Simple synthesis of γ-carbolines

Full text of DOI:10.1007/s10593-009-0310-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 5, 2009
SIMPLE SYNTHESIS OF γ-CARBOLINES
A. V. Butin1*, A. S. Pilipenko1, A. A. Milich1, and A. V. Finko1
Keywords: indoles, γ-carbolines, Bischler-Napieralski reaction, Leuckart-Wallach reaction.
γ-Carboline derivatives and their hydrogenated analogs are less popular than the structurally isomeric
β-carbolines [1]. None the less, γ-carbolines are of interest pharmacologically since compounds having various
forms of biological activity are found in this class [2-5] and so the development of novel routes of synthesizing
the γ-carboline framework is timely. Thanks to the availability of tryptamine derivatives, electrophilic
cyclizations of the Pictet-Spengler, Bischler-Napieralski and related type processes are widely used for the
synthesis of β-carbolines [1]. Analogous reactions amongst methods for preparing γ-carbolines [2, 6-9] occupy a
modest placement [10, 11] and this is likely related to the lesser availability of the corresponding amines.
In this work we report preliminary data regarding a novel synthesis of γ-carbolines in which the key
stage is a Bischler-Napieralski reaction. As a result of a Leuckart-Wallach type reductive amination the indole 1
[12] gave the amide 2. Refluxing compound 2 in ethyl polyphosphate led to the dihydro-γ-carboline 3 which we
were unable to separate in a pure state. TLC analysis of the reaction mixture after work up showed the basic
product 3 and, unexpectedly, compound 4 was also formed, likely through a disproportionation reaction. Work
up of this mixture with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave the γ-carboline 4 in 38% yield
for the two stages.
Ts
Ts
Ts
Ts
N
N
N
N
Et–PPA
Me
CHO
HCONH2
Me
DDQ
Me
Me
HN
O
N
N
1
2
4
3
1H and 13C NMR spectra were recorded on a Bruker DPX 300 instrument (300 and 75 MHz
respectively) using CDCl3 with TMS as internal standard. IR spectra were taken on a Shimadzu IR Prestige-21
instrument for KBr tablets.
_______
* To whom correspondence should be addressed, e-mail: alexander_butin@mail.ru.
1Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Krasnodar
350072, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 774-776, May, 2009. Original
article submitted April 2, 2009.
0009-3122/09/4505-0613©2009 Springer Science+Business Media, Inc.
613

N-[1-(Tosyl-1H-indol-2-yl)-2-propyl]formamide (2). A mixture of compound 1 (5 g, 15 mmol) in
formamide (100 ml) was refluxed for 40 min (TLC monitoring). The reaction mixture was poured into water (1
litre). The precipitate formed was filtered off and recrystallized from a mixture of dichloromethane and hexane.
Yield 4 g (75%) as a white powder. The compound obtained was used in the subsequent stage without further
purification.
3-Methyl-5-tosyl-5H-pyrido[4,3-b]indole (4). A mixture of compound 2 (2 g, 5.6 mmol) in ethyl
polyphosphate (Et-PPA) (40 ml) was refluxed for 4 h (TLC monitoring). The reaction mixture was poured into
water (300 ml), neutralized with NaHCO3, and extracted with ethyl acetate (3×50 ml). The extract was dried
over Na2SO4, filtered, treated with carbon, and the solvent was removed in vacuo. DDQ (0.2 g) was added and
the product was refluxed for 5-7 min (TLC monitoring). The reaction mixture was then poured into water
(100 ml) and extracted with ethyl acetate (3×30 ml). Solvent was removed in vacuo and the residue was column
chromatographed using benzene–hexane (1:3). Yield 0.72 g (38%) as a light-cream powder; mp 173-174ºC
1
(mixture of benzene and hexane). IR spectrum, ν, cm-1: 1596, 1456, 1366, 1175, 1153, 980, 708. H NMR
spectrum, δ, ppm (J, Hz): 2.27 (3H, s, CH3); 2.74 (3H, s, CH3); 7.14 (2H, d, J = 8.1, H Ts); 7.34-7.39 (1H, m,
H Ar); 7.46-7.52 (1H, m, H Ar); 7.73 (2H, d, J = 8.1, H Ts); 7.92-7.94 (1H, m, H Ar); 8.05 (1H, s, H Py);
8.23-8.26 (1H, m, H Ar); 9.05 (1H, s, Py). 13C NMR spectrum, δ, ppm: 21.5, 25.1, 108.4, 114.7, 120.0, 120.1,
124.0, 124.4, 126.5 (2C); 127.8, 129.9 (2C); 134.7, 137.9, 141.8, 144.3, 145.5, 156.5. Found, %: C 67.98;
H 4.57; N 8.12. C19H16N2O2S. Calculated, %: C 67.84; H 4.79; N 8.33.
This work was carried out with the financial support of the Russian Fund for Basic Research (grant
07-03-00352-a), the Ministry of Education and Science, Russian Federation (project No. 2.1.1/4628 RNPVSh)
and the Bayer HealthCare AG Company (Germany).
REFERENCES
1.
V. I. Dulenko, I. V. Komissarov, A. T. Dolzhenko, and Yu. A. Nikolyukin, β-Carbolines. Chemistry
and Neurobiology [in Russian], Naukova Dumka, Kiev (1992).
2.
3.
P. A. S. Smith and J. H. Boyer, J. Amer. Chem. Soc., 73, 2626 (1951).
M. Abou-Gharbia, U. R. Patel, M. B. Webb, J. A. Moyer, T. H. Andree, and E. A. Muth, J. Med. Chem.,
30, 1818 (1987).
4.
C. A. Harbert, J. J. Plattner, W. M. Welch, A. Weissman, and B. K. Koe, Mol. Pharmacol., 17, 38
(1980).
5.
6.
C.-S. Lee, T. Ohta, K. Shudo, and T. Okamoto, Heterocycles, 16, 1081 (1981).
J. H. Wynne and W. M. Stalick, J. Org. Chem., 68, 4854 (2003).
7.
8.
T. Iwaki, A. Yasuhara, and T. Samamoto, J. Chem. Soc., Perkin Trans. 1, 1505 (1999).
H. Zhang and R. C. Larock, Org. Lett., 3, 3083 (2001).
9.
10.
M. Somei, F.Yamada, and G. Yamamura, Chem. Pharm. Bull., 46, 191 (1988).
N. N. Novikova, I. D. Silenko, N. F. Kucherova, and V. A. Zagorevskii, Khim. Geterotsikl. Soedin.,
1630 (1976). [Chem. Heterocycl. Comp., 12, 1340 (1976)].
11.
12.
H. Akimoto, A. Kawai, H. Nomura, M. Nagao, T. Kawachi, and T. Sugimura, Chem. Lett., 1061 (1977).
A. V. Butin, Tetrahedron Lett., 47, 4113 (2006).
614