An Expedient Synthesis of Highly Functionalized Naphthyridones and Quinolines from a Common N-Aryl Pyridinone Template

Article abstract of DOI:10.1021/ol025950z

(Matrix Presented) We describe herein a new base-mediated process for the formation of N-arylpyridinones 2 and their use for the preparation of naphthyridones and quinolines. The cyclization of various hindered enamines with methyl propiolate proceeds eff

Full text of DOI:10.1021/ol025950z

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2071-2074
An Expedient Synthesis of Highly
Functionalized Naphthyridones and
Quinolines from a Common N-Aryl
Pyridinone Template
Ce´cile G. Savarin,* Jerry A. Murry, and Peter G. Dormer
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
cecile_saVarin@merck.com
Received March 29, 2002
ABSTRACT
We describe herein a new base-mediated process for the formation of N-arylpyridinones 2 and their use for the preparation of naphthyridones
and quinolines. The cyclization of various hindered enamines with methyl propiolate proceeds efficiently in the presence of NaOH to afford
the corresponding N-arylpyridinones. These substrates were then found to undergo subsequent cyclizations to afford highly functionalized
naphthyridones and quinolines.
Pyridinones, naphthyridones, and quinolines are important
heterocyclic templates. Many members of this class of
heterocycles have significant biological activity.1,2 As a result,
the preparation of these heterocycles has become of great
interest for the design of potential pharmaceutical agents.1-3
We recently required a flexible method for the preparation
of several members of this class of compounds. While many
of the known protocols are suitable for the preparation of
the parent heterocycle (Scheme 1),3 which can be function-
alized in later steps, we found it cumbersome and sometimes
Kondo, K.; Yamashita, H.; Nakaya, K.; Tanaka, M.; Kitano, K.; Kan, K.;
Tominaga, M.; Yabuuchi, Y. JP Patent WO 9401113, 1994. (j) Micheletti,
R.; Doods, H. N.; Turconi, M.; Sagrada, A.; Donetti, A.; Schiavi, B. G. EP
Patent 0382687A3, 1989.
(1) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Elsevier Science Ltd.: New York, 1996;
Vols. 5 (quinolines) and 7 (naphthyridones).
(2) For pyridinones, see: (a) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang,
H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem.
Soc. 2002 ASAP April 5. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 5,
674-676. (c) Chiba, T.; Takahashi, T. Chem. Pharm. Bull. 1985, 33, 2731-
2734. (d) Carlson, G. R. U.S. Patent 77-816051, 1980. For naphthyridones,
see: (e) Snyder, S. A.; Vosburg, D. A.; Jarvis, M. G.; Markgraf, J. H.
Tetrahedron 2000, 56, 5329-5335. (f) Markgraf, J. H.; Snyder, S. A.;
Vosburg, D. A. Tetrahedron Lett. 1998, 39, 1111-1112. (g) Sherlock, M.
H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.; Wong, S. C.; Kreutner, W.;
Bryant, R. W.; McPhail, A. T. J. Med. Chem. 1988, 31, 2108-2121. For
quinolines, see: (h) Mederski, W. K. R., Lefort, M., Germann, M.; Kux,
D. Tetrahedron 1999, 55, 12757-12770. (i) Ogawa, H.; Miyamoto, H.;
(3) A review of the relevant literature indicated that although pyridinones
had been formed from enamines and methyl propiolate, the N-aryl variant
had not been reported: Singh, B.; Lesher, G. Y.; Pluncket, K C.; Pagani,
E. D.; Bode, D. C.; Bentley, R. G.; Connel, M. J.; Hamel, L. T.; Silver, P.
J. J. Med. Chem. 1992, 35, 4858-4865 and references herein. Also, N-alkyl
â-amino ester and N-aryl â-enaminonitrile derivatives were shown to
efficiently undergo cyclization with unsaturated esters, whereas ketone
analogues proceeded in very low yield: (a) Erian, A. W.; Ali, M. S.;
Mohamed, N. R.; Gad, W. A.; Nada, A. A. Sci. Pharm. 1999, 67, 253-
262. (b) Wang, M.-X.; Miao, W.-S.; Cheng, Y.; Huang, Z.-T. Tetrahedron
1999, 55, 14611-14622. (c) Caballero, E.; Madrigal, B.; Medarde, M.;
Puebla, P.; Honores, Z.; Martin, E.; San Feliciano, A. ACH-Models Chem.
1998, 135, 457-473.
10.1021/ol025950z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/14/2002

Scheme 1
Table 1. Synthesis of N-Arylpyridinones
impossible to prepare several desired quinolines and naph-
thyridones of interest. In particular, naphthyridones and
quinolines containing a sterically hindered aryl group on the
amide nitrogen were not accessible by these approaches
(Scheme 2). Because this functionality could not be added
Scheme 2
on the amide moiety at a later stage of the synthesis, we
needed to design a new route that would incorporate the aryl
group in the early stages of the synthesis. We envisioned a
strategy involving the preparation of N-arylpyridinones as
templates, which could serve as precursors to the highly
functionalized naphthyridone and quinoline bicyclic deriva-
tives. In this communication we report a base-mediated
synthesis of N-arylpyridinones from 1,3-diketones, methyl
propiolate, and the corresponding aniline and demonstrate
their use in the efficient syntheses of naphthyridones and
quinolines.
We initiated our investigation by preparing various N-aryl
enamines of 1,3-diketones and investigated their subsequent
reaction with methyl propiolate and other appropriate
Michael acceptors. Sterically hindered enamines 1a,b were
obtained upon Dean Stark condensation of the ketone and
2,6-dichloroaniline with catalytic amount of p-TsOH in high
yields.4 These compounds were crystallized from the reaction
mixture and used without further purification. Enamines 1c,d
were obtained following the known literature procedures.5
The subsequent cyclization of the N-aryl enamine 1a was
next investigated. Employing the literature conditions3 (room
temperature to 100 °C in dioxane or DMF), we were unable
to observe any of the desired N-arylpyridinone. However,
we could effect the cyclization of enamine 1a to N-
arylpyridinone 2a in 50% yield by heating the mixture to
140 °C for 5 days. Under these reaction conditions, an excess
of methyl propiolate was required. Indeed, the desired
cyclization of the enamine to the methyl propiolate was
competing with the thermal cyclotrimerization of methyl
propiolate, giving benzene tricarboxylate as a substantial
byproduct. To improve the reaction conditions and yields,
the influence of Lewis acid catalysts (BF3 etherate, ZnCl2,
Ti(O-i-Pr)4) on the cyclization reaction was investigated with
moderate success. We were able to reduce the reaction time
to 1-2 days by using catalytic amount of p-TsOH or
(4) For reviews on the preparation of enamines: (a) Haynes, L. W. In
Enamines: Synthesis, Structure, and Reactions; Cook, A. G., Ed.; Marcel
Dekker: New York, 1969; pp 55-100. (b) Pitacco, G.; Valentin, E.; In
The Chemistry of Amino, Nitroso and Nitro Compounds and their
DeriVatiVes; Patai, S., Ed.; John Wiley & Sons: New York, 1982; Part 1,
Chapter 15, pp 624-714. (c) Boatman, S.; Hauser, C. R. J. Org. Chem.
1966, 31, 1785-1788. For a review on the addition of amines to triple
bonds: Chekulaeva, I. A.; Kondrat’eva, L. V. Russ. Chem. ReV. 1965, 34,
669.
(5) (a) Maroni, P.; Cazaux, L.; Tisnes, P.; Zambeti, M. Bull. Soc. Chim.
Fr. 1980, 2, 179-186. (b) Tsuge, O.; Koga, M.; Shinkai, I. Tetrahedron
1973, 29, 259-265.
2072
Org. Lett., Vol. 4, No. 12, 2002

MeSO3H and heating in DMAc, but the required tempera-
tures were still very high and resulted in undesired triester.
We next turned our attention to base catalysis. We were
pleased to find that premixing the enamine 1a with either
Na-tert-pentoxide or NaOH in THF, followed by adding
methyl propiolate, led to a much cleaner reaction at 50 °C.
Most importantly, the problematic benzene tricarboxylate was
not produced under these conditions. Other bases (NaOMe,
NaH, LiHMDS, KHMDS, Et3N, pyridine, DABCO, and
DBU) did not lead to improved reactions. The best results
were obtained using NaOH to provide the desired pyridone
2a-e in 51-70% yield (Table 1).
Table 2. Synthesis of Quinolines
The cyclization is believed to occur via a stepwise
mechanism: Michael addition of the deprotonated enamine
to methyl propiolate followed by amide formation (Scheme
3). The intermediate 5 resulting from the Michael addition
Scheme 3
desired N,N-dimethyl enamine intermediate. This crude
enamine was then treated with NH2OH‚HCl in DMF, and
the corresponding naphthyridone N-oxide 3 was precipitated
quantitatively out of water. It was possible to synthesize the
parent naphthyridone by substituting ammonium acetate for
NH2OH‚HCl; however, preparing the N-oxide opened room
for further functionalization of the naphthyridone ring.
Indeed, the naphthyridone N-oxide 3 could be further
functionalized by treatment with neat POCl3 to afford
chloronaphthyridone 3a in 75% yield. 2-Chloronaphthyri-
done 3a could be further functionalized by various transition-
metal-catalyzed cross-coupling reactions yielding 2-C and
N-substituted naphthyridones. This further demonstrates the
versatility of this methodology to prepare highly function-
alized naphthyridones.
of the enamine to methyl propiolate could be detected by
HPLC/MS, and the structure of the trans adduct was
confirmed by NMR.6
With a variety of key pyridinones in hand, we next turned
our attention to naphthyridone and quinoline formation. We
developed a one-pot, two-step protocol to provide the desired
naphthyridones (Scheme 4). First, N-arylpyridinone 2a was
Scheme 4
During the course of our study of the sodium-tert-
pentoxide mediated cyclization of enamine 1a and methyl
propiolate, a byproduct was observed. This product was
determined to be quinoline 4a and was formed in 41%
unoptimized yield using an excess of methyl propiolate and
base. Although this yield is marginal, it represents a one-
pot synthesis of a quinoline from an enamine and methyl
propiolate. Further investigation showed that N-arylpyridi-
nones 2a in the presence of sodium-tert-pentoxide and methyl
propiolate led to the same product in 91% yield at room
treated with Bredereck’s reagent7 in DMF to afford the
(6) The protonated form of intermediate 5 was identified after quenching
with TFA. See Experimental Section for details.
(7) For a similar use of the Bredereck’s reagent, see ref 3.
Org. Lett., Vol. 4, No. 12, 2002
2073

Scheme 5
Scheme 6
demonstrated their use for the preparation of N-arylnaph-
thyridones and quinolines. These protocols are especially
attractive as they allow for the synthesis of these specifically
functionalized heterocycles in very few steps. Expanding the
scope of this methodology to include hindered tertiary alkyl
substituents as well as applying it to the synthesis of other
interesting heterocycles will be the focus of future work.
temperature (Scheme 5). Disubstituted alkynes could also
be reacted with N-arylpyridinone, yielding other substituted
quinolines 4b,c albeit in lower yields (Table 2).
Acknowledgment. We thank Drs. Z. Guan and B. Choi
for their help performing the high resolution mass spectrom-
etry analysis. We acknowledge Drs. David Hughes, Paul
Reider, Edward J. J. Grabowski, and Richard Tillyer for their
help in editing this manuscript and Dr. Jeff Marcoux for
helpful discussion.
A proposed mechanism for the quinoline synthesis is
depicted in Scheme 6. The sequence is triggered by depro-
tonation of the R-methyl group, which produces a vinologous
enolate. This enolate then reacts with methyl propiolate by
either a concerted reaction or a stepwise Michael addition-
aldol condensation. NMR experiments confirmed the forma-
tion of the vinologous enolate 6 when N-arylpyridinone 2a
was treated with sodium-tert-pentoxide in THF-d8.
Supporting Information Available: Experimental details
and characterization for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, we have demonstrated a base-mediated
synthesis of N-arylpyridinones under mild conditions and
OL025950Z
2074
Org. Lett., Vol. 4, No. 12, 2002