SYNTHESIS: To a solution of 43.2 g flaked KOH in 250 mL hot EtOH there
was added 96 g 4-methoxyphenol followed by 90 g 2-methylallyl chloride
over the course of 2 h. The mixture was held at reflux for 24 h, then
added to 1.6 L H2O. There was sufficient 25% NaOH added to make the
phase strongly basic, and this was then extracted with 3x200 mL
CH2Cl2. The pooled extracts were washed with H2O, and the solvent
removed under vacuum. The residue, 125 g of a pale amber oil, was
crude 4-(2-methylallyloxy)anisole and was used without further
purification in the following reaction.
In a round-bottomed flask containing an internal thermometer, there
was placed 125 g of unpurified 4-(2-methylallyloxy)anisole, and this
was heated with an open flame. At an internal temperature of 190 °C
an exothermic reaction set in, raising the temperature to 250 °C,
where it was held for an additional 2 min. After the reaction mixture
had cooled to room temperature, it was poured into 500 mL H2O, made
strongly basic with 25% NaOH, and extracted repeatedly with 100 mL
portions of CH2Cl2 until the extracts were essentially colorless.
These extracts were pooled and the solvent removed to provide 80.0 g
of a deeply colored oil that proved to be largely the appropriately
substituted dihydrobenzofuran. The aqueous residue from above was
acidified with concentrated HCl, and again extracted with CH2Cl2.
Removal of the solvent gave 17.7 g of
4-methoxy-2-(2-methylallyl)phenol as an amber oil which eventually set
down as white crystals with a mp of 52.5-54 °C.
A solution of 17 g of 4-methoxy-2-(2-methylallyl)phenol in 56 g acetic
acid was treated with 8.4 g zinc chloride followed with 28 mL
concentrated HCl. This mixture was heated at reflux temperature with
a mantle for 1 h. After cooling, this was poured into H2O and
extracted with 2x150 mL CH2Cl2. The pooled extracts were washed with
several portions of 8% NaOH, until the extracts were colorless. The
organic fraction was then washed with H2O, and the solvent removed to
yield 5.8 g of 2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran as a pale
amber oil with a pungent smell. This was purified by distillation,
giving a fraction of an off-white oil with a bp of 136-138 °C at 33
mm/Hg.
To a mixture of 8.0 g N-methylformanilide and 9.2 g POCl3 which had
been allowed to stand for 0.5 h, there was added 4.0 g
2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran, and the mixture held at
the steam bath temperature for 2.5 h. This was then poured into 200
mL H2O which produced a black oily phase that gave no hint of
crystallization. This mixture was extracted with 3x150 mL CH2Cl2 and
the solvent was removed from the pooled extracts under vacuum. The
residual oil (which was shown by GC to contain approximately equal
quantities of two isomeric benzaldehydes A and B) was extracted with
three 75 mL portions of boiling hexane, each of which on cooling
deposited a reddish oil that partially crystallized. A fourth hexane
extract gave nothing more. The solvent was decanted from these three
extracts, and the semi-solid residues were ground under 3.0 mL MeOH
giving 1.4 g of pale yellow crystals of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydrobenzo-furan, isomer RBS.
After recrystallization from MeOH, the color was almost white, and the
mp was 79.5-80.5 °C. The combined mother liquors were enriched in
isomer RAS which proved, following preparative GC separation and NMR
analysis, to be the 7-formyl isomer. The 80 g of impure
dihydrobenzofuran isolated from the Claisen rearrangement above was
distilled and a fraction (43.8 g) that boiled from 138-153 °C at 30
mm/Hg was processed as described here to the aldehyde mixture.
Following similar hexane extractions, a yield of 4.0 g of a 95% pure
isomer RBS was finally obtained. The remaining components of this
fraction were not determined, but it is possible that there were some
that contained the six-membered benzopyran ring system.
To a solution of 5.2 g of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL
glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g
anhydrous ammonium acetate. This mixture was heated for 4 h on the
steam bath, and then a small amount of H2O was added to the hot
solution. This instigated the formation of a copious deposition of
brick-red crystals which were, after cooling, removed by filtration,
and recrystallized from 50 mL boiling MeOH. After air drying there
was thus obtained 2.7 g of day-glo yum-yum orange crystals of
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran.
An additional 0.6 g of product was obtained by working the mother
liquors.
A suspension of 2.5 g LAH in 300 mL refluxing anhydrous Et2O was
treated with a solution of 3.1 g
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in
Et2O. The mixture was held at reflux temperature for 18 h. After
cooling, the excess hydride was destroyed by the cautious addition of
400 mL H2O which contained 15 g H2SO4. The aqueous phase was
separated, washed once with Et2O, and then once with CH2Cl2. There
was then added 60 g potassium sodium tartrate, and the pH was brought
to above 10 by the addition of 25% NaOH. This was extracted with
3x250 mL CH2Cl2, the extracts pooled, and the solvent removed under
vacuum. There remained 2.8 g of an amber oil with an ammoniacal
smell. This was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas. There was the immediate formation of an oil,
from which the supernatent Et2O was decanted. The residual oil was
resuspended in a second 200 mL anhydrous Et2O, again decanted, and
finally a third 200 mL Et2O effected the dissolving of the remaining
oil to give a clear solution. All three solutions became gelatinous
over the following few h, and each deposited a crop of white crystals
over the following few days. From the first there was obtained 1.4 g
of product with a mp of 153-154 °C; from the second, 0.2 g with a mp
of 153-154 °C; and from the third, 1.2 g with a mp of 155-156 °C.
These crops were combined, and recrystallized from 10 mL of boiling
CH3CN to give 1.7 g
6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran
hydrochloride (F-22) as a white crystalline solid which had a mp of
154-155 °C. This material, even when dry, showed a tendency to
discolor with time.
DOSAGE: greater than 15 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: And here is yet another dihydrobenzofuran
which is not of a very high potency if, indeed, it is active at all.
This particular dihydrobenzofuran analogue, F-22, had sort of tickled
my fancy as being an especially good candidate for activity. It had a
certain swing to it. F-22, like LSD-25. And here it was finished,
just five days before I had to deliver a paper concerning the
syntheses (and activities!) of all these dihydrobenzofurans to the
marijuana congress. Could this possibly be another LSD? I was
sufficiently convinced that the possibility was real, that I actually
started the screening process at a most unusually low level of 10
micrograms. Two days later, I upped this to a dose of 25 micrograms
(no activity again) and three days after that, at 1 AM on the polar
flight to Copenhagen, I swallowed the "monstrous" dose of 50
micrograms. Shoot the works. If I were to blossom all over the
tourist section of the SAS plane, well, it would be quite a paper to
give. If not, I could always say something like, "The active level
has not yet been found." No activity. Another Walter Mitty fantasy
down the tubes.
And, as it turned out, the entire project pretty much ran out of
steam. A number of clever analogs had been started, and would have
been pursued if there had been any activity promised of any kind with
any of these dihydrobenzofurans. The "other" benzaldehyde described
above, could have been run in a manner parallel to that proposed for
the counterpart with F-2, to make the eventual amphetamine,
7-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran. Great
strides had been made towards F-233 (I have discussed the naming
system under F-2, with the F standing for the furan of benzofuran and
the 2 and 3 and 3 being the positions of the methyl groups on it).
The reaction of 4-methoxyphenol with 1-chloro-3-methyl-2-butene gave
the ether which underwent the thermal Claisen rearrangement to
2-(1,1-dimethylallyl)-4-methoxyphenol with a bp of 148-157 °C at 30
mm/Hg. This was cyclized to the intermediate cycle
2,3,3-trimethyl-2,3-dihydrobenzofuran which, after distillation, was
shown to be only 80% pure by GC analysis. This was, nonetheless, (and
with the hope that is in the very fiber of a young innocent chemist),
pushed on to the benzaldehyde stage (and there were a
not-too-surprising four benzaldehydes to be found in the oil that was
produced, which refused to crystallize). And then (when sheer
desperation replaced hope) these were condensed with nitroethane to
form an even worse mixture. Maybe something might crystallize from
it? Nothing ever did. Junk. Everything was simply put on the shelf
where it still rests today, and F-233,
6-(2-aminopropyl)-5-methoxy-2,3,3-trimethyl-2,3-dihydrobenzofuran,
remains the stuff of speculation.
And a start towards F-23,
6-(2-aminopropyl)-2,3-dimethyl-5-methoxy-2,3-dihydrobenzofuran, got
just as far as the starting ether, when it occurred to me that the
final product would have an unprecedented three chiral centers, and so
a total of four racemic pairs of diastereoisomers. And then I
discovered that the starting allyl halide, crotyl chloride, was only
80% pure, with the remaining 20% being 3-chloro-1-butene. This would
have eventually produced a 2-ethyl-analogue,
6-(2-aminopropyl)-2-ethyl-5-methoxy-2,3-dihydrobenzofuran, with its
two chiral centers and two more pairs of stereoisomers (not to speak
of the need to devise an entirely new coding system). Unless
something were to fall into my lap as a crystalline intermediate, the
final mess could have had at least six discreet compounds in it, not
even considering optical isomers. And I haven't even begun to think
of making the six-membered dihydrobenzopyrans which were the THC
analogues that presented the rationale that started the whole project
in the first place. A recent issue of the Journal of Medicinal
Chemistry has just presented an article describing the reaction of
6-methoxytetrahydrobenzopyran with dichloromethyl methyl ether, and
approximately equal amounts of all three of the possible isomers were
obtained. That would have been the first step towards making the
prototypic compound 7-(2-aminopropyl)
6-methoxy-1,2,3,4-tetrahydrobenzopyran. Just as the benzofurans were
all named as F-compounds, this, as a benzopyran, would have been a P
compound, but P also is used for proscaline, and there would have been
some repair-work needed for these codes.
Time to abandon ship. The fact that I had just synthesized and
discovered the strange activity of ARIADNE at about this time, made
the ship abandonment quite a bit easier to accept.
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