LETTER
Synthesis of Isocryptolepine via a Pd-Catalyzed ‘Amination–Arylation’ Approach
617
(2) (a) Grellier, P.; Ramiaramanana, L.; Millerioux, V.; Deharo,
E.; Schrével, J.; Frappier, F.; Trigalo, F.; Bodo, B.; Pousset,
J.-L. Phytotherapy Res. 1996, 10, 317. (b) Kirby, G. C.;
Paine, A.; Warhurst, D. C.; Noamese, B. K.; Phillipson, J. D.
Phytotherapy Res. 1995, 9, 359. (c) Cimanga, K.; De
Bruyne, T.; Pieters, L.; Vlietinck, A.; Turger, C. A. J. Nat.
Prod. 1997, 60, 688.
(3) Jonckers, T. H. M.; Van Miert, S.; Cimanga, K.; Bailly, C.;
Colson, P.; De Pauw, M.-C.; Lemière, F.; Esmans, E. L.;
Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.;
Lemière, G. L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem.
2002, 45, 3497.
(4) For the synthesis of 11H-indolo[3,2-c]quinolines see:
(a) Arcadi, A.; Cacchi, S.; Cassetta, A.; Fabrizi, G.; Parisi, L.
M. Synlett 2001, 1605. (b) Mouaddib, A.; Joseph, B.;
Hasnaoui, A.; Mérour, J.-Y. Synthesis 2000, 549.
(c) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett
1999, 620. (d) Go, M.-L.; Ngiam, T.-L.; Tan, A. L.-C.;
Kuaha, K.; Wilairat, P. Eur. J. Pharm. Sci. 1998, 6, 19.
(e) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-
Builla, J.; Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.;
Ballesteros, M. J. Org. Chem. 1996, 61, 5587. (f) Trécourt,
F.; Mongin, F.; Mallet, M.; Quéguiner, G. Synth. Commun.
1995, 25, 4011. (g) Go, M. L.; Ngiam, T. L.; Phillipson, J.
D.; Kirby, G. C.; O’Neill, M. J.; Warhurst, D. C. Eur. J. Med.
Chem. 1992, 27, 301. (h) Molina, P.; Alajarin, M.; Vidal, A.
Tetrahedron 1990, 46, 1063. (i) Dave, V.; Warnhoff, E. W.
Tetrahedron 1975, 31, 1255.
Finally, the title compound was obtained by methylation
of the 11H-indolo[3,2-c]quinoline (7)23 skeleton
(Scheme 1). Although different procedures have been re-
ported in the literature, we opted to use similar conditions
(CH3I, DMF, 80 °C; then aq Na2CO3) as developed for the
methylation of 6H-indolo[2,3-b]quinolines.3 In this way
isocryptolepine (1)24 was obtained in 57.7% overall yield.
In the literature four total syntheses of isocryptolepine
have been reported. 5-Methyl-5H-indolo[3,2-c]quinoline
(1) has been prepared by a Fischer-indole approach
(Novikov et al., 5 steps, 19.2% overall yield),18 a ther-
mocyclisation of an azide on a quinoline (Timári et al., 5
steps, 46.7% overall yield)19 or a quinolin-2(1H)-one
(Molina et al., 9 steps, 18.7% overall yield)20 involving
the formation of a nitrene, and via a photochemical cycli-
sation of the Schiff base formed between aniline and in-
dole-3-carbaldehyde (Mohan et al., 3 steps, 47.2% overall
yield).21 In this last approach an indole precursor is used
and the quinoline ring is built up in an intramolecular pho-
tochemical reaction. This is totally different from our new
and the three other literature procedures where quinoline
precursors are used and the indole ring is formed via in-
tramolecular arylation, Fischer-indole or thermocyclisa-
tion reaction. It is therefore obvious that the three-step
method of Mohan and co-workers can be especially useful
for the preparation of A-ring substituted derivatives using
anilines, while our three-step procedure looks attractive to
obtain D-ring isocryptolepine-analogues starting from
substituted 2-chloroanilines.
(5) For recent reviews on the Buchwald–Hartwig reaction see:
(a) Barañano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem.
1997, 1, 287. (b) Frost, C. G.; Mendonça, P. J. Chem. Soc.,
Perkin Trans. 1 1998, 2615. (c) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046. (d) Muci, A. R.; Buchwald,
S. L. Top. Curr. Chem. 2002, 219, 131.
(6) For examples on intramolecular Pd-catalyzed arylation of N-
(o-bromoazaheteroaryl)anilines and N-azaheteroaryl-2-
bromoanilines see: (a) Ames, D. E.; Bull, D. Tetrahedron
1982, 38, 383. (b) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J.
Chem. Soc., Perkin Trans. 1 1999, 1505.
(7) Just before submitting this manuscript an article appeared
dealing with intramolecular Pd-catalyzed arylation of N-(2-
chloroaryl)-N-methylanilines and N-benzyl-N-(2-
chloroaryl)-anilines: Bedford, R. B.; Cazin, C. S. J. Chem.
Commun. 2002, 2310.
In conclusion, we have developed a new method for the
synthesis of the alkaloid isocryptolepine based on two
consecutive palladium-catalyzed reactions. In comparison
with literature procedures 5-methyl-5H-indolo[3,2-
c]quinoline was obtained in the highest overall yield
(57.7%) in only three synthetic steps. Besides the synthe-
sis of the parent natural product, this approach looks very
promising to prepare D-ring substituted analogues.
(8) Several examples of the beneficial effect of the use of large
excesses of inorganic bases in Pd-catalyzed aminations
using Pd(BINAP) catalyst have already been reported by our
research group: (a) Košmrlj, J.; Maes, B. U. W.; Lemière,
G. L. F.; Haemers, A. Synlett 2000, 1581. (b) Jonckers, T.
H. M.; Maes, B. U. W.; Lemière, G. L. F.; Dommisse, R.
Tetrahedron 2001, 57, 7027. (c) Maes, B. U. W.; Loones, K.
T. J.; Jonckers, T. H. M.; Lemière, G. L. F.; Dommisse, R.
A.; Haemers, A. Synlett 2002, 1995.
Acknowledgement
Dr. B. Maes thanks the Fund for Scientific Research (FWO-Vlaan-
deren) for an appointment as post-doctoral fellow. The authors wish
to thank the University of Antwerp (RAFO-RUCA) for financial
support, Prof. Dr. E. Esmans and Dr. F. Lemière for the use of their
MS facilities and our technical staff (J. Aerts, J. Schrooten, W. Van
Dongen, W. Van Lierde and J. Verreydt) for their assistance.
(9) No attempts to reduce the excess of K2CO3 were performed.
(10) For the Pd-catalyzed amination of 2-chloroquinoline with
ethyl 2-amino-4-phenyl-1,3-thiazole-5-carboxylate see:
Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M.
Org. Lett. 2002, 4, 3481.
(11) For the Ni-catalyzed amination of 2-chloroquinoline see:
Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002,
67, 3029.
References
(1) (a) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.;
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G. E. J. Heterocycl. Chem. 1996, 33, 239. (c)Pousset, J.-L.;
Martin, M.-T.; Jossang, A.; Bodo, B. Phytochemistry 1995,
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(12) For the SNAr model of oxidative addition see: Fitton, P.;
Rick, E. A. J. Organomet. Chem. 1971, 28, 287.
(13) 2-(Dicyclohexylphosphino)biphenyl, 2-(di-t-butyl-
phosphino)biphenyl and tri-t-butylphosphine are
commercially available from Strem Chemicals.
Synlett 2003, No. 5, 615–618 ISSN 0936-5214 © Thieme Stuttgart · New York