tuted 2-pyridinones is from acyclic starting materials which often
incorporate a Michael addition as the key synthetic step.7
However, these methods are not general for the preparation of
halogenated or N-substituted 2(1H)-pyridinones which are
essential for further elaboration of the 2(1H)-pyridinone core.8
To the best of our knowledge, only one method has been
reported in the literature describing the synthesis of halogenated
N-substituted 2(1H)-pyridinones starting from acyclic substrates.
Dechoux and co-workers recently reported a synthetic route to
this class of compounds which centered on a Michael-type
addition between an amine and a methyl propiolate followed
by bromocyclization of the ensuing δ-dienaminoester (Scheme
1).9 This method was demonstrated with benzyl amine substrates
and required long reaction times (ca. 48 h). As such, an
extension of this methodology for the preparation of polysub-
stituted 3-bromo-2(1H)-pyridinones that facilitates functional
group variation on the pyridone nucleus, as well as reduced
reaction times, is highly desirable.
Microwave-Assisted Synthesis of New
Polysubstituted Dienaminoesters and Their
Cyclization to 3-Bromo-2(1H)-Pyridinones
Jeff Adams, Alison Hardin, and Filisaty Vounatsos*
Chemistry Process Research and DeVelopment, Custom
Synthesis Laboratory, Amgen Inc., One Amgen Centre DriVe,
Thousand Oaks, California 91320
ReceiVed September 7, 2006
Herein, we report that a variety of δ-dienaminoesters were
prepared via microwave-assisted Michael-type additions em-
ploying methyl propiolate and a variety of amines. In addition
to providing access to diene derivatives, the products can be
easily telescoped and transformed into polysubstituted 3-bromo-
2(1H)-pyridinones 3 via microwave-assisted bromocyclization
(Scheme 2).10
A microwave-assisted, telescoped synthesis, involving a
Michael-type addition followed by intramolecular cyclization,
provides an effective entry to the polysubstituted 3-bromo-
2(1H)-pyridinone core.
The effect of microwave heating on the aforementioned
Michael-type addition was hoped to show a reduction in reaction
times from the previously reported 2 days to minutes. Table 1
shows the variation in time (min), temperature (°C), and
equivalents of methyl propiolate (5) tested to find the optimum
conditions for the microwave-assisted reaction. The initial
conditions (entry 1) did not fully convert all of the starting
materials to δ-dienaminoester, and instead, they resulted in a
mixture of δ-dienaminoester (6)/enaminoester (7) addition
products in a ratio of 1:2.11 Prolonged reaction times (entries 2
and 3) resulted in a modest improvement of the ratio to 2:1.
The use of 2.5 equiv of methyl propiolate and systematically
increasing the reaction temperature from 80 to 110 °C resulted
in higher ratios of δ-dienaminoester formation (entries 4-7).
With increasing frequency, molecules possessing a 3-bromo-
2(1H)-pyridinone ring system, such as that represented by 3,
are being evaluated as useful platforms in natural product
synthesis1 and are of particular interest as potential therapeutics.2
Furthermore, the 3-bromo-2(1H)-pyridinone core is a common
template utilized for the synthesis of a wide variety of nitrogen
heterocycles such as pyridine, piperidine, quinolizidine, and
indolizidine alkaloids.3
Several methods have been developed for the synthesis of
these compounds which include, among others,4-6 oxidation of
pyridinium salts to produce the corresponding 2-pyridinones,4a
cycloaddition of 2(1H)-pyrizinones with (m)ethyl propynoate
to give amino-substituted pyridinone derivatives,5 and intramo-
lecular vinylketene cyclizations onto the CdN bond of nitrogen
heteroaromatics to provide access to ring-fused pyrid-5-ones.6a
Although useful, most of these methods have limited substrate
scope, require harsh reaction conditions, and often require
several steps. The most general approach for accessing substi-
(7) (a) Aggarwal, V.; Singh, G.; Ila, H.; Junjappa, H. Synthesis 1982,
214. (b) Datta, A.; Ila, H.; Junjappa, H. J. Org. Chem. 1990, 55, 5589. (c)
Chuit, C.; Corriu, R. J. P.; Perz, R.; Reye, C. Tetrahedron 1986, 42, 2293.
(d) Cainelli, G.; Panunzio, M.; Giacomini, D.; Di Simone, B.; Camerini,
R. Synthesis 1994, 805. (e) Marcoux, J. F.; Marcotte, F. A.; Wu, J.; Dormer,
P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem. 2001, 66,
4194.
(8) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Choi,
W. B.; Houpis, I. N.; Churchill, H.; Molina, O.; Lynch, J. E.; Volante, R.
P.; Reider, P. J.; King, A. O. Tetrahedron Lett. 1995, 36, 4571. (c) Houpis,
I. N.; Choi, W. B.; Reider, P. J.; Molina, O.; Churchill, H.; Lynch, J. E.;
Volante, R. P. Tetrahedron Lett. 1994, 35, 9355. (d) Domagala, J. M. J.
Heterocycl. Chem. 1984, 21, 1705.
(9) Agami, C.; Dechoux, L.; Hebbe, D.; Moulinas, J. Synthesis 2002, 1,
79.
(10) For cyclizations of dehalogenated δ-dienaminoesters, see: (a) Cocco,
M. T.; Congiu, C.; Maccioni, A.; Onnis, V. Synthesis 1992, 371. (b) Palacios,
F.; Garcia, J.; Ochoa de Retana, A.; Oyarzabal, J. Heterocycles 1995, 41,
1915.
(1) (a) Wagenaar, M. M.; Gibson, D. M.; Clardy, J. Org. Lett. 2002, 4,
671. (b) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691.
(2) Pierce, J. B.; Ariyan, Z. S.; Ovenden, G. S. J. Med. Chem. 1982, 25,
131.
(3) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In ComprehensiVe
Heterocyclic Chemistry; Pergamon Press: Oxford, 1996; Vol. 5.
(4) (a) Decker, H. Chem Ber. 1892, 25, 443 (b) Sieburth, S. M.; Hiel,
G.; Lin, C. H.; Kuan, D. P. J. Org. Chem. 1994, 59, 80. (c) Comins, D. L.;
Jianhua, G. Tetrahedron Lett. 1994, 35, 2819. (d) Schmidhauser, J. C.;
Khouri, F. F. Tetrahedron Lett. 1993, 34, 6685. (e) Sieburth, S. M.; Chen,
J. L. J. Am. Chem. Soc. 1991, 113, 8163.
(5) (a) Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J.;
Hoornaert, G. J. J. Org. Chem. 1992, 57, 2935. (b) Padwa, A.; Sheehan, S.
M.; Straub, C. S. J. Org. Chem. 1999, 64, 8648.
(6) (a) Gurski Birchler, A.; Liu, F.; Liebeskind, L. S. J. Org. Chem.
1994, 59, 7737. (b) Zhang, S.; Liebeskind, L. S. J. Org. Chem. 1999, 64,
4042.
(11) Dienaminoesters of type 6 were first reported by Bottomley who
observed that an excess of methyl propiolate reacted with primary amines
at 100 °C to give diadducts by a two-stage mechanism proceeding via an
enaminoester (7). See: (a) Bottomley, W. Tetrahedron Lett. 1967, 21, 1997.
(b) Bottomley, W.; Phillips, J. N.; Wilson, J. G. Tetrahedron Lett. 1967,
31, 2957.
10.1021/jo0618526 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/22/2006
J. Org. Chem. 2006, 71, 9895-9898
9895