A facile four-component tandem protocol for the synthesis of novel 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2007.06.024

A one-pot, four-component reaction of 1-(phenylsulfinyl)- or 1-(4-chlorophenylsulfinyl)propan-2-one, aromatic aldehydes and ammonium acetate in a 1:2:1 molar ratio affords a series of new 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones. This reaction proceeds pr

Full text of DOI:10.1016/j.tetlet.2007.06.024

Tetrahedron Letters 48 (2007) 5627–5629
A facile four-component tandem protocol for the synthesis of
novel 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones
Natarajan Savitha Devi and Subbu Perumal*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
Received 3 May 2007; revised 1 June 2007; accepted 7 June 2007
Available online 9 June 2007
Abstract—A one-pot, four-component reaction of 1-(phenylsulfinyl)- or 1-(4-chlorophenylsulfinyl)propan-2-one, aromatic alde-
hydes and ammonium acetate in a 1:2:1 molar ratio affords a series of new 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones. This reaction
proceeds presumably via a double Mannich reaction–elimination tandem sequence.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Dihydropyridinones are interesting building blocks for
the synthesis of alkaloids and pharmacologically active
agents.1 They are also of great interest in medicinal
chemistry in the design of ligands for the neuronal nico-
tinic receptor.2 Pyridinones also display a wide range of
biological activities,3 and they are exemplified by the
elfamycin antibiotics.4
is only one report on the synthesis of 2,3-dihydro-1H-
pyridin-4-ones bearing two aryl rings at the 2,6-posi-
tions with an ambiguous structural assignment (vide
infra).10
Tandem reactions11 are important from the perspective
of green chemistry12,13 as they are one-pot, multi-step
processes providing a rapid, convergent and elegant syn-
thesis of complex organic molecules without isolation
and/or purification of intermediates. Our interest in
employing tandem reactions for the construction of
novel organic molecules14 in conjunction with the
biological and synthetic importance of pyridinones
prompted us to report herein the synthesis of novel
2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones via tandem
reactions.
Previous syntheses of 2-alkyl-6-aryl-2,3-dihydro-1H-
pyridin-4-ones5–7 include multi-step protocols com-
mencing from b-amino-b-arylpropionic acids,5 4-meth-
oxypyridine6 and t-butyl enamino esters.7 The
syntheses of N-benzyl-2,3-dihydro-2-phenyl-5-alkyl-
1H-pyridin-4-ones8 using the aza-Diels–Alder reaction
and 2-methylamino-6-phenyl-3-aroyl-5,6-dihydro-1H-
pyridin-4-ones9 from the reaction of a ketene dithioester
with methylamine have also been reported. Despite the
above syntheses of 2,3-dihydro-1H-pyridin-4-ones bear-
ing different substituents at the 2- and 6-positions, there
The one-pot, four-component reaction of 1-(phenyl-
sulfinyl)- or 1-(4-chlorophenylsulfinyl)propan-2-one 1,
H
H
O
O
S
O
EtOH
H
Ar'
2 Ar'CHO
NH4OAc
+
+
Ar
N
H
Ar'
H
1
2a-i
3a-i
Ar = Ph, 4-ClC6H4
Scheme 1.
Keywords: Pyridinone; 1-(Arylsulfinyl)propan-2-one; Mannich; Elimination; Tandem.
*
Corresponding author. Tel./fax: +91 452 2459845; e-mail: subbu.perum@gmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.024

5628
N. Savitha Devi, S. Perumal / Tetrahedron Letters 48 (2007) 5627–5629
Table 1. Synthesis of 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones 3
H
H
O
4
6
Compound 3 Ar
Ar0
Mp (ꢁC) Yield (%)
3
5
H
2
a
b
c
c
d
e
f
C6H5
C6H5
240
223
210
210
58
69
53
55
55
57
58
53
52
50
N
H
4-ClC6H4 4-ClC6H4
4-ClC6H4 4-MeC6H4
C6H5
H
1
Cl
4-MeC6H4
H,H-COSY
HMBC
Cl
4-ClC6H4 4-MeOC6H4 180
C6H5
C6H5
C6H5
3-FC6H4
2,4-Cl2C6H3 221
2-ClC6H4
208
Figure 1. Selected H,H-COSY and HMBC correlations for 3b.
g
h
i
177
165
4-ClC6H4 2-MeC6H4
4-ClC6H4 2-MeOC6H4 202
5.47 ppm was assigned to H-5 from its HMBC correla-
tion with the carbonyl carbon (C-4) at 192.0 ppm and
C-6 at 160.2 ppm. These assignments were also sup-
ported by H,H-COSY and HMBC correlations
(Fig. 1). Unambiguous assignment of carbons C-2, C-3
and C-5 of 3b to the signals at 58.0, 43.6 and
99.7 ppm was made from their proton chemical shifts,
and their respective C,H-COSY correlations. The aro-
matic carbons appeared in the range, 127.4–138.4 ppm.
aromatic aldehydes 2a–i and ammonium acetate in a
1:2:1 molar ratio in ethanol affords 2,6-diaryl-2,3-dihy-
dro-1H-pyridin-4-ones 3a–i (Scheme 1) in moderate
yields (50–69%).15 1-(Arylsulfinyl)acetones16 1 were pre-
pared by the NaIO4 oxidation of the corresponding 1-
(arylsulfanyl)acetones,16 which, in turn, were obtained
from the reaction of chloroacetone and the respective
arenethiol (Table 1).
A previous report10 describes the synthesis of only 2,6-
diphenyl-2,3-dihydro-1H-pyridin-4-one, 3a by the base
catalyzed dehydrochlorination of 3-chloro-2,6-diph-
enylpiperidin-4-one. However, the reported assignment
Presumably, 3 is formed via a tandem double Mannich
reaction–elimination sequence through a labile interme-
diate, 3-(arylsulfinyl)-2,6-diarylpiperidin-4-one 5, which
undergoes spontaneous elimination of ArSOH to afford
the 2,6-diaryl-2,3-dihydro-1H-pyridin-4-ones (Scheme
2). Intermediate 5 is proposed on the basis of the analo-
gous reaction between ketones, aldehydes and ammo-
nium acetate in a 1:2:1 molar ratio affording cis-2,6-
diaryl-4-piperidones.17 Intermediate 4 is visualized to
arise from an initial Mannich reaction at the methylene
carbon instead of the methyl of 1, as the enol or enolate
ion can be formed more readily involving the former.
Elimination of ArSOH from 5 is probably assisted by
the phenylsulfinyl group to afford 3. Our efforts to inter-
cept the reaction before completion to isolate and char-
acterize the intermediates did not succeed.
1
of the H NMR spectroscopic data of 3a10 in CDCl3
[dH 2.27–2.34 (1H, d, Ar–C–CH2CO), 2.78–2.79 (1H,
d, Ar–C–CH2CO), 3.24–3.25 (1H, d, Ar–C–CH2CO),
4.64–4.67 (1H, d, Ar–C–CH2CO), 7.23–7.39 (10H,
ArH)] appear to be at variance with structure 3a or its
imino tautomer, 5,6-dihydro-2,6-diphenyl-3H-pyridin-
4-one (6) (Fig. 2) as (i) 3a cannot have four protons,
namely, two methylenes at the carbon a- to the car-
bonyl, and (ii) the expected signal in the alkenic region
for H-5 and a signal for NH are absent. The data are
also not in accord with 6 as the signal due to the benzylic
proton, H-6 is missing.10 In contrast, the spectroscopic
data for 3a in the present work in CDCl3 [dH 7.58–
1
O
4
The H NMR spectrum of 2,6-bis(4-chlorophenyl)-2,3-
dihydro-1H-pyridin-4-one 3b is described as an example.
A doublet of doublets at 4.87 ppm was ascribable to H-2
with JH2,H3ax and JH2,H3eq corresponding to 14.3 and
4.7 Hz, respectively. The doublet of doublets at
2.74 ppm (J = 16.2 and 14.3 Hz) was assigned to H-
3ax and the doublet of doublets at 2.59 ppm (J = 16.2
and 4.7 Hz) was assigned to H-3eq. The 1H singlet at
3
5
Ph
N
1
Ph
2
6
6
Figure 2. 5,6-Dihydro-2,6-diphenyl-3H-pyridin-4-one, tautomer of 3a.
O
O
S
H
O
S
O
Ar'CHO
Ar'CHO
O
S
O
Ar
Ar'
HN
NH4OAc
Mannich reaction
Ar
Mannich reaction
H2N
Ar'
Ar'
Ar
1
5
4
-ArSOH
Elimination
H
H
O
H
Ar'
N
H
Ar'
H
3
Scheme 2. Proposed mechanism for the formation of pyridinones 3.

N. Savitha Devi, S. Perumal / Tetrahedron Letters 48 (2007) 5627–5629
5629
7. Leflemme, N.; Dallemagne, P.; Rault, S. Synthesis 2002,
1740.
8. Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
9. Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Commun. 2005,
3580.
7.38 (m, 10H, 2Ph), 5.52 (s, 1H, H-5), 5.24 (br s, 1H,
NH), 4.92 (dd, J = 14.7, 4.5 Hz, 1H, H-2), 2.90–2.70
(m, 1H, H-3ax), 2.62 (dd, J = 16.2, 4.5 Hz, 1H, H-
3eq)] corresponds with the structure of 3a. The melting
point of 3a from our work (240 ꢁC) and that from
Krishna Pillay’s10 study (118 ꢁC) also differ greatly.
From the above, it is clear that the products from these
two studies are quite different, although the correct
structure of the compound reported previously as 3a
could not be deduced from the available data.10
10. Krishna Pillay, M.; Fazal Mohamed, M. I. J. Indian
Chem. Soc. 1993, 70, 257.
11. (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New
York, 1992; (b) Tietze, L. F.; Brasche, C.; Gericke, K. M.
Domino Reactions in Organic Synthesis; Wiley-VCH, 2006;
(c) Tietze, L. F. Chem. Rev. 1996, 96, 115; (d) Bunce, R. A.
Tetrahedron 1995, 51, 13103.
12. Anastas, P. T.; Williamson, T. C. Green Chemistry:
Frontiers in Benign Chemical Synthesis and Processes;
Oxford University Press: Oxford, 1998, p 166.
13. Anastas, P. T.; Warner, J. C. Green Chemistry Theory
and Practice; Oxford University Press: New York, NY,
1998.
In summary, a facile one-pot synthesis of novel 2,6-di-
aryl-2,3-dihydro-1H-pyridin-4-ones has been accom-
plished for the first time employing a tandem protocol
involving
a double Mannich reaction–elimination
sequence under mild reaction conditions.
14. (a) Alex Raja, V. P.; Perumal, S. Tetrahedron 2006, 62,
4892; (b) Savitha Devi, N.; Perumal, S. Tetrahedron 2006,
62, 5931; (c) Srinivasan, M.; Perumal, S. Tetrahedron
2006, 62, 7726; (d) Indumathi, S.; Ranjith Kumar, R.;
Perumal, S. Tetrahedron 2007, 63, 1411; (e) Srinivasan,
M.; Perumal, S. Tetrahedron 2007, 63, 2865; (f) Kamal
Nasar, M.; Ranjith Kumar, R.; Perumal, S. Tetrahedron
Lett. 2007, 48, 2155; (g) Karthikeyan, S. V.; Perumal, S.
Tetrahedron Lett. 2007, 48, 2261.
Acknowledgements
S.P. thanks the Council of Scientific and Industrial
Research, New Delhi, for a Major Research Project
[No. 01(1926/04/EMR II)], the University Grants
Commission, New Delhi, for funds under the DRS
and ASIST programmes and the Department of
Science and Technology for funds under the IRHPA
programme for the purchase of a high resolution
300 MHz NMR spectrometer.
15. Representative experimental procedure: A mixture of 1-(4-
chlorophenylsulfinyl)propan-2-one 1 (2.3 mmol), 4-chloro-
benzaldehyde 2b (4.6 mmol) and ammonium acetate
(2.3 mmol) in ethanol (10 mL) was gently heated to
boiling and allowed to cool to room temperature and
the reaction mixture set aside for 3–5 days to ensure
completion of the reaction (TLC). The reaction mixture
was extracted with chloroform (25 mL), the organic layer
washed with water (3 · 25 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
residue was chromatographed over silica gel (230–400
mesh) using petroleum ether/ethyl acetate (4:1 v/v) to
afford 2,6-bis(4-chlorophenyl)-2,3-dihydro-1H-pyridin-4-
one 3b (Table 1, entry 2): pale yellow solid; mmax (KBr):
References and notes
1. Chen, C.; McDonald, I. A.; Munoz, B. Tetrahedron Lett.
1998, 39, 217.
2. Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem.
1997, 40, 4169.
3. (a) Mederski, W. W. K. R.; Dorsch, D.; Bokel, H.-H.;
Beier, N.; Lues, I.; Schelling, P. J. Med. Chem. 1994, 37,
1632; (b) Mederski, W. W. K. R.; Dorsch, D.; Osswald,
M.; Schwartz, H.; Beier, N.; Christadler, M.; Minck, K.
O.; Schelling, P.; Schmitges, C. J. Eur. J. Med. Chem.
1997, 32, 479; (c) Leflemme, N.; Freret, T.; Boulouard, M.;
Dallemagne, P.; Rault, S. J. Enzyme Inhib. Med. Chem.
2005, 20, 551; (d) Aytemir, M. D.; Hider, R. C.; Erol, D.
D.; Ozalp, M.; Ekizoglu, M. Turk. J. Chem. 2003, 27, 445.
4. Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107,
1691.
3457, 1635 cmꢀ1
.
Mp = 223 ꢁC; 1H NMR (CDCl3,
300 MHz): dH 7.51–7.33 (m, 8H), 5.47 (s, 1H), 5.09 (s,
1H), 4.87 (dd, J = 14.3, 4.7 Hz, 1H), 2.74 (dd, J = 16.2,
14.3 Hz, 1H), 2.59 (dd, J = 16.2, 4.7 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): dC 192.0, 160.2, 138.4, 137.2, 134.5,
133.7, 129.4, 129.3, 128.1, 127.4, 99.7, 58.0, 43.6. Anal.
Calcd for C17H13Cl2NO: C, 64.17; H, 4.12; N, 4.40.
Found: C, 64.14; H, 4.14; N, 4.37%.
16. Crumbie, R. L.; Deol, B. S.; Nemorin, J. E.; Ridley, D. D.
Aust. J. Chem. 1978, 31, 1965.
17. (a) Noller, C. R.; Baliah, V. J. Am. Chem. Soc. 1948, 70,
3853; (b) Srinivasan, M.; Perumal, S.; Selvaraj, S. Arkivoc
2005, 201.
5. Renault, O.; Guillon, J.; Dallemagne, P.; Rault, S.
Tetrahedron Lett. 2000, 41, 681.
6. Leflemme, N.; Dallemagne, P.; Rault, S. Tetrahedron
2004, 60, 4861.