Facile one-pot, multicomponent synthesis of pyridines under microwave irradiation

Article abstract of DOI:10.1080/00397910802531930

A series of 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-carbo-nitriles were synthesized by the one-pot, multicomponent reaction of 3-acetyl-coumarin, aromatic aldehydes, malononitrile, and ammonium acetate in acetic acid under microwave irradiation. Th

Full text of DOI:10.1080/00397910802531930

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Facile One-Pot,
Multicomponent Synthesis of
Pyridines Under Microwave
Irradiation
Jian-Feng Zhou a b , Yuan-Zhi Song a , Jin-Shun Lv a ,
Gui-Xia Gong b & Shujiang Tu c
a Department of Chemistry, Huaiyin Teachers
College, Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials, Huaian, China
b School of Chemistry and Chemical Engineering,
Suzhou University, Suzhou, China
c Department of Chemistry, Xuzhou Normal
University, Xuzhou, China
Version of record first published: 19 Mar 2009.
To cite this article: Jian-Feng Zhou, Yuan-Zhi Song, Jin-Shun Lv, Gui-Xia Gong &
Shujiang Tu (2009): Facile One-Pot, Multicomponent Synthesis of Pyridines Under
Microwave Irradiation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:8, 1443-1450
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Synthetic Communications1, 39: 1443–1450, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802531930
Facile One-Pot, Multicomponent Synthesis
of Pyridines Under Microwave Irradiation
Jian-Feng Zhou,1,2 Yuan-Zhi Song,1 Jin-Shun Lv,1 Gui-Xia Gong,2
and Shujiang Tu3
1Department of Chemistry, Huaiyin Teachers College, Jiangsu Key
Laboratory for Chemistry of Low-Dimensional Materials, Huaian, China
2School of Chemistry and Chemical Engineering, Suzhou University,
Suzhou, China
3Department of Chemistry, Xuzhou Normal University, Xuzhou, China
Abstract: A series of 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-carbo-
nitriles were synthesized by the one-pot, multicomponent reaction of 3-acetyl-
coumarin, aromatic aldehydes, malononitrile, and ammonium acetate in acetic
acid under microwave irradiation. The reactions were completed in 10–13 min with
61–86% yields, were environmental benign, and had easy workup. Their structures
1
were confirmed by H NMR, IR, and MS spectra and elemental analysis.
Keywords: 3-Acetylcoumarin, 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-
carbonitrile, microwave irradiation, multicomponent reaction
Heteroaromatic rings containing nitrogen atoms often play important
roles as the scaffolds of bioactive substances.[1] Pyridine is one of the
most popular N-heteroaromatics incorporated into the structure of
many pharmaceuticals. Among them, 2-amino-3-cyano-4-(3-(5-oxo-2-
tetrahydrofuran)carboxyanilido)-6-(2-hydroxyphenyl)pyridine has been
identified as a IKK-b inhibitor.[2] Besides, pyridine derivatives are also
important and useful intermediates in preparing a variety of heterocyclic
compounds.[3] It has been reported that the 2-amino-6-aryl-3-cyano-4-
piperidinylpyridine core structure can be constructed using a one-pot
Received June 7, 2008.
Address correspondence to Jian-Feng Zhou, Department of Chemistry, Huaiyin
Teachers College, 223300 Huaian, China. E-mail: orgjfzhou@yahoo.com.cn
1443

1444
J.-F. Zhou et al.
coupling reaction of acetophenone, piperidine, malononitrile, and
ammonium acetate in conventional heating mode.[4]
It is well known that coumarin is a biologically active substance, with
numerous metabolites, and is widespread in nature.[5] Coumarin deriva-
tives constitute an important class of heterocyclic compounds that has
attracted significant attention in recent years.[6] Abdel-latif,[7] Birada
and Anekal,[8] and Mulwad and Pawal[9] reported synthesis of 2-oxo-
2H-chromen-3-yl pyridine derivatives by conventional heating. Neverthe-
less, the protocols give comparatively lower yields and longer reaction
times. Therefore, the synthesis of 2-amino-4-aryl-3-cyano-pyridine deri-
vatives continues to attract much interest in organic chemistry.[10]
Multicomponent reactions (MCRs) are powerful tools in modern
medicinal chemistry, enabling straightforward access to large libraries
of structurally related, drug-like compounds and thereby facilitating
lead generation. Hence, combined with the use of combinatorial
chemistry and high-throughput parallel synthesis, such reactions have
constituted an increasingly valuable approach to drug discovery efforts
in recent years.[11–16] Continuing our interest in the synthesis of
organic compounds by MCRs under microwave irradiation,[17–19] we
report the synthesis of 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-
3-carbonitriles by the one-pot MCR of 3-acetyl coumarin, aromatic
aldehydes, malono-nitrile, and ammonium acetate in acetic acid under
microwave irradiation. The reactions were completed in 10–13 min
with 61–86 ꢀC yields, were environmental benign, and had easy
workup.
The synthetic route is shown in Scheme 1.
Scheme 1. Ar: (a) C6H5, (b) 4-ClC6H4, (c) 4-NO2C6H4, (d) 3-NO2C6H4, (e) 4-
HOC6H4, (f) 4-CH3C6H4, (g) 3,4-(OCH2O)C6H3, and (h) 4-CH3OC6H4.

One-Pot Synthesis of Pyridines
1445
RESULTS AND DISCUSSION
When a mixture of 3-acetylcoumarin 3, aromatic aldehyde 4, malononitrile
5, and ammonium acetate was irradiated in a microwave oven (Scheme 1),
the reactions were almost completed in 10–13min. The reaction mixtures
were then washed with a small amount of ethanol. The crude products were
purified by recrystallization from 95% ethanol to afford products with good
yields (61–86%). However, the yields are only 55–72% after refluxing 2–
4.5 h. The main results for the synthesis of these compounds are given in
Table 1. This procedure has the advantage of a short routine, good yields,
convenient workup, and environmental friendliness. Their structures were
confirmed by 1H NMR, IR, and MS spectra and elemental analysis.
The reaction may proceed via imine 8, formed from aldehyde and
ammonium acetate. Imine 8 reacts with alkylidenemalononitrile 7 (from
condensation of aromatic aldehyde with malononitrile) to give 10,
followed by cycloaddition, isomerization, and aromatization to afford
the 2-amino-3-cyanopyridine 6 (Scheme 2).
In conclusion, an efficient, one-pot MCR for the synthesis of
2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-carbonitrile from the
corresponding 3-acetyl coumarin, aromatic aldehydes, and malononitrile
has been developed.
EXPERIMENTAL
Melting points were determined on a XT-5 digital melting-point instru-
ment and are uncorrected. IR spectra were recorded on a Nicolet Avatar
1
360 FT-IR instrument. H NMR were measured on a Burke 400-MHz
Table 1. Microwave irradiation synthesis of compounds 6a–6h
Heating
Microwave
Time Yielda Time Yielda
Compound
Ar
(h)
(%) (min) (%)
Mp (ꢀC)
6a
6b
6c
6d
6e
6f
C6H5
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
4-HOC6H4
4-CH3C6H4
3,4-(OCH2O)C6H3
4-CH3OC6H4
4.5
4.5
2
2
4
4
4
4
65
65
72
71
55
60
60
61
11
10
10
10
13
13
13
13
75 234–236 (202–204)[7]
79 245–247
86 252–254 (227–229)[7]
79 286–288
61 263–264 (263–265)[7]
65
70
70
271–273
223–225
268–270
6g
6h
aYields of the isolated products.

1446
J.-F. Zhou et al.
Scheme 2.
spectrometer in dimethyl sulfoxide (DMSO)-d6 with terramethyl silane
(TMS) as internal standard. Mass spectra were recorded on an LCQ
Advantage instrument. Elemental analyses were determined using a
Perkin-Elmer 240C elemental analyses. The reactions were carried out
with a modified commercial microwave oven (Sanle WP650D 650 W)
under atmospheric pressure. All the reagents are commercially available.
General Procedure for the 2-Amino-6-(2-oxo-2 H-chromen-3-yl)-
4-3-carbonitriles (6a–6h)
A mixture of the aromatic aldehyde (1 mmol), 3-acetylcoumarin
(1 mmol), malononitrile (1 mmol), ammonium acetate (2 mmol), and
acetic acid (5 mL) in an Erlenmeyer flask (25 ml) equipped with reflux
condenser was irradiated in a microwave oven for 10–13 min (as indicated
by thin-layer chromatography TLC). The reaction mixture was allowed
to stand at room temperature to solidify. The crude product was
collected, washed with ethanol, and recystallized from 95% ethanol.

One-Pot Synthesis of Pyridines
1447
Data
Compound 6a
1H NMR (400 MHz, DMSO-d6) d 8.82 (s, 1H, coumarin 4-H), 7.86 (s, 1H,
PyrH), 7.64–7.40 (m, 9H, ArH), 7.09 (s, 2H, NH2); IR (KBr): 3450, 3359,
3132, 2215, 1725, 1612 cmꢁ1; LC-MS (ESI): m=e ¼ 340.6 (M þ H)þ. Anal.
calcd. for C21H13N3O2: C, 74.33; H, 3.86; N, 12.38. Found: C, 73.95;
H, 3.84; N 12.29.
Compound 6b
1H NMR (400 MHz, DMSO-d6) d 8.81 (s, 1H, coumarin 4-H), 7.88 (s, 1H,
PyrH), 7.65–7.41 (m, 8H, ArH), 7.13 (s, 2H, NH2); IR (KBr): 3458, 3347,
3126, 2217, 1728, 1625 cmꢁ1; LC-MS (ESI): m=e ¼ 374.6 (M þ H)þ. Anal.
calcd. for C21H12ClN3O2: C, 67.48; H, 3.24; N, 11.24. Found: C, 67.13;
H, 3.22; N, 11.16.
Compound 6c
1H NMR (400 MHz, DMSO-d6) d 8.84 (s, 1H, coumarin 4-H), 8.40 (s, 1H,
PyrH), 7.91–7.43 (m, 8H, ArH), 7.24 (s, 2H, NH2); IR (KBr): 3455, 3365,
3127, 2211, 1725, 1647 cmꢁ1; LC-MS (ESI): m=e ¼ 385.7 (M þ H)þ. Anal.
calcd. for C21H12N4O4: C, 65.63; H, 3.15; N, 14.58. Found: C, 65.20;
H, 3.13; N, 14.48.
Compound 6d
1H NMR (400 MHz, DMSO-d6) d 8.83 (s, 1H, coumarin 4-H), 8.43
(s, 1H, PyrH), 7.89–7.43 (m, 8H, ArH), 7.22 (s, 2H, NH2); IR (KBr):
3452, 3395, 3130, 2203, 1723, 1606 cmꢁ1; LC=MS (ESI): m=e ¼ 385.7
(M þ H)þ. Anal. calcd. for C21H12N4O4: C, 65.63; H, 3.15; N, 14.58.
Found: C, 65.18; H, 3.13; N, 14.49.
Compound 6e
1H NMR (400 MHz, DMSO-d6) d 9.06 (s, 1H, OH), 8.80 (s, 1H,
coumarin 4-H), 7.86 (s, 1H, PyrH), 7.69–7.43 (m, 9H, ArH), 6.98
(s, 2H, NH2); IR (KBr): 3362, 3130, 2208, 1723, 1606 cmꢁ1; LC-MS
(ESI):m=e ¼ 356.6 (M þ H)þ. Anal. calcd. for C21H13N3O3: C, 70.98;
H, 3.69; N, 11.82. Found: C, 70.62; H, 3.67; N, 11.74.

1448
J.-F. Zhou et al.
Compound 6f
1H NMR (400 MHz, DMSO-d6) d 8.61 (s, 1H, coumarin 4-H), 7.85 (s, 1H,
PyrH), 7.74–7.45 (m, 8H, ArH), 7.10 (s, 2H, NH2), 2.42 (s, 3H, CH3);
IR (KBr): 3440, 3376, 3130, 2207, 1726, 1608 cmꢁ1; LC-MS (ESI):
m=e ¼ 354.0 (M þ H)þ. Anal. Calcd. for C22H15N3O2: C, 74.78; H, 4.28;
N, 11.89. Found: C, 74.40; H, 4.26; N, 11.81.
Compound 6g
1H NMR (400 MHz, DMSO-d6) d 8.80 (s, 1H, coumarin 4-H), 7.85 (s, 1H,
PyrH), 7.69–7.43 (m, 7H, ArH), 7.13 (s, 2H, NH2), 6.14 (s, 2H, OCH2O);
IR (KBr): 3450, 3376, 3129, 2208, 1727, 1606 cmꢁ1; LC-MS (ESI):
m=e ¼ 385.0 (M þ H)þ. Anal. calcd. for C22H14N3O4: C, 68.88; H, 3.42;
N, 10.96. Found: C, 68.53; H, 3.40; N, 10.88.
Compound 6h
1H NMR (400 MHz, DMSO-d6) d 8.61 (s, 1H, coumarin 4-H), 7.87 (s, 1H,
PyrH), 7.75–7.45 (m, 8H, ArH), 7.07 (s, 2H, NH2), 3.84 (s, 3H, OCH3);
IR (KBr): 3420, 3360, 3126, 2213, 1724, 1605 cmꢁ1; LC-MS (ESI):
m=e ¼ 370.0 (M þ H)þ. Anal. calcd. for C22H15N3O3: C, 71.54; H, 4.09;
N, 11.38. Found: C, 71.18; H, 4.07; N, 11.30.
ACKNOWLEDGMENT
We thank the Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials for financial support (JSKC07041).
REFERENCES
1. Temple, C.; Rener, Jr. G. A.; Raud, W. R.; Noker, P. E. Antimitotic agents:
Structure-activity studies with some pyridine derivatives. J. Med. Chem. 1992,
35(20), 3686–690.
2. Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda,
T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita,
K.; Niki, T.; Umeda, M.; Bacon, K. B.; Ziegelbauer, K. B.; Lowinger, T. B.
Discovery of novel and selective IKK-b serine-threonine protein kinase
inhibitors. Part 1. Bioorg. Med. Chem. Lett. 2003, 13(5), 913–918.
3. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Ananthan, S.; Ullas, G. V. Reaction
of nitriles under acidic conditions: A novel, direct formation of condensed
4-chloropyrimidines. Tetrahedron Lett. 1983, 24(42), 4611–4612.

One-Pot Synthesis of Pyridines
1449
4. Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Masuda, T.; Shintani,
T.; Sato, T.; Koriyama, Y.; Fukushima, K.; Nunami, N.; Yamauchi, M.;
Fuchikami, K.; Komura, H.; Watanabe, A.; Ziegelbauer, K. B.; Bacon, K.
B.; Lowinger, T. B. Synthesis and structure–activity relationships of novel
IKK-b inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg.
Med. Chem. Lett. 2004, 14(15), 4019–4022.
5. O’Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications and Mode
of Actions; John Wiley: Chichester, England, 1997, pp. 333–336.
6. Kotali, A.; Lafazanis, I. S.; Harris, P. A. A novel and facile synthesis of
7,8-diacylcoumarins. Tetrahedron Lett. 2007, 48(40), 7181–7183.
7. Abdel-latif, N. A. Synthesis and antidepressant activity of some new
coumarin derivatives. Sci. Pham. 2005, 74, 195–216.
8. Biradar, J. S.; Anekal, D. Synthesis of 2-amino-4-(50,20-disubstituted-10H-
in-dol-30-yl)-6-(200-oxo-200-H-chromen-300-yl)pyridine-3-carbonitriles and related
systems as biologically active agents. Indian J. of Heterocyclic Chem. 2007,
16(4), 375–378.
9. Mulwad, V. V.; Pawar, R. B. Synthesis of biologically active 5-benzopyranyl-
pyridines and triazolopyridines. Indian J. of Chem. B 2003, 42B(11),
2901–2904.
10. Paul, S.; Gupta, R.; Loupy, A. Improved synthesis of 2-amino-3-cyanopyri-
dines in solvent free conditions under microwave irradiation. J. Chem. Res.,
synap., 1998, 330–331.
11. Hulme, C.; Gore, V. Multi-component reactions: Emerging chemistry in
drug discovery ‘from xylocain to crixivan.’ Curr. Med. Chem. 2003, 10, 51–80.
12. Mohammad, A. A.; Azimeh, S. One-pot, four-component reaction of aryl
aldehydes, aryl ketones, phosphorus trichloride, and acetonitrile catalyzed
by acetyl chloride: Synthesis of b-acetamido ketones. Synth. Commun.
2008, 38(3), 354–360.
13. Rong, L.; Han, H.; Jiang, H.; Shi, D.; Tu, S. One-Pot Synthesis of
4,6-Diary-l2-oxo-1,2-dihydropyridine-3-carbonitriles via three-component cyclo-
condensation under solvent-free conditions. Synth. Commun., 2008, 3(2),
217–224.
14. Shintani, T.; Kadono, H.; Kikuchi, T.; Schubert, T.; Shogase, Y.;
Shimazaki, M. Efficient synthesis of 3-cyano-6-(2-hydroxyphenyl)pyridines
by multi-component condensations on beads. Tetrahedron Lett. 2003, 44,
6567–6569.
15. Rao, V. R.; Kumar, P. V. Facile one-pot synthesis of 3-[2-[5-hydroxy-4-
(2-hydroxyethyl)-3-methyl-pyrazol-1-yl]-thiazol-4-yl]-chromen-2-ones via a three-
component reaction. Synth. Commun. 2006, 36(15), 2157–2161.
16. Palimkar, S. S.; More, V. S.; Srinivasan, K. V. Simple and efficient one-
pot, three-component, solvent-free synthesis of b-enaminones via sonogashira
coupling–Michael addition sequences. Synth. Commun. 2008, 38(9), 1456–
1469.
17. Zhou, J. F.; Song, Y. Z.; Yang, Y. L.; Zhu, Y. L.; Tu, S. J. One-step synthesis of
2-aryl-4,5-diphenylimidazoles under microwave irradiation. Synth. Commun.
2005, 35, 1369–1373.

1450
J.-F. Zhou et al.
18. Zhou, J. F.; Tu, S. J.; Zhu, H. Q.; Zhi, S. J. A facile one pot synthesis of
pyrano[2,3-c]pyrazole derivatives under microwave irradiation. Synth. Commun.
2002, 32(21), 3363–3366.
19. Tu, S. J.; Li, C. M.; Li, G. G.; Cao, L. J.; Shao, Q. Q.; Zhou, D. X.; Jiang, B.;
Zhou, J. F.; Xia, M. Microwave-assisted combinatorial synthesis of poly-
substituent imidazo[1,2-a]quinoline, pyrimido[1,2-a]quinoline, and quinolino-
[1,2-a]quinazoline derivatives. J. Comb. Chem. 2007, 9, 1144–1148.