Substituent-dictated concise synthesis of 4,6-disubstituted N-alkyl-2-pyridones and 2-aminopyridines

Article abstract of DOI:10.1055/s-2005-872232

Functionalized N-alkyl-2-pyridones and 2-aminopyridines are useful precursors for the synthesis of various heterocyclic compounds of therapeutic importance. In this paper we have delineated and illustrated a direct methodology for the synthesis of 6-aryl-

Full text of DOI:10.1055/s-2005-872232

LETTER
2027
Substituent-Dictated Concise Synthesis of 4,6-Disubstituted N-Alkyl-2-
pyridones and 2-Aminopyridines1
S
A
ynthesis of 4,6-D
t
isubstit
u
uted
N
-
Alky
l
l-2-pyridones
G
and 2-Aminopyrid
o
ines el,* Fateh V. Singh, Deepti Verma
Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: agoel13@yahoo.com
Received 30 May 2005
Though palladium-catalyzed amination has been
to be of immense value as an alternative ap-
proach to preparing aminopyridines, the applicability of
Abstract: Functionalized N-alkyl-2-pyridones and 2-aminopy-
ridines are useful precursors for the synthesis of various heterocy-
clic compounds of therapeutic importance. In this paper we have
shown2
7,28
delineated and illustrated a direct methodology for the synthesis of several of these methods suffers from a lack of generality,
-aryl-N-hydroxyethyl-4-methylsulfanyl-2-pyridones through the intolerance of many functional groups, or incompatibility
6
ring transformation of 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-
with ring or N-alkyl chain substitution. Due to the difficul-
ty in selective N-alkylation of 2-pyridone and the limita-
tions of existing methodologies, we sought to develop a
general synthetic route, which could directly provide N-
alkylated pyridones and 2-aminopyridines. Herein, we re-
port a one-pot synthesis of N-hydroxyethyl-2-pyridones
and 2-aminopyridines through nucleophile-induced ring
transformation of 2H-pyran-2-ones by ethanolamine.
2
6
-ones by ethanolamine. Surprisingly, the analogous reaction with
-aryl-3-cyano-4-piperidin-1-yl-2H-pyran-2-ones afforded 2-ami-
nopyridines in high yield instead of the corresponding 2-pyridones.
Keywords: N-alkyl-2-pyridone, 2-aminopyridine, ethanolamine,
pyran-2-one, ring transformation reaction
Substituted N-alkyl-2-pyridones and 2-aminopyridines in
a flexible or rigid conformation are common structural
features found in many biologically important synthetic
The 2H-pyran-2-ones 1a–e used as parent precursors have
been conveniently prepared by the reaction of methyl 2-
cyano-3,3-di(methylsulfanyl)acrylate with acetophe-
nones as described earlier.29 The unique features of the
2H-pyran-2-one 1 is the presence of three electrophilic
centres; C2, C4, and C6 where the latter two are highly
susceptible to nucleophiles due to the extended conjuga-
tion and the presence of the electron-withdrawing substit-
uent at position three on the pyran ring. Our approach to
synthesize N-alkyl-2-pyridones 2a–e involved the reac-
tion of 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-
ones 1a–e with ethanolamine in ethanol at reflux temper-
ature (Scheme 1). The reaction was monitored by TLC,
which was complete in one to four hours. The resulting
mixture was cooled to room temperature and left over-
night. The white crystalline solid was filtered off and
characterized as 6-aryl-3-cyano-4-(2-hydroxyethylami-
no)-2H-pyran-2-ones 3a–e. The filtrate was evaporated to
dryness and the desired pyridone (Table 1) was isolated in
good yield by passing the crude material through a col-
2
and natural products. Molecules embedded with these
scaffolds are known to exhibit diverse pharmacological
3
activities as neuropeptide Y1 receptor antagonists, mus-
4
5
6
7
cle relaxants, antitumor, antifungal, and antiviral activ-
ities, free radical scavenging,8 hypotensive,9 and
1
0
cardiotropic activities, and inactivation of voltage-de-
+
11
pendent K channels. From a chemical perspective, sev-
eral dialkylaminopyridines such as DMAP, 4-pyrrolidino-
pyridine (PPY) and their analogues have been extensively
used as catalysts in acylation and alkylation reactions. In
addition, 2-aminopyridines and 2-pyridinones are key in-
termediates in the synthesis of a variety of heterocyclic
1
2
1
3
compounds of therapeutic importance.
In general, the alkylation of 2-pyridone leads to both N-
and O-alkylated product and the regioselectivity depends
on the nature of the base, the structure of the alkyl halide,
substituents on the pyridone ring, and the solvent em-
1
4
ployed. Selective N-alkylation of 2-pyridone predomi-
nates in the presence of sodium salts but an increase in the
size of alkyl halide favors O-alkylation. Numerous syn-
thetic methodologies are available for the synthesis of 2-
30,31
umn using chloroform as an eluent.
In order to confirm that the isolated products 2a–e were 1-
(
2-hydroxyethyl)-4-methylsulfanyl-6-phenyl-1H-pyridin-
1
5–22
2-ones and not 2-(6-aryl-2-imino-4-methylsulfanyl-2H-
pyridin-1-yl)ethanols 4a–e, an independent reaction with
pyridones
but the methods for direct access to N-
alkyl-2-pyridones are rare. Similarly, various approaches
3
-carbomethoxy-4-methylsulfanyl-6-phenyl-2H-pyran-2-
are known in the literature for the synthesis of aminopy-
2
3–25
one (5) was carried out as shown in Scheme 2. After the
usual work-up, we isolated two products 6-phenyl-N-
hydroxyethyl-4-methylsulfanyl-2-pyridone (6) and 3-car-
bomethoxy-4-(2-hydroxyethylamino)-6-phenyl-2H-pyran-
ridines.
Recently, we reported a regioselective ap-
proach to access 2-pyridones and 2-aminopyridines
through nucleophile-induced ring transformation of 2H-
pyran-2-ones using urea as the nucleophilic source.26
2
-ones (7). The spectroscopic data of compound 6 exactly
matched the data of compound 2a suggesting that the
assigned structures for compounds 2a–e were correct.
SYNLETT 2005, No. 13, pp 2027–2030
Advanced online publication: 20.07.2005
1
9
.0
8
.2
0
0
5
DOI: 10.1055/s-2005-872232; Art ID: G18105ST
©
Georg Thieme Verlag Stuttgart · New York

2
028
A. Goel et al.
LETTER
Scheme 1
Table 1 Synthesis of Pyridone
Compound Ar Reaction time (h)
The lack of selectivity between compounds 2 and 3 under
these reaction conditions prompted us to examine the
course of the reaction in different solvents such as DMF,
DMSO, benzene, and pyridine as well as vary the reaction
temperatures. Unfortunately, all such efforts led to a mix-
ture of compounds with different side products as indicat-
ed by TLC of various reaction mixtures. Even after many
attempts, we could not selectively prepare 2-pyridones
a
Yield (%)
2
3
a
b
c
C H
1.0
2.5
2.0
2.0
3.5
47
42
40
39
41
51
46
51
55
53
6
5
4-FC H
6
4
4-ClC H
6
4
2
a–e from 2H-pyran-2-ones 1a–e. From the reaction
d
4-BrC H
6 4
mechanism described in Scheme 1, we found that the
methylsulfanyl group at position 4 on the 2H-pyran-2-one
e
4-CH C H
3 6 4
1
3
is playing a leading role in the formation of side product
due to the presence of the electron-withdrawing group at
a
All the reactions were carried out at 80 °C in ethanol.
position 3 on the pyran ring and the good leaving group
ability of the methyl sulfanyl group.
A plausible reaction mechanism for the formation of 6-
aryl-N-hydroxyethyl-4-methylsulfanyl-2-pyridones 2 is In order to prepare 2-pyridones exclusively, we attempted
depicted in Scheme 1. The reaction is possibly initiated by to reduce the electrophilicity at position 4 of lactone 1 by
attack of the amino functionality of ethanolamine on the replacing a methyl sulfanyl group with a secondary
highly vulnerable electrophilic center C6 of 2H-pyran-2- amine. We then prepared 6-aryl-2-oxo-4-piperidin-1-yl-
one, followed by intramolecular cyclization involving the 2H-pyran-3-carbonitriles 8a–f by refluxing a solution of
secondary amine and the nitrile functionality present at lactone 1 with piperidine in methanol for six to eight
position 3 of 2H-pyran-2-one, this is followed by decar- hours. Surprisingly, when we carried out the reaction with
boxylation to give N-(2-hydroxyethyl)-1H-pyridin-2- lactones 8a–f and ethanolamine under the same reaction
ylideneamine intermediate. The imino group of the inter- conditions as described in Scheme 1, we isolated new
mediate was readily hydrolyzed to the corresponding car- compounds 6¢-aryl-3,4,5,6-tetrahydro-2H-[1,4¢]bipyridi-
bonyl functionality to afford 6-aryl-N-hydroxyethyl-4- nyl-2¢-ylamines 9a–f in high yields instead of the corre-
3
1
methylsulfanyl-2-pyridone in good yield.
sponding pyridones (Scheme 3). The 2-aminopyridines
(
Table 2) are the sole products of the reaction and are eas-
ily isolated by column chromatography and were charac-
terized by spectroscopic means.31 Distinctive
characteristics of 2-aminopyridine 9d include two sharp
–
1
NH signals in the IR spectrum at 3352 and 3456 cm and
2
1
a broad singlet in the H NMR spectrum at 4.30 ppm for
two protons, which disappeared after a D O shake. The re-
2
placement of the SMe group in 1 with a piperidine func-
tionality did not yield 2-pyridones 10, which showed that
the functional groups (methylsulfanyl, piperidine) at posi-
tion 4 in 2H-pyran-2-ones 1 dictated the direction of the
reaction either towards the formation of 2-pyridones or 2-
aminopyridines.
Scheme 2
Synlett 2005, No. 13, 2027–2030 © Thieme Stuttgart · New York

LETTER
Synthesis of 4,6-Disubstituted N-Alkyl-2-pyridones and 2-Aminopyridines
2029
Scheme 3
Table 2 Synthesis of 2-Aminopyridine
Acknowledgment
a
Compound
Ar
Reaction time (h)
Yield (%)
The authors thank the Department of Science and Technology
DST), New Delhi for financial support under SERC Fast Track
Scheme (SR/FTP/CSA-08/2003) and members of Sophisticated
Analytical Instrumentation Facility (SAIF), CDRI, Lucknow for
providing elemental analyses and spectroscopic data of synthesized
compounds.
(
9
a
b
c
C H
12
12
11
10
11
12
88
87
92
90
90
84
6
5
4-BrC H
6
4
4-ClC H
6
4
References
d
e
4-MeC H
6 4
(
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Thienyl
a
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by intramolecular cyclization involving secondary amine
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(
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-aminopyridines 9a–f in high yields.
1
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(
(
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H-pyran-2-ones with ethanolamine yielded 2-pyridones,
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Synlett 2005, No. 13, 2027–2030 © Thieme Stuttgart · New York

2
030
A. Goel et al.
LETTER
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methylsulfanyl-2H-pyran-2-ones (1, 1 mmol) and
ethanolamine (1.2 mmol) was refluxed in EtOH for 1–4 h.
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(
(
(
2
(
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(
(
(
(
(
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chromatography using CHCl as an eluent.
3
(31) Spectroscopic and elemental analyses data of selected
compounds. 2a: white solid; mp 140–142 °C; IR (KBr):
–
1
1
1630 (CO), 3427 cm (OH); H NMR (200 MHz, CDCl ):
3
20) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synthesis 2000,
d = 2.44 (s, 3 H, SCH ), 3.72–3.75 (m, 2 H, CH ), 4.03 (t, J
3
2
2
73.
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= 4.9 Hz, 2 H, CH ), 4.16 (t, J = 4.9 Hz, 1 H, OH), 6.03 (d,
2
J = 2.0 Hz, 1 H, CH), 6.33 (d, J = 2.0 Hz, 1 H, CH), 7.28–
1
7.33 (m, 2 H, ArH), 7.43–7.48 (m, 3 H, ArH); MS (FAB):
+
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A.; Lu, K.-L.; Snead, T. E.; Geoffroy, G. L.; Rheingold, A.
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m/z = 262 (M + 1); Anal. Calcd for C H NO S: C, 64.34;
1
4
15
2
H, 5.79; N, 5.36. Found: C, 64.07; H, 5.92; N, 5.25. 3a:
white solid; mp 248–250 °C; IR (KBr): 1687 (CO), 2216
–
1
1
(23) Vorbrüggen, H. Adv. Heterocycl. Chem. 1990, 49, 117.
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(CN), 3271 (NH), 3401 cm (OH); H NMR (200 MHz,
(
DMSO-d ): d = 3.57 (s, 4 H, 2 CH ), 4.90 (br s, 1 H, OH),
6
2
1
993, 36, 769. (b) Manna, F.; Chimenti, F.; Bolasco, A.;
7.04 (s, 1 H, CH), 7.55–7.58 (m, 3 H, ArH), 7.93–7.97 (m, 2
H, ArH), 8.30 (br s, 1 H, NH); MS (FAB): m/z = 257 (M +
+
Bizzarri, B.; Filippelli, W.; Filippelli, A.; Gagliardi, L. Eur.
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1); Anal. Calcd for C H N O : C, 65.62; H, 4.72; N, 10.93.
1
4
12
2
3
Found: C, 65.65; H, 4.51; N, 10.83. 7: white solid; mp 236–
–
1
1
(
25) (a) Cuperly, D.; Gros, P.; Fort, Y. J. Org. Chem. 2002, 67,
237 °C; IR (KBr): 1657, 1688 (CO), 3403 cm (OH); H
238. (b) Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A.
NMR (200 MHz, DMSO-d ): d = 3.63–3.66 (m, 4 H, 2 CH ),
6
2
E.; Henderson, S. A.; Chen, J. J. Org. Chem. 1997, 62, 6210.
26) Goel, A.; Singh, F. V.; Sharon, A.; Maulik, P. R. Synlett
3.74 (s, 3 H, OCH ), 5.08 (br s, 1 H, OH), 6.97 (s, 1 H, CH),
3
(
(
7.53–7.58 (m, 3 H, ArH), 7.96–8.00 (m, 2 H, ArH), 10.05 (br
+
2005, 623.
s, 1 H, NH); MS (FAB): m/z = 290 (M + 1); Anal. Calcd for
27) (a) Hartwig, J. F. Synlett 1997, 116. (b) Hartwig, J. F.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2046. (c) Frost, C.
G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998,
C H NO : C, 62.28; H, 5.23; N, 4.84. Found: C, 62.31; H,
1
5
15
5
5.26; N, 4.48. 9a: white solid; mp 124–126 °C; IR (KBr):
–
1 1
3370 (NH), 3469 (NH) cm ; H NMR (200 MHz, CDCl ):
3
2615. (d) Belfield, A. J.; Brown, G. R.; Foubister, A. J.
d = 1.56–1.60 (m, 4 H, 2 CH ), 1.65–1.68 (m, 2 H, CH ),
2
2
Tetrahedron 1999, 55, 11399.
3.34–3.37 (m, 4 H, 2 CH ), 4.51 (br s, 2 H, NH ), 5.84 (d,
2
2
J = 2.0 Hz, 1 H, PyH), 6.59 (d, J = 2.0 Hz, 1 H, PyH), 7.38–
.42 (m, 3 H, ArH), 7.84–7.88 (m, 2 H, ArH); MS (FAB):
7
+
m/z = 254 (M + 1); Anal. Calcd for C H N : C, 75.85; H,
1
6
19
3
7.56; N, 16.59. Found: C, 75.38; H, 7.06; N, 16.37.
Synlett 2005, No. 13, 2027–2030 © Thieme Stuttgart · New York