4520
J. Am. Chem. Soc. 1998, 120, 4520-4521
Synthesis of Furopyridines via Cycloaddition of
Unactivated Nitriles with Tungsten-Substituted
1,3-Diene
Scheme 1
†
†
‡
Wen-Tai Li, Fang-Chun Lai, Gene-Hsian Lee,
‡
,†
Shie-Ming Peng, and Rai-Shung Liu*
Departments of Chemistry
National Tsing-Hua UniVersity
Hsinchu, 30043, Taiwan, R. O. China
National Taiwan UniVersity
Taipei, 10764, Taiwan, R. O. China
Scheme 2
ReceiVed NoVember 17, 1997
Dials-Alder cycloaddition is recognized as one of the most
valuable reactions in organic synthesis;1-6 it is widely applicable
to a variety of dienophiles such as olefins, alkynes, aldehydes,
ketones, imines, N-acylimines, and nitroso compounds.1 Most
of these dienophiles do not require an activating group to achieve
cycloadditions under ambient conditions. Cycloadditions of
organic dienes with unactivated nitriles proceed only with extreme
-6
difficulty except with prolonged heating at high temperatures
3
(
>350 °C) to afford pyridine exclusively. Under such conditions,
intermolecular Diels-Alder cycloaddition of organic dienes
becomes a serious problem. Only highly electron-deficient nitriles
2
such as TsCN and NCCO R appear to be good dienophiles at
ambient conditions.7 Cobalt catalyst CpCo(COD)8 (COD )
cyclooctadiene) effects the cycloaddition of alkoxydiene with
TsCN to give a good yield of pyridines at 50 °C (eq 1 of Scheme
1), but the reaction fails to proceed with common aliphatic and
aryl nitriles. [4 + 2] Cycloaddition of unactivated nitriles at
ambient conditions remains a challenging issue in synthetic
organic chemistry.
The furopyridine functionality has emerged as a useful phar-
macophore in several therapeutic areas including treatment of skin
disease and relief of intraoccular pressure among others.9,10
A
straightforward synthesis of this functionality via cyano [4 + 2]
B that forms pyridine with cleavage of the C-O bond (eqs 1 and
cycloaddition is prohibited by kinetic instability of intermediate
2
of Scheme 1).8b In this paper, we report a remarkably feasible
†
National Tsing-Hua University.
cyano [4 + 2] cycloaddition at 23 °C and its application to
synthesis of furopyridines. Most importantly this reaction is
applicable to unactivated nitriles in both inter- and intramolecular
fashions.
‡
National Taiwan University.
(
1) For review articles, see: (a) Oppolzer, W.; Weinreb, S. M.; Boger, D.
L.; Roush, W. R. In ComprehensiVe Organic Synthesis: Combining C-C
π-Bonds; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, Chapters 4.1-4.4, p 81.
Shown in Scheme 2 (eq 1) is the general synthetic protocol
(2) (a) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087. (b)
1
for the starting tungsten-η -dienes 1-5 involving the cycloalk-
Kametani, T.; Hibino, S. AdV. Heterocycl. Chem. 1987, 42, 245. (c) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: Orlando, FL, 1987.
enation11 of tungsten-alkynols with R′CH
CHO, followed by
deprotonation of the resulting tungsten-oxacarbenium C with
excess Et N; the yields of 1-5 exceeded 87%. Further use of
2
(
3) Hammer, J. 1,4-Cycloaddition Reactions, the Diels-Alder Reaction in
Heterocyclic Synthesis; Academic Press: New York, 1967.
3
(
4) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49.
these dienes to achieve a cyano [4 + 2] cycloaddition at 23 °C
are illustrated in Scheme 2. A variety of unactivated nitriles are
applicable to the reactions including aliphatic nitriles RCN (R )
(
5) For representative examples of transition-metal-catalyzed Diels-Alder
reaction in non-Lewis acid pathway, see: (a) Wender, P. A.; Jenkins, T. E. J.
Am. Chem. Soc. 1989, 111, 6432. (b) Mckinstry, L.; Livinghouse, T.
Tetrahedron Lett. 1994, 50, 6145. (c) tom Dieck, H.; Diercks, R. Angew.
Chem., Int. Ed. Engl. 1983, 22, 778. (d) Garratt, P. J.; Wyatt, M. J. Chem.
Soc., Chem. Commun. 1974, 251. (e) Gibertson, S. R.; Zhao, X.; Dawson, D.
P.; Marshall, K. L. J. Am. Chem. Soc. 1993, 115, 8517.
i
Et, Pr ) and benzonitrile that are used as reaction solvents (entries
1
3
-5). In entries 1 and 2, the reaction is activated by either Me -
NO‚2H O (5.0 equiv) or by photolysis (λ ) 300 nm); the former
was more effective to yield furopyridines 6 in a better yield (58%).
2
(
6) For representative examples of Lewis acid-catalyzed Diels-Alder
reaction, see: (a) Maruoka, K.; Murase, N.; Yamamoto, H. J. Org. Chem.
993, 58, 2938. (b) Corey, E. J.; Nobuyuki, I.; Zhang, H. Y. J. Am. Chem.
1
(9) (a) Rapoport, H.; Van Sickle, A. P. J. Org. Chem. 1990, 55, 895. (b)
Prisbylla, M. P. U.S. Pat. 5,260,261 (C1 504-246; A 01N43/90). (c) Hwang,
D. R.; Driscoll, J. S. J. Pharmacol. 1979, 68, 816. (d) Shiotani, S.; Morita,
H. J. Heterocycl. Chem. 1982, 19, 1207.
Soc. 1991, 113, 728. (c) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem.
Soc. 1993, 115, 3814. (d) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada,
T.; Nakashima, M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340.
(7) For representative examples of thermal cyano [4 + 2] cycloaddition,
(10) For the syntheses of furopyridines, see: (a) Buysens, K. J.; Vanden-
berghe, D. M.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron 1995, 51, 12463.
(b) Houpis, I. N.; Choi, W. B.; Reider, P. J.; Molina, A.; Churchill, H.; Lynch,
J.; Volante, P. R. Tetrahedron Lett. 1994, 9355. (c) Meth-Cohn, O.; Rhouati,
S.; Tarnowski, B. Tetrahedron Lett. 1979, 4885. (d) Taylor, E. C.; Macor, J.
E.; Pont, J. L. Tetrahedron 1987, 43, 5145. (e) Sekiba, T. Bull. Chem. Soc.
Jpn. 1973, 46, 577.
see: (a) Jagt, J. C.; van Leusen, A. M. J. Org. Chem. 1974, 39, 564. (b) Jagt,
J. C.; van Leusen, A. M. Tetrahedron Lett. 1970, 971. (c) Bayard, P.; Sainte,
R.; Ghosez, L. Tetrahedron Lett. 1988, 29, 3799. (d) Pews, R. G.; Nuqquist,
E. G.; Corson, F. P. J. Org. Chem. 1970, 35, 4096. (e) Janz, G. T.; Monohan,
A. R. J. Org. Chem. 1964, 29, 569.
(
8) For transition metal-catalyzed cyano [4 + 2] cycloaddition of activated
nitriles, see: (a) Breitmaier, E.; Ruffer, U. Synthesis 1986, 584. (b) Breitmaier,
E.; Ruffer, U. Synthesis 1989, 623.
(11) Liang, K.-W.; Li, W.-T.; Peng, S.-M.; Wang, S.-L.; Liu, R.-S. J. Am.
Chem. Soc. 1997, 119, 4404.
S0002-7863(97)03915-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998