A facile and efficient synthesis of polyfunctionalized pyridin-2(1H)-ones from β-oxo amides under Vilsmeier conditions

Article abstract of DOI:10.1021/ol702846t

(Chemical Equation Presented) A facile and efficient one-pot synthesis of polysubstituted pyridin-2(1H)-ones from a variety of β-oxo amides under Vilsmeier conditions is described, and a mechanism involving sequential halogenation, formylation and intramo

Full text of DOI:10.1021/ol702846t

ORGANIC
LETTERS
2008
Vol. 10, No. 2
345-348
A Facile and Efficient Synthesis of
Polyfunctionalized Pyridin-2(1H)-ones
from
Conditions
â-Oxo Amides under Vilsmeier
Dexuan Xiang,† Kewei Wang,† Yongjiu Liang,‡ Guangyuan Zhou,*,‡ and
Dewen Dong*,†,‡
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, China,
and Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130022, China
dongdw663@nenu.edu.cn
Received November 25, 2007
ABSTRACT
A facile and efficient one-pot synthesis of polysubstituted pyridin-2(1H)-ones from a variety of
â
-oxo amides under Vilsmeier conditions is
described, and a mechanism involving sequential halogenation, formylation and intramolecular nucleophilic cyclization is proposed.
The vast number of bioactive natural products and pharma-
ceutical drugs based on the pyridin-2(1H)-one ring system,
such as elfamycin and ilicolicin, have become very important
in the area of natural product and pharmacetical chemistry.1,2
In addition, functionalized pyridin-2(1H)-ones have been
used as versatile intermediates in the synthesis of a wide
range of nitrogen-containing heterocycles, such as pyridine,
piperidine, quinolizidine, and indolizidine alkaloids.3,4 Ex-
tensive work has generated many synthetic approaches for
pyridin-2(1H)-ones involving pyridinium salt chemistry,5
Guareschi-Thorpe reaction,6 Dieckmann-type condensation,7
hetero Diels-Alder reaction,8 and metal-mediated cycload-
dition.9 Other notable methods starting from polarized ketene
S,S- and N,N-acetals were reported.10 However, many of the
established approaches are still severely limited in their use
by the lack of substrate scope and selectivity, the harsh
(4) (a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
(b) Jayasinghe, L.; Abbas, H. K.; Jacob, M. R.; Herath, W. H. M. W.;
Nanayakkara, N. P. D. J. Nat. Prod 2006, 69, 439. (c) Angibaud, P. R.;
Venet, M. G.; Filliers, W.; Broeckx, R; Ligny, Y. A.; Muller, P.; Poncelet,
V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479. (d) Litvinov, V. P. Russ.
Chem. ReV. 2003, 72, 69.
(5) (a) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623. (b)
Du, W. Tetrahedron, 2003, 59, 8649. (c) Comins, D. L.; Gao, J. L.
Tetrahedron Lett. 1994, 35, 2819. (d) Hu, T.; Li, C. Org. Lett. 2005, 7,
2035. (e) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2004, 10, 5607.
† Northeast Normal University.
‡ Chinese Academy of Sciences.
(1) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1981;
Vol. 5, p 1. (b) Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. ReV. 2000,
20, 231. (c) Nagarajan, M.; Xiao, X. S.; Antony, S.; Kohlhagen, G.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2003, 46, 5712.
(2) (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691.
(b) Cox, R. J.; O’Hagan, D. J. Chem. Soc., Perkin Trans. 1 1991, 2537.
(3) (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 5, p 167. (b) Scriven, E. F. V. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 2.
(6) (a) Baron, H.; Renfry, H.; Thorpe, J. J. Chem. Soc. 1904, 85,
1726. (b) Aggarwal, V.; Sing, G.; Ila, H.; Junjappa, H. Synthesis 1982,
214.
(7) Chung, K. H.; Cho, K. Y.; Asami, Y.; Takahashi, N.; Yoshida, S.
Heterocycles 1991, 32, 4040.
(8) (a) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Tetrahedron
Lett. 2004, 45, 9557. (b) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque,
A.; Ghosez, L. J. Am. Chem. Soc. 1982, 104, 1428.
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10.1021/ol702846t CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/28/2007

reaction conditions involved, or the multistep procedure
required. Therefore, to match the increasing scientific and
practical demands, it is still of continued interest and great
importance to explore simple and efficient synthetic ap-
proaches for the construction of pyridin-2(1H)-ones, espe-
cially those with wide applicability to achieve more elaborate
and flexible substitution patterns.
Halogenated pyridin-2(1H)-ones are an important subset
of pyridin-2(1H)-ones, which have been utilized as useful
intermediates for the synthesis of various aza-heterocycles
and evaluated as a scaffold in natural product synthesis.11
Unfortunately, the most available approaches for accessing
pyridin-2(1H)-ones are not general for the preparation of
halogenated pyridin-2(1H)-ones. To date, the direct synthesis
of such halogenated heterocycles from acyclic substrates is
much less documented.12 Chen et al. recently reported the
synthesis of 4-halogenated pyridin-2(1H)-ones from R-oxo
ketene S,S-acetals (Scheme 1).13
combination of construction of the pyridin-2(1H)-one skel-
eton and creation of its dense substitution patterns. In
connection with these studies and the aim to extend the
substrate scope and further clarify the mechanism involved,
we examined the reactions of a variety of â-oxo amides under
different Vilsmeier conditions. By this research, we achieved
a facile and efficient synthesis of polysubstituted pyridin-
2(1H)-ones in good to high yields. Herein, we report our
experimental results and present a proposed mechanism for
the cyclization.
The substrates, R-monosubstituted â-oxo amides 1, were
prepared from commercially available R-unsubstituted â-oxo
amides and alkyl bromides in the presence of K2CO3 in high
yields. A few of the alkylation products 1 were purified and
characterized with the help of spectral and analytical data,
whereas in the subsequent reactions, they are used as
obtained without further purification.
Thus, the Vilsmeier cyclization of 2-benzyl-3-oxo-N-
phenyl butanamide 1a was initially attempted. Upon treat-
ment of 1a with Vilsmeier reagent PBr3/DMF (3.0 equiv)
below 60 °C, the resulting mixture quickly became viscous,
and finally turned into a brown solid. Unfortunately, no major
product could be isolated from the intractable reaction
mixture. When 1a was heated with PBr3/DMF (3.0 equiv)
at 70 °C for 3.0 h, the reaction proceeded smoothly as
indicated by TLC and furnished a white solid after workup
and purification by column chromatography of the resulting
reaction mixture. From the spectral and analytical data, the
exclusive product was characterized as 5-benzyl-4-bromo-
6-oxo-1-phenyl-1,6-dihydropyridine-3-carbaldeh-yde 2a1
(Scheme 2). The reaction conditions, including reaction
Scheme 1. Synthesis of Halogenated Pyridin-2(1H)-ones via
Vilsmeier-Haack Reactions
Scheme 2. Reaction of 1a with POCl3/DMF
During the course of our studies on Vilsmeier-Haack
reactions,14 we developed a facile one-pot synthesis of
halogenated pyridin-2(1H)-ones from either cyclopropyl
amides or cyclic enaminones under Vilsmeier conditions
(Scheme 1).15 The significance of the protocol relies on the
temperature and the feed ratio of 1a and PBr3/DMF, were
then investigated. A series of experiments revealed that 3.0
equiv of PBr3/DMF was effective for the synthesis of 2a1,
and the optimal results were obtained when the reaction of
1a was carried with 5.0 equiv of PBr3/DMF at 80 °C for 2.0
h, whereby the yield of 2a1 reached 71% (Table 1, entry 1).
(10) (a) Anabha, E. R.; Asokan, C. V. Synthesis 2006, 151. (b)
Chakrabarti, S.; Panda, K.; Misara, N. C.; Ila, H.; Junjappa, H. Synlett 2005,
1437. (c) Mahata, P. K.; Syam, Kumar, U. K.; Sriram, V.; Ila, H.; Junjappa,
H. Tetrahedron 2003, 59, 2631.
(11) (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.; Volante, R. P. Tetrahedron Lett. 1994, 35, 9355.
(12) (a) 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. (b) Agami,
C.; Dechoux, L.; Hebbe, S.; Moulinas, J. Synthesis 2002, 79. (c) Adams,
J.; Hardin, A.; Vounatsos, F. J. Org. Chem. 2006, 71, 9895.
(13) Chen, L.; Zhao, Y.; Liu, Q.; Cheng, C.; Piao, C. J. Org. Chem.
2007, 72, 9259.
(14) (a) Sun, S.; Liu, Y.; Liu, Q.; Zhao, Y.; Dong, D. Synlett 2004, 1731.
(b) Liu, Y.; Dong, D.; Liu, Q.; Qi, Y.; Wang, Z. Org. Biomol. Chem. 2004,
2, 28. (c) Dong, D.; Liu, Y.; Zhao, Y.; Qi, Y.; Wang, Z. Liu, Q. Synthesis
2005, 85.
Having established the optimal conditions for the cycliza-
tion, we intended to determine its scope with respect to the
amide motif. Thus, a series of R-benzyl â-oxo amides 1b-e
were subjected to PBr3/DMF (5.0 equiv) at 80 °C, and some
of the results are summarized in Table 1. The efficiency of
the cyclization proved to be suitable for 1b-e bearing
variable aryl and alkyl amide groups affording the corre-
sponding substituted pyridin-2(1H)-ones 2b1-e1 in good
yields (Table 1, entries 2-5). The versatility of this facile
pyridin-2(1H)-one synthesis was evaluated by performing
the Vilsmeier reaction on â-oxo amides 1f-o with different
(15) (a) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.;
Liu, Q. Org. Lett. 2007, 9, 2421. (b) Xiang, D.; Yang, Y.; Zhang, R.; Liang,
Y.; Pan, W.; Huang, J.; Dong, D. J. Org. Chem. 2007, 72, 8693.
346
Org. Lett., Vol. 10, No. 2, 2008

and reported that two isomeric 2-arylimino-4-chloro-2H-
pyrancarboxaldehydes were obtained.16 These studies in-
spired us to recheck the reaction of R-unsubstituted â-oxo
amides 1 under Vilsmeier conditions. Thus, the reaction of
3-oxo-N-phenylbutanamide 1p was performed with POCl3/
DMF at 80 °C for 2.0 h. As indicated by TLC, two main
products were formed. Workup and purification of the
resulting reaction mixture furnished two products, which
surprisingly were characterized as 4-chloro-6-oxo-1-phenyl-
1,6-dihydropyridine-3-carbaldehyde (2p2) and 4-chloro-2-
oxo-1-phenyl-1,2-dihydropyridine-3-carbaldehyde (3p2) on
the basis of the spectral and analytical data (Scheme 3). The
Table 1. Vilsmeier-Haack Reaction of â-Oxo Amides 1a
entry
1
R1
R2
X
2
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
4-MePh
4-MeOPh Bn
4-ClPh
Me
Ph
4-MePh
4-MeOPh Me
2-MePh
Ph
4-MePh
Bn
Bn
Br 2a1
Br 2b1
Br 2c1
Br 2d1
Br 2e1
Br 2f1
Br 2g1
Br 2h1
Br 2i1
Br 2j1
Br 2k1
Br 2l1
71
67
54
74
62
68
65
53
41
69
63
58
70
72
55
68
63
60
73
71
Bn
Bn
Me
Me
Scheme 3. Reactions of 1p/1q with POCl3/DMF
Me
allyl
allyl
1j
1k
1l
4-MeOPh allyl
1m Ph
CH2COOEt Br 2m1
CH2COOEt Br 2n1
1n
1o
1a
1b
1c
1d
1f
4-MePh
4-MeOPh CH2COOEt Br 2o1
Ph
4-MePh
4-MeOPh Bn
4-ClPh
Ph
Bn
Bn
Cl 2a2
Cl 2b2
Cl 2c2
Cl 2d2
Cl 2f2
Bn
Me
structure of 2p2 was further confirmed by the X-ray single-
crystal analysis (Figure 1). Comparison of NMR spectra
a Reagents and conditions: 1 (1.0 mmol), POCl3/DMF or PBr3/DMF
(5.0 mmol), 80 °C, 2.0-3.0 h. b Isolated yields.
substituted groups, e.g., methyl, allyl, and ethyl methylene
carboxy (-CH2COOEt), at R position. All the reactions of
1f-o with Vilsmeier reagent, PBr3/DMF, proceeded smoothly
to give the corresponding substituted pyridin-2(1H)-ones
2f1-o1 in moderate to good yields (Table 1, entries 6-15).
Lower yield was observed in the case of 1i (Table 1, entry
9), which might stem from the steric hindered effect of the
ortho-substituted methyl group on the benzene ring of aryl
amide.
The protocol was next extended for the synthesis of
4-chloropyridin-2(1H)-ones by subjecting â-oxo amides 1
to the cyclization with a different type of Vilsmeier reagent,
POCl3/DMF. Thus, the reaction of 1a with POCl3/DMF (5.0
equiv) was conducted at 80 °C for 2.0 h. Workup and
purification of the resulting mixture afforded only one
product, which was characterized as 5-benzyl-4-chloro-6-
oxo-1-phenyl-1,6-dihydropyridine-3-carbaldehyde (2a2) on
the basis of the spectral and analytical data (Table 1, entry
16). Similarly, â-oxo amides 1b-d and 1f underwent rapid
spontaneous Vilsmeier cyclization to furnish the respective
substituted pyridin-2(1H)-ones 2 in good yields (Table 1,
entry 17-20). The results shown above have demonstrated
the efficiency and interest of the cyclization reaction for the
synthesis of halogenated pyridin-2(1H)-ones 2 with respect
to substrates 1 bearing variable amide and R-alkyl functional
groups, i.e., R1 and R2.
Figure 1. ORTEP drawing of 2p2.
between 2p2 and 3p2 led us further confirm the structure of
3p2 without difficulty. In the 1H NMR spectra, 2p2 displayed
three single peaks at δ 6.73, 8.19, and 10.08, respectively,
which were assigned to 5-H, 2-H, and 3-formyl hydrogen
of pyridin-2(1H)-one ring. With respect to 3p2, two single
peaks disappeared, while two doublet peaks (J ) 7.0 Hz)
were observed, one at δ 6.40 for 5-H and another at δ 7.36
for 6-H. The single peak at δ 10.39 was assigned to the
3-formyl hydrogen of 3p2. In the 13C NMR spectra of 3p2,
the peak for the 3-formyl carbon appeared at δ 188.5.
In contrast with our results, Amaresh and co-workers
investigated the Vilsmeier-Haack reaction of â-oxo amides
(16) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1999, 55, 8083.
Org. Lett., Vol. 10, No. 2, 2008
347

Additionally, from mass spectrometry analysis, same mo-
lecular ion peaks were observed for 2p2 and 3p2 (233.6-
[M]+). This is consistent with the NMR results, and confirms
that 2p2 and 3p2 are a pair of isomers. In the same fashion,
chlorogenated pyridin-2(1H)-ones 2q2 and 3q2 were ob-
tained in 35% and 30% yields, respectively (Scheme 3). The
results reveal that the cyclization efficiency of R-unsubsti-
tuted â-oxo amides 1 to 2 is suitable, and therefore the
previous report by Amaresh and co-workers on the structural
identity and proposed mechanism seems to be ambiguous.16
To gain insight into the mechanism of the cyclization, a
separate experiment was conducted. The reaction of 1a with
5.0 equiv of Vilsmeier reagent (POCl3/DMF) was performed
at 80 °C for 10 min and then quenched with water.
Compounds 4a and 2a2 were obtained in 47% and 25%
yields, respectively (Scheme 4).
Scheme 5. Plausible Mechanism of the Vilsmeier-Haack
Reaction of â-Oxo Amides 1
Scheme 4. Reaction of 1a with POCl3/DMF
On the basis of all the results obtained, a plausible
mechanism for the synthesis of substituted pyridin-2(1H)-
ones of types 2 and 3 is presented in Scheme 5. The overall
transformation commences from the halogenation of 1,
mediated by Vilsmeier reagent, to generate enolate A, which
can be converted into compound 4 upon treatment with
water. Activated by the adjacent enolate, sequential Vils-
meier-Haack reactions of the acetyl group of A leads to
the formation of intermediates B and C,17 and intramolecular
aza-cyclization reaction of C gives the intermediate D, which
is exclusively converted into substituted pyridin-2(1H)-ones
of type 2. In another pathway, intermediate B undergoes
intramolecular aza-cyclization to E, which also can be
transformed into intermediate D and finally to 2. When R2
is H, a competitive, regioselective formylation occurs on E
to give intermediates D and F, the latter leads the formation
of pyridin-2(1H)-ones of type 3.
In summary, a facile and efficient one-pot synthesis of
polyfunctionalized pyridin-2(1H)-ones of types 2 and 3 has
been developed from the Vilsmeier-Haack reaction of
readily available R-monosubstituted/unsubstituted â-oxo
amides 1, which involves sequential halogenation, formy-
lation, and intramolecular nucleophilic cyclization reactions.
This protocol is associated with readily available starting
materials, mild conditions, high yields, a wide range of
substrate scope, dense and flexible substitution patterns, and
important synthetic potential of the final products.
Acknowledgment. Financial support of this research by
the National Natural Science Foundation of China (20572013
and 20711130229) is greatly acknowledged.
Supporting Information Available: Experimental details
and spectral characterization data for 1-4. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) (a) Marson, C. M. Tetrahedron 1992, 48, 3659. (b) Thomas, A. D.;
Asokan, C. V. Tetrahedron 2004, 60, 5069.
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