 24 h, cooled to
|
|
room temperature, and the excess hydride destroyed with 25 mL IPA.
|
|
There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The
|
|
granular gray mass was filtered, and the filter cake washed with 2x50
|
|
mL THF. The combined filtrate and washes were stripped of their
|
|
volatiles under vacuum to give a residue weighing 7.7 g which was
|
|
distilled at 90-115 !C at 0.3 mm/Hg to provide 4.90 g of a clear,
|
|
white oil, which crystallized in the receiver. This was dissolved in
|
|
25 mL IPA, and neutralized with concentrated HCl which produced
|
|
immediate crystals of the salt. These were dispersed with 80 mL
|
|
anhydrous Et2O, filtered, and washed with Et2O to give, after air
|
|
drying to constant weight, 4.9 g of fluffy white crystals of
|
|
2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D). The mp was
|
|
213-214 !C which was not improved by recrystallization from CH3CN/IPA
|
|
mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 !C.
|
|
The acetamide, from the free base in pyridine treated with acetic
|
|
anhydride, was a white crystalline solid which, when recrystallized
|
|
from aqueous MeOH, had a mp of 116-117 !C.
|
|
|
|
DOSAGE: 20 - 60 mg.
|
|
|
|
DURATION: 4 - 6 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 10 mg) There is something going on, but
|
|
it is subtle. I find that I can just slightly redirect my attention
|
|
so that it applies more exactly to what I am doing. I feel that I can
|
|
learn faster. This is a TsmartU pill!S
|
|
|
|
(with 20 mg) Butterflies in stomach whole time. OK. This is about
|
|
the right level. In retrospect, not too interesting. Primarily a
|
|
stimulant, not entirely physically pleasant. The visual is not too
|
|
exciting. I am easily distracted. One line of thought to another. I
|
|
feel that more would be too stimulating.
|
|
|
|
(with 30 mg) I was into it quite quickly (not much over
|
|
three-quarters of an hour) and got up to a ++ by the end of an hour.
|
|
There is something unsatisfactory about trying to classify this level.
|
|
I had said that I was willing to increase the dose to a higher level,
|
|
to break out of this not-quite-defined level into something
|
|
psychedelic. But I may not want to go higher. Under different
|
|
circumstances I would not mind trying it at a considerably lower
|
|
dosage, perhaps at the 10 or 15 milligrams. I do not have a
|
|
comfortable label on this material, yet.
|
|
|
|
(with 45 mg) There was a rocket from the half-hour to the one and a
|
|
half hour, from nothing up to a +++. Somehow the intimacy and the
|
|
erotic never quite knit, and I feel that I am always waiting for the
|
|
experience to come home. Talking is extremely easy, but something is
|
|
missing. Appetite is good. I am down by the fifth hour, and sleep is
|
|
comfortable. This compound will take some learning.
|
|
|
|
(with 75 mg) This is a +++, but the emphasis is on talking, not on
|
|
personal interacting. I am putting out, but my boundaries are intact.
|
|
I was able to sleep at the sixth hour. Communication was excellent.
|
|
This is fast on, but not too long lived. Maybe a therapy tool?S
|
|
|
|
(with 150 mg) A truly remarkable psychedelic, one which could compare
|
|
favorably with 2C-B. There are intense colors, and I feel that more
|
|
would be too much.
|
|
|
|
EXTENSIONS AND COMMENTARY: Wow! This particular compound is what I
|
|
call a pharmacological tofu. It doesnUt seem to do too much by
|
|
itself, always teasing, until you get to heroic levels. But a goodly
|
|
number of experimental therapists have said that it is excellent in
|
|
extending the action of some other materials. It seems to boost the
|
|
waning action of another drug, without adding its own color to the
|
|
experience. Yet, the comment above, on the high level of 150
|
|
milligrams, is a direct quote from the use of this compound in Germany
|
|
(where it is called LE-25) in therapeutic research.
|
|
|
|
This is probably the most dramatic example of the loss of potency from
|
|
an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine
|
|
(only one tenth as active). It is so often the case that the first of
|
|
a series is not the most interesting nor the most potent member. As
|
|
intriguing and as difficult-to-define as the 2C-D story might be, the
|
|
next higher homologue of this set, 2C-E, is maximally active at the 15
|
|
to 20 milligram level, and is, without any question, a complete
|
|
psychedelic.
|
|
|
|
The N-monomethyl and the N,N-dimethyl homologues of 2C-D have been
|
|
synthesized from 2C-D. The N-monomethyl compound was obtained by the
|
|
quaternization of the Schiff's base formed between 2C-D and
|
|
benzaldehyde with methyl sulfate, followed by hydrolysis; the
|
|
hydrochloride salt had a melting point of 150-151 !C, from EtOH. The
|
|
N,N-dimethyl compound resulted from the action of formaldehyde-formic
|
|
acid on 2C-D; the hydrochloride salt had a melting point of 168-169 !C
|
|
from EtOH/ether. These two compounds were some ten times less
|
|
effective in interfering with conditioned responses in experimental
|
|
rats. There is no report of their having been explored in man.
|
|
|
|
I have learned of an extensive study of ethoxy homologues of a number
|
|
of the phenethylamines in the 2C-X series; they have been collectively
|
|
called the RTweetios.S This Sylvester and Tweety-bird allusion came
|
|
directly from the compulsive habit of trying to alleviate the boredom
|
|
of driving long distances (not under the influence of anything) by the
|
|
attempt to pronounce the license plates of cars as they passed. The
|
|
first of this series of compounds had a name that indicated that there
|
|
was an ethoxy group at the 2-position, or 2-EtO, or Tweetio, and the
|
|
rest is history. In every compound to be found in the 2C-X family,
|
|
there are two methoxy groups, one at the 2-position and one at the
|
|
5-position. There are thus three possible tweetio compounds, a
|
|
2-EtO-, a 5-EtO- and a 2,5-di-EtO-. Those that have been evaluated in
|
|
man are included after each of the 2C-X's that has served as the
|
|
prototype. In general, the 2-EtO- compounds have a shorter duration
|
|
and a lower potency, the 5-EtO- compounds have a relatively unchanged
|
|
potency and a longer time duration; the 2,5-di-EtO- homologues are
|
|
very weak, if active at all.
|
|
|
|
The 2-EtO-homologue of 2C-D is
|
|
2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO. The
|
|
benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point
|
|
of 60.5-61 !C, the nitrostyrene intermediate a melting point of
|
|
110.5-111.5 !C, and the final hydrochloride a melting point of 207-208
|
|
!C. The hydrobromide salt had a melting point of 171-173 !C. At
|
|
levels of 60 milli-grams, there was the feeling of closeness between
|
|
couples, without an appreciable state of intoxication. The duration
|
|
was about 4 hours.
|
|
|
|
The 5-EtO- homologue of 2C-D is
|
|
5-ethoxy-2-methoxy-4-methylphenethylamine, or 2CD-5ETO. The
|
|
benzaldehyde (5-ethoxy-2-ethoxy-4-tolualdehyde) had a melting point of
|
|
81-82 !C, and the details of this synthesis are given in the recipe
|
|
for IRIS. The nitrostyrene intermediate had a melting point of
|
|
112.5-113.5 !C and the final hydrochloride salt had a melting point of
|
|
197-198 !C. The hydro-bromide salt had a melting point of 158-159 !C.
|
|
At dosage levels of 40 to 50 milli-grams, there was a slow, gradual
|
|
climb to the full effects that were noted in about 2 hours. The
|
|
experience was largely free from excitement, but with a friendly
|
|
openness and outgoingness that allowed easy talk, interaction, humor,
|
|
and a healthy appetite. The duration of effects was 12 hours.
|
|
|
|
The 2,5-di-EtO- homologue of 2C-D is
|
|
2,5-diethoxy-4-methylphenethylamine, or 2CD-2,5-DIETO. The
|
|
benzaldehyde (2,5-diethoxy-4-tolualdehyde) had a melting point of
|
|
102-103 !C, the nitrostyrene intermediate a melting point of 108-109
|
|
!C, and the final hydrochloride salt a melting point of 251-252 !C.
|
|
At a level of 55 milligrams, a plus one was reached, and what effects
|
|
there were, were gone after four hours.
|
|
|
|
|
|
|
|
#24 2C-E; 2,5-DIMETHOXY-4-ETHYLPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was
|
|
treated with 100 g acetyl chloride. This slurry was added to a
|
|
vigorously stirred solution of 110 g p-dimethoxybenzene in 300 mL
|
|
CH2Cl2. Stirring was continued at ambient temperature for an
|
|
additional 40 min, then all was poured into 1 L water and the phases
|
|
separated. The aqueous phase was extracted with 2x100 mL CH2Cl2 and
|
|
the combined organic phases washed with 3x150 mL 5% NaOH. These
|
|
washes, after combination and acidification, were extracted with 3x75
|
|
mL CH2Cl2 and the extracts washed once with saturated NaHCO3.
|
|
Re-moval of the solvent under vacuum provided 28.3 g of
|
|
2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on
|
|
recrystallization from 2 volumes of boiling MeOH and air drying,
|
|
provided 21.3 g of product with a mp of 49-49.5 !C. Ethyl-ation of
|
|
this material serves as the starting point for the synthesis of
|
|
2CE-5ETO. The CH2Cl2 fraction from the base wash, above, was stripped
|
|
of solvent on the rotary evaporator to give a residual oil that, on
|
|
distillation at 147-150 !C at the water pump, provided 111.6 g of
|
|
2,5-dimethoxyacetophenone as an almost white oil.
|
|
|
|
In a round bottom flask equipped with a reflux condenser, a take-off
|
|
adapter, an immersion thermometer, and a magnetic stirrer, there was
|
|
placed 100 g 2,5-dimethoxyacetophenone, 71 g 85% KOH pellets, 500 mL
|
|
of triethylene glycol, and 125 mL 65% hydrazine. The mixture was
|
|
brought up to a boil by heating with an electric mantle, and the
|
|
distillate was removed, allowing the temperature of the pot contents
|
|
to continuously increase. When the pot temperature had reached 210
|
|
!C, reflux was established and maintained for an additional 3 h.
|
|
After cooling, the reaction mixture and the distillate were combined,
|
|
poured into 3 L water, and extracted with 3x100 mL hexane. After
|
|
washing the pooled extracts with water, the solvent was removed
|
|
yielding 22.0 g of a pale straw-colored liquid that was free of both
|
|
hydroxy and carbonyl groups by infrared. This was distilled at
|
|
120-140 !C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a
|
|
white fluid product. Acidification of the spent aqueous phase with
|
|
concentrated HCl produced a heavy black oil which was extracted with
|
|
3x100 mL CH2Cl2. Removal of the solvent on the rotary evaporator
|
|
yielded 78 g.of a black residue that was distilled at 90-105 !C at 0.5
|
|
mm/Hg to provide 67.4 g of an orange-amber oil that was largely
|
|
2-ethyl-4-methoxyphenol. This material could eventually be used as a
|
|
starting material for ethoxy homologues. However, remethylation (with
|
|
CH3I and KOH in methanol) provided some 28 g additional
|
|
2,5-dimethoxyethylbenzene.
|
|
|
|
A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene in 30 mL CH2Cl2
|
|
was cooled to 0 !C with good stirring and under an inert atmosphere of
|
|
He. There was then added 11.7 mL anhydrous stannic chloride, followed
|
|
by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5
|
|
h. The stirred reaction mixture was allowed to come up to room
|
|
temperature, then held on the steam bath for 1 h. The reaction
|
|
mixture was poured into 1 L water, extracted with 3x75 mL CH2Cl2, and
|
|
the pooled extracts washed with dilute HCl. The organic phase was
|
|
stripped under vacuum yielding 10.8 g of a dark viscous oil. This was
|
|
distilled at 90-110 !C at 0.2 mm/Hg to yield a colorless oil that, on
|
|
cooling, set to white crystals. The yield of
|
|
2,5-dimethoxy-4-ethylbenzaldehyde was 5.9 g of material that had a mp
|
|
of 46-47 !C. After purification through the bisulfite complex, the mp
|
|
increased to 47-48 !C. The use of the Vilsmeier aldehyde synthesis
|
|
(with POCl3 and N-methylformanilide) gave results that were totally
|
|
unpredictable. The malononitrile derivative (from 0.3 g of this
|
|
aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of
|
|
triethylamine) formed red crystals which, on recrystallization from
|
|
toluene, had a mp of 123-124 !C.
|
|
|
|
A solution of 21.0 g of the unrecrystallized
|
|
2,5-dimethoxy-4-ethylbenzaldehyde in 75 g nitromethane was treated
|
|
with 4 g of anhydrous ammonium acetate and heated on the steam bath
|
|
for about 2 h. The progress of the reaction was best followed by TLC
|
|
analysis of the crude reaction mixture on silica gel plates with
|
|
CH2Cl2 as the developing solvent. The excess solvent/reagent was
|
|
removed under vacuum yielding granular orange solids that were
|
|
recrystallized from seven volumes of boiling MeOH. After cooling in
|
|
external ice-water for 1 h, the yellow crystalline product was removed
|
|
by filtration, washed with cold MeOH and air dried to give 13.4 g of
|
|
2,5-dimethoxy-4-ethyl-'-nitrostyrene. The mp was 96-98 !C which
|
|
improved to 99-100 !C after a second recrystallization from MeOH.
|
|
|
|
A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M)
|
|
was transferred to a 3 neck 500 mL flask, under an inert atmosphere
|
|
with good magnetic stirring. This solution was cooled to !C with an
|
|
external ice-water bath, and there was then added 3.0 mL of 100% H2SO4
|
|
over the course of 0.5 h. This was followed by a solution of 5.85 g
|
|
of 2,5-dimethoxy-4-ethyl-'-nitrostyrene, in 40 mL of warm THF. The
|
|
reaction mixture was stirred for 0.5 h, brought to room temperature,
|
|
heated on the steam bath for 0.5 h, and then returned to room
|
|
temperature. The addition of IPA dropwise destroyed the excess
|
|
hydride, and some 4.5 mL of 5% NaOH produce a white cottage cheese, in
|
|
a basic organic medium. This mixture was filtered, washed with THF,
|
|
and the filtrate evaporated to produce 2.8 g of an almost white oil.
|
|
The filter cake was resuspended in THF, made more basic with
|
|
additional 15 mL of 5% NaOH, again filtered, and the filtrate removed
|
|
to provide an additional 2.8 g of crude product. These residues were
|
|
combined and distilled at 90-100 !C at 0.25 mm/Hg to give a colorless
|
|
oil. This was dissolved in 30 mL IPA, neutralized with concentrated
|
|
HCl, and diluted with 50 mL anhydrous Et2O to provide, after
|
|
spontaneous crystallization, filtration, washing with Et2O, and air
|
|
drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride
|
|
(2C-E) as magnificent white crystals. A similar yield can be obtained
|
|
from the reduction of the nitrostyrene in a suspension of LAH in THF,
|
|
without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there
|
|
was added, dropwise, a solution of 13.4 g of
|
|
2,5-dimethoxy-4-ethyl-'-nitrostyrene in 75 mL THF over the course of 2
|
|
h. The mixture was kept at reflux for an additional 8 h, and killed
|
|
by the careful addition of 11 mL H2O, followed with 11 mL 15% NaOH,
|
|
and finally another 33 mL of H2O. This mass was filtered, washed with
|
|
THF, and the combined filtrates and washes evaporated to a residue
|
|
under vacuum The approximately 15 mL of residue was dissolved in 300
|
|
mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated
|
|
HCl. On shaking the mixture, there was deposited a mass of the
|
|
hydrochloride salt which was diluted with a quantity of additional
|
|
H2O. The organic phase was extracted with additional dilute HCL, and
|
|
these aqueous phases were combined. After being made basic with 25%
|
|
NaOH, this phase was again extracted with 3x75 mL CH2Cl2 and after the
|
|
removal of the solvent, yielded 12.6 g of a colorless oil. This was
|
|
dissolved in 75 mL of IPA and neutralized with concentrated HCl. The
|
|
solidified mass that formed was loosened with another 50 mL IPA, and
|
|
then filtered. After Et2O washing and air drying there was obtained
|
|
7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) as
|
|
lustrous white crystals. Anal. (C12H20ClNO2) C,H.
|
|
|
|
DOSAGE: 10 - 25 mg.
|
|
|
|
DURATION: 8 - 12 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 16 mg) There was a strange devil-angel
|
|
pairing. As I was being told of the ecstatic white-light ascent of my
|
|
partner into the God-space of an out-of-body experience, I was
|
|
fighting my way out of a brown ooze. She saw the young Jesus at the
|
|
bottom of a ladder drifting upwards step by step to some taking-off
|
|
place, and I saw all the funny gargoyles around the base of the ladder
|
|
surrounded by picnic bunting. For me it was the 4th of July, rather
|
|
than Easter!S
|
|
|
|
(with 20 mg) The view out of the window was unreal. The garden was
|
|
painted on the window, and every petal of flower and tuft of grass and
|
|
leaf of tree was carefully sculptured in fine strokes of oil paint on
|
|
the surface of the glass. It was not out there; it was right here in
|
|
front of me. The woman who was watering the plants was completely
|
|
frozen, immobilized by Vermeer. And when I looked again, she was in a
|
|
different place, but again frozen. I was destined to become the
|
|
eternal museum viewer.
|
|
|
|
(with 25 mg) I have a picture in my living room that is a stylized
|
|
German scene with a man on horseback riding through the woods, and a
|
|
young girl coming out to meet him from the nearby trees. But she was
|
|
not just 'coming out.' He was not just riding through the woods. The
|
|
wind was blowing, and his horse was at full gallop, and his cape was
|
|
flapping in the storm, and she was bearing down upon him at full bore.
|
|
The action never ceased. I became exhausted.
|
|
|
|
(with 25 mg) Within minutes I was anxious and sweaty. Each person
|
|
has his own brand of toxic psychosis Q mine always starts with the
|
|
voices in my head talking to me, about all my worst fears, a jumble of
|
|
warnings and deep fears spinning faster. Twenty minutes later this
|
|
complex chaos passed as quickly as it had come. At lower dosages 2C-E
|
|
has been a truly enjoyable esthetic enhancer. But it really has a
|
|
steep dose/response curve.
|
|
|
|
EXTENSIONS AND COMMENTARY: Here is another of the magical half-dozen.
|
|
The range is purposefully broad. At 10 milligrams there have been
|
|
some pretty rich +++ experiences, and yet I have had the report from
|
|
one young lady of a 30 milligram trial that was very frightening. My
|
|
first experience with 2C-E was really profound, and it is the
|
|
substance of a chapter within the story. The amphet-amine homologue
|
|
is DOET, which is not only much longer in action, but considerably
|
|
more potent. Several people have said, about 2C-E, RI donUt think I
|
|
like it, since it isnUt that much fun. But I intend to explore it
|
|
again.S There is something here that will reward the experimenter.
|
|
Someday, the full character of 2C-E will be understood, but for the
|
|
moment, let it rest as being a difficult and worth-while material. A
|
|
very much worth-while material. One Tweetio of 2C-E is known. The
|
|
5-EtO-homologue of 2C-E is 5-ethoxy-4-ethyl-2-methoxyphenethylamine,
|
|
or 2CE-5ETO. The nitrostyrene intermediate had a melting point of
|
|
110-110.5 !C, and the final hydrochloride a melting point of 184-185
|
|
!C. The effective level of 2CE-5ETO is in the 10 to 15 milligram
|
|
range. It is gentle, forgiving, and extremely long lived. Some 3 to
|
|
4 hours were needed to achieve plateau, and on occasion experi-ments
|
|
were interrupted with Valium or Halcion at the 16 hour point. After a
|
|
night's sleep, there were still some effects evident the next day.
|
|
Thus, the dose is comparable to the parent compound 2C-E, but the
|
|
duration is 2 to 3 times longer. It was given the nickname REternityS
|
|
by one subject.
|
|
|
|
|
|
|
|
#25 3C-E; 3,5-DIMETHOXY-4-ETHOXYAMPHETAMINE
|
|
|
|
SYNTHESIS: A solution of 3.6 g syringaldehyde (3,5-dimethoxy-4-
|
|
hydroxybenzaldehyde) in 50 mL MeOH was combined with a solution of 3.7
|
|
g 85% KOH in 75 mL warm MeOH. This clear solution suddenly set up to
|
|
crystals of the potassium salt, too thick to stir satisfactorily. To
|
|
this suspension there was added 7.4 g ethyl iodide (a large excess)
|
|
and the mixture was held at reflux temperature with a heating mantle.
|
|
The solids eventually loosened and redissolved, giving a clear
|
|
amber-colored smooth-boiling solution. Refluxing was maintained for 2
|
|
days, then all volatiles were removed under vacuum. The residue was
|
|
dissolved in 400 mL H2O, made strongly basic with 25% NaOH, and
|
|
extracted with 4x100 mL CH2Cl2. The pooled extracts were washed with
|
|
saturated brine, and the solvent removed under vacuum to give 3.3 g of
|
|
a pale amber oil which set up as crystals of
|
|
3,5-dimethoxy-4-ethoxybenzaldehyde with a mp of 47-48 !C. A small
|
|
sample recrystallized from methanol had a mp of 48-49 !C.
|
|
|
|
A solution of 3.3 g 3,5-dimethoxy-4-ethoxybenzaldehyde in 25 mL
|
|
nitroethane was treated with 0.5 g anhydrous ammonium acetate and
|
|
heated on the steam bath for 36 h. The solvent/reagent was removed
|
|
under vacuum giving a thick yellow-orange oil that was dissolved in
|
|
two volumes hot MeOH. As this cooled, crystals appeared
|
|
spontaneously, and after cooling in ice for a short time, these were
|
|
removed by filtration and washed sparingly with cold MeOH, Air drying
|
|
to constant weight provided 2.2 g
|
|
1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene with a mp of 84-85 !C.
|
|
The mother liquors, on standing overnight, deposited large chunks of
|
|
crystalline material which was isolated by decantation, ground up
|
|
under a small amount of methanol, then recrystallized from 60% EtOH.
|
|
A second crop of 0.7 g of the nitrostyrene was thus obtained, as
|
|
canary-yellow crystals with a mp of 83-85 !C.
|
|
|
|
A solution of 2.7 g 1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene in
|
|
20 mL anhydrous THF was added to a suspension of 2.0 g LAH in 150 mL
|
|
warm THF. The mixture was held at reflux for 48 h. After stirring at
|
|
room temperature for another 48 h, the excess hydride was destroyed by
|
|
the addition of 2.0 mL H2O in 10 mL THF, followed by 2.0 mL 15% NaOH
|
|
and then an additional 6.0 mL H2O. The inorganic salts were removed
|
|
by filtration, and the filter cake washed with THF. The combined
|
|
mother liquor and washings were stripped of solvent under vacuum
|
|
leaving a yellow oil with some inorganic salts still in it. This was
|
|
dissolved in 300 mL CH2Cl2, washed with dilute NaOH, and extracted
|
|
with 3x150 mL 1 N HCl. The pooled extracts were washed once with
|
|
CH2Cl2 made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2.
|
|
The combined organics were washed with saturated brine, and the
|
|
solvent removed under vacuum to yield about 2 mL of a colorless oil.
|
|
This was dissolved in 10 mL IPA, neutralized with concentrated HCl (10
|
|
drops were required), and diluted with 125 mL anhydrous Et2O. The
|
|
slight cloudiness gradually became the formation of fine white
|
|
crystals. After standing at room temperature for 2 h, these were
|
|
removed, Et2O washed, and air dried. There was thus obtained 1.9 g of
|
|
3,5-dimethoxy-4-ethoxyamphetamine hydrochloride (3C-E) as brilliant
|
|
white crystals.
|
|
|
|
DOSAGE: 30 - 60 mg.
|
|
|
|
DURATION: 8 - 12 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 40 mg) It developed into a strange and
|
|
indefinable something. It is unworldly. I am very much in control,
|
|
but with an undertone of unreality that is a little reminiscent of
|
|
high doses of LSD. If there were a great deal of sensory input, I
|
|
might not see it. And if I were in complete sensory quiet I would
|
|
miss it, too. But just where I am, I can see it. Eerie state of
|
|
awareness. And by the 8th hour I am sober, with no residue except for
|
|
some slight teeth clenching, and pretty much disbelieving the whole
|
|
thing.
|
|
|
|
(with 60 mg) Visuals very strong, insistent. Body discomfort
|
|
remained very heavy for first hour. Sense of implacable imposition of
|
|
something toxic for a while. I felt at the mercy of uncomfortable
|
|
physical effects Q faint or pre-nausea, heavy feeling of tremor
|
|
(although tremor actually relatively light) and general dis-ease,
|
|
un-ease, non-ease. Kept lying down so as to be as comfortable as
|
|
possible. Fantasy began to be quite strong. At first, no eyes closed
|
|
images, and certainly anti-erotic. 2nd hour on, bright colors,
|
|
distinct shapes Q jewel-like Q with eyes closed. Suddenly it became
|
|
clearly not anti-erotic. That was the end of my bad place, and I shot
|
|
immediately up to a +++. Complex fantasy which takes over Q hard to
|
|
know what is real, what is fantasy. Continual erotic. Image of
|
|
glass-walled apartment building in mid-desert. Exquisite sensitivity.
|
|
Down by ? midnight. Next morning, faint flickering lights on looking
|
|
out windows.
|
|
|
|
EXTENSIONS AND COMMENTARY: This is an interesting closing of the
|
|
circle. Although mescaline launched the entire show, the first half
|
|
could be called the amphetamine period, with variations made on all
|
|
aspects of the molecule except for that three-carbon chain. And it
|
|
was found that the 4-substitution position was of paramount importance
|
|
in both the potency and the quality of action of a compound. Then,
|
|
looking at the long-ignored chain, lengthening it by the addition of a
|
|
carbon atom eliminated all psychedelic effects and gave materials with
|
|
reduced action. The action present was that of an antidepressant.
|
|
But removing a carbon atom? This returned the search to the world of
|
|
mescaline, but with the knowledge of the strong influence of the
|
|
4-position substituent. The two-carbon side-chain world was
|
|
rediscovered, principally with 2C-B and 2C-D, and the
|
|
4-ethoxy-analogue of mescaline, E. This second half of the show could
|
|
be called the phenethylamine period. And with compounds such as 3C-E
|
|
which is, quite simply, Escaline (or E) reextended again to a 3-carbon
|
|
chain amphetamine, there is a kind of satisfying closure. A
|
|
fascinating compound, but for most subjects a little too heavy on the
|
|
body.
|
|
|
|
|
|
|
|
#26 2C-F; 2,5-DIMETHOXY-4-FLUOROPHENETHYLAMINE
|
|
|
|
SYNTHESIS: A solution of 76.6 g 2,5-dimethoxyaniline in 210 mL H2O
|
|
containing 205 mL fluoroboric acid was cooled to 0 !C. with an
|
|
external ice bath. There was then added, slowly, a solution of 35 g
|
|
sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the
|
|
precipitated solids were removed by filtration, washed first with cold
|
|
H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g
|
|
of the fluoroborate salt of the aniline as dark purple-brown solids.
|
|
This salt was pyrolyzed with the cautious application of a flame, with
|
|
the needed attention paid to both an explosion risk, and the evolution
|
|
of the very corrosive boron trifluoride. The liquid that accumulated
|
|
in the receiver was distilled at about 120 !C at 20 mm/Hg, and was
|
|
subsequently washed with dilute NaOH to remove dissolved boron
|
|
trifluoride. The product, 2,5-dimethoxyfluorobenzene, was a fluid,
|
|
straw-colored oil that weighed 7.0 g.
|
|
|
|
To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene
|
|
in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135
|
|
g of anhydrous stannic chloride. There was then added, dropwise, 26 g
|
|
of dichloromethyl methyl ether at a rate that precluded excessive
|
|
heating. The reaction mixture was allowed to come to room temperature
|
|
over the course of 0.5 h, and then quenched by dumping into 500 g
|
|
shaved ice containing 75 mL concentrated HCl. This mixture was
|
|
stirred for an additional 1.5 h. The separated organic layer was
|
|
washed with 2x100 mL dilute HCl, then with dilute NaOH, then with H2O
|
|
and finally with saturated brine. Removal of the solvent under vacuum
|
|
yielded a solid residue that was recrystallized from aqueous EtOH
|
|
yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde with a mp of 99-100
|
|
!C.
|
|
|
|
A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde in 15 mL acetic
|
|
acid containing 1 g nitromethane was treated with 0.2 g anhydrous
|
|
ammonium acetate, and heated on the steam bath for 4 h. After
|
|
cooling, and following the judicious addition of H2O, crystals
|
|
separated, and additional H2O was added with good stirring until the
|
|
first signs of oiling out appeared. The solids were removed by
|
|
filtration, and recrystallized from acetone to give 2.0 g of
|
|
2,5-dimethoxy-4-fluoro-'-nitrostyrene with a mp of 159-162 !C.
|
|
|
|
To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an
|
|
inert atmosphere, there was added a THF solution of 2.0 g
|
|
2,5-dimethoxy-4-fluoro-'-nitrostyrene. The reaction mixture was
|
|
stirred at room temperature for 2 h and then heated briefly at reflux.
|
|
After cooling, the excess hydride was destroyed by the cautious
|
|
addition of H2O, and when the reaction was finally quiet, there was
|
|
added 2 mL of 15% NaOH, followed by another 6 mL of H2O. The basic
|
|
insolubles were removed by filtration, and washed with THF. The
|
|
combined filtrate and washes were stripped of solvent, yielding a
|
|
residual oil that was taken up in 10 mL of IPA, neutralized with
|
|
concentrated HCl, and the generated solids diluted with anhydrous
|
|
Et2O. The white crystalline 2,5-dimethoxy-4-fluorophenethylamine
|
|
hydrochloride (2C-F) was recrystallized from IPA to give an air-dried
|
|
product of 0.5 g with a mp of 182-185 !C.
|
|
|
|
DOSAGE: greater than 250 mg.
|
|
|
|
DURATION: unknown
|
|
|
|
QUALITATIVE COMMENTS: (with 250 mg) Even at 250 milligrams, the
|
|
effects were slight and uncertain. There may have been some
|
|
eyes-closed imagery above normal, but certainly not profound. At
|
|
several hours there was a pleasant lethargy; sleep was completely
|
|
normal that night.
|
|
|
|
EXTENSIONS AND COMMENTARY: A number of graded acute dosages were
|
|
tried, and it was only with amounts in excess of 100 milligrams that
|
|
there were any baseline disturbances at all. And at no dose that was
|
|
tried was there any convincing indication of believable central
|
|
effects.
|
|
|
|
The three-carbon amphetamine analogue of 2C-F would quite logically be
|
|
called DOF (2,5-dimethoxy-4-fluoroamphetamine). It has been prepared
|
|
by reaction of the above benzaldehyde with nitroethane (giving
|
|
1-(2,5-dimethoxy-4-fluorophenyl)-2-nitropropene, with a melting point
|
|
of 128-129 !C from ethanol) followed by LAH reduction to DOF (the
|
|
hydrochloride salt has a melting point of 166-167 !C, after
|
|
recrystallization from ether/ethyl acetate/ethanol). Animal studies
|
|
that have compared DOF to the highly potent DOI and DOB imply that the
|
|
human activity will be some four to six times less than these two
|
|
heavier halide analogues. As of the present time, no human trials of
|
|
DOF have been made.
|
|
|
|
|
|
|
|
|
|
|
|
#27 2C-G; 2,5-DIMETHOXY-3,4-DIMETHYLPHENETHYLAMINE
|
|
|
|
SYNTHESIS: To a clear solution of 40.4 g flake KOH in 400 mL warm EtOH
|
|
there was added 86.5 g 2,3-xylenol followed by 51.4 g methyl iodide.
|
|
This mixture was held at reflux for 2 days, stripped of volatiles
|
|
under vacuum, the residues dissolved in 1 L of H2O, and extracted with
|
|
4x200 mL CH2Cl2. The pooled extracts were washed with 5% NaOH until
|
|
the washes remained basic. Following a single washing with dilute
|
|
HCl, the solvent was removed under vacuum, and the residue, 41.5 g of
|
|
a pungent smelling amber oil, spontaneously crystallized. The mp of
|
|
2,3-dimethylanisole was 25-26 !C and it was used without further
|
|
purification in the next step. From the aqueous basic washes,
|
|
following acidification, extraction, and solvent removal, there was
|
|
obtained 46.5 g crude unreacted xylenol which could be recycled.
|
|
|
|
A mixture of 205 g POCl3 and 228 g N-methylformanilide was allowed to
|
|
incubate at room temperature until there was the development of a deep
|
|
claret color with some spontaneous heating. To this, there was added
|
|
70.8 g 2,3-dimethylanisole, and the dark reaction mixture heated on
|
|
the steam bath for 2.5 h. The product was then poured into 1.7 L H2O,
|
|
and stirred until there was a spontaneous crystallization. These
|
|
solids were removed by filtration, H2O washed and air dried to give
|
|
77.7 g of crude benzaldehyde as brown crystals. This was distilled at
|
|
70-90 !C at 0.4 mm/Hg to give 64.8 g of
|
|
2,3-dimethyl-4-methoxybenzaldehyde as a white crystalline product with
|
|
a mp of 51-52 !C. Recrystallization from MeOH produced an analytical
|
|
sample with a mp of 55-55.5 !C. Anal. (C10H12O2) C,H. The
|
|
malononitrile derivative (from the aldehyde and malononitrile in EtOH
|
|
with a drop of triethylamine) had a mp of 133-133.5 !C from EtOH.
|
|
Anal. (C13H12N2O) C,H,N. Recently, this aldehyde has become
|
|
commercially available.
|
|
|
|
A solution of 32.4 g 2,3-dimethyl-4-methoxybenzaldehyde in 800 mL
|
|
CH2Cl2 was treated with 58.6 g 85% m-chloroperoxybenzoic acid and held
|
|
at reflux for 3 days. After cooling to room temperature, the white
|
|
solids (m-chlorobenzoic acid) were removed by filtration (about 40 g
|
|
when dry). The filtrate was extracted with several portions of
|
|
saturated NaHCO3 (on acidification, this aqueous wash yielded
|
|
additional m-chlorobenzoic acid) and the organic solvent removed under
|
|
vacuum. The crystalline residue (weighing 32 g and deeply colored)
|
|
was dissolved in 150 mL boiling MeOH to which there was added 18 g of
|
|
solid NaOH and the solution heated on the steam bath for a few min.
|
|
The mixture was added to 800 mL H2O, and a little surface scum
|
|
mechanically removed with a piece of filter paper. The solution was
|
|
acidified with concentrated HCl, depositing 30.9 g of a tan solid.
|
|
Recrystallization from H2O gave 2,3-dimethyl-4-methoxyphenol as white
|
|
needles, with a mp of 95-96 !C. Anal. (C9H12O2) H; C: calcd, 71.06;
|
|
found 70.20. The N-methyl carbamate was made by the treatment of a
|
|
solution of the phenol (1 g in 75 mL hexane with 5 mL CH2Cl2 added)
|
|
with 2 g methyl isocyanate and a few drops of triethyl amine. The
|
|
pale pink solids that separated were recrystallized from MeOH to give
|
|
a product that had a mp of 141-142 !C. Anal. (C11H15NO3) C,H,N.
|
|
|
|
To a solution of 23.1 g flake KOH in 250 mL hot EtOH there was added
|
|
61.8 g 2,3-dimethyl-4-methoxyphenol followed by 60 g methyl iodide.
|
|
This was held under reflux for 12 h, then stripped of solvent under
|
|
vacuum. The residue was dissolved in 1.2 L H2O, acidified with HCl,
|
|
and extracted with 3x200 mL CH2Cl2. The combined extracts were washed
|
|
with 3x100 mL 5% NaOH, and the solvent was removed under vacuum. The
|
|
residue set up as an off-white mass of leaflets weighing 37.7 g after
|
|
filtering and air drying. Recrystallization from MeOH gave
|
|
2,3-dimethyl-1,4-dimethoxybenzene as white solids, with a mp of 78-79
|
|
!C. Anal. (C10H14O2) C,H. An alternate route leading from
|
|
2,3-xylenol to this diether via nitrogen-containing intermediates was
|
|
explored. The sequence involved the reaction of 2,3-xylenol with
|
|
nitrous acid (4-nitroso product, mp 184 !C dec.), reduction with
|
|
sodium dithionite (4-amino product, mp about 175 !C), oxidation with
|
|
nitric acid (benzoquinone, mp 58 !C), reduction with sodium dithionite
|
|
(hydro-quinone) and final methylation with methyl iodide. The yields
|
|
were inferior with this process.
|
|
|
|
A mixture of 88 g POCl3 and 99 g N-methylformanilide was allowed to
|
|
incubate until a deep claret color had formed, then it was treated
|
|
with 36.5 g 2,3-dimethyl-1,4-dimethoxybenzene and heated on the steam
|
|
bath for 3 h. It was then poured into 1 L H2O, and stirred until the
|
|
formation of a loose, crumbly, dark crystalline mass was complete.
|
|
This was removed by filtration, and dissolved in 300 mL CH2Cl2. After
|
|
washing first with H2O, then with 5% NaOH, and finally with dilute
|
|
HCl, the solvent was removed under vacuum yielding 39.5 g of a black
|
|
oil that solidified. This was extracted with 2x300 mL boiling hexane,
|
|
the extracts were pooled, and the solvent removed under vacuum. The
|
|
yellowish residue crystallized to give 32.7 g
|
|
2,5-dimethoxy-3,4-dimethylbenzaldehyde with a mp of 46-47 !C.
|
|
Repeated recrystallization from MeOH raised the mp to 59-60 !C. The
|
|
malononitrile derivative was prepared (aldehyde and malononitrile in
|
|
EtOH with a few drops triethyl amine) as yellow crystals from EtOH,
|
|
with a mp of 190-191 !C. Anal. (C14H14N2O2) C,H; N: calcd, 11.56;
|
|
found, 11.06, 11.04.
|
|
|
|
To a solution of 16.3 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde in 50
|
|
mL nitromethane there was added 3.0 g anhydrous ammonium acetate, and
|
|
the mixture was heated on the steam bath overnight. There was then
|
|
added an equal volume of MeOH, and with cooling there was obtained a
|
|
fine crop of yellow crystals. These were removed by filtration,
|
|
washed with MeOH, and air dried to provide 4.4 g of
|
|
2,5-dimethoxy-3,4-dimethyl-'-nitrostyrene with a mp of 120-121 !C
|
|
which was not improved by recrystallization from MeOH (50 mL/g). The
|
|
mother liquors of the above filtration were diluted with H2O to the
|
|
point of permanent turbidity, then set aside in a cold box. There was
|
|
a chunky, granular, tomato-red crystal deposited which weighed 2.5 g
|
|
when dry. It had a mp of 118-119.5 !C, which was undepressed in mixed
|
|
mp with the yellow sample. Both forms had identical NMR spectra
|
|
(2.20, 2.25 CH3; 3.72, 3.84 OCH3; 6.80 ArH; 7.76, 8.28 CH=CH, with 14
|
|
cycle splitting), infrared spectra, ultra violet spectra (max. 324 nm
|
|
with shoulder at 366 nm in EtOH, two peaks at 309 and 355 nm in
|
|
hexane), and microanalyses. Anal. (C12H15NO4) C,H,N.
|
|
|
|
A solution of LAH (56 mL of a 1 M solution in THF) was cooled, under
|
|
He, to 0 !C with an external ice bath. With good stirring there was
|
|
added 1.52 mL 100% H2SO4 dropwise, to minimize charring. This was
|
|
followed by the addition of 3.63 g
|
|
2,5-dimethoxy-3,4-dimethyl-'-nitrostyrene in 36 mL anhydrous THF over
|
|
the course of 1 h. After a few minutes further stirring, the
|
|
temperature was brought up to a gentle reflux on the steam bath for
|
|
about 5 min, then all was cooled again to 0 !C. The excess hydride
|
|
was destroyed by the cautious addition of 9 mL IPA followed by 2.5 mL
|
|
15% NaOH and finally 7.5 mL H2O. The reaction mixture was filtered,
|
|
and the filter cake washed first with THF and then with IPA. The
|
|
filtrate was stripped of solvent under vacuum and the residue was
|
|
distilled at 110-120 !C at 0.2 mm/Hg to give 2.07 g of
|
|
2,5-dimethoxy-3,4-dimethylphenethylamine as a clear white oil. This
|
|
was dissolved in 10 mL IPA, neutralized with concentrated HCl, and
|
|
then diluted with 25 mL anhydrous Et2O. The crystals that formed were
|
|
filtered, Et2O washed, and air dried to constant weight. There was
|
|
obtained 2.13 g of beautiful white crystals of
|
|
2,5-dimethoxy-3,4-dimethylphenethylamine hydrochloride (2C-G) with a
|
|
mp of 232-233 !C. Anal. (C12H20ClNO2) C,H.
|
|
|
|
DOSAGE: 20 - 35 mg.
|
|
|
|
DURATION: 18 - 30 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 22 mg) I am completely functional, with
|
|
writing and answering the telephone, but the coffee really tastes most
|
|
strange. While the mental effects (to a ++ only) were dispersing, the
|
|
body still had quite a bit of memory of the day. Sleep was fine, and
|
|
desirable, in the early evening.
|
|
|
|
(with 32 mg) Superb material, to be classified as a 'true
|
|
psychedelic' unless one is publishing, in which case it could be best
|
|
described as an 'insight-enhancer' and obviously of potential value in
|
|
psychotherapy (if one would wish to spend 30 hours in a therapy
|
|
session!). I suppose it would be best to simply stick with the
|
|
insight-enhancing and skip the psychotherapy. Just too, too long.
|
|
There was not any particular visual impact, at least for me. The
|
|
non-sexual and the anorexic aspects might indeed change, with
|
|
increasing familiarity. Remains to be seen. The length of the
|
|
experience is against its frequent use, of course, which is a pity,
|
|
since this one is well worth investigating as often as possible.
|
|
|
|
(with 32 mg) There was, at the very beginning, a certain feeling of
|
|
non-physical heat in the upper back which reminded me of the onset of
|
|
various indoles, which this ainUt. The energy tremor was quite strong
|
|
throughout, but somehow the body was generally at ease.
|
|
|
|
(with 32 mg) At a plateau at two hours, with just a bit of tummy
|
|
queasi-ness. And I am still at the plateau several hours later.
|
|
Sleep finally at the 18th hour, but even after getting up and doing
|
|
all kinds of things the next day, I was not completely baseline until
|
|
that evening. And a couple of days more for what is certainly
|
|
complete repair. That is a lot of mileage for a small amount of
|
|
material.
|
|
|
|
EXTENSIONS AND COMMENTARY: Here is the first example, ever, of a
|
|
phen-ethylamine that is of about the same potency as therelated
|
|
three-carbon amphetamine. At first approximation, one is hard put to
|
|
distinguish, from the recorded notes, any major differences either in
|
|
potency, in duration, or in the nature of activity, between 2C-G and
|
|
GANESHA itself.
|
|
|
|
I had always thought of the phenethylamines as being somewhat weaker
|
|
than the corresponding amphetamines. Sometimes a little weaker and
|
|
sometimes a lot weaker. But that is a totally prejudiced point of
|
|
view, an outgrowth of my earliest comparisons of mescaline and TMA.
|
|
That's the kind of thing that can color oneUs thinking and obscure
|
|
what may be valuable observations. It is equally valid to think of
|
|
the phenethylamines as the prototypes, and that the amphetamines are
|
|
somewhat stronger than the corresponding phenethylamines. Sometimes a
|
|
little stronger and sometimes a lot stronger. Then the question
|
|
suddenly shifts from asking what is different about the
|
|
phenethylamines, to what is different about the amphetamines? It is
|
|
simply a historic fact, that in most of my exploring, the amphetamine
|
|
was made and evaluated first, and so tended to slip into the role of
|
|
the prototype. In any case, here the two potencies converge.
|
|
|
|
|
|
|
|
#28 2C-G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)PHENETHYLAMINE;
|
|
5-(2-AMINOETHYL)-4,7-DIMETHOXYINDANE)
|
|
|
|
SYNTHESIS: To a solution of 22 g of KOH in 250 mL of hot EtOH, there
|
|
was added 50 g of 4-indanol and 75 g methyl iodide. The mixture was
|
|
held at reflux for 12 h. There was then added an additional 22 g KOH
|
|
followed by an additional 50 g of methyl iodide. Refluxing was
|
|
continued for an additional 12 h. The mixture was poured into 1 L
|
|
H2O, acidified with HCl, and extracted with 3x75 mL CH2Cl2. The pooled
|
|
extracts were washed with 5% NaOH, then with dilute HCl, and the
|
|
solvent was removed under vacuum. The residue of crude
|
|
2,3-(trimethylene)anisole weighed 56.5 g and was used without further
|
|
purification in the following reaction.
|
|
|
|
A mixture of 327 g N-methylformanilide and 295 g POCl3 was allowed to
|
|
incubate until a deep claret color had formed. To this there was then
|
|
added 110 g of crude 2,3-(trimethylene)anisole, and the mixture heated
|
|
on the steam bath. There was a vigorous evolution of gases, which
|
|
largely quieted down after some 4 h of heating. The reaction mixture
|
|
was added to 4 L H2O and stirred overnight. The oily aqueous phase
|
|
was extracted with 3x200 mL CH2Cl2, and after combining the extracts
|
|
and removal of the solvent there was obtained 147 g of a black,
|
|
sweet-smelling oil. This was distilled at 182-194 !C at the water
|
|
pump to yield 109.1 g of a pale yellow oil. At low temperature, this
|
|
crystallized, but the solids melted again at room temperature. Gas
|
|
chromatography of this product on OV-17 at 185 !C showed detectable
|
|
starting anisole and N-methylformanilide (combined, perhaps 5% of the
|
|
product) and a small but real isomeric peak, (about 5%, slightly
|
|
faster moving than the title aldehyde, again about 5% of the product)
|
|
of what was tentatively identified as the ortho-aldehyde
|
|
(2-methoxy-3,4-(trimethylene)-benzaldehyde). The bulk of this crude
|
|
product (74 g) was redistilled at 110-130 !C at 0.3 mm/Hg to give 66 g
|
|
of 4-methoxy-2,3-(trimethylene)benzaldehyde as a nearly colorless oil
|
|
which set up as a crystalline solid. A portion on porous plate showed
|
|
a mp of 28-29 C. A gram of this aldehyde and a gram of malononitrile
|
|
in 25 mL of EtOH was treated with a few drops of triethylamine and
|
|
gave pale yellow crystals of the malononitrile derivative. This, upon
|
|
recrystallization from 50 mL boiling EtOH, had a mp of 176-176.5 !C.
|
|
Anal. (C14H12N2O) C,H,N. A side path, other than towards the intended
|
|
targets 2C-G-3 and G-3, was explored. Reaction with nitroethane and
|
|
anhydrous ammonium acetate gave the 2-nitropropene analogue which was
|
|
obtained in a pure state (mp 74-75 !C from MeOH) only after repeated
|
|
extraction of the crude isolate with boiling hexane. Reduction with
|
|
elemental iron gave the phenylacetone analogue which was reductively
|
|
aminated with dimethylamine and sodium cyanoborohydride to give
|
|
N,N-dimethyl-4-methoxy-2,3-(trimethylene)amphetamine. This was
|
|
designed for brain blood-flow volume studies after iodination at the
|
|
5-position, a concept that has been discussed under IDNNA. It has
|
|
never been tasted by anyone. The corresponding primary amine,
|
|
4-methoxy-2,3-(trimethylene)amphetamine has not yet even been
|
|
synthesized.
|
|
|
|
A solution of 34.8 g 4-methoxy-2,3-(trimethylene)benzaldehyde in 800
|
|
mL CH2Cl2 was treated with 58.6 g of 85% m-chloroperoxybenzoic acid
|
|
and held at reflux for 3 days. After cooling and standing for a few
|
|
days, the solids were removed by filtration and washed sparingly with
|
|
CH2Cl2. The combined filtrate and washings were washed with 200 mL
|
|
saturated NaHCO3, and the solvent removed, yielding 43.5 g of a deeply
|
|
colored oil. This was dissolved in 150 mL MeOH to which was added 9 g
|
|
NaOH and all heated to reflux on the steam bath. After 1 h, a
|
|
solution of 9 g NaOH in 20 mL H2O was added, heated further, then
|
|
followed by yet another treatment with 9 g NaOH in 20 mL H2O followed
|
|
by additional heating. All was added to 800 mL H2O, washed once with
|
|
CH2Cl2 (which removed a trivial amount of material) and then acidified
|
|
with HCl. The dark crystals that were generated were filtered and air
|
|
dried to constant weight, yielding 27.5 g dark but nice-looking
|
|
crystals with a mp of 89-91 !C. By all counts, this should have been
|
|
the product phenol, 4-methoxy-2,3-(trimethylene)phenol, but the
|
|
microanalysis indicated that the formate ester was still there. Anal.
|
|
(C10H12O2) requires C = 73.08, H = 7.37. (C11H12O3) requires C =
|
|
68.73, H = 6.29. Found: C = 69.04, 68.84; H = 6.64, 6.58. Whatever
|
|
the exact chemical status of the phenolic hydroxyl group might have
|
|
been, it reacted successfully in the following methylation step.
|
|
|
|
To a solution of 10 g KOH in 100 g EtOH (containing 5% IPA) there was
|
|
added 27.5 g of the above 89-91 !C melting material, followed by 25 g
|
|
methyl iodide. The mixture was held at reflux overnight. All was
|
|
added to 800 mL H2O, acidified with HCl, and extracted with 3x100 mL
|
|
CH2Cl2. The combined extracts were washed with 3x100 mL 5% NaOH, then
|
|
once with dilute HCl, and the solvent removed under vacuum yielding
|
|
20.4 g of a fragrant crystalline residue. This was recrystallized
|
|
from 60 mL boiling MeOH to give, after filtering and air drying, 16.0
|
|
g of 1,4-dimethoxy-2,3-(trimethylene)benzene (4,7-dimethoxyindane)
|
|
with a mp of 86-88 !C. Anal. (C11H14O2) C,H.
|
|
|
|
To a mixture of 39.0 g of N-methylformanilide and 35.9 g POCl3 that
|
|
had been allowed to stand at ambient temperature until deeply claret
|
|
(about 45 min) there was added 15.8 g of
|
|
1,4-dimethoxy-2,3-(trimethylene)benzene. The mixture was heated on
|
|
the steam bath for 4 h and then poured into 600 mL H2O. After
|
|
stirring overnight there was produced a heavy crystalline mass. This
|
|
was removed by filtration and, after air drying, was extracted with
|
|
3x100 mL boiling hexane. Pooling and cooling these extracts yielded
|
|
9.7 g of salmon-colored crystals with a mp of 67-68 !C. This was
|
|
recrystallized from 25 mL boiling EtOH to give, after filtration, EtOH
|
|
washing, and air drying to constant weight, 7.4 g of
|
|
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde, with a mp of 71-72 !C.
|
|
The mother liquors on cautious treatment with H2O, yielded, after EtOH
|
|
recrystallization, 1 g additional product. Anal. (C12H14O3) C,H. A
|
|
solution of 150 mg aldehyde and an equal weight of malononitrile in
|
|
2.3 mL EtOH treated with 3 drops triethylamine gave immediate yellow
|
|
crystals of the malononitrile derivative, with a mp of 161-162 !C.
|
|
Anal. (C15H14N2O2) C,H,N.
|
|
|
|
A solution 3.7 g 2,5-dimethoxy-3,4-(trimethylene)benzaldehyde in 15 g
|
|
nitromethane was treated with 0.7 g anhydrous ammonium acetate and
|
|
heated on the steam bath for 14 h. The volatiles were removed under
|
|
vacuum, and the residue set up to 3.5 g dark crystals, which melted
|
|
broadly between 126-138 !C. Recrystallization of the entire mass from
|
|
70 mL boiling EtOH gave 3.2 g burnished gold crystals with a mp of
|
|
129-137 !C. A further recrystallization of an analytical sample from
|
|
MeOH gave 2,5-dimethoxy-3,4-(trimethylene)-'-nitrostyrene as yellow
|
|
crystals with a mp of 146-147 !C. Anal. (C13H15NO4) C,H.
|
|
|
|
To a cold solution of LAH in THF (40 mL of a 1 M solution) well
|
|
stirred and under an inert atmosphere, there was added dropwise 1.05
|
|
mL freshly prepared 100% H2SO4. There was then added, dropwise, a
|
|
solution of 2.39 g 2,5-dimethoxy-3,4-(trimethylene)-'-nitrostyrene in
|
|
25 mL THF. The bright yellow color was discharged immediately. After
|
|
the addition was complete, stirring was continued for an additional 20
|
|
min, and the reaction mixture brought to a reflux on the steam bath
|
|
for another 0.5 h. After cooling, the excess hydride was destroyed
|
|
with IPA (8 mL required) followed by sufficient 15% NaOH to convert
|
|
the inorganics into a loose, filterable mass. This was removed by
|
|
filtration, and the filter cake washed with THF. The combined
|
|
filtrate and washes were stripped of solvent under vacuum, and the
|
|
residue dissolved in dilute H2SO4. After washing with CH2Cl2, the
|
|
aqueous phase was made basic with 25% NaOH and extracted with 3x75 mL
|
|
CH2Cl2. After removal of the solvent under vacuum, the residue was
|
|
distilled at 125-160 !C at 0.45 mm/Hg to yield 0.80 g of a white oil.
|
|
This was dissolved in 8 mL IPA, neutralized with 20 drops of
|
|
concentrated HCl (the salt crystals started to form before this was
|
|
completed) followed with the addition of 65 mL anhydrous Et2O. The
|
|
white crystalline mass was filtered, washed with Et2O, and air dried
|
|
to provide 1.16 g of 2,5-dimethoxy-3,4-(trimethylene)phenethylamine
|
|
hydrochloride (2C-G-3) with a mp of 214-216 !C with decomposition.
|
|
Anal. (C13H20ClNO2) C,H.
|
|
|
|
DOSAGE: 16 - 25 mg.
|
|
|
|
DURATION: 12 - 24 h.
|
|
|
|
QUALITATIVE COMMENTS: (with 16 mg) It came on in little leaps and
|
|
bounds. All settled, and then it would take another little jump
|
|
upwards. I am totally centered, and writing is easy. My appetite is
|
|
modest. Would I drive to town to return a book to the library? No
|
|
ever-loving way! I am very content to be right here where I am safe,
|
|
and stay with the writing. It does take so much time to say what
|
|
wants to be said, but there is no quick way. A word at a time.
|
|
|
|
(with 22 mg) I walked out for the mail at just about twilight. That
|
|
was the most courageous thing that I could possibly have done, just
|
|
for one lousy postcard and a journal. What if I had met someone who
|
|
had wanted to talk? Towards evening I got a call from Peg who said
|
|
her bean soup was bubbling in a scary way and what should she do, and
|
|
I said maybe better make soap. It was that kind of an experience!
|
|
Way up there, lots of LSD-like sparkles, and nothing quite really
|
|
making sense. Marvelous.
|
|
|
|
(with 25 mg) There was easy talking, and no hint of any body concern.
|
|
Sleep that evening was easy, and the next day was with good energy.
|
|
|
|
EXTENSIONS AND COMMENTARY: The positives of a completely intriguing
|
|
altered state free from apparent physical threats, are here coupled
|
|
with the negative of having to invest such a long period of time.
|
|
There is a merry nuttiness which can give a joyous intoxication, but
|
|
with the underlying paranoia of how it looks to others. There is an
|
|
ease of communication, but only within surroundings that are
|
|
well-known and friendly. This might be a truly frightening experience
|
|
if it were in an unfamiliar or unstructured environment.
|
|
|
|
The numbering of this compound, and all the extensions of GANESHA,
|
|
have been made on the basis of the nature of the stuff at the
|
|
3,4-position. Here there are three atoms (the trimethylene bridge)
|
|
and so 2C-G-3 seems reasonable. With this logic, the dimethylene
|
|
bridge would be 2C-G-2 (and the corresponding amphetamine would be
|
|
G-2, of course). But these compounds call upon a common intermediate
|
|
which is a benzocyclobutene, OK in principle but not yet OK in
|
|
practice. The right benzyne reaction will be there someday, and the
|
|
dimethylene analogues will be made and assayed. But, in the meantime,
|
|
at least the names have been assigned.
|
|
|
|
|
|
|
|
#29 2C-G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)PHENETHYLAMINE;
|
|
6-(2-AMINOETHYL)-5,8-DIMETHOXY-TETRALIN
|
|
|
|
SYNTHESIS: To a solution of 49.2 g 5,6,7,8-tetrahydronaphthol
|
|
(5-hydroxytetralin) in 100 mL MeOH, there was added 56 g methyl iodide
|
|
followed by a solution of 24.8 g KOH pellets (85% purity) in 100 mL
|
|
boiling MeOH. The mixture was heated in a 55 !C bath for 3 h (the
|
|
first white solids of potassium iodide appeared in about 10 min). The
|
|
solvent was stripped under vacuum, and the residues dissolved in 2 L
|
|
H2O. This was acidified with HCl, and extracted with 4x75 mL CH2Cl2.
|
|
After washing the organic phase with 3x75 mL 5% NaOH, the solvent was
|
|
removed under vacuum to give 48.2 g of a black residue. This was
|
|
distilled at 80-100 !C at 0.25 mm/Hg to provide 33.9 g
|
|
5-methoxy-1,2,3,4-tetrahydronaphthalene as a white oil. The NaOH
|
|
washes, upon acidification and extraction with CH2Cl2 gave, after
|
|
removal of the solvent under vacuum and distillation of the residue at
|
|
0.35 mm/Hg, 11.4 g of recovered starting phenol.
|
|
|
|
A mixture of 61.7 g POCl3 and 54.3 g N-methylformanilide was heated on
|
|
the steam bath for 15 min which produced a deep red color. This was
|
|
added to 54.3 g of 5-methoxy-1,2,3,4-tetrahydronaphthalene, and the
|
|
mixture was heated on the steam bath for 2 h. The reaction mixture
|
|
was quenched in 1.2 L H2O with very good stirring. The oils generated
|
|
quickly turned to brown granular solids, which were removed by
|
|
filtration. The 79 g of wet product was finely triturated under an
|
|
equal weight of MeOH, filtered, washed with 20 mL ice-cold MeOH, and
|
|
air dried to yield 32.0 g of
|
|
4-methoxy-5,6,7,8-tetrahydronaphthaldehyde as an ivory-colored solid.
|
|
The filtrate, on standing, deposited another 4.5 g of product which
|
|
was added to the above first crop. An analytical sample was obtained
|
|
by recrystallization from EtOH, and had a mp of 57-58 !C. Anal.
|
|
(C12H14O2) C,H.
|
|
|
|
To a solution of 25.1 g 4-methoxy-5,6,7,8-tetrahydronaphthaldehyde in
|
|
300 mL CH2Cl2 there was added 25 g 85% m-chloroperoxybenzoic acid at a
|
|
rate that was commensurate with the exothermic reaction. Solids were
|
|
apparent within a few min. The stirred reaction mixture was heated at
|
|
reflux for 8 h. After cooling to room temperature, the solids were
|
|
removed by filtration and washed lightly with CH2Cl2. The pooled
|
|
filtrate and washes were stripped of solvent under vacuum and the
|
|
residue dissolved in 100 mL MeOH and treated with 40 mL 25% NaOH.
|
|
This was heated on the steam bath for an hour, added to 1 L H2O, and
|
|
acidified with HCl, producing a heavy crystalline mass. This was
|
|
removed by filtration, air dried, and distilled at up to 170 !C at 0.2
|
|
mm/Hg. There was thus obtained 21.4 g of
|
|
4-methoxy-5,6,7,8-tetrahydronaphthol as an off-white solid with a mp
|
|
of 107-114 !C. An analytical sample was obtained by recrystallization
|
|
from 70% EtOH, and melted at 119-120 !C. Hexane is also an excellent
|
|
recrystallization solvent. Anal. (C11H14O2) C,H. As an alternate
|
|
method, the oxidation of the naphthaldehyde to the naphthol can be
|
|
achieved through heating the aldehyde in acetic acid solution
|
|
containing hydrogen peroxide. The yields using this route are
|
|
consistently less than 40% of theory.
|
|
|
|
A solution of 21.0 g of 4-methoxy-5,6,7,8-tetrahydronaphthol in 100 mL
|
|
acetone in a 1 L round-bottomed flask, was treated with 25 g finely
|
|
ground anhydrous K2CO3 and 26 g methyl iodide. The mixture was held
|
|
at reflux on the steam bath for 2 h, cooled, and quenched in 1 L H2O.
|
|
Trial extraction evaluations have shown that the starting phenol, as
|
|
well as the product ether, are extractable into CH2Cl2 from aqueous
|
|
base. The aqueous reaction mixture was extracted with 3x60 mL CH2Cl2,
|
|
the solvent removed under vacuum, and the residue (19.6 g) was
|
|
distilled at 90-130 !C at 0.3 mm/Hg to give 14.1 g of an oily white
|
|
solid mixture of starting material and product. This was finely
|
|
ground under an equal weight of hexane, and the residual crystalline
|
|
solids removed by filtration. These proved to be quite rich in the
|
|
desired ether. This was dissolved in a hexane/CH2Cl2 mixture (3:1 by
|
|
volume) and chromatographed on a silica gel preparative column, with
|
|
the eluent continuously monitored by TLC (with this solvent system,
|
|
the Rf of the ether product was 0.5, of the starting phenol 0.1). The
|
|
fractions containing the desired ether were pooled, the solvent
|
|
removed under vacuum and the residue, which weighed 3.86 g, was
|
|
dissolved in 1.0 mL hexane and cooled with dry ice. Glistening white
|
|
crystals were obtained by filtration at low temperature. The weight
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|
of 5,8-dimethoxytetralin isolated was 2.40 g and the mp was 44-45 !C.
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|
GCMS analysis showed it to be largely one product (m/s 192 parent peak
|
|
and major peak), but the underivitized starting phenol has abysmal GC
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|
properties and TLC remains the best measure of chemical purity.
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|
A well-stirred solution of 3.69 g 5,8-dimethoxytetralin in 35 mL
|
|
CH2Cl2 was placed in an inert atmosphere and cooled to 0 !C with an
|
|
external ice bath. There was then added, at a slow rate, 4.5 mL
|
|
anhydrous stannic chloride, which produced a transient color that
|
|
quickly faded to a residual yellow. There was then added 2.0 mL
|
|
dichloromethyl methyl ether, which caused immediate darkening. After
|
|
a few min stirring, the reaction mixture was allowed to come to room
|
|
temperature, and finally to a gentle reflux on the steam bath. The
|
|
evolution of HCl was continuous. The reaction was then poured into
|
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200 mL H2O, the phases separated, and the aqueous phase extracted with
|
|
2x50 mL CH2Cl2. The organic phase and extracts were pooled, washed
|
|
with 3x50 mL 5% NaOH, and the solvent removed under vacuum. The
|
|
residue was distilled at 120-140 !C at 0.3 mm/Hg to give 3.19 g of a
|
|
white oil that spontaneously crystallized. The crude mp of
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|
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde was 70-72 !C. An
|
|
analytical sample from hexane had the mp 74-75 !C. The GCMS analysis
|
|
showed only a single material (m/s 220, 100%) with no apparent
|
|
starting dimethoxytetralin present. Attempts to synthesize this
|
|
aldehyde by the Vilsmeier procedure (POCl3 and N-methylformanilide)
|
|
gave complex mixtures of products. Synthetic efforts employing
|
|
butyllithium and DMF gave only recovered starting material.
|
|
|
|
To a solution of 1.5 g
|
|
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 g nitromethane
|
|
there was added 0.14 g anhydrous ammonium acetate and the mixture
|
|
heated on the steam bath for 50 min. The rate of the reaction was
|
|
determined by TLC monitoring, on silica gel with CH2Cl2 as the moving
|
|
solvent; the Rf of the aldehyde was 0.70, and of the product
|
|
nitrostyrene, 0.95. Removal of the volatiles under vacuum gave a
|
|
residue that spontaneously crystallized. The fine yellow crystals
|
|
that were obtained were suspended in 1.0 mL of MeOH, filtered, and air
|
|
dried to yield 1.67 g
|
|
2,5-dimethoxy-'-nitro-3,4-(tetramethylene)styrene with a mp of
|
|
151.5-152.5 !C. Anal. (C14H17NO4) C,H.
|
|
|
|
DOSAGE: unknown.
|
|
|
|
DURATION: unknown
|
|
|
|
EXTENSIONS AND COMMENTARY: The road getting to this final product
|
|
reminded me of the reasons why, during the first few billion years of
|
|
the universe following the big bang, there was only hydrogen and
|
|
helium. Nothing heavier. When everything had expanded enough to cool
|
|
things sufficiently for the first actual matter to form, all was
|
|
simply very energetic protons and neutrons. These were banging into
|
|
one-another, making deuterium nuclei, and some of these got banged up
|
|
even all the way to helium, but every time a helium nucleus collided
|
|
with a particle of mass one, to try for something with mass five, the
|
|
products simply couldnUt exist. Both Lithium-5 and Helium-5 have the
|
|
impossible half-lives of 10 to the minus 21 seconds. Hence, in the
|
|
primordial soup, the only way to get into something heavier than
|
|
helium was to have a collision between a couple of the relatively
|
|
scarcer heavy nuclei, or to have a three body collision. Both of
|
|
these would be extremely rare events, statistically. And if a few got
|
|
through, there was another forbidden barrier at mass 8, since
|
|
Beryllium-8 has a half life of 10 to the minus 16 seconds. So
|
|
everything had to wait for a few suns to burn down so that they could
|
|
process enough helium into heavy atoms, to achieve some nuclear
|
|
chemistry that was not allowed in the early history of the universe.
|
|
|
|
And in the same way, there were two nearly insurmountable barriers
|
|
encountered in getting to 2C-G-4 and G-4. The simple act of
|
|
methylating an aromatic hydroxyl group provided mixtures that could
|
|
only be resolved into components by some pretty intricate maneuvers.
|
|
And when that product was indeed gotten, the conversion of it into a
|
|
simple aromatic aldehyde resisted the classic procedures completely,
|
|
either giving complex messes, or nothing. And even now, with these
|
|
two hurdles successfully passed, the presumed simple last step has not
|
|
yet been done. The product 2C-G-4 lies just one synthetic step (the
|
|
LAH reduction) away from completion, and the equally fascinating G-4
|
|
also that one last reduction step from being completed. Having gotten
|
|
through the worst of the swamp, let's get into the lab and finish up
|
|
this challenge. They will both be active compounds.
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