Preparation of indoles from α-aminonitriles: A short synthesis of FGIN-1-27

Article abstract of DOI:10.1021/ol061617+

α-Aminonitriles derived from 2-aminocinnamic acid esters and amides can be cyclized under basic conditions to furnish substituted indole-3-acetic acid derivatives in quantitative yield. The reaction provides a simple access to a class of biologically acti

Full text of DOI:10.1021/ol061617+

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4473-4475
Preparation of Indoles from
-Aminonitriles: A Short Synthesis of
FGIN-1-27
r
Till Opatz* and Dorota Ferenc
Institut fu¨r Organische Chemie, UniVersita¨t Mainz, Duesbergweg 10-14,
D-55128 Mainz, Germany
opatz@uni-mainz.de
Received June 30, 2006
ABSTRACT
r
-Aminonitriles derived from 2-aminocinnamic acid esters and amides can be cyclized under basic conditions to furnish substituted indole-
3-acetic acid derivatives in quantitative yield. The reaction provides a simple access to a class of biologically active compounds.
The indole ring system is one of the most prevalent structural
motifs found in biologically active compounds of both natural
and synthetic origin. For example, the neurotransmitter
serotonin (5-HT), the semisynthetic hallucinogen lysergic
acid diethylamide (LSD), and the alkaloid strychnine, as well
as the pharmaceuticals ondansetron (zofran),1 sumatriptan
(imigran),2 or tadalafil (cialis),3 are indole derivatives. The
first synthesis of substituted indoles was conducted by
Fischer and Jourdan as early as 1883, and since then the
bicyclic heteroaromatic core has been the target of many
synthetic approaches.4-7 In the past three decades, advances
in the field of transition-metal-catalyzed reactions have led
to the development of a variety of indole syntheses in which
either the formation of the N-C2,8,9 the C3-C3a,10,11 or the
C2-C3 bond12 is the key step.13 Among the methods relying
on the transition-metal-free formation of the C2-C3 bond,
the Madelung synthesis, which makes use of C2 as an elec-
tron acceptor, has an important position.14,15 Other processes
that use the same disconnection involve the cyclization of
deprotonated 2-alkylphenyl isonitriles16 or the generation of
radicals at C2.17,18 Herein, we report on a novel and short
synthesis of indoles via the cyclization of R-aminocarbanions
derived from 2-aminocinnamic acid derivatives.19
(8) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A.
Tetrahedron Lett. 1985, 26, 5963-5966.
(9) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 647-
649.
(10) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 1037-
1040.
(11) Chen, C.-y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1997, 62, 2676-2677.
(12) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 5662-5663.
(13) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920.
(14) Madelung, W. Ber. Dtsch. Chem. Ges. 1912, 45, 1128-1134.
(15) Houlihan, W. J.; Parrino, V. A.; Uike, Y. J. Org. Chem. 1981, 46,
4511-4515.
(1) Costall, B.; Gunning, S. J.; Naylor, R. J.; Tyers, M. B. Br. J.
Pharmacol. 1987, 91, 263-264.
(2) Doenicke, A.; Brand, J.; Perrin, V. L. Lancet 1988, 1, 1309-1311.
(3) Daugan, A. C.-M.; Patent Application WO95/19978, 1995.
(4) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241-
2245.
(5) Fischer, E.; Hess, O. Ber. Dtsch. Chem. Ges. 1884, 17, 559-568.
(6) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
(7) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875-2911.
(16) Ito, Y.; Kobayashi, K.; Saegusa, T. J. Am. Chem. Soc. 1977, 99,
3532-3534.
(17) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis
2000, 429-434.
10.1021/ol061617+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/01/2006

The umpolung of imines by addition of HCN allows the
facile generation of stabilized R-aminocarbanions, which can
be used, for example, for the preparation of highly substituted
pyrrolidines,20 pyrroles,21 or vicinal diamines.22 The Strecker
reaction of esters or amides of 2-aminocinnamic acid deriv-
atives 1 with an aromatic or heteroaromatic aldehyde or with
cinnamaldehyde furnishes R-aminonitriles 2. These com-
pounds can undergo a clean cyclization to furnish 2-substi-
tuted indole-3-acetic acid derivatives 5 upon treatment with
a suitable base. The course of the reaction involves the
R-deprotonation of the aminonitrile, 5-exo-trig-cyclization
by means of an intramolecular Michael addition, elimination
of HCN and tautomerization to the 1H-indole (Scheme 1).
Scheme 2
Scheme 1
Presumably as a result of lack of stabilization of the
carbanions resulting from deprotonation, no conditions could
be found that allowed the cyclization of Strecker products
derived from aliphatic aldehydes. Experiments on the cy-
clization of imines from 2-aminocinnamic acid esters and
aromatic aldehydes with catalytic amounts of cyanide, phos-
phanes, or N-heterocyclic carbenes were also unsuccessful.
Esters and amides of 2-aminocinnamic acid can be easily
obtained from commercially available 2-nitrocinnamic acid
or via Heck reaction from 2-iodoaniline.23-25 The latter
procedure also permits the facile introduction of substituents
to positions 4-7 of the indole skeleton. As an example, the
5-fluoro-substituted products 5h-j could be readily prepared
from 4-fluoroaniline (Scheme 3).26
The retro-Strecker reaction in the last step requires an
N-deprotonation by an external base, and the reaction will
stop at the stage of the cyclic aminonitrile 4 if conducted
under nonequilibrating conditions (e.g., KHMDS, THF, -78
°C). Compounds 4 are, however, unstable and can be con-
verted to indoles 5 by warming in alcoholic solvents in
quantitative yield. Whereas DBU in ethanol suffices to effect
both cyclization and elimination of HCN at 60 °C, an
alcoholic solution of potassium tert-butyl alcoholate allows
the same transformation to be performed at room temperature
(Scheme 2).
Although the Strecker reaction is normally carried out
under acidic conditions, the reaction temperature of 60 °C,
chosen to ensure complete conversion of 1 to 2, already leads
to the formation of small amounts of indoles 5. Therefore,
the cyclization of the crude aminonitriles 2 not only sim-
plifies the overall procedure but in some cases even leads to
improved yields.
Scheme 3
(18) Bowman, W. R.; Fletcher, A. J.; Lovell, P. J.; Pedersen, J. M. Synlett
2004, 1905-1908.
(19) Nakao, K.; Murata, Y.; Koike, H.; Uchida, C.; Kawamura, K.;
Mihara, S.; Hayashi, S.; Stevens, R. W. Tetrahedron Lett. 2003, 44, 7269-
7271.
(20) Meyer, N.; Werner, F.; Opatz, T. Synthesis 2005, 945-956.
(21) Meyer, N.; Opatz, T. Eur. J. Org. Chem. 2006, 3997-4002.
4474
Org. Lett., Vol. 8, No. 20, 2006

The results of the preparation of various 2-substituted
indole-3-acetic acid derivatives are summarized in Table 1.
Table 1. Preparation of Substituted Indoles from
2-Aminocinnamates
indole
R1
R2
OEt
OEt
OEt
OEt
OEt
On-Bu
On-Bu
On-Bu
N(CH2)5
N(CH2)5
N(CH2)5
N(n-Hex)2
R3
2-naph-
3,4-(MeO)2-C6H3-
4-Ph-C6H4-
3-MeO-C6H4-
4-Pyr-
4-Cl-C6H4-
3-Pyr-
3,4-(MeO)2-C6H3-
(E)-styryl-
2-thienyl-
yield (%)
Figure 1. Biologically active 2-arylindole derivatives.
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
H
H
H
H
H
F
F
F
H
H
H
H
73
56
55
65
37
64
69
59
53
51
95
73
an affinity to the gonadotropin releasing hormone (GnRH)
receptor have also been reported (see Figure 1).30
In summary, the described synthetic protocol permits the
facile preparation of a variety of 2-aryl, 2-hetaryl-, and
2-styryl-substituted indole-3-acetic acid derivatives without
the use of expensive or sensitive reagents or catalysts.31 The
products as well as the corresponding tryptamines accessible
via reduction of the amide group belong to a class of
biologically active compounds.
5m
5n
3-Pyr-
4-F-C6H4-
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft. We thank H. Kolshorn
from the institute of organic chemistry for the 2D-NMR
spectroscopic measurements.
A number of 2-aryl- and 2-hetaryl-substituted indole-3-
acetamides exhibit remarkable affinities to various G-protein
coupled receptors or enzymes. For example, FGIN-1-27
(compound 5n) is a ligand of the mDRC receptor complex
(Ki ) 4.4 nM),27 and 7 is an inhibitor of farnesyl transferase
(IC50 ) 31 nM).28 Tryptamine 8, which can be obtained by
reduction of amide 5a with lithium aluminum hydride in 99%
yield, is a known antagonist of the human 5-HT2A receptor
(Ki ) 2.7 nM),29 and 2-aryltryptamines such as 9 that have
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data as well as 1H and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061617+
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2001, 11, 1077-1080.
(22) Kison, C.; Meyer, N.; Opatz, T. Angew. Chem., Int. Ed. 2005, 44,
5662-5664.
(31) Typical Procedure. Preparation of 5i. To a solution of butyl (E)-
2-amino-5-fluorocinnamate 2c (300 mg, 1.26 mmol) and pyridine-3-
carbaldehyde (162.5 mg, 1.52 mmol) in dry n-butanol (5 mL) was added
acetic acid (87 µL, 1.52 mmol), and the solution was stirred for 1 h at 60
°C under argon. Potassium cyanide (181 mg, 2.78 mmol) and acetic acid
(145 µL, 2.53 mmol) were added to the mixture, and stirring at 60 °C was
continued for 16 h. The reaction mixture was partitioned between saturated
aqueous NaHCO3 solution and dichloromethane, the organic phase was dried
over Na2SO4, and the solvent was removed in vacuo to yield a yellow oil
(588 mg). A portion of the crude Strecker product (558 mg) was dissolved
in dry n-butanol (3 mL), and after addition of potassium tert-butyl alcoholate
(142 mg, 1.26 mmol), the solution was stirred for 30 min at room
temperature under argon. The reaction mixture was partitioned between
saturated aqueous NaHCO3 solution and dichloromethane, the organic phase
was dried over Na2SO4, and the solvent was removed in vacuo to yield a
yellow oil (492 mg). A portion of the crude indole (461 mg) was purified
by flash chromatography (SiO2, eluent cyclohexane/ethyl acetate 1:1) to
afford butyl [5-fluoro-2-(3-pyridyl)-1H-indol-3yl]-acetate 5i (252 mg,
68.7%) as yellowish crystals, mp 105-107 °C.
(23) Horaguchi, T.; Hosokawa, N.; Tanemura, K.; Suzuki, T. J. Het-
erocycl. Chem. 2002, 39, 61-67.
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