of biological activity, the development of new efficient and
more viable routes for this class of compounds would be of
great relevance to both synthetic and medicinal chemists. In
this Letter we report a facile synthetic entry to substituted
and fused benzo[a]quinolizine-4-thiones involving highly
regioselective [3 + 3] annulation of 3,4-dihydro-6,7-
dimethoxy-1-methylisoquinoline 1 with â-oxodithioesters.
The new methodology allows facile introduction of substit-
uents in the C ring of the nitrogen heterocycle and flexibility
for the construction of novel benzo[a]quinolizine fused ring
systems.
we became interested in examining enamine reactivity of
imine 1 toward unsymmetrical 1,3-bielectrophiles with a
view to developing a facile one-pot synthesis of benzo[a]-
quinolizines. Our initial efforts to react 1 with readily
available â-ketoesters such as ethyl acetoacetate or ethyl
â-benzoylacetate in the presence of various acidic and basic
catalysts under different conditions did not meet with any
success. However, to our surprise, when 1 was reacted with
â-oxodithioester 2a in refluxing benzene (12 h) in the
presence of triethylamine, workup and column chromatog-
raphy of the reaction mixture furnished only one product
(66%) which was characterized as 6,7-dihydro-9,10-dimethoxy-
2-methylbenzo[a]quinolizine-4-thione 3a on the basis of
spectral and analytical data.17 The corresponding â-aroyl
dithioesters 2b and 2c also reacted with 1 smoothly under
identical conditions to afford the corresponding 2-arylbenzo-
[a]quinolizine-4-thiones 3b and 3c in 80 and 71% yields,
respectively (Scheme 1). Similarly, the 2,3-disubstitured
Several elegant approaches for the construction of benzo-
[a]quinolizine ring systems are described in the literature,2
most of which involve closure of ring B by formation of the
C11a-C11b bond either by Bischler-Napieralski type9 or by
related palladium-catalyzed cyclization.1a,b,2a Other methods
rely upon elaboration of the piperidine/pyridine (ring C) by
formation of the C1-C11b bond via Mannich type cyclization
of a dihydroisoquinolinium ion10 or closure of ring B by
formation of the C2-C7a bond1c,3b from appropriately N-
substituted 2-arylpiperidine or pyridine derivatives. On the
other hand, examples of direct synthesis of the benzo[a]-
quinolizine framework utilizing the enamine character of
easily accessible 3,4-dihydro-6,7-dimethoxy-1-methyliso-
quinoline 1 in cyclocondensation with 1,3-bielectrophilic
components are very few in the literature.11-13 It should be
noted that the imine 1 has been successfully employed as a
useful precursor for the synthesis of protoberberine alkaloids
via photochemical and thermal cyclization of N-aroylena-
mides.14 During the course of our investigations on dihy-
droisoquinoline-derived enaminones15 and enaminoesters,16
Scheme 1
(8) (a) Spurr, P. R. Tetrahedron Lett. 1995, 16, 2745-2748. (b) Fischer,
U.; Mohler, H.; Schneider, F.; Widmer, U. HelV. Chim. Acta 1990, 73,
763-781. (c) Scherschlicht, R. R.; Widmer, U. Eur. Pat. EP 496274, 29.07,
1992; Chem. Abstr. 1992, 117, 191707c.
(9) (a) Itoh, N.; Sugasawa, S. J. Org. Chem. 1959, 24, 2042-2043. (b)
Osbond, J. M. J. Chem. Soc. 1961, 4711-4718. (c) Akaboshi, S.; Kato, T.
Chem. Pharm. Bull. 1963, 11, 1446-1451. (d) Teuber, H. J.; Laudien, D.
Angew Chem., Int. Ed. Engl. 1964, 3, 507-508. (e) Teuber, H. J. Schroder,
K. D. Chem. Ber. 1969, 102, 1779-1783. (f) Battersby, A. R.; Staunton, J.
Wiltshire, H. R.; Bircher, B. J.; Fuganti, C. J. Chem. Soc., Perkin Trans. 1
1975, 1162-1171. (h) Shamma, M.; Nugent, J. F. Tetrahedron 1973, 29,
1265-1272.
(10) (a) Szantay, C.; Rohaly, J. Chem. Ber. 1965, 98, 557-566. (b)
vonStrandtmann, M.; Cohen, M. P.; Shavrel, J., Jr. J. Org. Chem. 1966,
31, 797-802. (c) Whittaker, N. J. Chem. Soc. 1969, 85-89. (d) Chapman,
D. D. J. Chem. Soc., Chem. Commun. 1975, 489. (e) Shono, T.; Hamaguchi,
H.; Sasaki, M.; Fujita, S.; Nagami, K. J. Org. Chem. 1983, 48, 1621-
1628.
benzo[a]quinolozine-4-thiones 3d and 3e could be easily
synthesized in high yields from the respective R-methyl-â-
acylidioates and 1.
(11) (a) Ninomiya, I.; Tada, Y.; Kiguchi, T.; Yamamoto, O.; Naito, T.
J. Chem. Soc., Perkin Trans. 1 1984, 2035-2038. (b) Ninomiya, I.; Kiguchi,
T.; Tada, Y. Heterocycles 1977, 6, 1799-1803.
To further demonstrate the scope of the reaction, the cyclic
â-ketodithioesters 2f-h derived from cyclohexanone, cy-
clopentanone, and N-benzylpiperidine-4-ones were chosen
as cyclocondensation partners and reacted with 1 under
similar conditions (Scheme 2). Thus, the dithioester 2f
afforded the hexahydrodibenzo[a,g]quinolizine-8-thione in
high yield (70%) whereas the corresponding benzo[a]-
quinolizine-4-thiones 3g and 3h were obtained in moderate
yields from the respective dithioesters 2g and 2h.18 The
versatility of this novel cyclization reaction was further
demonstrated by facile formation of novel pentacyclic benzo-
[a]quinolizine frameworks 3i-j in highly convergent fashion
when the bicyclic â-oxodithioesters 2i-j from tetralones
(12) Kametani, T.; Terasawa, H.; Ihara, M. J. Chem. Soc., Perkin Trans.
1 1976, 2547-2550.
(13) Kametani, T.; Suzuki, Y.; Terasawa, H.; Ihara, M. J. Chem. Soc.
Perkin Trans. 1 1979, 1211-1217.
(14) (a) Lenz, G. R. J. Org. Chem. 1974, 39, 2839-2851. (b) Ninomiya,
I.; Naito, T.; Takasugi, H. J. Chem. Soc., Perkin Trans. 1 1976, 1865-
1868. (c) Ninomiya, I.; Naito, T.; Takasugi, H. J. Chem. Soc., Perkin Trans.
1 1975, 1791-1795. (d) Ninomiya, I.; Naito, T.; Takasugi, H. J. Chem.
Soc., Perkin Trans. 1 1975, 1720-1724. (e) Naito, T.; Ninomiya, I.
Heterocycles 1980, 959-961. (f) Kametani, T.; Sugai, T.; Shoji, Y.; Honda,
T.; Satoh, F.; Fukumoto, K. J. Chem Soc. Perkin Trans. 1 1977, 1151-
1155.
(15) For a related cyclization, see: Kobayashi, G.; Matsuda, Y.; Natsuki,
R.; Sone, M. Chem. Pharm. Bull. 1972, 20, 657-663.
(16) Barun, O.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synlett 2000, 653-
657.
230
Org. Lett., Vol. 3, No. 2, 2001