Solvent-free one-pot synthesis of 2-pyridone derivatives

Article abstract of DOI:10.1016/j.cclet.2012.01.018

An efficient synthesis of methyl 4-hydroxy-6-oxo-1,6-dihydro-2-pyridine carboxylates is described. This involves three component reactions between primary alkyl amines, malonyl dichloride and methyl propiolates.

Full text of DOI:10.1016/j.cclet.2012.01.018

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 512–514
www.elsevier.com/locate/cclet
Solvent-free one-pot synthesis of 2-pyridone derivatives
b
a
Zinatossadat Hossaini a, , Faramarz Rostami-Charati , Rahimeh Hajinasiri ,
*
Mohammad A. Khalilzadeh a
a Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
b Department of Chemistry, Faculty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
Received 14 November 2011
Available online 7 April 2012
Abstract
An efficient synthesis of methyl 4-hydroxy-6-oxo-1,6-dihydro-2-pyridine carboxylates is described. This involves three
component reactions between primary alkyl amines, malonyl dichloride and methyl propiolates.
# 2012 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: One-pot reactions; Multicomponent reactions; Methyl propiolate; Green chemistry
The methods of green chemistry continue to grow in importance. Alternative processes help to conserve resources
and can even reduce costs. The replacement of convention solvents with water or solvent-free conditions, which is
harmless to health and is available in large quantities, is one of the most interesting basic approaches along these lines.
The 2-pyridone core structure is an important heterocyclic framework that can be found in numerous biologically
active compounds. It is also a versatile synthon that can be further transformed to pyridine, piperidine, quinolizidine,
and indolizidine alkaloids [1]. N-Alkylated 2-pyridones are important intermediates in the synthesis of polycyclic
compounds of biological significance [2]. The broad range of applications of the 2-pyridone structural motif has
resulted in several synthetic methods [3]. The most versatile and useful strategy to produce pyridine derivatives is
condensation between 1,3-dicarbonyl compounds and 3-aminoenones,3-aminoacrylates, or cyanoacetamides [4,5].
Recently, multicomponent condensation reactions have become a powerful method for the synthesis of small-
molecule libraries, due to the fact that products are formed in a single step by simultaneous reactions of several
reagents and the molecular diversity required for such combinatorial libraries can be achieved by simply varying each
component [6–8]. Herein, we describe an efficient synthesis of functionalized 2-pyridones via the reaction of alkyl
amines 1 with methyl propiolate 2 in the presence of malonyl dichloride 3 under solvent-free conditions at 508C
(Scheme 1).
1
The structures of compounds 4a–g were apparent from the H NMR, 13C NMR and IR spectra which are in
agreement with the proposed structures [9]. The 1H NMR spectrum of 4a in CDCl3 showed five singlets for methoxy
(d 3.75), methylene (d 5.20), methine (d 6.12 and 6.27), and OH (d 10.75) protons, along with characteristic multiplets
for the aromatic protons. The 13C NMR spectrum of 4a exhibited 12 signals in agreement with the proposed structure.
* Corresponding author.
E-mail address: zshossaini@yahoo.com (Z. Hossaini).
1001-8417/$ – see front matter # 2012 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.018

Z. Hossaini et al. / Chinese Chemical Letters 23 (2012) 512–514
513
OH
H
Yield (%) of 4
R
1, 2, 4
a
O
O
MeO2C
H
Solvent-free
50oC, 6h
92
R-NH2
+
+
Bn
Cl
Cl
4-Me-C6H4-CH2
b
c
N
R
4
O
90
87
89
CO2Me
4-MeO-C6H4-CH2
2
4-Cl-C6H4-CH2
2-Me-C6H4-CH2
1-naphthylmethyl
n-Butyl
1
3
d
e
92
90
90
f
g
Scheme 1. Three component reaction of alkyl amines with methyl propiolate in the presence of malonyl dichloride.
H
CO2Me
+
R
H
H
H
O
N
_
+ 3
_
HCl
CO2Me
R
+
H
CHCO2Me
1 + 2
_
N
H
N
Cl
H
R
Cl
O
H
6
5
7
H
H
CO2Me
_
HCl
+
R
CO2Me
R
4
H
O
N
N
_
H
O
Cl
O
Cl
O
9
8
Scheme 2. Proposed mechanism for the one-pot synthesis of 2-pyridones.
The 1H NMR and 13C NMR spectra of 4b–g were similar to those of 4a which showed characteristic resonances in
appropriate regions of the spectrum. A tentative mechanism for this transformation is proposed in Scheme 2. It is
conceivable that the initial event is the formation of enaminone 6 from the amine and propiolate [10,11] which is
subsequently attacked by malonyl dichloride to produce 7. Intermediate 7 undergoes cyclization reaction, HCl
elimination and keto-enol tautomerism to generate 4.
In conclusion, we have described a convenient route to functionalized 2-pyridones, from malonyl dichloride and
methyl propiolate in the presence of primary amines. The advantage of the present procedure is that the reaction is
performed under solvent-free conditions by simple mixing of the starting materials. The procedure described here
provides an acceptable one-pot method for the preparation of functionalized 2-pyridones.
Acknowledgment
We gratefully acknowledge financial and spiritual support from the National Endowment for the Elite.
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[9] General procedure for preparation of compounds 4a–g. To a mixture of alkyl propiolate (2.5 mmol) and primary amine (2.5 mmol) malonyl
˚
dichloride (0.19 mL, 2 mmol) was added slowly at 50 C. The reaction mixture was then stirred for 6 h. The reaction mixture was purified by
flash column chromatography on silica gel (Merck 230–400 mesh) using n-hexane–EtOAc as eluent to afforded pure compounds. Methyl 1-
˚
benzyl-4-hydroxy-6-oxo-1,6-dihydro-2-pyridinedicarboxylate (4a). White powder; mp 114–116 C; yield: 0.48 g (92%). IR (KBr): 3442 (OH),
1730, 1627, 1542, 1385 cmÀ1. 1H NMR (500 MHz, CDCl3): d 3.75 (s, 3 H, MeO), 5.20 (s, 2 H, CH2), 6.12 (s, 1 H, CH), 6.27 (s, 1 H, CH), 7.14
(d, 2 H, 3J = 7.0 Hz, 2 CH), 7.24–7.30 (m, 3 H, 3 CH), 10.75 (s, 1 H, OH). 13C NMR (125 MHz, CDCl3): d 47.8 (NCH2), 52.8 (MeO), 97.8
(CH), 100.2 (CH), 102.6 (C), 127.4 (2 CH), 128.0 (CH), 128.6 (2 CH), 135.5 (C), 162.5 (C), 165.3 (C O), 167.1 (C O). MS: m/z (%) = 259
(15) [M+], 228 (64), 168 (15), 91 (100), 77 (20), 31 (28). Anal. Calcd for C14H13NO4 (259.26): C, 64.86; H, 5.05; N, 5.40. Found: C, 64.92; H,
˚
5.12; N, 5.45. Methyl 1-(4-methylbenzyl)-4-hydroxy-6-oxo-1,6-dihydro-2-pyridine dicarboxylate (4b). White powder; mp 119–121 C; yield:
0.49 g (90%). IR (KBr): 3445 (OH), 1734, 1635, 1584, 1373 cmÀ1. 1H NMR (500 MHz, CDCl3): d 2.45 (s, 3H, Me), 3.82 (s, 3 H, MeO), 5.24 (s,
2 H, CH2), 6.15 (s, 1 H, CH), 6.34 (s, 1 H, CH), 7.15 (d, 2 H, 3J = 7.3 Hz, 2 CH), 7.30 (d, 2 H, 3J = 7.3 Hz, 2 CH), 10.68 (s, 1 H, OH). 13C NMR
(125 MHz, CDCl3): d 21.5 (CH3), 48.2 (NCH2), 53.0 (MeO), 98.2 (CH), 100.4 (CH), 105.7 (C), 127.5 (2 CH), 128.4 (2 CH), 130.7 (C), 135.4
(C), 160.7 (C), 165.5 (C O), 167.6 (C O). Methyl 1-(4-methoxylbenzyl)-4-hydroxy-6-oxo-1,6-dihydro-2-pyridine dicarboxylate (4c). White
powder; mp 128–130 C; yield: 0.50 g (87%). IR (KBr): 3440 (OH), 1737, 1636, 1580, 1287 cmÀ1. 1H NMR (500 MHz, CDCl3): d 3.83 (s, 3H,
˚
MeO), 3.89 (s, 3 H, MeO), 5.25 (s, 2 H, CH2), 6.08 (s, 1 H, CH), 6.23 (s, 1 H, CH), 7.08 (d, 2 H, 3J = 7.5 Hz, 2 CH), 7.45 (d, 2 H, 3J = 7.6 Hz, 2
CH), 10.75 (s, 1 H, OH). 13C NMR (125 MHz, CDCl3): d 48.5 (NCH2), 52.8 (CH3O), 53.3 (OMe), 98.5 (CH), 99.7 (CH), 104.8 (C), 117.4 (2
CH), 131.7 (2 CH), 135.4 (C), 154.4 (C), 158.7 (C), 164.6 (C O), 168.2 (C O). Methyl 1-(4-chlorobenzyl)-4-hydroxy-6-oxo-1,6-dihydro-2-
pyridine dicarboxylate (4d). White powder; mp 138–140 C; yield: 0.52 g (89%). IR (KBr): 3452 (OH), 1733, 1645, 1557, 1235 cmÀ1. 1H NMR
˚
(500 MHz, CDCl3): d 3.80 (s, 3H, MeO), 5.14 (s, 2 H, CH2), 6.12 (s, 1 H, CH), 6.27 (s, 1 H, CH), 7.16 (d, 2 H, 3J = 7.8 Hz, 2 CH), 7.32 (d, 2 H,
3J = 7.8 Hz, CH), 10.82 (s, 1 H, OH). 13C NMR (125 MHz, CDCl3): d 49.2 (NCH2), 53.3 (OMe), 97.4 (CH), 99.5 (CH), 106.7 (C), 125.4 (2
CH), 131.5 (2 CH), 137.4 (C), 140.4 (C), 159.4 (C), 165.0 (C O), 168.5 (C O). Methyl 1-(2-methylbenzyl)-4-hydroxy-6-oxo-1,6-dihydro-2-
pyridine dicarboxylate (4e). White powder; mp 125–127 C; yield: 0.50 g (92%). IR (KBr): 3450 (OH), 1738, 1647, 1489, 1325 cmÀ1. 1H NMR
˚
(500 MHz, CDCl3): d 2.52 (s, 3H, Me), 3.85 (s, 3 H, MeO), 5.27 (s, 2 H, CH2), 6.18 (s, 1 H, CH), 6.35 (s, 1 H, CH), 6.78 (d, 1 H, 3J = 7.4 Hz,
CH), 7.05 (d, 1 H, 3J = 7.3 Hz, CH), 7.34 (t, 2 H, 3J = 7.5 Hz, 2 CH), 10.79 (s, 1 H, OH). 13C NMR (125 MHz, CDCl3): d 22.4 (CH3), 48.7
(NCH2), 53.2 (OMe), 100.2 (CH), 100.5 (CH), 110.4 (C), 125.4 (CH), 128.2 (CH), 128.9 (CH), 130.4 (CH), 131.4 (C), 139.4 (C), 156.7 (C),
163.8 (C O), 167.5 (C O). Methyl 1-(1-naphthylmethyl)-4-hydroxy-6-oxo-1,6-dihydro-2-pyridine dicarboxylate (4f). Pale yellow powder;
mp 137–139 C; yield: 0.56 g (90%). IR (KBr): 3452 (OH), 1742, 1598, 1365, 1287 cmÀ1. 1H NMR (500 MHz, CDCl3): d 3.87 (s, 3 H, MeO),
˚
5.24 (s, 2 H, CH2), 6.23 (s, 1 H, CH), 6.45 (s, 1 H, CH), 7.27 (d, 1 H, 3J = 7.3 Hz, CH), 7.32 (t, 1 H, 3J = 7.3 Hz, CH), 7.34 (t, 1 H, 3J = 7.5 Hz,
CH), 7.74 (t, 1 H, 3J = 7.5 Hz, CH), 7.85 (d, 1 H, 3J = 7.4 Hz, CH), 8.02 (t, 1 H, 3J = 7.5 Hz, CH), 8.67 (t, 1 H, 3J = 7.5 Hz, CH), 11.29 (s, 1 H,
OH). 13C NMR (125 MHz, CDCl3): d 49.5 (NCH2), 52.7 (OMe), 105.2 (CH), 111.4 (CH), 124.5 (CH), 125.3 (C), 126.7 (CH), 127.2 (3 CH),
128.7 (CH), 130.2 (CH), 131.7 (C), 135.4 (C), 140.7 (C), 160.7 (C), 164.5 (C O), 168.3 (C O). Methyl 1-butyl-4-hydroxy-6-oxo-1,6-dihydro-
2-pyridinedicarboxylate (4g). Yellow powder; mp 107–109 C; yield: 0.56 g (90%). IR (KBr): 3435 (OH), 1737, 1625, 1478, 1325 cmÀ1. 1H
˚
NMR (500 MHz, CDCl3): d 1.02 (t, 3 H, 3J = 7.3 Hz, Me), 1.34 (m, 2 H, CH2), 1.65 (m, 2 H, CH2), 3.25 (t, 3 H, 3J = 7.4 Hz, NCH2), 3.86 (s, 3
H, MeO), 5.96 (s, 1 H, CH), 6.24 (s, 1 H, CH), 10.85 (s, 1 H, OH). 13C NMR (125 MHz, CDCl3): d 14.2 (CH3), 21.2 (CH2), 32.0 (CH2), 48.3
(NCH2), 52.8 (OMe), 106.7 (CH), 110.5 (CH), 135.4 (C), 158.7 (C), 165.3 (C O), 167.6 (C O).
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