Synthesis of 5,6-diarylpyridin-2(1H)-ones from isoflavones

Article abstract of DOI:10.1002/cjoc.201300279

A simple method for the cyclocondensation of substituted isoflavones with cyanoacetamide in the presence of sodium hydroxide to give an array of 3-cyano-5,6-diarylpyridin-2(1H)-ones in good yields is reported. A method for the cyclocondensation of substituted isoflavones with cyanoacetamide in the presence of sodium hydroxide to give 3-cyano-5,6-diaryl-2(1H)-pyridones in good yields is reported. Copyright

Full text of DOI:10.1002/cjoc.201300279

FULL PAPER
DOI: 10.1002/cjoc.201300279
Synthesis of 5,6-Diarylpyridin-2(1H)-ones from Isoflavones
Mulin Zhu,a Zunting Zhang,*,a Dong Xue,a Jinfeng Qiao,a Yong Liang,b and Stanislaw F. Wnuk*,b
a Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry,
National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China,
and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, Shannxi 710062, China
b Department of Chemistry and Biochemistry, Florida International University,
Miami, Florida 33199, United States
A simple method for the cyclocondensation of substituted isoflavones with cyanoacetamide in the presence of
sodium hydroxide to give an array of 3-cyano-5,6-diarylpyridin-2(1H)-ones in good yields is reported.
Keywords isoflavones, cyclocondensation, 3-cyano-5,6-diarylpyridin-2(1H)-ones
Introduction
strates containing two nitrogen atoms, for example hy-
drazines, guanidines, amidines, amino-azoles among
others.[9,15] Herein, a convenient strategy for the synthe-
sis of 5,6-diaryl-diarylpyridin-2(1H)-ones involving the
cyclocondensation reactions of isoflavones with the ac-
tive methylene carbon atom and nitrogen atoms of
cyanoacetamide is reported.
Substituted 2-pyridones posses interesting biological
and pharmacological activities.[1,2] For example, 2-pyri-
dones have shown antimicrobial,[3] antidepressant,[4]
cardiotonic,[5] and anticancer activities.[6] A few reports
have appeared on the synthesis of 2-pyridones, which
include the cyclocondensation of acetonitrile derivatives
such as cyanoacetate ester, cyanoacetamide, or malono-
nitrile with an appropriate α,β-unsaturated carbonyl or
1,3-dicarbonyl substrate.[7-9] The preparation of 3-cyano-
5,6-diarylpyridin-2(1H)-ones requires multistep synthe-
sis and harsh reaction conditions (Scheme 1).[10,11]
Chromone fragment present in isoflavones can pro-
duce a 1,3-dicarbonyl intermediate in the presence of
base. And the intermediate readily condenses with ami-
dines,[12] guanidine,[13] hydrazine,[14] to form the corre-
sponding 2-substituted pyrimidines and diarylpyrazoles.
Experimental
General Information
1H NMR (300 MHz) and 13C NMR (75 MHz) spec-
tra were recorded in DMSO-d6 solution, using tetra-
methylsilane (TMS) as an internal standard unless oth-
erwise noted. HRMS spectra were recorded using ESI
technique and IR spectra were recorded in KBr pellet.
The crystal diffraction data were collected on a Bruker
Smart-1000 CCD diffractometer. Melting points were
measured on micro melting point apparatus and are un-
corrected. TLC was performed on Merck kieselgel
60-F254 and products were detected with 254 nm light.
Merck kieselgel 60 (230－400 mesh) was used for
column chromatography.
Pyrimido[1,2-a]benzimidazoles,
triazolopyrimidines
and pyrazolo[3,4-b]pyridines were synthesized by
2-aminobenzimidazole,[15] triazole,[16] and 3-amino-5-
hydroxypyrazole[17] condensed with substituted isofla-
vones, respectively. These heterocyclic compounds are
constructed by condensation of isoflavones with sub-
Scheme 1 Routes for the synthesis of 3-cyano-5,6-diaryl-2-pyridones
O
(1) LDA
O
NaCl, H2O
Ar2CH2CO2Me
CO2Me
Ar2
(2)
Ar1
O
Ar1
DMSO
O
Ar2
CN
Ar1
lm
(1) DMF-DMA
HN
(2) NaOMe
OTMS
CN
O
Ar1
(1) LDA
NH2
TMSCN
ZnI2
Ar1CHO
NC
Ar2
Ar1
(2) Ar2CH2Cl
(3) H+ or TBAF
Ar1
O
Ar2
*
E-mail: zhangzunting@sina.com
Received April 12, 2013; accepted June 15, 2013; published online July 5, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300279 or from the author.
Chin. J. Chem. 2013, 31, 1027—1032
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1027

Zhu et al.
FULL PAPER
General procedure for the synthesis of 3-cyano-5,6-
111.8, 113.9, 117.2, 119.4, 129.5, 130.2, 131.9, 149.8,
diaryl-diarylpyridin-2(1H)-ones (3a－3v)
150.6, 156.7, 158.5, 160.3; IR (KBr) ν: 3247, 2997,
1654, 1605, 1517, 1260, 1027, 892 cm−1; HRMS m/z
Isoflavone 1a－1v (1 mmol), cyanoacetamide 2 (92
mg, 1.1 mmol), and NaOH (120 mg, 3 mmol) were re-
fluxed in EtOH (10 mL) for 1－5 h. The reactions were
monitored by TLC until the disappearance of 1a－1v.
After cooling to room temperature, water (50 mL) was
poured into the reaction mixture and the resulting mix-
ture was acidified with 5% HCl/H2O to the neutral pH.
The precipitation was filtered off and purified on silica
gel column (CHCl3/MeOH, 40∶1). The corresponding
products 3a－3v as colorless amorphous powders were
obtained, the yields were 45% to 85%. The single crys-
tal of 3a was got by recrystallization in acetone.
＋
calcd for [C19H14N2O4 ＋ Na]
357.0851, found
357.0844.
3-Cyano-6-(5-fluoro-2-hydroxylphenyl)-5-phenyl-
1
pyridin-2(1H)-one (3e) m.p. 248－250 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 6.77－7.22 (m, 7H), 8.25 (s,
1H), 9.93 (s, 1H), 12.71 (s, 1H); 13C NMR (DMSO-d6,
75 MHz) δ: 102.2, 116.8, 117.1, 117.2, 117.3, 117.4,
2
118.1 (d, J＝23.0 Hz), 127.5, 128.5, 129.1, 136.5,
1
148.1, 150.7, 151.9, 155.0 (d, J＝236.0 Hz), 160.2; IR
(KBr) ν: 3433, 2955, 2225, 1659, 1547, 1020, 892 cm−1;
HRMS m/z calcd for [C18H11FN2O2＋Na]＋ 329.0702,
found 329.0696.
3-Cyano-6-(2-hydroxy-4-isopropoxyphenyl)-5-
phenylpyridin-2(1H)-one (3a) m.p. 261 －262 ℃
3-Cyano-6-(5-fluoro-2-hydroxylphenyl)-5-(4-methy-
phenyl)-pyridin-2(1H)-one (3f) m.p. 288－290 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 2.22 (s, 3H); 6.77－
7.04 (m, 7H), 8.20 (s, 1H), 10.20 (s, 1H), 12.40 (s, 1H);
13C NMR (DMSO-d6, 75 MHz) δ: 21.1, 102.7, 116.9,
117.1, 117.2, 117.3, 117.4, 118.1 (d, 2J＝22.7 Hz), 129.0,
1
(Me2CO); H NMR (DMSO-d6, 300 MHz) δ: 1.21 (d,
J＝6.0 Hz, 6H), 4.49 (septet, J＝6.0 Hz, 1H), 6.25 (d,
J＝8.5 Hz, 1H), 6.31 (s, 1H), 6.77 (d, J＝8.5 Hz, 1H),
7.05 (s, 2H), 7.12－7.19 (m, 3H), 8.16 (s, 1H), 9.97 (s,
1
1H), 12.48 (s, 1H); H NMR (DMSO-d6＋D2O, 300
1
129.2, 133.6, 136.8, 148.0, 150.8, 152.0, 154.9 (d, J＝
MHz) δ: 1.22 (d, J＝6.0 Hz, 6H), 4.49 (s, septet, J＝6.0
Hz, 1H), 6.24 (m, 2H), 6.77 (d, J＝8.5 Hz, 1H), 7.07 (s,
233.1 Hz), 160.3; IR (KBr) ν: 3430, 2958, 2223, 1648,
1617, 1515, 1030, 898 cm−1; HRMS m/z calcd for
[C19H13FN2O2＋Na]＋ 343.0859, found 343.0848.
13
2H), 7.19 (s, 3H), 8.17 (s, 1H); C NMR (DMSO-d6＋
D2O, 75 MHz) δ: 22.2, 69.7, 103.1, 106.7, 113.0, 117.0,
119.6, 127.2, 128.5, 129.1, 132.0, 137.2, 149.9, 150.7,
156.9, 160.3; IR (KBr) ν: 3274, 3054, 2977, 2222, 1645,
1607, 1553, 1512, 1427, 1377, 992, 794, 700 cm−1;
HRMS calcd for [C21H18N2O3 ＋Na]＋ 369.1215, found
369.1200.
3-Cyano-6-(5-fluoro-2-hydroxylphenyl)-5-(4-meth-
oxyphenyl)-pyridin-2(1H)-one (3g) m.p. 288－290
℃; 1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 3H), 6.78
(d, J＝8.2 Hz, 2H), 6.82 (s, 1H), 6.90 (dd, J＝2.4, 8.8
Hz, 1H), 7.00 (d, J＝8.2 Hz, 2H), 7.07 (s, 1H), 8.20 (s,
1H), 10.00 (s, 1H), 12.63 (s, 1H); 13C NMR (DMSO-d6,
75 MHz) δ: 55.5, 102.8, 114.0, 116.9, 117.1, 117.2,
3-Cyano-6-(2-hydroxyl-4,6-dimethoxyphenyl)-5-
(4-methoxyphenyl)-pyridin-2(1H)-one (3b)
m.p.
2
1
117.3, 117.4, 118.0 (d, J＝23.0 Hz), 128.7, 130.3,
300－304 ℃; H NMR (DMSO-d6, 300 MHz) δ: 3.53
(s, 3H), 3.69 (s, 6H), 5.99 (s, 1H), 6.01 (s, 1H), 6.77 (d,
J＝8.5 Hz, 2H), 7.00 (d, J＝8.5 Hz, 2H), 8.10 (s, 1H),
9.81 (s, 1H), 12.46 (s, 1H); 13C NMR (DMSO-d6, 75
MHz) δ: 55.4, 55.5, 56.0, 90.2, 93.8, 101.7, 113.7, 117.1,
120.7, 129.6, 147.0, 150.2, 156.9, 158.6, 159.0, 160.6,
162.5; IR (KBr) ν: 3446, 3275, 3082, 2220, 1646, 1446,
818 cm−1; HRMS calcd for [C21H18N2O5 ＋ Na] ＋
401.1113, found 401.1083.
1
147.7, 150.8, 151.9, 155.0 (d, J＝233.0 Hz), 158.7,
160.2; IR (KBr) ν: 3434, 2948, 2226, 1650, 1607, 1513,
1020, 888 cm−1; HRMS m/z calcd for [C19H13FN2O3＋
Na]＋ 359.0808, found 359.0795.
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-(4-
methoxyphenyl)-pyridin-2(1H)-one (3h) m.p. 235－
237 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 6H),
6.32 (d, J＝8.5 Hz, 1H), 6.37 (s, 1H), 6.77 (d, J＝8.3
Hz, 2H), 6.84 (d, J＝8.5 Hz, 1H), 7.01 (d, J＝8.3 Hz,
2H), 8.14 (s, 1H), 9.99 (s, 1H), 12.49 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 55.46, 55.51, 101.7, 105.3,
113.5, 114.0, 117.1, 119.4, 129.3, 130.3, 132.0, 149.5,
150.7, 156.9, 158.6, 160.4, 161.9; IR (KBr) ν: 3288,
3046, 2950, 2219, 1644, 1513, 1435, 1295, 1030, 801
cm−1; HRMS m/z calcd for [C20H16N2O4 ＋ Na] ＋
371.1008, found 371.0987.
3-Cyano-6-(4-methoxy-6-methyl-2-hydroxyphenyl)-
5-phenylpyridin-2(1H)-one (3c) m.p. 279－282 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 1.80 (s, 3H), 3.66 (s,
3H), 6.18 (s, 1H), 6.25 (s, 1H), 7.11 (s, 2H), 7.29 (s, 3H),
8.23 (s, 1H), 9.88 (s, 1H), 12.57 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 19.8, 55.5, 99.0, 102.5, 106.5,
113.7, 117.0, 120.3, 127.5, 128.5, 136.8, 138.1, 149.3,
150.6, 156.9, 160.7, 161.3; IR (KBr) ν: 3440, 3268,
2226, 1646, 1153, 989, 853 cm−1; HRMS calcd for
[C20H16N2O3＋Na]＋ 355.1059, found 355.1053.
3-Cyano-6-(2-hydroxylphenyl)-5-(4-methylphenyl)-
1
pyridin-2(1H)-one (3i) m.p. 289－291 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 2.19 (s, 3H), 6.68 (s, 1H), 6.84
(s, 1H), 6.97 (s, 5H), 7.17 (s, 1H), 8.19 (s, 1H), 9.94 (s,
1H), 12.64 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ:
21.0, 102.8, 116.1, 116.9, 119.1, 120.0, 129.0, 131.0,
131.6, 133.9, 136.6, 150.7, 155.4, 160.1; IR (KBr) ν:
3249, 2969, 2224, 1652, 1606, 1143, 856 cm−1; HRMS
m/z calcd for [C19H14N2O2 ＋Na]＋ 325.0953, found
3-Cyano-6-(2,4-dihydroxylphenyl)-5-(4-methoxy-
phenyl)-pyridin-2(1H)-one (3d) m.p. 286－289 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 3H), 6.13 (d,
J＝8.8 Hz, 1H), 6.28 (s, 1H), 6.70 (d, J＝8.8 Hz, 1H),
6.74 (d, J＝8.3 Hz, 2H), 6.98 (d, J＝8.3 Hz, 2H), 8.12
(s, 1H), 9.63 (s, 1H), 9.78 (s, 1H), 12.42 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz) δ: 55.5, 101.3, 102.9, 107.0,
1028
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Chin. J. Chem. 2013, 31, 1027—1032

Synthesis of 5,6-Diarylpyridin-2(1H)-ones from Isoflavones
325.0939.
3-Cyano-6-(3-bromo-2-hydroxy-4-isopropoxyphe-
nyl)-5-phenylpyridin-2(1H)-one (3o) m.p. 270－272
℃; 1H NMR (DMSO-d6, 300 MHz) δ: 1.27 (s, 6H), 4.50
(s, 1H), 6.50 (s, 1H), 7.24－7.09 (m, 6H), 8.19 (s, 1H),
10.08 (s, 1H), 12.52 (s, 1H); 13C NMR (DMSO-d6, 75
MHz) δ: 22.0, 71.7, 100.9, 102.7, 114.4, 116.9, 127.4,
128.5, 129.1, 134.4, 136.9, 150.6, 155.9, 156.3, 160.3;
IR (KBr) ν: 3550, 3341, 2957, 2226, 1652, 1600, 1553,
1209, 1006, 886 cm−1; HRMS m/z calcd for
[C21H17BrN2O3＋Na]＋ 447.0320, found 447.0283.
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-(3,5-
diisopropyl-4-methoxyphenyl)-pyridin-2(1H)-one (3p)
3-Cyano-6-(4-benzyloxy-2-hydroxylphenyl)-5-(4-
methoxyphenyl)-pyridin-2(1H)-one (3j) m.p. 247－
249 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 3H),
5.03 (s, 2H), 6.38－6.44 (m, 2H), 6.75－7.41 (m, 10H),
8.12 (s, 1H), 12.50 (s, 1H); 13C NMR (DMSO-d6, 75
MHz) δ: 55.5, 69.6, 102.5, 106.0, 113.7, 114.0, 117.1,
119.4, 128.2, 128.4, 128.9, 129.4, 130.3, 132.0, 137.2,
149.5, 150.7, 157.0, 158.5, 160.4, 161.0; IR (KBr) ν:
3421, 2908, 2222, 1644, 1610, 1511, 1153, 859 cm−1;
HRMS m/z calcd for [C26H20N2O4＋Na]＋ 447.1321,
found 447.1312.
1
m.p. 270－271 ℃; H NMR (DMSO-d6, 300 MHz) δ:
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-(4-
methoxyphenyl)-pyridin-2(1H)-one (3k) m.p. 235－
237 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 6H),
6.32 (d, J＝8.5 Hz, 1H), 6.37 (s, 1H), 6.77 (d, J＝8.3
Hz, 2H), 6.84 (d, J＝8.5 Hz, 1H), 7.01 (d, J＝8.3 Hz,
2H), 8.14 (s, 1H), 9.99 (s, 1H), 12.49 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 55.5, 101.7, 105.3, 113.5, 114.0,
117.1, 119.4, 129.3, 130.3, 132.0, 149.5, 150.7, 156.9,
158.6, 160.4, 161.9; IR (KBr) ν: 3288, 3046, 2950, 2219,
1.01 (s, 12H), 3.14 (s, 2H), 3.69 (s, 3H), 3.73 (s, 3H),
6.38 (s, 2H), 6.82 (s, 3H), 8.28 (s, 1H), 9.96 (s, 1H),
12.50 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 24.1,
26.2, 55.5, 62.3, 101.3, 105.3, 113.7, 117.2, 119.6, 124.8,
131.7, 132.5, 141.9, 149.5, 150.6, 153.2, 156.8, 160.3,
162.0; IR (KBr) ν: 3457, 2968, 2223, 1652, 1599, 1553,
1208, 1049, 845 cm−1; HRMS m/z calcd for
[C26H28N2O4＋Na]＋ 455.1947, found 455.1939.
3-Cyano-6-(4-benzyloxy-2-hydroxylphenyl)-5-(4-
1644, 1513, 1435, 1295, 1030, 801 cm−1; HRMS m/z
calcd for [C20H16N2O4 ＋ Na]
371.0987.
3-Cyano-6-(4-methoxy-2,6-dihydroxyphenyl)-5-
(4-methoxyphenyl)-pyridin-2(1H)-one (3l) m.p. 335
－338 ℃; H NMR (DMSO-d6, 300 MHz) δ: 3.62 (s,
＋
benzyloxyphenyl)-pyridin-2(1H)-one (3q)
m.p.
371.1008, found
1
253－255 ℃; H NMR (DMSO-d6, 300 MHz) δ: 5.03
(s, 4H), 6.42 (s, 2H), 6.84 (s, 2H), 6.99 (s, 3H), 7.39 (s,
10H), 8.13 (s, 1H), 9.98 (s, 1H), 12.40 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz) δ: 69.6, 102.5, 106.0, 114.7,
117.1, 128.3, 130.3, 137.3, 150.7, 156.8, 157.6, 160.3,
160.9; IR (KBr) ν: 3309, 2979, 2223, 1652, 1607, 1429,
1013, 895, 796 cm−1; HRMS m/z calcd for [C32H24N2O4＋
Na]＋ 523.1634, found 523.1617.
1
13H), 3.69 (s, 3H), 5.85 (s, 2H), 6.77 (d, J＝8.5 Hz, 2H),
7.08 (d, J＝8.5 Hz, 2H), 8.10 (s, 1H), 9.63 (s, 2H),
12.41 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 55.4,
92.8, 101.6, 102.5, 113.7, 117.2, 120.7, 129.7, 146.7,
150.2, 157.1, 158.5, 160.7, 162.0; IR (KBr) ν: 3375,
3248, 2943, 2226, 1653, 1513, 1246, 1101, 992, 835
cm−1; HRMS m/z calcd for [C20H16N2O5 ＋ Na] ＋
387.0957, found 387.0934.
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-(4-
hydroxyphenyl)-pyridin-2(1H)-one (3m) m.p. 263－
265 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 3.69 (s, 3H),
6.31 (d, J＝8.5 Hz, 1H), 6.37 (s, 1H), 6.58 (d, J＝8.1
Hz, 2H), 6.81 (d, J＝8.5 Hz, 1H), 6.86 (d, J＝8.1 Hz,
2H), 8.11 (s, 1H), 9.39 (s, 1H), 9.97 (s, 1H), 12.46 (s,
1H); 13C NMR (DMSO-d6, 75 MHz) δ: 60.2, 101.6,
105.1, 113.6, 115.4, 117.1, 119.7, 128.3, 130.2, 149.2,
150.7, 156.7, 160.3, 161.8; IR (KBr) ν: 3404, 3247,
3040, 2223, 1643, 1512, 1226, 1038, 886 cm−1; HRMS
m/z calcd for [C21H18N2O5 ＋Na]＋ 357.0851, found
357.0833.
3-Cyano-6-(2,4-dihydroxyphenyl)-5-(2-hydroxy-
phenyl)-pyridin-2(1H)-one (3r) m.p. 271－273 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 6.11 (d, J＝8.3 Hz,
1H), 6.28 (s, 1H), 6.59 (d, J＝8.3 Hz, 2H), 6.66 (d, J＝
8.3 Hz, 1H), 6.86 (d, J＝8.3 Hz, 2H), 8.09 (s, 1H), 9.38
(s, 1H), 9.61 (s, 1H), 12.37 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 102.4, 106.5, 111.4, 114.8,
119.1, 127.3, 129.7, 131.4, 150.1, 156.2, 159.8; IR (KBr)
ν: 3303, 2979, 2219, 1643, 1603, 1512, 1195, 828 cm−1;
HRMS m/z calcd for [C18H12N2O4＋Na]＋ 343.0695,
found 343.0683.
3-Cyano-6-(2-hydroxyphenyl)-5-phenyl-2(1H)-
1
pyridin-2(1H)-one (3s) m.p. 251－253 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 6.69－7.18 (m, 9H), 8.22 (s,
1H), 10.02 (s, 1H), 12.69 (s, 1H); 13C NMR (DMSO-d6,
75 MHz) δ: 116.1, 116.9, 119.1, 127.3, 128.5, 129.2,
131.0, 131.6, 136.8, 151.2, 155.5, 160.2; IR (KBr) ν:
3249, 2962, 2222, 1646, 1602, 1116, 950, 856 cm−1;
HRMS m/z calcd for [C18H12N2O2＋Na]＋ 311.0796,
found 311.0780.
3-Cyano-6-(2-hydroxy-4,5,6-trimethoxyphenyl)-5-
(4-methoxyphenyl)-pyridin-2(1H)-one (3n)
m.p.
1
277－280 ℃; H NMR (DMSO-d6, 300 MHz) δ:
3.50－3.72 (m, 12H), 6.22 (s, 1H), 6.78 (s, 2H), 7.04 (s,
2H), 8.18 (s, 1H), 9.73 (s, 1H), 12.54 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 55.2, 60.8, 95.5, 102.1, 107.1,
113.8, 117.0, 120.4, 129.7, 134.1, 146.5, 150.4, 151.4,
155.3, 158.7, 160.5; IR (KBr) ν: 3426, 2979, 2226, 1665,
1600, 1553, 1106, 995, 885 cm−1; HRMS m/z calcd for
[C22H20N2O6＋Na]＋ 431.1219, found 431.1210.
3-Cyano-6-(2-hydroxyphenyl)-5-(4-methoxyphenyl)-
1
pyridin-2(1H)-one (3t) m.p. 261－264 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 3.67 (s, 3H), 6.60－7.00 (m,
7H), 7.20 (s, 1H), 8.17 (s, 1H), 10.04 (s, 1H), 12.57 (s,
1H); 13C NMR (DMSO-d6, 75 MHz) δ: 55.4, 114.0,
116.2, 117.0, 119.1, 120.7, 129.0, 130.3, 131.0, 131.6,
149.4, 150.7, 155.4, 158.6, 160.2; IR (KBr) ν: 3248,
Chin. J. Chem. 2013, 31, 1027—1032
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Zhu et al.
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2967, 2219, 1655, 1607, 1557, 1142, 941, 854 cm−1;
HRMS m/z calcd for [C19H14N2O3＋Na]＋ 341.0902,
found 341.0884.
EtOH was the solvent of choice, although condensation
in MeOH afforded 3a in comparable yield (Table 1, En-
tries 3, 5－8). Changing the molecular ratios of 1a, 2,
and NaOH in EtOH indicated that the condensation
yield of 3a was improved to 71% by using 3 equiv. of
NaOH (Table 1, Entry 9). The yield was further im-
proved to 77% when a 10% excess of 2 was used (Table
1, Entry 10).
3-Cyano-6-(2,4-dihydroxyphenyl)-5-phenyl-
pyridin-2(1H)-one (3u) m.p. 290－292 ℃; H NMR
1
(DMSO-d6, 300 MHz) δ: 6.09 (d, J＝7.9 Hz, 1H), 6.27
(s, 1H), 6.68 (d, J＝7.9 Hz, 1H), 7.08 (s, 2H), 7.18 (s,
3H), 8.14 (s, 1H), 9.61 (s, 2H), 12.35 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ: 102.9, 107.0, 111.6, 117.1,
119.4, 127.1, 128.4, 129.1, 131.9, 137.3, 150.6, 156.8,
160.2; IR (KBr) ν: 3432, 2955, 2225, 1647, 1600, 1452,
1259, 977 cm−1; HRMS m/z calcd for [C18H12N2O3＋
Na]＋ 327.0746, found 327.0724.
3-Cyano-6-(4-benzyloxy-2-hydroxylphenyl)-5-(4-
hydroxyphenyl)-pyridin-2(1H)-one (3v) m.p. 263－
265 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 5.04 (s, 2H),
6.42 (s, 2H), 6.60－6.39 (m, 4H), 6.89－6.83 (m, 3H),
7.42－7.33 (m, 5H), 8.12 (s, 1H), 9.39 (s, 1H), 9.98 (s,
1H), 12.45 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ:
69.7, 101.7, 102.6, 106.0, 113.9, 115.4, 117.1, 119.7,
127.7, 128.1, 128.4, 128.9, 129.1, 130.3, 132.0, 137.3,
149.3, 150.7, 156.7, 156.9, 160.3, 161.0; IR (KBr) ν:
3340, 2985, 2222, 1650, 1617, 1430, 1020, 890, 790
cm−1; HRMS m/z calcd for [C26H28N2O4 ＋ Na] ＋
433.1164, found 433.1155.
A structurally divergent range of 3-cyano-5,6-diaryl-
pyridin-2(1H)-ones (3a－3v) were obtained in good
yields (45%－85%, Table 2) by the cyclocondensation
of the substituted isoflavones 1a－1v with cyanoaceta-
mide 2 under the screening conditions [1/2/NaOH (1∶
1.1∶3) EtOH/1－5 h/reflux]. When a fluorine EWG
was present at ring A of 1, the highest yields of the ap-
propriate pyridin-2(1H)-ones (3a－3v) were obtained
(80%－85%; Table 2, Entries 5, 6 and 7). Yields were
slightly lower when the substituents on the isoflavones 1
had electron-donating character, especially when a hy-
droxyl group was present in the ring A (Entry 4). It
seems plausible that phenolate ions generated under
basic conditions from the hydroxyl group locating at
isoflavones might have a greater electron-donating abil-
ity than the corresponding alkoxy and benzoxyisofla-
vones, thereby affecting the yields (see Scheme 2). The
substituents at ring B of 1, had a limited effect on the
efficiency of the condensation reactions, although a
methoxy substituent (EDG) consistently led to slightly
lower yields. Compounds 3a－3v were characterized by
spectroscopic techniques. Moreover, the structure of 3a
was determined by single crystal X-ray diffraction
analysis (Figure 1).
Results and Discussion
At beginning, the reaction of 4-isopropoxyisoflavone
1a (1 mmol) and cyanoacetamide 2 was optimized with
different bases and under refluxing solvents (Table 1).
NaOH (s) was found to be best base examined for the
synthesis of 2-pyridone 3a (Table 1, Entries 1－4).
Table 1 Screening of conditions of cyclocondensation of isoflavone 1a with cyanoacetamide 2a
OH
HN
O
O
O
O
O
CN
base
NCCH2CONH2
+
solvent
reflux
2
1a
3a
Entry
Solvent
Base
Molar ratios of 1a∶2∶base
Yield of 3ab/%
1
2
3
4
5
EtOH
EtOH
EtOH
EtOH
MeOH
Et3N
1∶1∶1
1∶1∶1
1∶1∶1
1∶1∶1
1∶1∶1
trace
34
K2CO3
NaOH
NaOMe
NaOH
52
41
50
6
7
8
9
10
MeCN
DMF
THF
EtOH
EtOH
NaOH
NaOH
NaOH
NaOH
NaOH
1∶1∶1
1∶1∶1
1∶1∶1
1∶1∶3
1∶1.1∶3
26
33
30
71c
77d
a Reagents and conditions: 1a (1 mmol), solvent (10 mL) at reflux, completion of the reaction was monitored by disappearance of 1a by
TLC. Isolated product yields. Reactions with 1.5, 2, or 4 equiv. of NaOH gave 3a in 60%, 65% and 67% yields, respectively. Reac-
tions with 1.2 and 1.3 equiv. of 2 gave 3a in 75% and 73% yields, respectively.
b
c
d
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Chin. J. Chem. 2013, 31, 1027—1032

Synthesis of 5,6-Diarylpyridin-2(1H)-ones from Isoflavones
Table 2 The cyclocondensation of isoflavones with cyanoacetamide in EtOHa
R1
O
OH
R1
A
HN
R2
R3
R2
O
C
A
CN
R7
R6
R4
R5
R3
NaOH, EtOH
reflux
+
NCCH2CONH2
B
R4
O
B
2
R7
R5
1
R6
3
Entry Substrate R1
R2
R3
R4
H
R5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
i-Pi
H
H
H
H
H
H
R6
R7 Product Time/h Yieldb/%
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
i-OPr
OMe
OMe
OH
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
i-Pi
H
H
H
H
H
H
1
77
75
78
53
85
82
80
73
77
70
73
48
62
78
76
70
65
45
60
55
50
62
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
OMe
Me
H
OMe
H
1.5
1.5
3
3
4
OMe
H
5
H
H
1
6
H
F
H
Me
1.5
2
7
H
F
H
OMe
H
1g
1h
1i
3g
3h
3i
8
OMe
H
H
H
H
H
H
H
H
1.5
2
9
H
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
OBn
OMe
OMe
OMe
OMe
i-OPr
OMe
OBn
OH
H
OMe
OMe
OMe
OH
OMe
H
2
1j
3j
H
2.5
3.0
3.5
2.0
1.5
1.5
3.5
5.0
4.0
3.5
4.5
3.5
1k
1l
3k
3l
OH
H
1m
1n
1o
1p
1q
1r
1s
3m
3n
3o
3p
3q
3r
3s
OMe OMe
H
H
H
H
H
H
H
H
H
H
OMe
OBn
H
H
OH
H
H
H
H
H
OMe
H
1t
3t
OH
H
1u
1v
3u
3v
OBn
H
OH
a
Reagents and conditions: 1a－1v (1 mmol), 1/2/NaOH (1∶1.1∶3), EtOH (10 mL) at refluxing, the substrates 1a－1v had completely
disappeared by TLC. b Isolated yields.
Scheme 2 Mechanism for the formation of 3
O
H2N
O
O
OH
H2N
O
O
O
CN
HN
H2N
O
O
O
-H2O, H+
CN
CN
CN
2
O
4
1
5
3
reaction between 1 and 2. Then, ring opening and the
intramolecular condensation between ketone and amino
group in 5 followed by dehydration would give substi-
One possible mechanism that would explain the
formation of 2-pyridones 3 is shown in Scheme 2. First,
intermediate 4 is produced by base-catalyzed Michael
Chin. J. Chem. 2013, 31, 1027—1032
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www.cjc.wiley-vch.de
1031

Zhu et al.
FULL PAPER
tuted 3-cyano-5,6-diarylpyridin-2(1H)-ones (3).
Supplementary Material
Crystal and structure refinement data for 3a are de-
posited in the Cambridge Crystallographic Data Centre,
CCDC number: 940736.
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Acknowledgement
This research was supported by the National Natural
Science Foundation of China (No. 20772076), and the
Fundamental Funds Research for the Central Universi-
ties (No. Gk200901010).
(Pan, B.; Qin, X.)
1032
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