Preparation of highly substituted 4-aminopyridones via the reaction of 2-methylene dihydrobenzimidazole with vinyl isocyanates

Article abstract of DOI:10.1021/ol034263k

(Matrix presented) The rapid construction of highly substituted 4-aminopyridones was achieved employing an efficient cyclization between various vinyl isocyanates and 2-methylene dihydrobenzimidazole.

Full text of DOI:10.1021/ol034263k

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1151-1153
Preparation of Highly Substituted
4-Aminopyridones via the Reaction of
2-Methylene Dihydrobenzimidazole with
Vinyl Isocyanates
James H. Rigby* and Chee-Seng Lee
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received February 14, 2003
ABSTRACT
The rapid construction of highly substituted 4-aminopyridones was achieved employing an efficient cyclization between various vinyl isocyanates
and 2-methylene dihydrobenzimidazole.
N,N-Dimethyl ketene aminals1 have been used as 2π partners
in inverse electron demand Diels-Alder reactions with a
variety of electron-poor dienes,2,3 tetrazines, and triazines.4
The utility of these reactants was further illustrated in a [3
+ 2] cycloaddition with methanesulfonyl azide.5,6 We now
disclose a simple, rapid, and efficient construction of
4-aminopyridones via a [4 + 2] cyclization of 2-methylene
dihydrobenzimidazole (4) with various vinyl isocyanates
(Scheme 1).
Recently, our laboratory reported an efficient synthesis of
functionalized hydroindolones through a powerful [4 + 1]
cycloaddition of vinyl isocyanates and N-heterocyclic car-
benes.7 This process allowed for the facile construction of
five-membered heterocycles, and a related transformation
using ketene aminals was envisioned to deliver the corre-
sponding six-membered ring system. Methods for the
synthesis of the pyridone ring system have received consid-
erable attention because it is an important substructure in a
range of pharmaceutical agents.8,9 Indeed, our laboratory has
reported several approaches for constructing these hetero-
cycles based on vinyl isocyanate cyclization chemistry.10
Scheme 1
(1) Gruseck, U.; Heuschmann, M. Chem. Ber. 1987, 120, 2053-
2064.
(2) Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28, 2681-
2684.
(3) Heuschmann, M. Chem. Ber. 1988, 121, 39-49.
(4) Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28, 6027-
6030.
(5) Quast, H.; Ivanova, S.; Peters, E.-M.; Peters, K.; Schnering, H. G.
Liebigs. Ann. 1996, 1541-1549.
(6) Quast, H.; Ach, M.; Kindermann, M. K.; Schindler, M. Chem. Ber.
1993, 126, 503-516.
(7) Rigby, J. H.; Wang, Z. Org. Lett. 2002, 4, 4289-4291.
(8) Girundon, M. F. The Alkaloids; The Chemical Society: London,
1977.
(9) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug
Synthesis; Wiley: New York, 1977.
10.1021/ol034263k CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/14/2003

Numerous other laboratories have disclosed approaches to
construct the pyridone moiety as well.11 However, these
approaches often require prolonged reaction times, harsh
reaction conditions, or a strong base.
Table 1. Reaction between Vinyl Isocyanates and
N,N-Dimethyl Ketene Aminal (4)
The relatively stable 2-methylene dihydrobenzimidazole
(4) was prepared using a precedure reported by Quast.5 A
variety of substituted and functionalized vinyl isocyanates
were used in this study to probe the scope and versatility of
the reaction. The vinyl isocyanates were generated easily and
cleanly through a Curtius rearrangement of the corresponding
vinyl acyl azides. The production of pyridone (5)12 is a
typical example of this protocol (Scheme 2).
Scheme 2
As shown in Table 1, several acyclic and cyclic substituted
4-amino pyridones were obtained through this process. One
benefit of this procedure is that the reaction required only 2
h to reach completion, while the reaction between conven-
tional enamines and vinyl isocyanates required reaction times
of at least 2 days to obtain reasonable yields and often
required much harsher reaction conditions as well. The
observations reported herein further confirm the strong
nucleophilicity of ketene aminals in comparison to other
enamines.
The result in entry 5, Table 1, is particularly noteworthy
in that acyclic isocyanates are often problematic reaction
partners in other cyclizations. Indeed, few enamines are
known to successfully engage acyclic isocyanates in produc-
tive reaction.10 Another distinctive feature of this process is
that the enamide function was obtained instead of the cyclic
aminal moiety. This allows for direct transformation into
various synthetically useful compounds, whereas the aminal
would require additional processing.
The successful formation of pyridone 7 (59%)12 through
reaction of cyclopentene isocyanate with 4 is another
significant outcome of this study (Scheme 3). Conventional
Scheme 3
(10) (a) Rigby, J. H.; Holsworth, D. D.; James, J. J. Org. Chem. 1989,
54, 4019-4020. (b) Rigby, J. H.; Burkhardt, F. J. J. Org. Chem. 1986, 51,
1374-1376. (c) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989,
54, 224-228. (d) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5852-
5853. (e) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1984, 49, 4569-
4571.
(11) For other pyridone syntheses, see: (a) Overman, L. E.; Tsuboi, S.;
Roos, J. P.; Taylor, G. F. J. Am. Chem. Soc. 1980, 102, 747-754. (b) Saunte,
F.; Serckx-Ponci, B.; Hesbain-Frisque, A.-M.; Ghosez, L. J. Am. Chem.
Soc. 1982, 104, 1428-1430. (c) Winters, G.; Sala, A.; DePaoli, A.; Ferri,
V. Synthesis 1984, 1052. (d) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.
J. Org. Chem. 1999, 64, 2038-2049. (e) Alberola, A.; Calvo, L. A.; Ortega,
A. G.; Ruiz, M. C.; Yustos, P.; Granda, G.; Garcia-Rodriguez, E. J. Org.
Chem. 1999, 64, 9493-9498. (f) Carles, L.; Narkunan, K.; Penlou, S.;
Rousset, L.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304-
4308. (g) Savarin, C. G.; Murry, J. A.; Dormer, P. G. Org. Lett. 2002, 4,
2071-2074.
enamines provided this pyridone in very modest yield, and
reactions with other 2π partners failed completely to deliver
pyridone products.
Another important difference between the current reaction
and previous enamine/isocyanate cyclizations is the ability
(12) All new compounds exhibit spectral (1H NMR, 13C NMR, IR) and
analytical (HRMS) data fully consistent with the assigned structures.
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Org. Lett., Vol. 5, No. 7, 2003

to construct quaternary carbon centers during the ring-
forming process as exemplified by the successful preparation
of 9,12 albeit in modest yield (Scheme 4). This represents a
Scheme 5
Scheme 4
reaction channel that is without precedent in our previous
six-membered heterocycle synthetic work10 but has been
observed in certain [4 + 1] cyclizations with carbenes.14
The putative mechanism of this cyclization is depicted in
Scheme 5. Treatment of isocyanate 1 with 2-methylene
dihydrobenzimidazole (4) would result in the formation of
zwitterionic iminium intermediate 10. This species could then
undergo cyclization to aminal 11, which is then further
transformed into the observed pyridone 12 via tautomeriza-
tion and elimination.15
tional enamines in reactions with vinyl isocyanates. The
ability of this N,N-dimethyl ketene aminal to deliver 4-amino-
pyridones rapidly and efficiently offers an attractive alterna-
tive approach to this class of heterocycles.
Further work is currently underway to explore the utility
of N,N-dimethyl ketene aminals for the synthesis of biologi-
cally significant compounds that possess a pyridone core
structure.
Acknowledgment. The authors wish to thank the Na-
tional Science Foundation for their generous support of this
research.
In summary, the nucleophilicity16 of 2-methylene dihy-
drobenzimidazole has been shown to be superior to conven-
Supporting Information Available: Characterization of
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Standard conditions: a solution of acyl azide (1 equiv) in benzene
or acetonitrile was refluxed for 1 h and then cooled to 0 °C. A solution of
2-methylene dihydrobenzimidazole in benzene or acetonitrile was added,
and the reaction was stirred at room temperature for 30 min and then
refluxed for 2 h, concentrated, and purified by column chromatography.
(14) (a) Rigby, J. H.; Laurent, S. J. Org. Chem. 1999, 64, 1766-1767.
(b) Rigby, J. H.; Laurent, S.; Dong, W.; Danca, M. D. Tetrahedron, 2000,
56, 10101-10111.
OL034263K
(16) For studies on the nucleophilicity of these species, see: Kuhn, N.;
Bohnen, H.; Kruetzberg, J.; Blaser, D.; Boese, R. J. Chem. Soc., Commun.
1993, 1136.
(15) Hydrolysis of the enamides has been problematic, but studies
continue in this direction.
Org. Lett., Vol. 5, No. 7, 2003
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