Synthesis of α-carbolines from β-(3-indolyl) ketone 0-2,4-dinitrophenyloximes

Article abstract of DOI:10.1246/cl.2001.146

α-Carbolines are synthesized from β-(3-indolyl) ketone O-2,4-dinitrophenyloximes by the treatment with sodium hydride and sodium cyanoborohydride.

Full text of DOI:10.1246/cl.2001.146

146
Chemistry Letters 2001
Synthesis of α-Carbolines from β-(3-Indolyl) Ketone O-2,4-Dinitrophenyloximes
Ayako Ono and Koichi Narasaka*
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received November 8, 2000; CL-001018)
α-Carbolines are synthesized from β-(3-indolyl) ketone O-
2,4-dinitrophenyloximes by the treatment with sodium hydride
and sodium cyanoborohydride.
2. Then the nitrogen–oxygen bond of the aryloxyimino group
cleaves with elimination of 2,4-dinitrophenolate and the
cyclization occurs simultaneously to give 3,4-dihydro-8-quino-
linol 3.
Based on these findings, it was expected that β-(3-indolyl)
ketone O-2,4-dinitrophenyloximes 6 might cyclize to α-dihy-
drocarbolines via similar anion radical intermediates. The
cyclization of 4-(3-indolyl)butan-2-one 2,4-dinitrophenyloxime
(6a)4 did not proceed unexpectedly by the treatment with sodi-
um hydride, whereas α-carboline 7a was obtained in 40% yield
when the reaction was carried out under the coexistence of 3,4-
methylenedioxyphenol (sesamol)6 (Table 1, entries 1 and 2)
without tetrahydro-α-carboline. To prepare tetrahydro-α-car-
boline, the reaction was carried out under the combined use of
NaH and NaBH3CN. The reaction proceeded more smoothly,
however, tetrahydro-α-carboline could not be obtained but 7a
was isolated in 60% yield (Table 1, entry 3)7 with small amount
of side products.8 No cyclization occurred by the use of
NaBH3CN in the absence of NaH and 6a was almost recovered.
Although the mechanism is not explained clearly, the reac-
tion may be initiated by the one electron reduction of the 2,4-
dinitrophenyl moiety of 6a with NaH–NaBH3CN, as the syner-
gistic effect of NaH and alcoholate was reported in a similar
reduction of benzophenone.9 The cyclization proceeds with
elimination of dinitrophenolate to give α-dihydrocarboline,
which is readily oxidized to α-carboline 7a during the isolation.
α-Carbolines have been received much attention due to
their pharmacological activities, such as cytostatic and anti-
tumor activity.1 Much effort has been devoted to develop the
preparative methods.2 One of the representative strategies for
the construction of α-carboline skeleton is the bond formation
between C(4a)–C(4b) by the Graebe–Ullmann reaction2 or the
Fischer reaction.2 These methods, however, exhibit low regio-
selectivity for constructing substituted indole moieties.
Another representative method is pyridine ring formation start-
ing from unstable 2-aminoindoles.2 Some other approaches
have been developed to overcome the drawbacks of these tradi-
tional methods; intramolecular Diels–Alder reaction of pyrazi-
none3a and 2-aminopyrimidine derivatives,3b intramolecular
cross-coupling of 2-boryl(2-bromopyridyl)aniline,3c and 6π
electron cyclization of indolyl 2-isocyanate intermediates.3d In
this article, we would like to report a convenient method for the
synthesis of α-carbolines by the cyclization of readily available
β-(3-indolyl) ketone O-2,4-dinitrophenyloximes.4
Recently we have reported a preparative method of 8-
qunolinols from 2-(m-hydroxyphenyl)ethyl ketone O-2,4-
dinitrophenyloximes by electron transfer process.5 For exam-
ple, the treatment of 4-(m-hydroxyphenyl)butan-2-one O-2,4-
dinitrophenyloxime (1) with sodium hydride and then with 2,3-
dichloro-4,5-dicyano-p-benzoquinone (DDQ) yields 2-methyl-
8-quinolinol (4). The tetrahydro derivative 5 is also prepared by
the reaction with sodium hydride and sodium cyanoborohydride
as shown in Scheme 1. In these reactions, single electron transfer
occurs from phenolate moiety and/or NaH–NaBH3CN to 2,4-
dinitrophenyl group, giving anion radical intermediates such as
The transformation of some β-(3-indolyl) ketone O-2,4-
dinitrophenyloxime derivatives 6 was attempted and the results
are listed in Table 2. β-Substituted ketone O-2,4-dinitrophenyl-
oxime 6b was transformed to 2,4-dimethyl-α-carboline 7b in
45% yield. Although α-substituted ketone oximes readily
undergo the Beckmann rearrangement, oxime 6c cyclized to
give 9H-2,3-dimethylpyrido[2,3-b]indole (7c) in 45% yield
without the Beckmann product.10 As a model reaction toward
the synthesis of 2-amino-α-carboline11 which has high muta-
genic activity toward Salmonella typhimurium was examined
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
147
the cyclization of 2,4-dinitrophenyloxime of α-keto ester. That
is, 9H-2-ethoxycarbonylpyrido[2,3-b]indole (7d) was obtained
from 2-O-2,4-dinitrophenyloxyimino-4-(3-indolyl)butanoic
acid ethyl ester (6d) in 72% yield.
(1989). c) P. Rocca, F. Marsais, A. Godard, and G.
Queguiner, Tetrahedron, 49, 49 (1993). d) S. Achab, M.
Guyot, and P. Potier, Tetrahedron Lett., 36, 2615 (1995).
Preparation of the starting materials: The O-2,4-dinitro-
phenyloximes 6 were synthesized from the corresponding
β-(3-indolyl) ketones 6' by the reported procedure; M. J.
Miller and G. M. Loudon, J. Org. Chem., 40, 126 (1975).
Ketones 6a' and 6b' were prepared by the reported proce-
dure; J. Szmuszkovicz, J. Am. Chem. Soc., 79, 2819
(1957). β-Substituted ketone 6c' was prepared by aldol
condensation of 3-indolecarbaldehyde and acetone fol-
lowed by 1,4-addition of methylcuprate. Keto ester 6d'
was prepared by the reported procedure; D. G. Hangauer,
Jr., Tetrahedron Lett., 22, 2439 (1981).
4
General experimental procedure is as follows (Table 2,
entry 1): To a 1,4-dioxane (10 mL) suspension of sodium
hydride (10 mmol) and sodium cyanoborohydride (5.0 mmol),
was added a 1,4-dioxane (10 mL) solution of 4-(3-
indolyl)butan-2-one O-2,4-dinitrophenyloxime (6a) (1.0 mmol)
at room temperature. After the mixture was stirred for 12 h at
room temperature, the reaction was quenched by adding water
and the organic materials were extracted with diethyl ether and
dried over potassium carbonate. After the solvent was removed
in vacuo, the crude products were purified by column chro-
matography (silica gel, hexane:ethyl acetate = 2:1) to afford
9H-2-methylpyrido[2,3-b]indole (7a) (0.60 mmol, 60%).
5
a) K. Uchiyama, Y. Hayashi, and K. Narasaka, Synlett,
1997, 445. b) A. Ono, K. Uchiyama, Y. Hayashi, and K.
Narasaka, Chem Lett., 1998, 437. c) K. Uchiyama, A. Ono,
Y. Hayashi, and K. Narasaka, Bull. Chem. Soc. Jpn., 71,
2945 (1998).
6
7
K. Uchiyama, Y. Hayashi, and K. Narasaka, Chem. Lett.,
1998, 1261.
In the preparation of 8-quinolinols, 4 and 5, the cyclization
is also accelerated by the combined use of NaH and
NaBH3CN as compared to the treatment with NaH alone.
Side products are about 10% of ketone 6a' and a trace
amount of amine 8a.
8
References and Notes
1
a) A. Badre, A. Boulanger, E. Abou-Mansour, B. Banaigs,
G. Combaut, and C. Francisco, J. Nat. Prod., 57, 528
(1994). b) T. P. Blackburn, D. Bolton, I. T. Forbes, C. N.
Johnson, R. T. Martin, D. R. Thomas, M. Thompson, and
N. Upton, Bioorg. Med. Chem. Lett., 4, 279 (1994). c) C.
Moquin-Pattey and M. Guyot, Tetrahedron, 45, 3445
(1989).
9
P. Caubere, Angew. Chem., Int. Ed. Engl., 22, 599 (1983).
10 a) K. I. Kuchkova, A. A. Semenov, and I. V. Terent'eva,
Khim. Geterotsikl. Soedin., 1970, 197. b) K. I. Kuchkova,
E. P. Styngach, F. Sh. Rivilis, N. M. Frolova, and A. A.
Semenov, Khim. Geterotsikl. Soedin., 1976, 386.
11 D. Yoshida, T. Matsumoto, R. Yoshimura, and T.
Matsuzaki, Biochem. Biophys. Res. Commun., 83, 915
(1978).
2
3
A review article for the preparation of α-carbolines: A. A.
Semenov and V. V. Tolstikhina, Chem. Heterocycl.
Compd. (English transl.), 1984, 345.
a) A. Tahri, K. J. Buysens, E. V. Van der Eycken, D. M.
Vandenberghe, and G. J. Hoornaert, Tetrahedron, 54,
13211 (1998). b) W. A. W. Stolle, A. T. M. Marcelis, A.
Koetsier, and H. C. van der Plas, Tetrahedron, 45, 6511