Simple, facile and one-pot conversion of the Baylis-Hillman acetates into 3,5,6-trisubstituted-2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2009.04.136

A facile route for the synthesis of novel 3,5,6-trisubstituted-2-pyridones from the acetylated Baylis-Hillman esters with β-enamino esters or β-enamino nitriles in one pot with good yields is described.

Full text of DOI:10.1016/j.tetlet.2009.04.136

Tetrahedron Letters 50 (2009) 4229–4232
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple, facile and one-pot conversion of the Baylis–Hillman acetates
into 3,5,6-trisubstituted-2-pyridones
Mettu Ravinder a, Partha Sarathi Sadhu a, Vaidya Jayathirtha Rao a,b,
*
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 607, India
b National Institute of Pharmaceutical Education & Research, Balanagar, Hyderabad 500 037, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile route for the synthesis of novel 3,5,6-trisubstituted-2-pyridones from the acetylated Baylis–Hill-
man esters with b-enamino esters or b-enamino nitriles in one pot with good yields is described.
Ó 2009 Published by Elsevier Ltd.
Received 23 February 2009
Revised 23 April 2009
Accepted 28 April 2009
Available online 6 May 2009
Keywords:
NaH
Enamines
Baylis–Hillman adducts
2-Pyridones
The 2-pyridone core structure is an important heterocyclic
framework that has attracted the attention of synthetic organic
chemists for many years because these structural motifs are found
in a very large number of biologically active natural alkaloids.1
Natural products with this structure have emerged during the last
ten years as a potent antitumor,2 antifungal,3 antiviral,4 psychother-
apeutic5 agents, and as an antibiotic.6 Moreover 2-pyridone deriva-
tives are the key intermediates in the synthesis of the corresponding
pyridine, quinoline, quinolizidine and indolizidine alkaloids.7 Amri-
none, milrinone and their analogues which have 2-pyridone moiety
are used as cardiotonic agents for the treatment of heart failure.8
Due to their immense biological properties, development of simple
and convenient methodologies for the synthesis of substituted
2-pyridone derivatives from easily available starting materials is
still in demand.9 In continuation of our research on the synthesis
of heterocyclic compounds and application of the Baylis–Hillman
chemistry,10 herein we report a facile and one-pot synthesis of
3,5,6-trisubstituted-2-pyridones upon treating the acetylated
Baylis–Hillman esters with b-enamino esters or b-enamino nitriles
(Scheme 1).
and useful heterocyclic molecules and natural products.11,12 One
recent report by Batra and co-workers informs the synthesis of
2-pyridones in two steps from acetylated BH nitriles.13
The starting substrates for the study, that is, enamines 1, 2 and
acetylated BH esters 4a–i were synthesised according to the liter-
ature procedure14 and the enamine 3 was obtained commercially.
Accordingly, we first examined ethyl-3-aminocrotonate 1 with the
acetylated BH ester 4a as a choice of substrate using various bases
under different reaction conditions15,16 (Table 1). After many trials
we finally report an efficient procedure for the synthesis of 2-pyri-
done 5a in good yield (82%), when the reaction was carried out in
THF as a solvent by using NaH as base at room temperature.
Encouraged by the successful results, we examined other
substituted BH acetates with various enamines 1–3 and the re-
sults17 are summarised in Table 2. A plausible mechanism for the
formation of 2-pyridone derivative 5a is shown in Scheme 2. This
reaction is interesting because the carbanion generated at a-posi-
tion of 1 (by the aid of NaH) attacks b-position of external double
bond of the acetylated BH ester 4a via SN20 mechanism by which C–
C bond formation takes place and subsequent migration of the
double bond with elimination of the acetate group occurs simulta-
In recent years products of the Baylis–Hillman (BH) reaction
and the derivatives produced from them have been effectively uti-
lised for the generation of attractive densely functionalised mole-
cules by employing simple alterations.11 Especially acetates of
the BH adducts have been successfully employed in a number of
transformations leading to the synthesis of various important
OAc
R
R
COOR2
R1
R1
NaH (3 equiv.)
+
NH2
N
H
O
THF, rt, 4-6 h
-R2OH
1-3
4a-i
5a-l
74-82%
* Corresponding author. Tel.: +91 40 27193933; fax: +91 40 27160757.
E-mail address: jrao@iict.res.in (V.J. Rao).
Scheme 1. (For 1–3, 4a–i and 5a–l see the Table 2).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.04.136

4230
M. Ravinder et al. / Tetrahedron Letters 50 (2009) 4229–4232
Table 1
neously to give intermediate I which was not isolated during the
reaction. Thus formed intermediate I undergoes intramolecular
cyclisation forming C–N bond by reacting with ester moiety to give
compound II, further in which the double bond migration takes
place to give 3,5,6-trisubstituted-2-pyridone 5a with good yield
involving three chemical transformations in one-pot procedure.
Thus proposed mechanism explains the requirement of 3 equiv of
base NaH (Scheme 2). This method worked well on both BH sub-
strates derived from aliphatic and aromatic aldehydes and not
much difference was observed in the yield whether the substrate
used was either ethyl 3-aminocrotonate 1 or methyl 3-aminocrot-
onate 2 or 3-aminocrotononitrile 3. In all cases, the reactions were
clean and afforded the 3,5,6-trisubstituted-2-pyridones 5a–l in
good yields.
Effect of base on the reaction of BH acetate 4a (2.2 mmol) with ethyl-3-aminocroto-
nate 1 (2 mmol)
Entry
Basea (equiv)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
NEt3 (3)
K2CO3 (3)
t-BuOK (3)
NaH (1)
NaH (2)
NaH (3)
NaH (3)
NaH (4)
EtOHc
24
24
06
24
08
04
04
04
0
0
CH3CNc
THF (rt)
THF (rt)
THF (rt)
THF (rt)
THF (reflux)
THF (rt)
60
12
50
82
61
66
a
The equivalents of the base used with respect to 1.
Isolated yields after column chromatography.
The reaction was carried out at rt and also under reflux.
b
c
Table 2
One-pot synthesis of 3,5,6-trisubstituted-2-pyridones from Baylis–Hillman acetates
Entry
BHacetate
Enamine
Yield a,b
(%)
Product
COOEt
COOEt
COOEt
COOEt
OAc
COOEt
COOEt
5a
5b
O
O
O
O
N
H
NH2
4a
4b
4c
1
1
OAc
OAc
COOEt
COOEt
N
H
1
1
1
5c
Cl
N
H
Cl
OAc
COOEt
5d
5e
Br
N
H
4d
4e
Br
Cl
Cl
OAc
OAc
COOEt
COOEt
O
O
N
H
COOMe
COOMe
NH2
COOMe
5f
N
H
4f
2
2
Cl
Cl
OAc
OAc
COOMe
COOMe
COOMe
COOMe
5g
4g
O
O
N
H
2
5h
Cl
N
H
4h
Cl
OAc
OAc
CN
CN
CN
COOEt
COOEt
NH2
O
O
N
H
5i
5j
4a
4d
3
3
Br
N
H
Br

M. Ravinder et al. / Tetrahedron Letters 50 (2009) 4229–4232
4231
Table 2 (continued)
a,b
BH acetate
Enamine
(%)
Entry
Product
Yield
Cl
Cl
OAc
CN
COOMe
COOEt
5k
5l
3
4g
4i
O
N
H
COOEt
OAc
1
O
N
H
a
All structures were characterised by NMR, IR and mass spectroscopy.
Isolated yields of products after column chromatography.
b
OAc
Ph
4a
O
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
NaH (3 equiv.)
EtO
THF, rt
NH
NH2
NH
NH
1
-CH3COONa
H
Ph
Ph
COOEt
H
EtOOC
EtOOC
Ph
Ph
COOEt
COOEt
NH
-EtOH
N
H
5a
O
N
H
II
O
NH2
I
Scheme 2.
Wang, L.; Zhang, H. Y.; Cohen, J.; Gu, W. Z.; Marsh, K.; Bauch, J.; Rosenberg, S.;
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Am. Chem. Soc. 1996, 118, 11357.
During the course of our synthesis, Kim et al. reported the syn-
thesis of tri-substituted 2-pyridone compounds in two steps from
the BH acetates.18 A quick comparison of our work with reported
work clearly indicates that the reported method is a two-step reac-
tion, requires 15 h reaction time, higher temperature, excess
amount of NH4OAc (20 equiv) and the product was formed along
with side products. Hence the procedure reported herein provides
significant advantages in both yield and practicality over recently
reported two-step routes to similar 2-pyridones. We believe that
this reaction has enough scope for further investigations.
In conclusion, we have prepared a series of 3,5,6-trisubstituted-
2-pyridones in very good yields from the acetylated Baylis–Hill-
man esters in a one-pot procedure.
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Ch.; Raju, B. C.; Jayathirtha Rao, V. Tetrahedron 2006, 62, 8398; (b) Narender, P.;
Gangadasu, B.; Ravinder, M.; Jayathirtha Rao, V. Tetrahedron 2006, 62, 954; (c)
Narender, P.; Srinivas, U.; Ravinder, M.; Ramesh, Ch.; Rao, B. A.; Harakishore,
K.; Gangadasu, B.; Murthy, U. S. N.; Jayathirtha Rao, V. Bioorg. Med. Chem. 2006,
14, 4600; (d) Narender, P.; Srinivas, U.; Gangadasu, B.; Biswas, S.; Jayathirtha
Rao, V. Bioorg. Med. Chem. Lett. 2005, 15, 5378.
Acknowledgements
We thank Director, IICT, Project Director, NIPER and Head of the
Division Organic II for the continued encouragement. M.R. and
P.S.S. thank CSIR, New Delhi for fellowships.
References and notes
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Sing, V.; Batra, S. Tetrahedron 2008, 64, 4511; (c) Lee, K. Y.; Gowrisankar, S.;
Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481; (d) Basavaiah, D.; Rao, P. S.;
Hyma, R. S. Tetrahedron 1996, 52, 8001.
Newkome, G. R., Ed.; Wiley: New York, 1984; Vol. 14, Part 5,
p 1; (d)
12. (a) Shigetomi, K.; Kishimoto, T.; Shoji, K.; Ubukata, M. Tetrahedron: Asymmetry
2008, 19, 1444; (b) Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481; (c) Garrido, N. M.;
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Balasubramanian, M.; Deay, J. g.. In Comprehensive Heterocyclic Chemistry II;
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p 245.
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M. J. Med. Chem. 2003, 46, 5712; (b) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992,
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Nelson, L. T. J.; Mantei, R. A.; Fakhoury, S. A.; Sullivan, G. M.; Li, Q.; Lin, N. H.;
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4232
M. Ravinder et al. / Tetrahedron Letters 50 (2009) 4229–4232
Krishnamacharyulu, M.; Hyma, R. S.; Sarma, P. K. S.; Kumaragurubaran, N. J.
2904, 1716, 1652, 1581, 1231, 1080; 1H NMR (CDCl3+DMSO-d6, 200 MHz) d
11.98 (br s, 1H), 7.63 (s, 1H), 7.20 (br s, 4H), 4.23 (q, J = 7.16 Hz, 2H), 3.70 (s,
2H), 2.54 (s, 3H), 1.32 (t, J = 7.16 Hz, 3H); 13C NMR (DMSO-d6 75 MHz) d 164.60,
162.47, 151.13, 138.86, 138.23, 130.57, 130.43, 128.10, 127.57, 106.06, 60.08,
34.20, 18.51, 14.11; HRMS (ESI) m/z calcd for C16H17NO3 [M+H]+ 306.0906,
found 306.0891. Compound 5f. Yield 78%; white solid, mp 210–213 °C; IR (KBr)
3415, 2897, 1719, 1653, 1278, 1234, 1195, 1084; 1H NMR (CDCl3, 200 MHz) d
13.07 (br s, 1H), 7.74 (s, 1H), 7.24–7.14 (m, 5H), 3.80 (s, 3H), 3.79 (s, 2H), 2.64
(s, 3H); 13C NMR (DMSO-d6 75 MHz) d 165.04, 162.54, 151.07, 139.72, 137.88,
128.66, 128.26, 128.15, 125.99, 105.78, 51.47, 34.76, 18.47; HRMS (ESI) m/z
calcd for C15H15NO3Na [M+Na]+ 280.0941, found 280.0944. Compound 5j. Yield
75%; white solid, mp 239–242 °C; IR (KBr) 3447, 3020, 2791, 2222, 1642, 1579,
1221; 1H NMR (CDCl3, 300 MHz) d 13.29 (br s, 1H), 7.43 (d, J = 8.30 Hz, 2H),
7.19 (s, 1H), 7.10 (d, J = 8.30 Hz, 2H), 3.72 (s, 2H), 2.53 (s, 3H); 13C NMR (DMSO-
d6 50 MHz) d 161.75, 153.37, 138.69, 137.44, 131.04, 130.86, 129.19, 119.15,
117.21, 88.20, 34.19, 17.81. HRMS (ESI) m/z calcd for C14H11N2ONaBr [M+Na]+
324.9948, found 324.9952. Compound 5l. Yield 77%; white solid, mp 149–
151 °C; IR (KBr) 3296, 3150, 2964, 2877, 1712, 1656, 1580, 1377, 1277, 1230;
1H NMR (CDCl3, 300 MHz) d 13.17 (br s, 1H), 7.78 (s 1H), 4.30 (q, J = 7.17 Hz,
2H), 2.70 (s, 3H), 2.47 (t, J = 7.36 Hz, 2H), 1.69–1.57 (sext, J = 7.55, 7.36 Hz, 2H),
1.38 (t, J = 7.17 Hz, 3H), 0.98 (t, J = 7.55 Hz, 3H); ESIMS m/z 224 [M+H]+.
18. Kim, S. H.; Lee, S.; Kim, S. H.; Kim, J. N. Bull. Korean Chem. Soc. 2008, 29,
1815.
Org. Chem. 1999, 64, 1197; (d) Lee, S.-g.; Zhang, Y. J. Org. Lett. 2002, 4, 2429; (e)
Cho, H.; Ueda, M.; Mizuno, A.; Ishihara, T.; Aisaka, K.; Noguchi, T. Chem.
Pharam. Bull. 1989, 37, 2117.
15. The rearrangement of the Baylis–Hillman acetate 4a into corresponding
primary acetate was observed while treating it with 1 by K2CO3 at both rt
and refluxing conditions.
16. As per one of the reviewers suggestion, we carried out the reaction between 4a
and 1 by taking mixture of bases NaH (1 equiv) and K2CO3 (2 equiv) but the
yield was similar to entry 4 in Table 1.
17. General experimental procedure: To a well-stirred solution of NaH (60% in
paraffin oil, 6 mmol) in dry THF (15 mL) was added b-enamino ester or b-
enamino nitrile (2 mmol) dissolved in dry THF (5 mL) at rt under nitrogen
atmosphere and allowed to stir for 15 min (at the same temperature).Then
acetylated Baylis–Hillman ester (2.2 mmol) disolved in THF (5 mL) was added
slowly and allowed to stir at rt for 4–6 h. On completion (monitored by TLC)
solvent was removed under reduced pressure and the residue was diluted with
H2O (20 mL) and extracted with EtOAc (3ꢀ30 mL). The combined organic
layers were dried over Na2SO4, solvent was evaporated in vacuo and purified
by silica gel column chromatography using ethyl acetate/hexane (1:4) as
eluent to afford pure compounds 5a–l. For analytical purpose it is further
purified by recrystallisation from MeOH. Spectral data for selected compounds:
Compound 5c: Yield 78%; white solid, mp 191–194 °C; IR (KBr) 3430, 2970,