Heterocyclization of Vinylic Derivatives of Imidazo[1,2-a]pyridines
J . Org. Chem., Vol. 66, No. 20, 2001 6577
or carbodiimide synthons, are representative examples.11
In contrast, the synthetic potential of the pyridinic moiety
has long remained unexplored.12a,c,d Recently, tricyclic
structures, such as 7 and isosteres in which the C(3) and
C(5) of IP are bridged, were obtained by peri annu-
lation.12c,f-h
We have been studying the reactivity of the nitrogen
bridgehead systems, and especially the bioactive imidazo-
[1,2-a]pyridine moiety, for several years. We report here
a new synthetic route for pyrroloazaindoles and naph-
thyridinoimidazoles by regioselective cyclization of vinyl
azide-, amine-, or heterocumulene-substituted imidazo-
[1,2-a]pyridines. The products form a potentially useful
class of agents for neurodegenerative disorders,5 could
be envisaged as a composite template of potent dual ACE/
NEP inhibitors,7u,13 and are also of interest as possible
inhibitors of HIV-l replication.14
Resu lts a n d Discu ssion
To access pyrrolo, pyridino, pyrimidino, and diazepino
moieties, three new models of IPs substituted by (A) an
aminovinylic group, (B) an azirine fragment derived from
an azidovinylic group,15 and (C) a heterocumulene were
(8) (a) Ning, R. Y.; Blount, J . F.; Madan, P. B.; Fryer, R. I. J . Org.
Chem. 1977, 42, 1791. (b) Takamura, T.; Chiba, T.; Tejima, S. Chem.
Pharm. Bull. 1978, 26, 2924. (c) Saint-Ruf, G.; Loukakou, B.; N′Zouzi,
C. J . Heterocycl. Chem. 1981, 18, 1565. (d) Hashimoto, Y.; Shudo, K.;
Okamoto, T. J . Am. Chem. Soc. 1982, 104, 7637. (e) Teulade, J . C.;
Escale, R.; Viols, H.; Chapat, J . P.; Grassy, G.; Carpy, A.; Le´ger, J . M.
J . Chem. Soc., Perkin Trans. 1 1983, 2663. (f) N’Goy, K.; De Meester,
C.; Pairon, D.; Fabry, L.; Loukakou, B.; N’Zouzi, C.; Saint-Ruf, G.;
Mercier, M.; Poncelet, F. Muta. Res. 1984, 136, 23. (g) Teulade, J . C.;
Gueiffier, A.; Chapat, J . P.; Grassy, G.; Carpy, A.; H’Naifi, A.; Perly,
B.; Couquelet, J . Chem. Pharm. Bull. 1989, 37, 2293. (h) Ollis, W. D.;
Stanforth, S. P.; Ramsden, C. A. J . Chem. Soc., Perkin Trans. 1 1989,
961. (i) Teulade, J . C.; Gueiffier, A.; Viols, H.; Chapat, J . P.; Grassy,
G.; Perly, B. J . Chem. Soc., Perkin Trans. 1 1989, 1895. (j) Kno¨lker,
H. J .; Boese, R.; Hitzemann, R. Chem. Ber. 1990, 123, 327. (k) Toth,
G.; Kovacs, A.; Balogh, M.; Hermecz, I. J . Heterocycl. Chem. 1991, 28,
497. (l) Gueiffier, A.; Blache, Y.; Viols, H.; Chapat, J . P.; Chavignon,
O.; Teulade, J . C.; Dauphin, G.; Debouzy, J . C.; Chabard, J . L. J .
Heterocycl. Chem. 1992, 29, 283. (m) Bogdanowicz-Szwed, K.; Czarny,
A. J . Prackt. Chem. 1993, 335, 279. (n) Diez, A.; Mavel, S.; Teulade, J .
C.; Chavignon, O.; Sinibaldi, M. E.; Troin, Y.; Rubiralta, M. Heterocycles
1993, 36, 2451. (o) J ouanisson, A.; Chavignon, O.; Couquelet, J .;
Teulade, J . C.; Chabard, J . L.; Dauphin, G. J . Heterocycl. Chem. 1995,
41, 21. (p) Chavignon, O.; Raihane, M.; Deplat, P.; Chabard, J . L.;
Gueiffier, A.; Blache, Y.; Dauphin, G.; Teulade, J . C. Heterocycles 1995,
41, 2019. (q) Delmas, G.; Deplat, P.; Chezal, J . M.; Chavignon, O.;
Gueiffier, A.; Blache, Y.; Chabard, J . L.; Dauphin, G.; Teulade, J . C.
Heterocycles 1996, 43, 1229. (r) Fletcher, N. C.; Abeln, D.; Von
Zelewsky, A. J .Org. Chem. 1997, 62, 8577. (s) Nath, M.; Srivastava,
P.; Goel, A.; Ram, V. J . Eur. J . Org. Chem. 1998, 2083. (t) Dupuy, M.;
Pinguet, F.; Blache, Y.; Chavignon, O.; Teulade, J . C.; Chapat, J . P.
Chem. Pharm. Bull. 1998, 46, 1820.
(9) (a) Henn, L.; Hickey, D. M. B.; Moody, C. J .; Rees, C. W. J . Chem.
Soc., Perkin Trans. 1 1984, 2189. (b) Hickey, D. M. B.; Moody, C. J .;
Rees, C. W. J . Chem. Soc., Perkin Trans. 1 1986, 1119.
(10) Molina, P.; Alajarin, M.; Vidal. A. J . Org. Chem. 1992, 57, 6703
and references therein.
(11) (a) Chavignon, O.; Teulade, J . C.; Roche, D.; Madesclaire, M.;
Blache, Y.; Gueiffier, A.; Chabard, J . L.; Dauphin, G. J . Org. Chem.
1994, 59, 6413. (b) Chezal, J . M.; Delmas, G.; Mavel, S.; Elhakmaoui,
H.; Me´tin, J .; Diez, A.; Blache, Y.; Gueiffier, A.; Rubiralta, M.; Teulade,
J . C.; Chavignon, O. J . Org. Chem. 1997, 62, 4085.
(12) (a) Takahashi, T.; Shibasaki, J . J . Pharm. Soc. J pn. 1949, 69,
496. (b) Almirante, L.; Mugnaini, A.; De Toma, N.; Murmann, W. Boll.
Chim. Farm. 1971, 110, 322. The reduction of the 3-nitroIP is quite
complex and the outcome is dependent on the acidic reaction conditions.
(4) (a) Feigon, J .; Denny, W. A.; Leupin, W.; Kearns, D. R. J . Med.
Chem. 1984, 27, 450. (b) Koenigsmann, M.; Zafferani, M.; Danhauser-
Rield, S.; Reuti, B.; Houlihan, W. J .; Thiel, E.; Berdel, W. E. Cancer
Lett. 1992, 67, 145. (c) Brana, M. F.; Castellano, J . M.; Keilhauer, G.;
Machuca, A.; Martin, Y.; Redondo, C.; Schlick, E.; Walker, N. Anti
cancer Drug Des. 1994, 9, 527. (d) Pastor, J .; Siro, J . G.; Garcia-Navio,
J . L.; Vaquero, J . J .; Rodrigo, M. M.; Ballesteros, M.; Alvarez-Builla,
J . Bioorg. Med. Chem. Lett. 1995, 5, 3043. (e) Pastor, J .; Siro, J . G.;
Garcia-Navio, J . L.; Vaquero, J . J .; Alvarez-Builla, J .; Gago, F.; de
Pascual-Teresa, B.; Pastor, M.; Rodrigo, M. M. J . Org. Chem. 1997,
62, 5476.
(5) (a) J ohnson, J . W.; Ascher, P. Nature 1987, 325, 529. (b) Hansen,
D.; Adelstein, G. 1989, WO 91 08 211. (c) Hamilton, G. S.; Huang, Z.;
Yang, X. J .; Patch, R. J .; Narayanan, B. A.; Ferkany, J . W. J . Org.
Chem. 1993, 58, 7263. (d) Leeson, P. D.; Iversen, L. L. J . Med. Chem.
1994, 37, 4053. (e) Cordi, A.; Sun, E. US Patent 5,252,563, 1993. (f)
Saab, A.; Webb, M. US Patent 5,571,819-A, 1996. (g) Treiber, H.;
Lubjsch, W.; Behi, B.; Hofmann, H. DE19503825-Al, 1996. (h) Bena-
vides, J .; George, P.; Ferzaz, B.; Scatton, B. FR2727864-A1, 1996. (i)
J imonet, P.; Boireau, A.; Cheve´, M.; Damour, D.; Genevois-Borella, A.;
Imperato, A.; Pratt, J .; Randle, J . C.; Ribeill, Y.; Stutzmann, J . M.;
Mignani, S. Bioorg. Med. Chem. Lett. 1999, 9, 2921.
(6) (a) Kelly, R. C.; Gebhard, I.; Wicnienski, N.; Aristoff, P. A.;
J ohnson, P. D.; Martin, D. G. J . Am. Chem. Soc. 1987, 109, 6837. (b)
Aloup, J .; Audiau, F.; Barreau, M. W09614318-A1, 1996.
(7) (a) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli,
P.; Biancotti, A.; Gamba, A.; Murmann, W. J . Med. Chem. 1965, 8,
305. (b) Yamamoto, T.; Tsuji, K.; Kosuge, T.; Okamoto, T.; Shudo, K.;
Takeda, K.; Itaka, Y.; Yamaguchi, K.; Seino, Y.; Yahagi, T.; Nagao,
M.; Sugimura, T. Proc. J pn. Acad. B 1978, 54, 248. (c) Grassy, G.;
Teulade, J . C.; Chapat, J . P.; Simeon de Buochberg, M.; Attisso, M.
Eur. J . Med. Chem. Chim. Ther. 1982, 17, 109. (d) Kaplan, J . P.;
George, P. EP 0050563, 1982; EP 0092458, 1983. (e) Kaplan, J . P.;
George, P.; Bernardon, J . M. EP 0092459, 1983. (f) Davey, D.; Erhardt,
P. W.; Lumma, W. C., J r.; Wiggins, J .; Sullivan, M.; Pang, D.; Cantor,
E. J . Med. Chem. 1987, 30, 1337. (g) Kaminski, J . J .; Hilbert, J . M.;
Pramanik, B. N.; Solomon, D. M.; Conn, D. J .; Rizvi, R. K.; Elliott, A.
J .; Guzik, H.; Lovey, R. G.; Domalski, M. S.; Wong, S. C.; Puchalski,
C.; Gold, E. H.; Long, J . F.; Chiu, P. J . S.; McPhail, A. J . Med. Chem.
1987, 30, 2031. (h) Kaminski, J . J .; Perkins, D. G.; Frantz, J . D.;
Solomon, D. M.; Elliott, A. J .; Chiu, P. J .; Long, J . F. J . Med. Chem.
1987, 30, 2047 and references therein. (i) George, P.; Rossey, G.;
Depoortere, H.; Monpon, B.; Allen, J .; Wick, A. In Imidazopyridines
in Sleep Disorders; Sauvanet, J . P., Langer, S., Morselli, P., Eds.; Raven
Press: New York, 1988; p 11. (j) Ager, I. R.; Barnes, A. C.; Danswan,
G. W.; Hairsine, P. W.; Kay, D. P.; Kennewell, P. D.; Matharu, S. S.;
Miller, P.; Robson, P.; Rowlands, D. A.; Tully, W. R.; Westwood, R. J .
Med. Chem. 1988, 31, 1098. (k) Spitzer, W. A.; Victor, F.; Pollock, G.
D.; Hayes, J . S. J . Med. Chem. 1988, 31, 1590. (l) Sanfilippo, P. J .;
Urbanski, M.; Press: J . B.; Dubinsky, B.; Moore, J . B., J r. J . Med.
Chem. 1988, 31, 2221. (m) Gueiffier, A.; Teulade, J . C.; Franc¸ois, C.;
Viols, H.; Michel, A.; Boucard, M.; Chapat, J . P. Fr. Patent 88 13882-
A1, 1988. (n) Gillespie, E. Biochem. Pharmacol. 1988, 37, 2866. (o)
Abignente, E.; De Caprariis, P.; Luraschi, E.; Marmo, E.; Berrino, L.;
Lo Sasso, C. Res. Commun. Chem. Pathol. Pharmacol. 1989, 65, 35.
(p) Abignente, E.; Sacchi, A.; Laneri, S.; Rossi, F.; D’Amico, M.; Berrino,
L.; Calderaro, V.; Parrillo, C. Eur. J . Med. Chem. 1994, 29, 279. (q)
Yoshitomi, M.; Tomoko, O.; Takashi, O.; Norifumi, N.; Yoshihisa, I.;
Hajime, E. J pn Kokai Tokkyo Koho J P06,184,148, 1994. (r) Adachi,
H.; Tanaka, H. J . Cardiovasc. Pharmacol. 1997, 29, 763. (s) Petrides,
P. E.; Trapp, O.; Beykirch, M. K. Blood 1997, 90, (10, Suppl. 1, Part
2). (t) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K.;
Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.; Oku, T.; Tanaka,
H. J . Med. Chem. 1998, 41, 564. (u) Hamdouchi, C.; de Blas, J .; del
Prado, M.; Gruber, J .; Heinz, B. A.; Vance, L. J . Med. Chem. 1999, 42,
50. (v) Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.;
Serra, M.; Sanna, E.; Biggio, G.; Liso, G. J . Med. Chem. 1999, 42, 3934.
(c) Rees, C. W.; Smith, D. J . Chem. Soc., Perkin Trans. 1 1987, 1159.
(d) Gueiffier, A.; Milhavet, J . C.; Blache, Y.; Chavignon, O.; Teulade,
J . C.; Madesclaire, M.; Viols, H.; Dauphin, G.; Chapat, J . P. Chem.
Pharm. Bull. 1990, 38, 2352. (e) Blache, Y.; Gueiffier, A.; Chavignon,
O.; Viols, H.; Teulade, J . C.; Chapat, J . P. Heterocycles 1994, 38, 1527.
(f) Wakimasu, M.; Ikemoto, T. J pn Kokai Tokkyo Koho J P 09,249,666
(97,249,666), 1997. (g) Ikemoto, T.; Kawamoto, T.; Tomimatsu, K.;
Takatani, M.; Wakimasu, M. Tetrahedron 2000, 56, 7915. (h) Kawa-
moto, T.; Tomimatsu, K.; Ikemoto, T.; Abe, H.; Hamamura, K.;
Takatani, M. Tetrahedron Lett. 2000, 41, 3447.
(13) Bohacek, R.; De Lombaert, S.; McMartin, C.; Priestle, J .;
Gru¨tter, M. J . Am. Chem. Soc. 1996, 118, 8231.