Vilsmeier-haack reactions of 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans toward the synthesis of highly substituted pyridin-2(1H)-ones

Article abstract of DOI:10.1021/jo7015482

(Chemical Equation Presented) A facile and efficient one-pot synthesis of highly substituted pyridin-2(1H)-ones was developed via Vilsmeier-Haack reactions of readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro-4H- pyrans, and a mechanism invol

Full text of DOI:10.1021/jo7015482

and metal-mediated cycloaddition.7-10 Each of these approaches
represents an important advance toward the objective of a
general method for the synthesis of pyridin-2(1H)-ones, how-
ever, some of them are still severely limited in their use by
their lack of generality, the harsh reaction conditions involved,
poor yields, a multistep procedure, or the formation of complex
mixtures of side products. In light of this, simple and efficient
synthetic protocols for the construction of more elaborate and
usefully functionalized pyridin-2(1H)-ones are still in demand.
On the other hand, the Vilsmeier-Haack reaction associated
with its mild reaction condition, commercial viability of the
reagents, and improved understanding of the reaction mechanism
has been widely used for the formylation of activated aromatic
compounds and carbonyl compounds.11 The versatile reactivity
of carbonyl compounds with halomethylene iminium salts and
a variety of cyclization reactions leading to heterocyclic
compounds induced by the Vilsmeier reagent have been well-
documented.12 In our recent work, we have demonstrated the
Vilsmeier-Haack Reactions of
2-Arylamino-3-acetyl-5,6-dihydro-4H-pyrans
toward the Synthesis of Highly Substituted
Pyridin-2(1H)-ones
Dexuan Xiang,† Yang Yang,† Rui Zhang,‡ Yongjiu Liang,‡
Wei Pan,† Jie Huang,† 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 July 15, 2007
(3) (a) Jones, G. Pyridines and Their Benzo Derivatives: Synthesis. In
ComprehensiVe Heterocyclic Chemistry II; McKillop, A., Ed.; Pergamon
Press: Oxford, 1996; Vol. 5, p 167. (b) Scriven, E. F. V. Pyridines and
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Chem. ReV. 2003, 72, 69.
A facile and efficient one-pot synthesis of highly substituted
pyridin-2(1H)-ones was developed via Vilsmeier-Haack
reactions of readily available enaminones, 2-arylamino-3-
acetyl-5,6-dihydro-4H-pyrans, and a mechanism involving
sequential ring-opening, haloformylation, and intramolecular
nucleophilic cyclization reactions is proposed.
(5) (a) Decker, H. Chem. Ber. 1892, 25, 443. (b) Comins, D. L.; Saha,
J. K. J. Org. Chem. 1996, 61, 9623. (c) Du, W. Tetrahedron 2003, 59,
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Over the past decades, pyridin-2(1H)-ones have emerged as
an important class of organic heterocycles since they are
distributed in numerous natural products and synthetic organic
compounds along with diverse useful bioactivities.1 In particular,
they constitute the skeleton of elfamycin antibiotics and the
antifungal compound ilicolicin.2 The pharmacological impor-
tance of pyridin-2(1H)-ones and their utility as versatile
intermediates in the synthesis of a wide variety of nitrogen
heterocycles, such as pyridine, piperidine, quinolizidine, and
indolizidine alkaloids, have directed considerable research
activity toward the construction of the skeleton of such kinds
of heterocycles.3,4 Many synthetic approaches for pyridin-2(1H)-
ones have been developed involving either the modification of
the pre-constructed heterocyclic ring by pyridinium salt chem-
istry and N-alkylation5,6 or through the construction of the
heterocyclic skeleton from appropriately substituted acyclic
precursors via Guareschi-Thorpe reactions, intramolecular
Dieckmann-type condensation, hetero Diels-Alder reactions,
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Hu, T.; Li, C. Org. Lett. 2005, 7, 2035. (c) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem.sEur. J. 2004, 10, 5607.
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(b) Aggarwal, V.; Sing, G.; Ila, H.; Junjappa, H. Synthesis 1982, 214. (c)
Gibson, K. R.; Hitzel, L.; Mortishire-Smith, R. J.; Gerhard, U.; Jelley, R.
A.; Reeve, A. J.; Rowley, M.; Nadin, A.; Owens, A. P. J. Org. Chem. 2002,
67, 9354.
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Heterocycles 1991, 32, 4040.
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Lett. 2004, 45, 9557. (b) Sainta, F.; Serckx-Poncin, B.; Hesbain-Frisque,
A. M.; Ghosez, L. J. Am. Chem. Soc. 1982, 104, 1428.
(10) (a) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787. (b)
Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117. (c) Padwa,
A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64, 8648. (d) Padwa,
A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368.
(11) (a) Jones, G.; Stanforth, S. P. The Vilsmeier Reaction of Non-
Aromatic Compounds. In Organic Reactions; Jones, G., Stanforth, S. P.,
Eds.; John Wiley: New York, 2000; Vol. 56, p 355. (b) Jutz, C. Iminium
Salts in Organic Chemistry. In AdVances in Organic Chemistry; Bo¨hme,
H., Viehe, H. G., Eds.; John Wiley: New York, 1976; Vol. 9, Part I, p
225.
(12) (a) Marson, C. M. Tetrahedron 1992, 48, 3659. (b) Tebby, J. C.;
Willetts, S. E. Phosphorus, Sulfur Silicon Relat. Elem. 1987, 30, 293. (c)
Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J.
Org. Chem. 2003, 68, 3966. (d) Smeets, S.; Asokan, C. V.; Motmans, F.;
Dehaen, W. J. Org. Chem. 2000, 65, 5882. (e) Gangadasu, B.; Narender,
P.; Bharath Kumar, S.; Ravinder, M.; Ananda Rao, B.; Ramesh, C.; China
Raju, B.; Jayathirtha Rao, V. Tetrahedron 2006, 62, 8398. (f) Amaresh, R.
R.; Perumal, P. T. Tetrahedron 1999, 55, 8083. (g) Thomas, A. D.; Asokan,
C. V. Tetrahedron 2004, 60, 5069. (h) Meth-Cohn, O.; Narine, B.
Tetrahedron Lett. 1978, 19, 2045. (i) Meth-Cohn, O.; Tarnowski, B. AdV.
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* Corresponding author. Fax: +86(431)85098635.
† Northeast Normal University.
‡ Chinese Academy of Sciences.
(1) (a) Elbein, A. D.; Molyneux, R. J. The Chemistry and Biochemistry
of Simple Indolizidine and Related Polyhydroxy Alkaloids. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New
York, 1987; 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.
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(b) Cox, R. J.; O’Hagan, D. J. Chem. Soc., Perkin Trans 1 1991, 2537.
10.1021/jo7015482 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/04/2007
J. Org. Chem. 2007, 72, 8593-8596
8593

TABLE 1. Vilsmeier-Haack Reactions of 5,6-Dihydro-4H-pyrans
SCHEME 1
2a
SCHEME 2. Vilsmeier-Haack Reaction of 2a
entry
2
Ar
X
3
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2b
2c
2d
2e
2f
2g
2h
2a
2b
2c
2d
2e
2f
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
91
84
82
88
85
86
79
89
90
88
81
86
84
86
83
87
4-MePh
4-MeOPh
4-ClPh
2-MePh
2-MeOPh
2-ClPh
2,4-Me2Ph
Ph
4-MePh
4-MeOPh
4-ClPh
utility of the Vilsmeier reagent in the synthesis of functionalized
heterocycles, such as substituted 2H-pyrans, pyridines, and
pyridin-2(1H)-ones.13 Thus, in connection with the previous
work and following with our interest in the synthesis of highly
valuable heterocycles from â-oxo amide derivatives,14 we
synthesized a series of enaminones (i.e., 2-arylamino-3-acetyl-
5,6-dihydro-4H-pyrans) and examined their reactivity toward
different Vilsmeier reagents. As a result, we report herein a
convenient and efficient synthesis of highly substituted pyridin-
2(1H)-ones 3 via the Vilsmeier-Haack reactions of the readily
available 5,6-dihydro-4H-pyrans 2.
2-MePh
2-MeOPh
2-ClPh
2g
2h
2,4-Me2Ph
a Reagents and conditions: (i) For entries 1-8: PBr3/DMF (5.0 equiv),
80 °C, 0.5-2.0 h. (ii) For entries 9-16: POCl3/DMF (5.0 equiv), 20 °C,
2.0-3.0 h. b Isolated yields.
The substrates 2 were synthesized from commercially avail-
able â-oxo amides 1 and 1,3-dibromoethane in the presence of
K2CO3 in DMF in excellent yields (up to 96%, Scheme 1). With
substrates 2 in hands, we selected 2-phenylamino-3-acetyl-5,6-
dihydro-4H-pyran 2a as the model compound to examine its
behavior under different conditions.
to be suitable for 5,6-dihydro-4H-pyrans 2b-h affording the
corresponding substituted pyridin-2(1H)-ones 3b-h in high
yields (Table 1, entries 2-8).
To extend the scope of this protocol, we next examined the
pyridin-2(1H)-one synthesis from 2 with a different type of
Vilsmeier reagent, POCl3/DMF, under the otherwise identical
conditions. Thus, the reaction of 2a with POCl3/DMF (5.0 equiv)
was conducted at 80 °C for 2 h, as indicated by TLC for the
complete conversion. The reaction furnished a white solid after
workup and purification by column chromatography of the
resulting mixture. However, the product was characterized as
an inseparable mixture containing the corresponding pyridin-
2(1H)-one of type 3 on the basis of the NMR spectral data.
When subjected to room temperature (20 °C), the reaction of
2a with POCl3/DMF (5.0 equiv) proceeded smoothly, and to
our delight, it afforded exclusively 4-chloro-5-(3-chloropropyl)-
6-oxo-1-phenyl-1,6-dihydropyridine-3-carbaldehyde 3i on the
basis of spectral and analytical data (Table 1, entry 9). Under
identical conditions, the substrates 2b-h rendered successfully
the corresponding pyridin-2(1H)-ones 3j-p in high yields
(Table 1, entries 10-16).
The results shown previously demonstrated the efficiency and
synthetic interest of the cyclization reaction with respect to
different Vilsmeier reagents and substrates 2 bearing variable
aryl amide groups. Although many methods for synthesizing
2(1H)-pyridinones have been reported, the halogenated 2(1H)-
pyridinones starting from acyclic substrates are much less
documented.13c,15 Indeed, halogenated 2(1H)-pyridinones are
essential since they allow a means of introducing an alkyl or
aromatic substituent through transition metal catalysis or
Thus, the reaction of 2a with the Vilsmeier reagent PBr3/
DMF (3.0 equiv) was first attempted at room temperature. The
resulting mixture quickly became viscous and finally turned into
a brown solid. Unfortunately, no predominant product was
formed as indicated by TLC. With treatment of 2a with PBr3/
DMF (3.0 equiv) beyond 70 °C, the mixture formed a solution.
The reaction proceeded smoothly and furnished a white solid
after workup and purification by column chromatography of
the resulting mixture. The product was characterized as 4-bromo-
5-(3-bromopropyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-car-
baldehyde 3a (68% yield) on the basis of its spectral and
analytical data (Scheme 2). The optimization of the reaction
conditions, including reaction temperature and the feed ratio of
2a and PBr3/DMF, was then investigated. Series of experiments
revealed that 3.0 equiv of PBr3/DMF was effective for the
synthesis of 3a, and the yield of 3a reached 91% when the
reaction of 2a with 5.0 equiv of PBr3/DMF was performed at
80 °C for 1 h (Table 1, entry 1).
Having established the optimal conditions for cyclization, we
aimed to determine its scope with respect to the amide motif.
Thus, a series of 5,6-dihydro-4H-pyrans 2 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
(13) (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) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu,
Q. Org. Lett. 2007, 9, 2421.
(14) For our recent work on the utilization of â-oxo amide derivatives,
see: (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem.
Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem.
Commun. 2005, 3580. (c) Wang, Y.; Dong, D.; Yang, Y.; Huang, J.;
Ouyang, Y.; Liu, Q. Tetrahedron 2007, 63, 2724.
(15) (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.
8594 J. Org. Chem., Vol. 72, No. 22, 2007

SCHEME 3. Vilsmeier-Haack Reaction of 2d
SCHEME 4. Plausible Mechanism of Vilsmeier-Haack
Reaction of 2
halogen-metal exchange.16 It should be noted that the richness
of the functionality (e.g., halogen, halogen alkyl, and formyl
groups) of the pyridin-2(1H)-ones of type 3 obtained may render
them extremely versatile as synthons in other synthetic trans-
formations. For example, the neighboring halogen and formyl
groups make it possible to establish new C-C and C-N bonds,
hence easily accessing the ring-fused heterocycles.17
In contrast with our results, Meth-Cohn and co-workers
revealed that the interaction of an acylanilide with the Vilsmeier
reagent offered an excellent method for the synthesis of
quinolines, pyridines, and related systems,12h-k and Amaresh
and Perumal achieved the synthesis 2-arylimino-2H-pyrancar-
boxaldehydes via the Vilsmeier-Haack reaction of â-oxo
amides.12f The different results encouraged us to carry out
separate experiments to gain insight into the mechanism of the
ring-opening/recyclization reaction of 2. Thus, the reaction of
2d with the Vilsmeier reagent (PBr3/DMF, 5.0 equiv) was
performed at 80 °C for 10 min and then quenched with brine.
Products 3d and 2-acetyl-5-bromo-N-phenylpentanamide 4d
were obtained in 22 and 25% yields, respectively (Scheme 3).
It is worthy noting that 4d could be converted into 3d in 91%
yield upon treatment with PBr3/DMF under identical conditions.
On the basis of all the obtained results combined with our
previous studies,13c a plausible mechanism for the synthesis of
substituted pyridin-2(1H)-ones of type 3 is presented in Scheme
4. The overall transformation commences from the ring-opening
of 2 mediated by the Vilsmeier reagent to generate enolate A,
which could be converted into 4 upon treatment with water.
Sequential Vilsmeier-Haack reactions of A lead to the forma-
tion of intermediates B and C,12a,g,h and intramolecular aza-
cyclization reaction of C gives the intermediate D,12e,f which is
exclusively converted into substituted pyridin-2(1H)-ones of type
3.13c
were purified by column chromatography over silica gel. 1H NMR
and 13C NMR spectra were recorded at 500 and 125 MHz,
respectively, with TMS as an internal standard at 25 °C. IR spectra
(KBr) were recorded on a FTIR spectrophotometer in the range of
400 to 4000 cm-1
.
Typical Procedure for the Synthesis of 2-Arylamino-3-acetyl-
5,6-dihydro-4H-pyranes 2 (2a as an Example). To a well-stirred
suspension of N-phenyl-3-oxobutanamide 1a (10 mmol) and
anhydrous K2CO3 (25 mmol) in DMF (25 mL) at room temperature
was added 1,3-dibromopropane (10 mmol) dropwise within 15 min.
The mixture was stirred for 6.0 h at room temperature and then
poured onto ice-water (100 mL) under stirring. The precipitated
solid was collected by filtration, washed with water (3 × 20 mL),
and dried in vacuo to afford the product 2a (2.08 g, yield: 96%).
1-[6-(Phenylamino)-3,4-dihydro-2H-pyran-5-yl]ethanone (2a).
1
White solid: mp 65-67 °C; H NMR (500 MHz, CDCl3) δ )
1.95-2.00 (m, 2H), 2.15 (s, 3H), 2.49 (t, J ) 6.0 Hz, 2H), 4.24 (t,
J ) 5.5 Hz, 2H), 7.03-7.06 (m, 1H), 7.25-7.29 (m, 4H), 13.16
(s, 1H); 13C NMR (125 MHz, CDCl3) δ ) 22.3, 22.6, 27.1, 68.2,
86.4, 122.0, 123.7, 129.1, 138.3, 162.2, 194.4; IR (KBr) 2939, 1630,
1569, 1500, 1466, 1299, 1230, 1133, 1075, 757 cm-1; Anal. calcd
for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.74; H,
7.05; N, 6.52.
In summary, a facile and efficient one-pot synthesis of highly
substituted pyridin-2(1H)-ones of type 3 is developed from the
Vilsmeier-Haack reactions of 2-arylamino-3-acetyl-5,6-dihy-
dro-4H-pyrans 2, which involves sequential ring-opening,
haloformylation, and intramolecular nucleophilic cyclization
reactions. The simple execution, readily available substrates,
mild conditions, high yields, and wide range of synthetic
potential of the products make this protocol very attractive.
Typical Procedure for the Synthesis of Pyridin-2(1H)-ones 3
(3a as an Example). The Vilsmeier reagent was prepared by adding
PBr3 (8.0 mmol) dropwise to ice cold dry DMF (5 mL) under
stirring. The mixture was then stirred for 10-15 min at 0 °C. To
the Vilsmeier reagent was added 2a (2 mmol) as a solution in DMF
(20 mL). Then, the mixture was heated to 80 °C and stirred for 1
h. After the staring material was consumed (monitored by TLC),
the reaction mixture was poured into water (50 mL). The mixture
was extracted with dichloromethane (2 × 30 mL), and the combined
organic phase was washed with brine (3 × 30 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, petroleum ether/diethyl
ether ) 5:1) to give 3a (0.723 g, 91%).
Experimental Section
General. All reagents were purchased from commercial sources
and used without treatment, unless otherwise indicated. The products
(16) (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,
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isawa, A. Angew. Chem., Int. Ed. 2006, 45, 5978. (b) Conreaux, D.;
Bossharth, E.; Monteiro, N.; Desbordes, P.; Vors, J.-P.; Balme, G. Org.
Lett. 2007, 9, 271. (c) Kawai, R.; Kimoto, M.; Ikeda, S.; Mitsui, T.; Endo,
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2441.
Selected data for 3a: white solid; mp 89-91 °C; 1H NMR (500
MHz, CDCl3) δ ) 2.14-2.20 (m, 2H), 3.00 (t, J ) 7.5 Hz, 2H),
3.51 (t, J ) 6.5 Hz, 2H), 7.36 (d, J ) 8.0 Hz, 2H), 7.48-7.55 (m,
3H), 8.10 (s, 1H), 10.11 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
) 25.6, 25.8, 28.7, 110.9, 121.7, 125.0, 125.1, 128.2, 130.5, 134.8,
136.6, 155.9, 184.3; IR (KBr) 2924, 1683, 1644, 1588, 1455, 1342,
1275, 1013, 671 cm-1; Anal. calcd for C15H13Br2NO2: C, 45.14;
H, 3.28; N, 3.51. Found: C, 45.27; H, 3.38; N, 3.42.
Selected data for 3i: white solid; mp 86-87 °C; 1H NMR (500
MHz, CDCl3) δ ) 2.08 (m, 2H), 2.96 (t, J ) 7.5 Hz, 2H), 3.63 (t,
J. Org. Chem, Vol. 72, No. 22, 2007 8595

J ) 6.5 Hz, 2H), 7.35 (d, J ) 7.5 Hz, 2H), 7.49-7.54 (m, 3H),
8.12 (s, 1H), 10.14 (s, 1H); 13C NMR (125 MHz, CDCl3) δ ) 26.2,
30.5, 44.9, 115.0, 126.5, 129.7, 129.8, 130.1, 139.6, 141.4, 143.5,
161.2, 186.8; IR (KBr) 2937, 1692, 1643, 1594, 1543, 1440, 1305,
1204, 1035, 837 cm-1; Anal. calcd for C15H13Cl2NO2: C, 58.08;
H, 4.22; N, 4.52. Found: C, 58.19; H, 4.13; N, 4.63.
C13H15BrClNO2: C, 46.94; H, 4.55; N, 4.21; Found: C, 46.79; H,
4.48; N, 4.16.
Acknowledgment. Financial support of this research by the
National Natural Science Foundation of China (20572013), the
Ministry of Education of China (105061), and the Department
of Science and Technology of the Jilin Province (20050392) is
acknowledged.
1
Selected data for 4d: white solid; mp 119-120 °C; H NMR
(500 MHz, CDCl3) δ ) 1.93-1.95 (m, 2H), 2.05-2.16 (m, 2H),
2.35 (s, 3 H), 3.43-3.48 (m, 2H), 3.54 (t, J ) 6.0 Hz, 3H), 7.29
(d, J ) 9.0 Hz, 2H), 7.48 (d, J ) 9.0 Hz, 2H), 8.39 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ ) 29.5, 29.9, 30.0, 32.7, 60.4, 121.4,
129.2, 129.9, 136.1, 166.3, 208.0; IR (KBr) 3249, 2925, 1722, 1647,
1534, 1489, 1395, 1264, 1162, 1012, 819 cm-1; Anal. calcd for
Supporting Information Available: Spectral data for 2b-h,
3b-h, 3j-p, and 4d and NMR spectra copies of 2a-h, 3a-p,
and 4d. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7015482
8596 J. Org. Chem., Vol. 72, No. 22, 2007