The kulinkovich reaction in the synthesis of constrained N,N-dialkyl neurotransmitter analogues

Article abstract of DOI:10.1021/ol0705907

An intermolecular Ti(IV)-mediated cyclopropanation reaction has been used to synthesize substituted 2-phenylcyclopropylamines and constrained analogues of the neurotransmitters histamine and tryptamine. Many hydroxy- and methoxy-substituted phenylcyclopropylamines are known to inhibit monoamine oxidase and have been shown to mimic hallucinogens. These compounds were made in 1 to 5 steps from readily available starting materials.

Full text of DOI:10.1021/ol0705907

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1987-1990
The Kulinkovich Reaction in the
Synthesis of Constrained N,N-Dialkyl
Neurotransmitter Analogues
Catherine A. Faler and Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
mjoullie@sas.upenn.edu
Received March 9, 2007
ABSTRACT
An intermolecular Ti(IV)-mediated cyclopropanation reaction has been used to synthesize substituted 2-phenylcyclopropylamines and constrained
analogues of the neurotransmitters histamine and tryptamine. Many hydroxy- and methoxy-substituted phenylcyclopropylamines are known
to inhibit monoamine oxidase and have been shown to mimic hallucinogens. These compounds were made in 1 to 5 steps from readily
available starting materials.
The conformational constraint of biologically significant
molecules has long been used as a technique to understand
and improve the activity of these compounds. Use of a
cyclopropane to rigidify a molecule is ideal because it
introduces minimal steric bulk and negligible influence on
electronics. There are examples of cyclopropyl analogues
of neurotransmitters that have shown interesting biological
properties beyond those held by their linear counterparts.
Burger and Yost1 first reported the synthesis and mono-
amine oxidase (MAO) inhibitory activity of trans-2-phenyl-
cyclopropylamine, a compound that is used to treat depres-
sion. Silverman elucidated the mechanism of inactivation
shown in Scheme 1, which illustrates that the cyclopropane
is necessary for inactivation.2 Similar cyclopropylamines
have also shown stimulatory activity in neurotransmitter
receptors.3
Typically, the synthetic approaches to these structures
involve the cyclopropanation of cinnamate derivatives by a
Simmons-Smith reaction,4 dimethylsulfoxonium methylide,5
or diazomethane.6 A Curtius rearrangement then produces
the amine.7 Scheme 2 outlines this basic route.
In addition, N,N-dialkylated aminocyclopropylamines have
shown activity in 5-hydroxytryptamine (5-HT) and dopamine
(DA) receptors. Particularly potent 5-HT-receptor agonists
were 2- and 3-hydroxyphenyl-N,N-dipropylcyclopropyl-
amines.8
(1) Burger, A.; Yost, W. L. J. Am. Chem. Soc. 1948, 70, 2198-2201.
(2) (a) Silverman, R. Acc. Chem. Res. 1995, 28, 335-342. (b) Silverman,
R. B. J. Biol. Chem. 1983, 258, 14766-14769.
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1974, 17, 1100-1111. (b) Nichols, D. E.; Woodard, R.; Hathaway, B. A.;
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(4) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M.
Org. React. 1973, 20, 1-131.
Scheme 1. Inactivation of Monoamine Oxidase
(5) Kaiser, C.; Trost, B. M.; Beeson, J.; Weinstock, J. J. Org. Chem.
1965, 30, 3972-3975.
(6) Arvidsson, L. E.; Johansson, A. M.; Hacksell, U.; Nilsson, J. L. G.;
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10.1021/ol0705907 CCC: $37.00
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made from urocanic acid, using an approach similar to the
synthetic route employed to make phenylcyclopropylamines
(Figure 1b). An analogous route was subsequently used by
de Esch,13 and diastereoselective syntheses have also been
reported by Shuto14 and Phillips.15 The 2-(4-imidazolyl)-
cyclopropylamine was reported to be a potent MAO inhibitor
in vitro.
Scheme 2. General Synthesis of Cyclopropylamines from
Cinnamic Acids
The interesting biological properties of these compounds
prompted us to report an alternate synthesis requiring fewer
steps than those described above. The amino variant of the
Kulinkovich reaction16 was applied to various styrenes to
obtain methyl- and propylcyclopropylamines. To access the
hydroxy-substituted phenylcyclopropylamines, commercially
available hydroxybenzaldehydes were protected before they
were converted to the corresponding styrene by a Wittig
reaction. The coupling of these olefins with dimethylform-
amide or dipropylformamide provided the cyclopropylamines
in good yields (Scheme 3).
Naturally occurring heterocyclic ethylamines, such as
tryptamine and histamine, are essential for normal biological
functions. Many tryptamine derivatives have been isolated
from nature and have shown interesting biological activity.
5-HT is a common neurotransmitter and several similar
compounds have found pharmacological use as serotonin
reuptake inhibitors, while others are known for their psycho-
active properties.
Scheme 3. Synthesis of Phenyl-Substituted
The syntheses of trans-2-(3-indoyl)cyclopropylamines
were reported by Nichols (Figure 1a).9 Some of these
Cyclopropylamines
Figure 1. 2-(4-Imidazolylcyclopropylamine) and 2-(3-indoyl)-
cyclopropylamine.
A variety of styrenes, easily obtainable from affordable
aldehydes, were cyclized to the products shown in Table
1.7,17,18
The primary amines of entries 1-7 are known, and many
analogues were found to be antagonists of the 5-HT2C
receptor. Much like the phenylamine analogues, the indolyl-
cyclopropane was made by reaction with diazomethane and
a subsequent Curtius rearrangement to afford the amine. A
slightly different approach was undertaken by Eftink to obtain
both cis- and trans-cyclopropanes.10
Various homeostatic processes are controlled by the
neurotransmitter histamine. The H3 receptor regulates the
synthesis and release of histamine, and exerts some influence
on other neurotransmitters.11 Conformationally restricted
analogues have been designed to bind to the H3 receptor
selectively. These compounds can have potential therapeutic
effects in a number of neurological disorders. The first
synthesis of 2-(4-imidazolylcyclopropylamine) was achieved
by Burger et al.12 An imidazole-substituted cyclopropane was
display significant MAO inhibitory activity19 or, in the case
(12) Burger, A.; Bernabe´, M.; Collins, P. J. Med. Chem. 1970, 13, 33-
35.
(13) De Esch, I. J. P.; Gaffar, A.; Menge, W. M. P. B.; Timmerman, H.
Bioorg. Med. Chem. 1999, 7, 3003-3009.
(14) (a) Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.; Kimura, R.;
Matsumoto, S.-i.; Furuichi, K.; Matsuda, A.; Shuto, S. J. Med. Chem. 2003,
46, 1980-1988. (b) Kazuta, Y.; Matsuda, A.; Shuto, S. J. Org. Chem. 2002,
67, 1669-1677.
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J. G. Bioorg. Med. Chem. Lett. 1997, 7, 3017-3022.
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1991, 234-234. (b) Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584-
1585. (c) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett
1997, 111-114.
(17) To avoid polymerization, the styrenes were used immediately after
their preparation.
(18) Wiedemann, S.; Rauch, K.; Savchenko, A.; Marek, I.; de Meijere,
A. Eur. J. Org. Chem. 2004, 631-635.
(19) (a) Sherry, R. L.; Coutts, R. T.; Baker, G. B. Drug DeV. Res. 1999,
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1990, 28, 539-543. (c) Coutts, R. T.; Rao, T. S.; Baker, G. B.; Micetich,
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R. W.; Kaiser, C. Biochem. Pharmacol. 1980, 29, 3328-3330. (e) Rao, T.
S.; Coutts, R. T.; Baker, G. B.; Hall, T. W.; Micetich, R. G. Proc. West.
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G. B.; Mousseau, D. D.; Coutts, R. T.; Dewhurst, W. G. Biol. Psychol.
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(8) Vallgaarda, J.; Appelberg, U.; Arvidsson, L.-E.; Hjorth, S.; Svensson,
B. E.; Hacksell, U. J. Med. Chem. 1996, 39, 1485-1493.
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Nichols, D. E. J. Med. Chem. 1998, 41, 4995-5001. (b) Vangveravong,
S.; Nichols, D. E. J. Org. Chem. 1995, 60, 3409-3413.
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1988
Org. Lett., Vol. 9, No. 10, 2007

nonselective and reversible MAO inhibitor.23 Entry 12 bears
resemblance to the psychoactive drug methylenedioxymetham-
phetamine (MDMA, Ecstasy). Although this compound has
been reported in a patent, which describes its synthesis in 8
steps,24 exact biological data and full characterization are
lacking. It is very likely that such a compound could have
stimulatory activity of neurotransmitter receptors similar to
MDMA.
Table 1. Substituted 2-Phenyldimethylcyclopropylamines
Deprotection of the 3,4-disiloxyphenylcyclopropylamine
(entry 11) did not result in the desired dihydroxyphenyl-
cyclopropylamine. While cyclopropane appeared to be
present in the crude product mixture, caffeic aldehyde was
isolated in 90% yield upon purification (Scheme 4). We
Scheme 4. Fragmentation of
Dihydroxyphenylcyclopropylamine
believe this transformation occurred through an oxidative
mechanism, which has been well-investigated by Cha25 and
Iwata.26 Facile fragmentation was likely due to the electron-
rich phenyl and the presence of ambient oxygen and water
during purification.
Our synthesis of tryptamine analogues is shown in Scheme
5. Although we have used the Kulinkovich reaction in the
a Isolated yields. b Yield over 2 steps: cyclopropanation and deprotection.
of (trimethoxyphenyl)cyclopropylamine (entry 7), psychoto-
mimetic properties.20 Because Arvidsson et al.7 showed that
phenolic N,N-dipropylcyclopropylamines were more potent
than primary cyclopropylamines, we believe the dimethyl-
amines in Table 1 will also exhibit activity. Entries 8-10
represent novel cyclopropylamines expected to possess
interesting biological properties because of the high activity
of the corresponding phenethylamines. For example, 3-hy-
droxy-4-methoxyphenethylamine is a plant alkaloid that can
be found, along with mescaline, in certain plants growing
in the southwestern United States.21 It has been hypothesized
that methylated catacholamines could play a role in Parkin-
son’s disease.22 Also, 4-dimethylaminophenethylamine is a
Scheme 5. Indolylcyclopropylamine
presence of unprotected indoles,27 indole carboxaldehyde
required protection before undergoing a Wittig reaction. The
resulting vinyl indole was cyclized with a formamide to give
15.
(20) (a) Cooper, P. D.; Walters, G. C. Nature 1972, 238, 96-98. (b)
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U. Lloydia 1971, 34, 183-187.
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Wende, C. Life Sci. 1967, 6, 2029-2035.
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G.; Tipton, K. F.; Cassels, B. K. Biochem. Pharmacol. 1994, 47, 1365-
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1956, 21, 1470-1472.
Org. Lett., Vol. 9, No. 10, 2007
1989

To use the Kulinkovich reaction in the synthesis of
imidazolyl cyclopropylamines, a slightly different approach
was used. As seen in Scheme 6, urocanic acid was decar-
Scheme 7. Synthesis of Primary and Secondary
Aminocyclopropanes
Scheme 6. Imidazolylcyclopropylamine
In conclusion, we have demonstrated a facile synthesis of
biologically important cyclopropylamines. The application
of the Kulinkovich reaction gives cyclopropane-constrained
N,N-dimethyl analogues of histamine, tryptamine, and sub-
stitued phenethylamines in fewer steps than previously
reported. Biological evaluation of the novel compounds is
underway.
boxylated to vinyl imidazole by distillation under reduced
pressure. Trityl protection of the imidazole preceded inter-
molecular cyclization with dimethylformamide.28 Deprotec-
tion of compound 18 gave cyclopropylamine 19.
N,N-Dimethylcyclopropylamines were synthesized largely
due to the simplicity of obtaining dimethylformamide. It may,
however, be desirable to synthesize primary and secondary
amines, as many of these compounds are known to be
biologically active. By coupling the olefins with benzyl-
formamides, benzylated cyclopropylamines are obtained.
These compounds can be deprotected easily by hydrogena-
tion (Scheme 7), as previously established by de Meijere.29
Acknowledgment. We thank the NSF (CHEM-1030958),
Wyeth, and the University of Pennsylvania for financial
support. Additionally, a fellowship provided by the NSF
(DGE-0231923 005) aided this work. We are also grateful
to Dr. George Furst and Dr. Rakesh Kohli (University of
Pennsylvania) for technical assistance.
Supporting Information Available: Experimental pro-
1
cedures and characterization data of all compounds and H
and 13C NMR spectra of the final products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Burger, A. 2-(3,4-methylenedioxyphenyl)cyclopropylamines. U.S.
Patent 2,934,542, April 26, 1960.
(25) Lee, J.; Sun U, J.; Blackstock, S. C.; Cha, J. K. J. Am. Chem. Soc.
1997, 119, 10241-10242.
OL0705907
(26) Takemoto, Y.; Yamagata, S.; Furuse, S.-i.; Iwata, C. Chem.
Commun. 1998, 651-652.
(27) Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1799-1801.
(28) Cyclization of unprotected vinyl imidazole results in reduction of
the olefin.
(29) de Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov, S. V.;
Chaplinski, V.; Kordes, M.; Savchenko, A. I.; Stratmann, C.; Noltemeyer,
M. Chem. Eur. J. 2002, 8, 3789-3801.
1990
Org. Lett., Vol. 9, No. 10, 2007