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J. Med. Chem. 14(4), 370-372 (1971)

Potential Psychotomimetics.
Bromomethoxyamphetamines

Charles F. Barfknecht AND David E. Nichols

In the study of psychotomimetic amphetamines, 2,5-dimethoxy-4-methylamphetamine (DOM) is the
most potent compound yet discovered (50-150 times mecaline).² At least part of its
potency is related to the nature of the para substituent. In the light of Knoll's³
studies on the psychotomimetic effects of p-bromo-methampethamine and its
cross-tolerance to LSD, the synthesis and evaluation of bromomethoxyamphetamines appeared to
be a logical extension. Br has a comparable size, but different electronic character than
Me. Kand and Green⁴ have recently demonstrated a correlation between the electronic
character of the ring and the hallucinogenic potency of the methoxylated amphetamines. The
substitution of Br into various ring positions of methoxylated amphetamines allows for several
electronic arrangements.

Chemistry.-- The general synthetic route involved preparation of the appropriately
substituted benzaldehydes, condensation with EtNO₂ and reduction to the
bromomethoxymethamphetamines. Tables I and II summarize the compounds which have been prepared.
 Attention is called to the report by Pandya and co-workers⁵ concerning the bromination
of m-hydroxybenzaldehyde. The product of this reaction is claimed to be
3-hydroxy-4-bromobenzaldehyde; however the product which we isolated proved to be
2-bromo-5-hydroxybenzaldehyde. This assignment was verified by nmr spectroscopy and chemical
conversion by O-methylation and permanganate oxidation to 2-bromo-5-methoxybenzoic acid. The
physical properties of this material agree with the literature values.⁶
 The LAH reduction of 1-(bromomethoxyphenyl)-2-nitropropenes was complicated by the extreme ease
of debromination. Low temperatures and equimolar amounts of reagents prevented the debromination,
but resulted in poor yields of the bromomethoxyamphetamines.
Biological Results.-- The compounds were tested for an effect on a conditioned avoidance
response in male rats. The detailed procedure has been reported previously.⁷ The effects
were compared with those produced by mescaline, 3,4-dimethoxymethamphetamine, DOM, and the
CNS-stimulant dextroamphetamine. This assay gives an indication wether the compound possesses
stimulant action or one more like that of mescaline, 3,4-DMA, and DOM. Table III summarizes
the biological data. All the compounds which exhibited an effect similar to mescaline-type
compounds have the p-Br substituent.⁸ The data on the 2-bromo-5-methoxy
analog(3) must be considered tentative, since 2,5-dimethoxyamphetamine which does not
have a para substituent is active in humans but inactive in rats.⁹ A correlation
has been demonstrated between the degree of fluorescence and the psychotomimetic potency for
methoxylated amphetamines; no such relationship seems to exist for this series.¹⁰
For example, 2 and 6 have nearly the same degree of fluorescence, but differ
widely in their biological effects. A detailed study of the pharmacology is in progress.

Experimental Section¹¹

Bromomethoxybenzaldehydes.--All substituted benzaldehydes have been reported previously
with the exception of 2,5-dimethoxy-4-bromobenzaldehyde and 3,5-dimethoxy-4-bromobenzaldehyde,
whose syntheses are described below.

3,5-Dimethoxy-4-bromobenzaldehyde.--3,5-Dihydroxy-4-bromobenzoic acid (K & K Laboratories,
 Inc.) was di-O-methylated with Me₂SO₄ in the usual manner: yield 78%
(EtOH-H₂O); mp 249-250° (lit.¹² 249-50°). The acid chloride was obtained
by reaction with SOCl₂. The crude product (mp 124-128°) was used in the next step
without further purification. The aldehyde was obtained by reduction of the acid chloride by
LiAlH(O-tert-Bu)₃ as described by Ho, et al.¹³ The crude
aldehyde was recrystd from MeOH-H₂O; yield 52%; mp 112-114°.

2,5-Dimethoxy-4-bromobenzaldehyde.--2,5-Dimethoxybenzaldehyde (66.5 g, 0.4 mole) was
dissolved in 300 ml of CH₂Cl₂. Anhyd SnCl₄ (115 g, 0.44 mole)
was added, followed by 64 g of Br₂ over a 1-hr period. The resulting soln was
refluxed for 2 hr and stirred overnight at room temp. The orange suspension was poured over
500 g of ice, and the layers were sepd. The CH₂Cl₂ layer was washed with
10% NaHCO₃ and H₂O and dried (Na₂SO₄). After
filtration the solvent was removed in vacuo, and the solid residue recrystd from
MeOH-H₂O to yield 64 g (66%) of the aldehyde, mp 132-3°. The structure was
confirmed by the oxidation with MnO₄- to 2,5-dimethoxy-4-brombenzoic acid, mp 170°
(lit.¹⁴ mp 170°).

Substitued-1-phenyl-2-nitropropenes.-- The substitued benzaldehydes were refluxed with
EtNO₂ and NH₄OAc in AcOH as described by Gairaud and Lappin.¹⁵

Bromomethoxyamphetamine Hydrochlorides.-- All amphetamines were prepared from the
corresponding 1-phenyl-2-nitropropenes by LAH reduction.¹⁶

Table I
Substitued 1-Phenyl-2-nitropropenes

R2	R3	R4	R5	R6	Mp, °C	Yield, %
Br	H	H	OCH3	H	73-74.5	61.8
H	Br	OCH3	H	H	73-74	45
H	OCH3	Br	H	H	73-74.5	36.8
Br	H	OCH3	OCH3	H	105-106	59.4
H	OCH3	Br	OCH3	H	121-121.5	46.8
OCH3	H	Br	OCH3	H	113.5-115	57

Table II
Bromomethoxyamphetamine hydrochlorides

Compd	R2	R2	R2	R2	R2	Mp, °C	Yield, %
1	Br	H	H	OCH3	H	151.5-153	20
2	H	Br	OCH3	H	H	210-213	28.8
3	H	OCH3	Br	H	H	161.5-163	32
4	Br	H	OCH3	OCH3	H	214-215.5	42
5	H	OCH3	Br	OCH3	H	221-222	36.8
6	OCH3	H	Br	OCH3	H	198-199	29.5

Table III
Biological Results

Compd	Tresholdalpha dose, mg/kg	Action
1	25	Inactive
2	9	CNS stimulation;onset of amphetamine-type toxicity at 18 mg/kg
3	7.5	Mescaline-like
4	25	Inactive
5	<10	Mescaline-like with some deaths at 10; inactive at 5 mg/kg
6	<2.5	Mescaline-like; effect much more profound than that caused by 2.5 mg/kg of DOM

alpha Dose at which action was observed; any compd which does not show mescaline-like
effect at 25 mg/kg (the "effective" dose of mescaline) is considered inactive. The treshold dose
of 3,4-dimethoxyamphetamine.Hcl and DOM.Hcl are 12.5 and 2.5, resp.

References:
(1)
(2) A.T. Shulgin, T. Sargent, and C. Naranjo, Nature(London), 221, 537 (1969).
(3) J. Knoll in "amphetamiens and Related Compounds," E. Costa and S. Garttini, Ed., Raven Press,
New York, N. Y., 1970, p 761.
(4) S. Kang and J.P. Green, Nature(London), 226, 645 (1970).
(5) K. C. Pandya, R. B. K. Pandya, and R. N. Singh. J. Indian Chem. Soc., 29, 363 (1952).
(6) P. H. Beyer, Red. Trav. Chim. Pays-Bas, 40, 621 (1921).
(7) C. F. Barfknecht, J. M. Miles, and J. L. Leseney, J. Pharm. Sci., 59, 1842(1970).
(8) During the revision of this manuscript, Dr. A. T. Shulgin informes us that
4-bromo-2,5-dimethoxyamphetamine has a potency in humans greater than DOM and an effect similar to
3,4-methylenedioxyamphetamine; Pharmacology, in press.
(9) J. R. Smythies, Neurosci. Res. Program Bull., S, 79(1970).
(10) F. Antun, J. R. Smythies, F. Benington, R. D. Morin, C. F. Barfknecht, and D. E. Nichols,
Experentia, in press.
(11) Melting points were taken on a Hoover Uni-Melt apparatus and are corrected. Where analyses are
indicated only by symbols of the elements, anal. results obtained for those elements were within +/- 0.4%
of the theoretical values. Nmr spectra for all compounds were obtained on a Varian Associates T-60 and
are consistent with the assigned structures.
(12) H. Erdtman and B. Leopold, Acta Chem. Scand., 2, 34(1948).
(13) B. T. Ho, W. M. McIssac, R. An, L. W. Tansey, K. E. Walker, L. F. Englert, Jr., and M. B. Noel,
J. Med. Chem., 13, 26(1970).
(14) A. Luttringhaus and H. Gralheer, Justus Liebigs Ann. Chem., 550, 67(1941).
(15) C. B. Gairaud and G. R. Lappin, J. Org. Chem., 18, 1(1953).
(16) L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis," Wiley, New York, N. Y., 1967, p 581.

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Edit: Some "minor" typos corrected, thanks Chimimanie!