ORGANIC
LETTERS
2008
Vol. 10, No. 16
3485-3488
A Versatile Cyclodehydration Reaction
for the Synthesis of Isoquinoline and
ꢀ-Carboline Derivatives
Mohammad Movassaghi* and Matthew D. Hill
Department of Chemistry, Massachusetts Institute of Technology,
77 Massachusetts AVenue, Cambridge, Massachusetts 02139
Received June 4, 2008
ABSTRACT
The direct conversion of various amides to isoquinoline and ꢀ-carboline derivatives via mild electrophilic amide activation, with
trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine, is described. Low-temperature amide activation followed by
cyclodehydration upon warming provides the desired products with short overall reaction times. The successful use of nonactivated and
halogenated phenethylene derived amides, N-vinyl amides, and optically active substrates is noteworthy.
The venerable Bischler-Napieralski reaction offers an
important strategy for the synthesis of various azahetero-
cycles.1,2 Isoquinolines and ꢀ-carbolines, including their
reduced derivatives, can be found as substructures in many
important natural products, pharmaceuticals, and other fine
chemicals.3 We have reported the syntheses of pyridine4a
and pyrimidine4b derivatives via the intermolecular conden-
sation of readily available N-vinyl- and N-arylamides5 with
various nucleophiles. Herein we report mild reaction condi-
tions for the Bischler-Napieralski based synthesis of iso-
quinoline and ꢀ-carboline derivatives from readily available
amides.
During our studies concerning the syntheses of pyridines
and quinolines via an intermolecular condensation reaction,4b
we observed a competitive intramolecular cyclization reaction
in a single case where a Morgan-Walls6 cyclization pathway
was possible. N-Phenethylbenzamide (1, Table 1) was used
to further investigate this intramolecular condensation reac-
tion. Consistent with our observations on amide activation
for the intermolecular addition of σ- or π-nucleophiles,4 the
use of trifluoromethanesulfonic anhydride (Tf2O)7 and 2-chlo-
ropyridine8 (2-ClPyr) as the base additive were found to be
(1) (a) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903. (b) Whaley,
W. M.; Govindachari, T. R. Org. React. 1951, 6, 74
.
(2) For representative reports, see: (a) To´th, J.; Nedves, A.; Dancso´,
A.; Blasko´, G.; To¨ke, L; Nyerges, M. Synthesis 2007, 1003. (b) Spaggiari,
A.; Davoli, P.; Blaszczak, L. C.; Prati, F. Synlett 2005, 661. (c) Banwell,
M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.; Hockless, D. C. R.; Holman,
J. W.; Read, R. W.; Wu, A. W. J. Chem. Soc., Chem. Commun. 1995, 2551.
(d) Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski,
E. J. J.; Reider, P. J.; Shinkai, I. J. Org. Chem. 1991, 56, 6034. (e)
Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett. 1975, 16, 277
.
(3) For reviews on isoquinolines and their reduced derivatives, see: (a)
Jones, G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon: Oxford,
1996; Vol. 5, p 167. (b) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444. (c)
Kartsev, V. G. Med. Chem. Res. 2004, 13, 325. (d) Chrzanowska, M.;
Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341. (e) Joule, J. A.; Mills,
K. In Heterocyclic Chemistry, 4th ed.; Blackwell Science Ltd.: Cambridge
MA, 2000; p 121. (f) Rozwadowska, M. D. Heterocycles 1994, 39, 903.
For a review on ꢀ-carbolines and their reduced derivatives, see: (g) Love,
B. E. Org. Prep. Proced. Int. 1996, 28, 3.
(5) For recent advances in synthesis of N-vinyl- and N-arylamides, see:
(a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b)
Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; p 1051.
(c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(d) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(6) (a) Morgan, G. T.; Walls, L. P. J. Chem. Soc. 1931, 2447. (b)
Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720. (c) Hutchinson,
I.; Stevens, M. F. G. Org. Biomol. Chem. 2007, 5, 114.
(4) (a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254.
(b) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096.
(7) (a) For an elegant prior report on amide activation, see: Charette,
A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694. (b) Review: Baraznenok,
I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000, 56, 3077.
10.1021/ol801264u CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society