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Subject: PiHKAL: The Chemical Story. File 1 of 6
This is part 1 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.
If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL. The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701. California residents
please add $1.38 State sales tax.
At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings.... No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man. To do
so is to risk legal action which might lead to the tragic ruination of
a life. It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.
A SHORT INDEX TO THE PHENETHYLAMINES
This short index to the phenethylamines lists the 179 entries that
follow in alphebetical order. The abbreviation PEA is for
phenethylamine, and A is for amphetamine. The long index includes all
synonyms and is in Appendix A.
Code Compact chemical name
1 AEM a-Ethyl-3,4,5-trimethoxy-PEA
2 AL 4-Allyloxy-3,5-dimethoxy-PEA
3 ALEPH 4-Methylthio-2,5-dimethoxy-A
4 ALEPH-2 4-Ethylthio-2,5-dimethoxy-A
5 ALEPH-4 4-Isopropylthio-2,5-dimethoxy-A
6 ALEPH-6 4-Phenylthio-2,5-dimethoxy-A
7 ALEPH-7 4-Propylthio-2,5-dimethoxy-A
8 ARIADNE 2,5-Dimethoxy-a-ethyl-4-methyl-PEA
9 ASB 3,4-Diethoxy-5-methoxy-PEA
10 B 4-Butoxy-3,5-dimethoxy-PEA
11 BEATRICE 2,5-Dimethoxy-4,N-dimethyl-A
12 BIS-TOM 2,5-Bismethylthio-4-methyl-A
13 BOB 4-Bromo-2,5,'-trimethoxy-PEA
14 BOD 2,5,'-Trimethoxy-4-methyl-PEA
15 BOH '-Methoxy-3,4-methylenedioxy-PEA
16 BOHD 2,5-Dimethoxy-'-hydroxy-4-methyl-PEA
17 BOM 3,4,5,'-Tetramethoxy-PEA
18 4-Br-3,5-DMA 4-Bromo-3,5-dimethoxy-A
19 2-Br-4,5-MDA 2-Bromo-4,5-methylenedioxy-A
20 2C-B 4-Bromo-2,5-dimethoxy-PEA
21 3C-BZ 4-Benzyloxy-3,5-dimethoxy-A
22 2C-C 4-Chloro-2,5-dimethoxy-PEA
23 2C-D 4-Methyl-2,5-dimethoxy-PEA
24 2C-E 4-Ethyl-2,5-dimethoxy-PEA
25 3C-E 4-Ethoxy-3,5-dimethoxy-A
26 2C-F 4-Fluoro-2,5-dimethoxy-PEA
27 2C-G 3,4-Dimethyl-2,5-dimethoxy-PEA
28 2C-G-3 3,4-Trimethylene-2,5-dimethoxy-PEA
29 2C-G-4 3,4-Tetramethylene-2,5-dimethoxy-PEA
30 2C-G-5 3,4-Norbornyl-2,5-dimethoxy-PEA
31 2C-G-N 1,4-Dimethoxynaphthyl-2-ethylamine
32 2C-H 2,5-Dimethoxy-PEA
33 2C-I 4-Iodo-2,5-dimethoxy-PEA
34 2C-N 4-Nitro-2,5-dimethoxy-PEA
35 2C-O-4 4-Isopropoxy-2,5-dimethoxy-PEA
36 2C-P 4-Propyl-2,5-dimethoxy-PEA
37 CPM 4-Cyclopropylmethoxy-3,5-dimethoxy-PEA
38 2C-SE 4-Methylseleno-2,5-dimethoxy-PEA
39 2C-T 4-Methylthio-2,5-dimethoxy-PEA
40 2C-T-2 4-Ethylthio-2,5-dimethoxy-PEA
41 2C-T-4 4-Isopropylthio-2,5-dimethoxy-PEA
42 Y-2C-T-4 4-Isopropylthio-2,6-dimethoxy-PEA
43 2C-T-7 4-Propylthio-2,5-dimethoxy-PEA
44 2C-T-8 4-Cyclopropylmethylthio-2,5-dimethoxy-PEA
45 2C-T-9 4-(t)-Butylthio-2,5-dimethoxy-PEA
46 2C-T-13 4-(2-Methoxyethylthio-2,5-dimethoxy-PEA
47 2C-T-15 4-Cyclopropylthio-2,5-dimethoxy-PEA
48 2C-T-17 4-(s)-Butylthio-2,5-dimethoxy-PEA
49 2C-T-21 4-(2-Fluoroethylthio)-2,5-dimethoxy-PEA
50 4-D 4-Trideuteromethyl-3,5-dimethoxy-PEA
51 '-D ','-Dideutero-3,4,5-trimethoxy-PEA
52 DESOXY 4-Me-3,5-Dimethoxy-PEA
53 2,4-DMA 2,4-Dimethoxy-A
54 2,5-DMA 2,5-Dimethoxy-A
55 3,4-DMA 3,4-Dimethoxy-A
56 DMCPA 2-(2,5-Dimethoxy-4-methylphenyl)-
cyclopropylamine
57 DME 3,4-Dimethoxy-'-hydroxy-PEA
58 DMMDA 2,5-Dimethoxy-3,4-methylenedioxy-A
59 DMMDA-2 2,3-Dimethoxy-4,5-methylenedioxy-A
60 DMPEA 3,4-Dimethoxy-PEA
61 DOAM 4-Amyl-2,5-dimethoxy-A
62 DOB 4-Bromo-2,5-dimethoxy-A
63 DOBU 4-Butyl-2,5-dimethoxy-A
64 DOC 4-Chloro-2,5-dimethoxy-A
65 DOEF 4-(2-Fluoroethyl)-2,5-dimethoxy-A
66 DOET 4-Ethyl-2,5-dimethoxy-A
67 DOI 4-Iodo-2,5-dimethoxy-A
68 DOM 4-Methyl-2,5-dimethoxy-A
69 Y-DOM 4-Methyl-2,6-dimethoxy-A
70 DON 4-Nitro-2,5-dimethoxy-A
71 DOPR 4-Propyl-2,5-dimethoxy-A
72 E 4-Ethoxy-3,5-dimethoxy-PEA
73 EEE 2,4,5-Triethoxy-A
74 EEM 2,4-Diethoxy-5-methoxy-A
75 EME 2,5-Diethoxy-4-methoxy-A
76 EMM 2-Ethoxy-4,5-dimethoxy-A
77 ETHYL-J N,a-diethyl-3,4-methylenedioxy-PEA
78 ETHYL-K N-Ethyl-a-propyl-3,4-methylenedioxy-PEA
79 F-2 Benzofuran-2-methyl-5-methoxy-6-
(2-aminopropane)
80 F-22 Benzofuran-2,2-dimethyl-5-methoxy-6-
(2-aminopropane)
81 FLEA N-Hydroxy-N-methyl-3,4-methylenedioxy-A
82 G-3 3,4-Trimethylene-2,5-dimethoxy-A
83 G-4 3,4-Tetramethylene-2,5-dimethoxy-A
84 G-5 3,4-Norbornyl-2,5-dimethoxy-A
85 GANESHA 3,4-Dimethyl-2,5-dimethoxy-A
86 G-N 1,4-Dimethoxynaphthyl-2-isopropylamine
87 HOT-2 2,5-Dimethoxy-N-hydroxy-4-ethylthio-PEA
88 HOT-7 2,5-Dimethoxy-N-hydroxy-4-(n)-propylthio-PEA
89 HOT-17 2,5-Dimethoxy-N-hydroxy-4-(s)-butylthio-PEA
90 IDNNA 2,5-Dimethoxy-N,N-dimethyl-4-iodo-A
91 IM 2,3,4-Trimethoxy-PEA
92 IP 3,5-Dimethoxy-4-isopropoxy-PEA
93 IRIS 5-Ethoxy-2-methoxy-4-methyl-A
94 J a-Ethyl-3,4-methylenedioxy-PEA
95 LOPHOPHINE 3-Methoxy-4,5-methylenedioxy-PEA
96 M 3,4,5-Trimethoxy-PEA
97 4-MA 4-Methoxy-A
98 MADAM-6 2,N-Dimethyl-4,5-methylenedioxy-A
99 MAL 3,5-Dimethoxy-4-methallyloxy-PEA
100 MDA 3,4-Methylenedioxy-A
101 MDAL N-Allyl-3,4-methylenedioxy-A
102 MDBU N-Butyl-3,4-methylenedioxy-A
103 MDBZ N-Benzyl-3,4-methylenedioxy-A
104 MDCPM N-Cyclopropylmethyl-3,4-methylenedioxy-A
105 MDDM N,N-Dimethyl-3,4-methylenedioxy-A
106 MDE N-Ethyl-3,4-methylenedioxy-A
107 MDHOET N-(2-Hydroxyethyl)-3,4-methylenedioxy-A
108 MDIP N-Isopropyl-3,4-methylenedioxy-A
109 MDMA N-Methyl-3,4-methylenedioxy-A
110 MDMC N-Methyl-3,4-ethylenedioxy-A
111 MDMEO N-Methoxy-3,4-methylenedioxy-A
112 MDMEOET N-(2-Methoxyethyl)-3,4-methylenedioxy-A
113 MDMP a,a,N-Trimethyl-3,4-methylenedioxy-PEA
114 MDOH N-Hydroxy-3,4-methylenedioxy-A
115 MDPEA 3,4-Methylenedioxy-PEA
116 MDPH a,a-Dimethyl-3,4-methylenedioxy-PEA
117 MDPL N-Propargyl-3,4-methylenedioxy-A
118 MDPR N-Propyl-3,4-methylenedioxy-A
119 ME 3,4-Dimethoxy-5-ethoxy-PEA
120 MEDA 3,4-Ethylenedioxy-5-methoxy-A
121 MEE 2-Methoxy-4,5-diethoxy-A
122 MEM 2,5-Dimethoxy-4-ethoxy-A
123 MEPEA 3-Methoxy-4-ethoxy-PEA
124 META-DOB 5-Bromo-2,4-dimethoxy-A
125 META-DOT 5-Methylthio-2,4-dimethoxy-A
126 METHYL-DMA N-Methyl-2,5-dimethoxy-A
127 METHYL-DOB 4-Bromo-2,5-dimethoxy-N-methyl-A
128 METHYL-J N-Methyl-a-ethyl-3,4-methylenedioxy-PEA
129 METHYL-K N-Methyl-a-propyl-3,4-methylenedioxy-PEA
130 METHYL-MA N-Methyl-4-methoxy-A
131 METHYL-MMDA-2 N-Methyl-2-methoxy-4,5-
methylenedioxy-A
132 MMDA 3-Methoxy-4,5-methylenedioxy-A
133 MMDA-2 2-Methoxy-4,5-methylenedioxy-A
134 MMDA-3a 2-Methoxy-3,4-methylenedioxy-A
135 MMDA-3b 4-Methoxy-2,3-methylenedioxy-A
136 MME 2,4-Dimethoxy-5-ethoxy-A
137 MP 3,4-Dimethoxy-5-propoxy-PEA
138 MPM 2,5-Dimethoxy-4-propoxy-A
139 ORTHO-DOT 2-Methylthio-4,5-dimethoxy-A
140 P 3,5-Dimethoxy-4-propoxy-PEA
141 PE 3,5-Dimethoxy-4-phenethyloxy-PEA
142 PEA PEA
143 PROPYNYL 4-Propynyloxy-3,5-dimethoxy-PEA
144 SB 3,5-Diethoxy-4-methoxy-PEA
145 TA 2,3,4,5-Tetramethoxy-A
146 3-TASB 4-Ethoxy-3-ethylthio-5-methoxy-PEA
147 4-TASB 3-Ethoxy-4-ethylthio-5-methoxy-PEA
148 5-TASB 3,4-Diethoxy-5-methylthio-PEA
149 TB 4-Thiobutoxy-3,5-dimethoxy-PEA
150 3-TE 4-Ethoxy-5-methoxy-3-methylthio-PEA
151 4-TE 3,5-Dimethoxy-4-ethylthio-PEA
152 2-TIM 2-Methylthio-3,4-dimethoxy-PEA
153 3-TIM 3-Methylthio-2,4-dimethoxy-PEA
154 4-TIM 4-Methylthio-2,3-dimethoxy-PEA
155 3-TM 3-Methylthio-4,5-dimethoxy-PEA
156 4-TM 4-Methylthio-3,5-dimethoxy-PEA
157 TMA 3,4,5-Trimethoxy-A
158 TMA-2 2,4,5-Trimethoxy-A
159 TMA-3 2,3,4-Trimethoxy-A
160 TMA-4 2,3,5-Trimethoxy-A
161 TMA-5 2,3,6-Trimethoxy-A
162 TMA-6 2,4,6-Trimethoxy-A
163 3-TME 4,5-Dimethoxy-3-ethylthio-PEA
164 4-TME 3-Ethoxy-5-methoxy-4-methylthio-PEA
165 5-TME 3-Ethoxy-4-methoxy-5-methylthio-PEA
166 2T-MMDA-3a 2-Methylthio-3,4-methylenedioxy-A
167 4T-MMDA-2 4,5-Thiomethyleneoxy-2-methoxy-A
168 TMPEA 2,4,5-Trimethoxy-PEA
169 2-TOET 4-Ethyl-5-methoxy-2-methylthio-A
170 5-TOET 4-Ethyl-2-methoxy-5-methylthio-A
171 2-TOM 5-Methoxy-4-methyl-2-methylthio-A
172 5-TOM 2-Methoxy-4-methyl-5-methylthio-A
173 TOMSO 2-Methoxy-4-methyl-5-methylsulfinyl-A
174 TP 4-Propylthio-3,5-dimethoxy-PEA
175 TRIS 3,4,5-Triethoxy-PEA
176 3-TSB 3-Ethoxy-5-ethylthio-4-methoxy-PEA
177 4-TSB 3,5-Diethoxy-4-methylthio-PEA
178 3-T-TRIS 4,5-Diethoxy-3-ethylthio-PEA
179 4-T-TRIS 3,5-Diethoxy-4-ethylthio-PEA
PHENETHYLAMINES
#1 AEM; a-ETHYLMESCALINE; 2-AMINO-1-(3,4,5-TRIMETHOXYPHENYL)BUTANE; 1-(3,4,5-TRIMETHOXYPHENYL)-2-AMINOBUTANE
SYNTHESIS: To a solution of 45 g 3,4,5-trimethoxybenzaldehyde in 1.2 L
IPA, there was added 125 g nitropropane and 67.5 g t-butylammonium
acetate and the reaction mixture was held at reflux for 16 h. This
was poured into 6 L H2O, and extracted with 2x250 mL hexane. The
pooled extracts were stripped of solvent under vacuum giving a residue
that slowly set to a crystalline mass. On filtering, there was
obtained 9.4 g of a crude yellow product which, on recrystallization
from hexane provided 8.7 g of slightly sticky bright yellow crystals
of 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1, with a mp of 71-73 !C.
A second recrystallization from hexane gave fine yellow crystals with
a mp of 72-73 !C. Attempts at the preparation of this nitrostyrene by
the more conventional methods with ammonium acetate in acetic acid led
either to the formation of a white product C23H30N2O8 which was
composed of a molecule of the nitrostyrene, one of the benzaldehyde
itself, and a molecule of ammonia, or to 3,4,5-trimethoxybenzonitrile,
from reaction with the decomposition products of nitropropane.
A stirred suspension of 5.9 g LAH in 310 mL anhydrous Et2O was held at
a gentle reflux in an inert atmosphere. A solution of 8.5 g
2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1 in 125 mL Et2O is added
drop-wise over the course of 0.5 h. The reaction was maintained at
reflux for 6 h, then cooled, and the excess hydride destroyed by the
cautious addition of 300 mL 1.8 N H2SO4. The phases were separated,
and the aqueous phase brought to a pH of 6 by the addition of a
saturated Na2CO3 solution. The neutral solution was brought to a
boil, and clarified by filtration through paper. To the hot filtrate
there was added a solution of 8.9 g picric acid in 100 mL boiling
EtOH. The mixture was stirred and cooled, with the formation of a
heavy yellow crystalline mass. After standing in the ice tub for
several hours the mixture was filtered, providing 8.0 g of the picrate
salt with a mp of 176-181 !C from H2O. A solution of this salt in 300
mL boiling H2O was treated with 60 mL concentrated HCl. On cooling,
there was a deposition of picric acid, which was removed by
filtration. The aqueous filtrate was washed with 3x50 mL
nitrobenzene, then with 3x50 mL Et2O. The pH was brought above 9 by
the addition of aqueous NaOH, and the filtrate was extracted with
3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave
a nearly colorless oil, which was dissolved in 300 mL anhydrous Et2O
and saturated with hydrogen chloride gas. The white crystals of
2-amino-1-(3,4,5-trimethoxyphenyl)butane hydrochloride (AEM) were
removed by filtration, Et2Owashed, and air dried. They weighed 4.72
g.
DOSAGE: greater than 220 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: The extension of the two-carbon chain of
mescaline by alpha-methylation to the three carbon chain of TMA
approximately doubled the potency of the compound. And it was felt to
be a completely logical possibility that, by extending it one more
carbon atom, to the four carbon chain of alpha-ethyl-mescaline, it
might double again. And following that logical progression, the
doubling of potency with each additional carbon atom, the factor would
be 2 to the 7th power by the alpha-octyl (or 256x that of mescaline,
or a milligram as active dose) and with a side chain of a 70-carbon
alkyl group (alpha-heptacontylmescaline) it would take just a single
molecule to be intoxicating. This was rich fantasy stuff. As an
active compound, just where would it go in the brain? With an
80-carbon side-chain, would one-thousandth of a single molecule be
enough for a person? Or might a single molecule intoxicate a thousand
people? And how long a chain on the alpha-position might be
sufficient that, by merely writing down the structure on a piece of
paper, you would get high? Maybe just conceiving the structure in
your mind would do it. That is, after all, the way of homeopathy.
Maybe it was just as well that this added two-carbon side-chain with
lowered activity was already enough to disprove the doubling pattern.
But by the time this non-activity had been learned, the alpha series
had already been pushed out quite aways. The machinery of making the
appropriate nitroalkane was straightforward, by reaction of the alkyl
halide with nitrous acid, and separating the unwanted nitrite ester
from the wanted nitroalkane by fractional distillation. The
nitrostyrenes all formed reasonably although often in terrible yields,
and reduced reasonably, and all formed crystalline picrates for
isolation and crystalline hydrochloride salts for pharmacological
manipulation. But since the first of these, AEM, was not active,
there was no enthusiasm for tasting anything higher. This family was
never published; why publish presumably inactive and thus
uninteresting material? The Table presents the properties of the
precursor nitrostyrenes, and the product picrate and hydrochloride
salts, at least whatever information I can still find after thirty
years:
TABLE. Physical Properties of the a-Alkylmescaline Homologues and
their Precursor Nitrostyrenes
Code Name NS mp !C picrate mp !C HCl mp !C
APM Alpha-propylmescaline 82-83 214-218
ABM Alpha-butylmescaline 73-74 169-174 182-184
AAM Alpha-amylmescaline 54-55 162-163 155-158
AHM Alpha-hexylmescaline 51-52
ASM* Alpha-heptylmescaline 43-44
AOM Alpha-octylmescaline **
ANM Alpha-nonylmescaline 46-47 ***
AUM Alpha-undecylmescaline ***
* S is for septyl, to distinguish heptyl from hexyl. **Never
made, as no nonylbromide could be located to make the needed
nitrononane. ***The synthesis got as far as the nitrostyrene stage
when the inactivity of AEM was determined, and the project was
dropped.
#2 AL; 4-ALLYLOXY-3,5-DIMETHOXYPHENETHYLAMINE;
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
of 5,8-dimethoxytetralin isolated was 2.40 g and the mp was 44-45 !C.
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
properties and TLC remains the best measure of chemical purity.
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
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
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.