One-step synthesis of 5,6-diaryl pyridine-2(1H)-thiones from isoflavones

Article abstract of DOI:10.1039/c3ob27247h

The one-step cyclocondensation of substituted isoflavones with cyanothioacetamide in the presence of sodium hydroxide gave an array of 3-cyano-5,6-diaryl pyridine-2(1H)-thiones in good yields. The procedure involves base-mediated ring opening of the isofl

Full text of DOI:10.1039/c3ob27247h

Organic &
Biomolecular Chemistry
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One-step synthesis of 5,6-diaryl pyridine-2(1H)-thiones
from isoflavones†
Cite this: Org. Biomol. Chem., 2013, 11,
2034
Juanjuan Wang, Zunting Zhang,* Wenli Wang and Fangfang Liu
The one-step cyclocondensation of substituted isoflavones with cyanothioacetamide in the presence of
sodium hydroxide gave an array of 3-cyano-5,6-diaryl pyridine-2(1H)-thiones in good yields. The pro-
cedure involves base-mediated ring opening of the isoflavones and subsequent Knoevenagel conden-
sation between the 1,3-dicarbonyl intermediate generated from the isoflavones and
cyanothioacetamide, followed by ring closure and dehydration.
Received 20th November 2012,
Accepted 18th January 2013
DOI: 10.1039/c3ob27247h
www.rsc.org/obc
However, the preparation of 6-phenyl pyridine-2(1H)-thiones
requires multistep synthesis and harsher reaction conditions
Introduction
Pyridine-2(1H)-thiones are the principal core structures (Scheme 1).12
present in a variety of natural products and have acquired sig-
It is known that the chromone fragment present in iso-
nificance. Substituted pyridine-2(1H)-thiones are known for flavones can generate a 1,3-dicarbonyl equivalent in the presence
their antimicrobial,1 antidepressant,2 anticancer,3 and anti- of alkali, which readily reacts with amidines,13 guanidine,14
schizophrenic activities.4,5 Palladium(II) complexes with pyri- hydrazine,15 to form the corresponding 2-substituted pyrimi-
dine-2(1H)-thiones and triphenylphosphine (PPh3) were dines and diarylpyrazoles. Recently we have reported that
screened for antitumor, brine shrimps lethality bioassay and 2-aminobenzimidazole,16 triazole,17 and 3-amino-5-hydroxypyr-
antibacterial effects activity. These complexes showed signifi- azole,18 condensed with isoflavones yielding pyrimido[1,2-a]-
cant activities in most of the cases against the tested bacteria benzimidazoles, triazolopyrimidines, pyrazolo[3,4-b]pyridines,
as compared to that of a standard drug. Their antitumor respectively. These heterocyclic compounds are usually con-
activity against prostate cancer cells (PC3) is comparable with structed by condensation of isoflavones with substrates con-
doxorubicin, together with no cytotoxic effects in brine taining two nitrogen atoms such as amidines, guanidines,
shrimps lethality bioassay study.6 And pyridine-2(1H)-thiones hydrazines, aminoazoles among others. We now report a mild
can be used for synthesis of pyrido-thieno-pyrimidines. These and efficient one-pot strategy for the synthesis of novel 5,6-
analogs are potent and selective inhibitors of Cdc7/Dbf4 diaryl pyridine-2(1H)-thiones involving the cyclocondensation
kinase in vitro. The representative compounds from these reactions of isoflavones with an active methylene carbon atom
series can penetrate cultured cancer cells, inhibit MCM2 phos- and nitrogen, sulfur atoms of cyanothioacetamide. To the best
phorylation and show a moderate antiproliferative effect in of our knowledge there are no reports on the synthesis of 5,6-
cancer cells.7 The most common synthetic route to pyridine-2- diaryl pyridine-2(1H)-thiones.
(1H)-thiones involve the cyclocondensation of α,β-unsaturated
carbonyl or 1,3-dicarbonyl substrate such as malonaldehyde,
β-carbonyl aldehyde, ethenyl aldehyde with cyanothioacet-
amide.8,9 Another synthetic route to pyridine-2(1H)-thiones
involves substitution reaction of 2-chloropyridine or 2-bromo-
pyridine with sodium hydrosulfide at 160 °C in BuOH.10,11
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 710062,
P. R. China. E-mail: zhangzt@snnu.edu.cn
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of all compounds; crystal and structure refinement data for 3a.
CCDC 921360. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob27247h
Scheme 1 Method for the synthesis of 3-cyano-6-phenyl pyridine-2(1H)-
thiones.
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Table 1 Optimization of cyclocondensation of isoflavone 1a with cyanothio-
acetamide 2a
Results and discussion
Initially, the reaction between the commercially available 7-iso-
propoxyisoflavone 1a and cyanothio-acetamide 2 was opti-
mized by varying the bases and solvents. The reaction results
are summarized in Table 1. DMF was the solvent of choice,
although condensation in DMSO afforded 3a in comparable
yield (entries 1–4). Solid NaOH was found to be the most
effective of the four bases examined for the preparation of pyri-
dine-2(1H)-thione 3a (entries 3, 5–7). Varying the molecular
ratios of 1a, 2, and NaOH in DMF revealed that the conden-
sation yield was improved to 68% by using 3.5 equiv. of NaOH
(entry 9). The yield was further improved to 73% when a 100%
excess of 2 was utilized (entry 10).
The optimized conditions were applied to the cycloconden-
sation of the substituted isoflavones 1a–u with cyanothioacet-
amide 2 [1–2–NaOH (1 : 2 : 3.5)/DMF/5–7 h/90 °C]. A structurally
divergent range of 3-cyano-5,6-diaryl pyridine-2(1H)-thiones
3a–u were produced in good yields (39–81%, Table 2). The
highest yields of the appropriate pyridine-2(1H)-thiones 3a–u
were obtained when a fluorine or bromine EWG was present
on the ring A (76%–81%; entries 7, 9, 12 and 15). Yields were
slightly lower when the substituents on the isoflavones 1a–u
had electron-donating character, especially when a hydroxyl
group was present on the ring A (entries 3, 4 and 18). It seems
Molar ratios
1a : 2 : base
Entry
Solventb
Base
Yield 3ac (%)
1
2
3
4
5
6
7
8
EtOH
CH3CN
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NaOH
NaOH
NaOH
NaOH
KOH
K2CO3
t-BuOK
NaOH
NaOH
NaOH
NaOH
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 3
1 : 1 : 3.5
1 : 2 : 3.5
1 : 2 : 3.5
35
12
58d
55
49
Trace
8
63
9
10
11
65e
73f
30g
a All reactions were carried out on 1 mmol scale of 1a in the indicated
solvent (10 mL) until complete disappearance of 1a. b Reactions at
reflux in EtOH and CH3CN, at 90 °C in DMF and DMSO. c Isolated
yields. d Reactions at 80, 90, or 100 °C in DMF gave 3a in 38, 58 and
52% yields, respectively. e Reactions with 1.5, 2.5, or 4 equiv. of NaOH
gave 3a in 58, 60 and 68% yields, respectively. f Reactions with 1.5 and
2.5 equiv. of 2 gave 3a in 67 and 74% yields, respectively. g Reactions
with 3.5 equiv. of 3.0 mol L−1 sodium hydroxide solution.
Table 2 Synthesis of 3-cyano-5,6-diaryl pyridine-2(1H)-thiones 3a–u by the cyclocondensation of various isoflavones 1a–u with cyanothioacetamide 2 in DMFa
Entry
Substrate
R1
R2
R3
R4
R5
R6
R7
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
i-OPr
OMe
OH
OMe
OMe
OMe
H
H
H
i-OPr
H
H
i-Opr
Obn
F
OMe
OBn
OH
H
H
H
H
H
H
H
F
H
Br
H
H
Br
H
H
H
OMe
H
H
H
H
H
H
H
H
OH
Me
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
5
79
73
52
51
76
78
81
69
76
70
68
78
76
60
78
59
57
39
60
55
63
OMe
OMe
OMe
H
H
Me
Cl
Me
Me
OMe
H
OMe
OH
H
OMe
OBn
OH
Me
OH
H
5.5
6.5
6.5
5
5
5.5
6
5.5
5
5.5
5
5.5
7
5
6.5
5.5
5.0
5.0
6.0
6.5
9
10
11
12
13
14
15
16
17
18
19
20
21
H
H
H
H
1s
1t
1u
3s
3t
3u
OMe
H
a All reactions were carried out on 1 mmol scale of 1a–u [1–2–NaOH (1 : 2 : 3.5)] at 90 °C in DMF (10 mL) until the substrates 1a–u had completely
disappeared. b Isolated yields.
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A plausible mechanism for the formation of pyridine-2(1H)-
thiones 3 is shown in Scheme 3. In brief, base-mediated ring
opening of the isoflavones20 should lead to the formation of
the 1,3-dicarbonyl intermediate 4. Knoevenagel condensation
between aldehyde group in 4 and cyanothioacetamide 2 would
generate 5, and subsequent ring closure and dehydration
yields substituted pyridine-2(1H)-thiones 3.
Scheme 2 Formation of the dimer 3a.
Conclusion
In summary, we have developed a convenient one-pot pro-
cedure for the synthesis of substituted 3-cyano-5,6-diaryl pyri-
dine-2(1H)-thiones under mild conditions in encouraging
yields, through the condensation of the substituted isoflavones
with cyanothioacetamide in the presence of NaOH in DMF.
The procedure involves base-mediated ring opening of the iso-
flavones and subsequent Knoevenagel condensation between
the 1,3-dicarbonyl intermediate generated from the isoflavones
and cyanothioacetamide, followed by ring closure and
dehydration.
Experimental procedures
General procedure for the synthesis of 3-cyano-5,6-diaryl
pyridine-2(1H)-thiones (3a–u)
The corresponding isoflavone 1a–u (1 mmol), cyanothioacet-
amide 2 (200 mg, 2 mmol), and solid NaOH (140 mg,
3.5 mmol) were reacted in DMF at 90 °C (10 mL) for 5–7 h. The
progress of the reaction was monitored by TLC till the dis-
appearance of 1a–u. The reaction mixture was poured into water
(40 mL) and acidified with 2% HCl/H2O to the neutral pH. The
precipitated yellow solid was filtered off and was purified on
silica gel column (CHCl3–MeOH, 100 : 1) to give the corres-
ponding products 3a–u as colorless amorphous powders.
3-Cyano-6-(2-hydroxy-4-isopropoxyphenyl)-5-phenylpyridine-2-
(1H)-thione (3a). Mp 253–254 °C; 1H NMR δ 1.21 (d, J = 5.4 Hz,
6H), 4.51 (septet, J = 5.7 Hz, 1H), 6.28 (t, J = 14.4, 7.9 Hz, 2H),
6.78 (d, J = 8.2 Hz, 1H), 7.08 (s, 2H), 7.19 (s, 3H), 8.18 (s, 1H),
Fig. 1 X-ray crystal structure of 3a dimer (crystallized from acetone).
plausible that phenolate ions generated under basic con-
ditions from the hydroxyl group present in isoflavones might
have a greater electron-donating ability of the hydroxyiso-
flavones than the corresponding alkoxy and benzoxyisoflavones,
thereby affecting the mechanism (see Scheme 2, vide infra).
The substituents on the ring B had a limited effect on the
efficiency of the condensation reactions, although a methoxy
substituent (EDG) consistently gave slightly lower yields. All
products were characterized by 1H, 13C NMR and HRMS
spectra. Single crystal X-ray diffraction analysis of 3a unequi-
vocally established the postulated structures (Fig. 1). The mole-
cular structure is a dimer of 3a and is linked by disulfide
bonds. Acetone with an oxidizing agent can oxidize thiophenol
into a disulfide bond dimer (Scheme 2).19
1
10.00 (s, 1H), 12.50 (s, 1H); H NMR (DMSO-d6 + D2O) δ 1.22
(d, J = 6.0 Hz, 6H), 4.49 (s septet, J = 6.0 Hz, 1H), 6.28 (s, 1H),
6.35 (m, 1H), 6.77 (d, J = 8.5 Hz, 1H), 7.07 (s, 2H), 7.19 (s, 3H),
8.17 (s, 1H); 13C NMR (DMSO-d6 + D2O) δ 21.7, 69.2, 102.3,
104.9, 106.6, 115.3, 117.5, 127.6, 128.2, 131.8, 134.9, 137.8,
143.1, 154.7, 156.1, 158.8, 159.7; IR ν (cm−1) 3224, 3081, 2967,
2223, 1621, 1574, 1403, 1260, 1109, 992, 694; HRMS m/z calcd
for [C21H18N2O2S + Na]+ 385.0987, found 385.0984.
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-(4-methoxyphenyl)-
pyridine-2(1H)-thione (3b). Mp 221–222 °C; 1H NMR δ 3.69
(s, 6H), 6.52–6.26 (m, 2H), 6.80 (dd, J = 20.1, 8.4 Hz, 3H), 6.98
(d, J = 8.4 Hz, 2H), 8.13 (s, 1H), 10.02 (s, 1H), 12.46 (s, 3H);
13C NMR δ 55.0, 101.2, 104.8, 113.1, 113.5, 116.6, 118.9, 128.9,
129.8, 131.5, 145.0, 150.2, 156.4, 158.1, 159. 9, 161.5;
IR ν (cm−1) 3292, 2945, 2841, 2223, 1648, 1609, 1436, 1297,
Scheme 3 Proposed mechanism for the formation of 3.
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1129, 957, 736; HRMS m/z calcd for [C20H16N2O3S + Na]+ 3H), 6.79 (d, J = 8.6 Hz, 1H), 7.03 (m, 4H), 7.20 (s, 1H), 7.34 (d,
387.0780, found 387.0778.
J = 6.8 Hz, 1H), 8.12 (s, 1H), 11.29 (s, 2H); 13C NMR δ 21.1,
3-Cyano-6-(2,4-dihydroxylphenyl)-5-(4-methoxyphenyl)pyri- 102.8, 109.8, 116.9, 118.4, 119.8, 122.9, 128.9, 129.2, 133.2,
dine-2(1H)-thione (3c). Mp 273–274 °C; 1H NMR δ 3.69 (s, 133.7, 134.1, 136.8, 147.8, 150.8, 154.9, 160.3; IR ν (cm−1
)
3H), 6.11 (d, J = 8.3 Hz, 1H), 6.28 (s, 1H), 6.68 (d, J = 8.3 Hz, 3290, 3089, 2908, 2226, 1649, 1600, 1283, 1183, 1083, 985, 859;
1H), 6.74 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 8.12 (s, HRMS m/z calcd for [C19H13FN2OS + Na]+ 418.9830, found
1H), 9.63 (s, 1H), 9.8 8 (s, 1H), 12.42 (s, 1H); 13C NMR δ 55.0, 418.9825.
101.3, 104.5, 112.7, 116.9, 118.8, 126.7, 128.1, 12 8.8, 131.5,
3-Cyano-6-(2-hydroxy-4-isopropoxyphenyl)-5-(4-methylphenyl)-
1
137.2, 149.9, 150.1, 157.6, 160.3, 161.6; IR ν (cm−1) 3274, 2989, pyridine-2(1H)-thione (3j). Mp 264–265 °C; H NMR δ 1.26 (s,
2225, 1676, 162 5, 1517, 1320, 1165, 1027, 983; HRMS m/z 6H), 2.24 (s, 3H), 4.58–4.45 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H),
calcd for [C19H14N2O3S + Na]+ 373.0623, found 373.0619.
6.37 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 2.9 Hz, 4H),
3-Cyano-6-(4-methoxy-2,6-dihydroxyphenyl)-5-(4-methoxy- 8.08 (s, 1H), 11.55 (s, 2H); 13C NMR δ 21.1, 22.2, 69.7, 103.1,
1
phenyl)pyridine-2(1H)-thione (3d). Mp 327–328 °C; H NMR δ 106.6, 113.1, 117.1, 129.0, 129.1, 132.0, 134.3, 136.4, 137.6,
3.61 (s, 3H), 3.68 (s, 3H), 5.84 (s, 2H), 6.76 (d, J = 8.4 Hz, 2H), 149.6, 150.7, 156.9, 160.2, 160.4; IR ν (cm−1) 3275, 2979, 2228,
7.06 (d, J = 8.4 Hz, 2H), 8.11 (s, 1H), 9.63 (s, 2H), 12.39 (s, 1H); 1656, 1612, 1296, 1121, 994, 948, 858; HRMS m/z calcd for
13C NMR δ 55.0, 92.3, 101.2, 102.1, 113.3, 114.2, 116.8, 120.2, [C22H20N2O2S + Na]+ 399.1143, found 399.1143.
129.1, 147.1, 149.8, 156.7, 158.1, 160.2, 161.5; IR ν (cm−1
)
3-Cyano-6-(2-hydroxyphenyl)-5-(4-methoxyphenyl)pyridine-
3295, 3184, 2843, 2224, 1643, 1563, 1267, 1109, 982, 843; 2(1H)-thione (3k). Mp 254–255 °C; 1H NMR δ 3.70 (s, 3H),
HRMS m/z calcd for [C20H16N2O4S + Na]+ 403.0729, found 6.80–6.69 (m, 3H), 6.85 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 17.7,
403.0728.
8.0 Hz, 3H), 7.20 (t, J = 7.1 Hz, 1H), 8.12 (s, 1H), 11.07 (s, 2H);
3-Cyano-6-(4-methoxy-6-methyl-2-hydroxyphenyl)-5-phenyl- 13C NMR δ 55.5, 102.2, 113.9, 116.2, 117.1, 119.1, 120.7, 129.0,
pyridine-2(1H)-thione (3e). Mp 268–269 °C; 1H NMR δ 1.81 (s, 130.3, 130.9, 131.6, 149.4, 150.9, 155.5, 158.6, 160.3; IR ν
3H), 3.67 (s, 3H), 6.18 (s, 1H), 6.25 (s, 1H), 7.11 (s, 2H), 7.29 (s, (cm−1) 3268, 2956, 2227, 1655, 1609, 1297, 1150, 1081, 990,
3H), 8.23 (s, 1H), 9.88 (s, 1H), 12.57 (s, 1H); 13C NMR δ 19.8, 861; HRMS m/z calcd for [C19H14N2O2S + Na]+ 357.0674, found
55.5, 99.0, 102.5, 106.5, 113.7, 117.0, 120.3, 127.5, 128.5, 136.8, 357.0669.
138.1, 149.3, 150.6, 156.9, 160.7, 161.3; IR ν (cm−1) 3436, 3073,
2996, 2228, 1652, 1606, 1257, 1176, 1029, 945, 868; HRMS m/z 2(1H)-thione (3l). Mp 300–304 °C; H NMR δ 6.79 (d, J = 8.6
calcd for [C20H16N2O2S + Na]+ 371.0830, found 371.0828. Hz, 1H), 7.52–7.05 (m, 7H), 8.17 (s, 1H), 11.34 (s, 2H); 13C NMR
3-Cyano-6-(5-bromo-2-hydroxylphenyl)-5-phenylpyridine-
1
3-Cyano-6-(2-hydroxy-4-methoxyphenyl)-5-phenylpyridine-2- δ 102.8, 109.8, 116.9, 118.3, 119.8, 122.8, 127.6, 128.6, 129.2,
1
(1H)-thione (3f). Mp 214–215 °C; H NMR δ 3.71 (s, 3H), 6.13 133.2, 134.2, 136.6, 150.7, 155.0, 160.3; IR ν (cm−1) 3299, 3066,
(d, J = 8.2 Hz, 1H), 6.29 (s, 1H), 7.13–6.60 (m, 4H), 7.00 (d, J = 2909, 2230, 1662, 1558, 1278, 1081, 989, 861; HRMS m/z calcd
8.4 Hz, 2H), 8.13 (s, 1H), 9.63 (s, 1H), 12.43 (s, 1H); 13C NMR δ for [C18H11BrN2OS + Na]+ 404.9673, found 404.9670.
54.9, 100.9, 102.6, 106.6, 111.4, 113.5, 116.7, 118.8, 129.1,
129.8, 131.4, 149.5, 150.2, 156.3, 158.0, 159.9; IR ν (cm−1
3-Cyano-6-(3-bromo-2-hydroxy-4-isopropoxyphenyl)-5-phenyl-
)
pyridine-2(1H)-thione (3m). Mp 267–268 °C; 1H NMR δ 1.22 (s,
3298, 3136, 2887, 2229, 1650, 1608, 1291, 1172, 1028, 981, 864; 6H), 4.55–4.22 (m, 1H), 6.31 (s, 1H), 6.89 (s, 1H), 7.27 (d, J =
HRMS m/z calcd for [C19H14N2O2S + Na]+ 357.0674, found 21.2 Hz, 5H), 8.27 (s, 1H), 9.72 (s, 1H), 12.58 (s, 1H); 13C NMR δ
354.0673.
22.0, 71.6, 101.2, 102.7, 105.1, 115.8, 119.6, 128.2, 128.7, 134.6,
3-Cyano-6-(5-fluoro-2-hydroxylphenyl)-5-(4-methylphenyl)- 135.4, 138.1, 143.9, 151.9, 154.5, 155.8, 157.5; IR ν (cm−1) 3245,
pyridine-2(1H)-thione (3g). Mp 275–276 °C; 1H NMR δ 2.22 3128, 2887, 2227, 1615, 1575, 1265, 1132, 1069, 954, 865; HRMS
(s, 3H), 6.77–7.04 (m, 7H), 8.20 (s, 1H), 10.20 (s, 1H), 12.40 (s, m/z calcd for [C21H17BrN2O2S + Na]+ 463.0092, found 463.0089.
1H); 13C NMR δ 21.1, 102.7, 116.9, 117.2, 117.4, 118.0, 118.3,
3-Cyano-6-(4-benzyloxy-2-hydroxylphenyl)-5-(4-hydroxyphenyl)-
1
119.7, 121.4, 129.2, 133.6, 136.8, 148.0, 150.8, 152.0, 153.4, pyridine-2(1H)-thione (3n). Mp 266–267 °C; H NMR δ 5.03 (s,
156.5, 160.3; IR ν (cm−1) 3230, 3029, 2854, 2222, 1650, 1607, 2H), 6.44–6.38 (m, 2H), 6.57 (d, J = 8.2, 2H), 6.88–6.80 (m, 3H),
1215, 1197, 1030, 918, 875; HRMS m/z calcd for [C19H13FN2OS 7.41–7.33 (m, 5H), 8.11 (s, 1H), 9.39 (s, 1H), 9.98 (s, 1 H), 12.54
+ Na]+ 359.0631, found 359.0626.
(s, 1H); 13C NMR δ 69.1, 101.2, 102.0, 105.5, 113.3, 114.9,
3-Cyano-6-(2-hydroxylphenyl)-5-(4-chlorophenyl)pyridine- 116.7, 119.3, 127.2, 127.9, 128.4, 129.8, 131.5, 136.8, 148.8,
1
2(1H)-thione (3h). Mp 300–304 °C; H NMR δ 6.75 (t, J = 7.2 150.3, 156.2, 156.3, 159.8, 160.4; IR ν (cm−1) 3291, 3098, 2890,
Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 7.10 2222, 1647, 1619, 1373, 1150, 1070, 954, 862; HRMS m/z calcd
(d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.9 Hz, 3H), 8.18 (s, 1H), 11.14 (s, for [C25H18N2O3S + Na]+ 449.0936, found 449.0933.
2H); 13C NMR δ 102.4, 116.3, 116.9, 118.4, 119.3, 120.4, 128.5,
130.9, 131.0, 131.9, 132.2, 135.9, 149.9, 150.6, 155.4, 160.4; IR 2(1H)-thione (3o). Mp 266–267 °C; H NMR δ 6.78–7.22 (m,
ν (cm−1) 3268, 3092, 2889, 2226, 1647, 1604, 1273, 1150, 1090, 8H), 8.24 (s, 1H), 9.93 (s, 1H), 12.71 (s, 1H); 13C NMR δ 116.8,
951, 860; HRMS m/z calcd for [C19H13FN2OS + Na]+ 361.0179, 117.1, 117.2, 117.3, 117.4, 118.0, 118.2, 127.5, 128.5, 129.1,
3-Cyano-6-(5-fluoro-2-hydroxylphenyl)-5-phenylpyridine-
1
found 361.0176.
136.5, 150.6, 152.0, 153.4, 156.4, 160.1; IR ν (cm−1) 3289, 3143,
3-Cyano-6-(5-bromo-2-hydroxylphenyl)-5-(4-methylphenyl)- 2913, 2220, 1645, 1606, 1296, 1170, 1131, 991, 843; HRMS m/z
pyridine-2(1H)-thione (3i). Mp 302–303 °C; 1H NMR δ 2.25 (s, calcd for [C18H11FN2OS + Na]+ 345.0474, found 345.0469.
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Organic & Biomolecular Chemistry
3-Cyano-6-(4,5,6-trimethoxy-2-hydroxyphenyl)-5-(4-methoxy-
phenyl)pyridine-2(1H)-thione (3p). Mp 279–281 °C; 1H NMR δ
Acknowledgements
3.35–3.73 (m, 12H), 6.22 (s, 1H), 6.77 (s, 2H), 7.06 (s, 2H), 8.18 This research was supported by the National Natural Science
(s, 1H), 9.74 (s, 1H), 12.54 (s, 1H); 13C NMR δ 55.5, 56.0, 60.9, Foundation of China (No. 20772076), and the Fundamental
95.6, 102.2, 107.1, 113.9, 117.1, 120.5, 129.8, 134.2, 146.5, Funds Research for the Central Universities (No.
150.4, 151.9, 155.4, 158.8, 160.4; IR ν (cm−1) 3436, 3079, 2901, Gk200901010).
2224, 1665, 1610, 1253, 1106, 1090, 995, 885; HRMS m/z calcd
for [C22H20N2O5S + Na]+ 447.0991, found 447.0889.
3-Cyano-6-(4-benzyloxy-2-hydroxylphenyl)-5-(4-benzyloxyphenyl)-
Notes and references
pyridine-2(1H)-thione (3q). Mp 268–270 °C; 1H NMR δ 5.04 (s,
4H), 6.43 (s, 2H), 6.84 (s, 2H), 6.99 (s, 3H), 7.40 (s, 10H), 8.15
(s, 1H), 9.99 (s, 1H), 12.48 (s, 1H); 13C NMR δ 69.6, 102.5,
106.0, 114.7, 117.1, 128.3, 128.9, 130.3, 132.0, 137.3, 150.7,
156.8, 157.7, 160.3, 161.1; IR ν (cm−1) 3299, 3108, 2877, 2229,
1656, 1614, 1265, 1170, 979, 858; HRMS m/z calcd for
[C31H22N2O3S + Na]+ 525.1249, found 525.1249.
3-Cyano-6-(2,4-dihydroxylphenyl)-5-(4-hydroxyphenyl)pyridine-
2(1H)-thione (3r). Mp 280–282 °C; 1H NMR δ 6.13 (d, J =
8.3 Hz, 1H), 6.29 (s, 1H), 6.60 (d, J = 8.3 Hz, 2H), 6.67 (d, J =
8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 2H), 8.10 (s, 1H), 9.38 (s, 1H),
9.62 (s, 1H), 12.38 (s, 1H); 13C NMR δ 102.5, 106.5, 111.5,
114.9, 116.7, 119.1, 127.3, 129.8, 131.4, 149.3, 150.1, 156.1,
159.9; IR ν (cm−1) 3209, 2999, 2223, 1645, 1613, 1512, 1195,
1078, 943, 828; HRMS m/z calcd for [C18H12N2O3S + Na]+
359.0467, found 359.0466.
1 U. Rosentreter, T. Kraemer and A. Vaupel, Pat. Appl., WO
2002-EP2121, 20 02070485, 2002, p. 69.
2 U. Rosentreter, R. Henning, M. Bauser, T. Kraemer,
A. Vaupel, W. Huebsch and K. Dembowsky, Pat. Appl., WO
2000-EP9153, 2001025210, 2001, p. 316.
3 U. Rosentreter, T. Kraemer, M. Shimada, W. Huebsch,
N. Diedrichs, T. Krahn, K. Henninger and J.-P. Stasch, Pat.
Appl., WO 2002-EP7324, 200300 8384, 2003, p. 36.
4 T. Birkinshaw, S. Connolly, T. Luker, A. Mete and
I. Millichip, Pat. Appl., WO 2002-SE876, 2002090332, 2002,
p. 123.
5 F. C. A. Gaeta and E. C. Stracker, Pat. Appl., US 95-535988,
5,770,613, 1998, p. 17.
6 S. Nadeem, M. Bolte, S. Ahmad, T. Fazeelat and
S. A. Tirmizi, Inorg. Chim. Acta, 2010, 363, 3261–3269.
7 C.-L. Zhao, C. Tovar, X.-F. Yin and Q. Xu, Bioorg. Med.
Chem. Lett., 2009, 19, 319–323.
8 F. A. Attaby, J. Chin. Chem. Soc., 2002, 49, 561.
9 F. A. Attaby, Phosphorus, Sulfur Silicon Relat. Elem., 2002,
177, 2753.
3-Cyano-6-(2-hydroxylphenyl)-5-(4-methylphenyl)pyridine-2-
(1H)-thione (3s). Mp 280–282 °C; 1H NMR δ 2.22 (s, 3H),
7.23–6.82 (m, 8H), 8.24 (s, 1H), 10.16 (s, 1H), 12.55 (s, 1H); 13
C
NMR δ 20.6, 102.3, 116.3, 116.7, 116.9, 117.5, 117.8, 127.1,
128.0, 128.5, 128.7, 136.3, 150.2, 151.5, 153.0, 156.1, 159.8; IR
ν (cm−1) 3259, 2899, 2225, 1647, 1605, 1209, 1143, 946, 856; 10 S.-Y. Liu, Faming Zhuanli Shenqing, 2011, 12, 101941942.
HRMS m/z calcd for [C19H14N2OS + Na]+ 341.0725, found 11 J. R. Thirtle, J. Am. Chem. Soc., 1946, 68, 342.
341.0720.
12 A. Lyudmila, J. Comb. Chem., 2008, 10, 313.
3-Cyano-6-(4-methoxy-2-hydroxyphenyl)-5-(4-hydroxyphenyl)- 13 G. W. K. B. Lythgoe, A. R. Todd and A. Topham, J. Chem.
1
pyridine-2(1H)-thione (3t). Mp 262–264 °C; H NMR δ 3.71 (s,
3H), 6.50–5.99 (m, 2H), 6.75 (dd, J = 23.2, 8.4 Hz, 3H), 7.00 (d, 14 F. Xie, H. Zhao, L. Zhao, L. Lou and Y. Hu, Bioorg. Med.
J = 8.4 Hz, 2H), 8.13 (s, 1H), 9.63 (s, 2H), 12.43 (s, 1H); Chem. Lett., 2009, 19, 275.
13C NMR δ 54.9, 100.9, 102.6, 106.6, 111.4, 113.5, 116.7, 118.7, 15 A. Levai, A. M. S. Silva, J. A. S. Cavaleiro, J. Elguero,
129.1, 129.8, 131.4, 149.5, 150.2, 156.3, 158.0, 159.9; I. Alkorta and J. Jeko, Aust. J. Chem., 2007, 60, 905.
Soc., 1943, 388.
IR ν (cm−1) 3424, 3265, 2946, 2223, 1645, 1603, 1532, 1209, 16 Z.-T. Zhang, L. Qiu, D. Xue, J. Wu and F.-F. Xu, J. Comb.
1038, 932, 886; HRMS m/z calcd for [C19H14N2O3S + Na]+
373.0623, found 373.0620.
Chem., 2010, 12, 225.
17 Z.-T. Zhang, J. Xie, M.-L. Zhu and D. Xue, Synlett, 2010,
3-Cyano-6-(2-hydroxylphenyl)-5-phenylpyridine-2(1H)-thione
1825.
(3u). Mp 287–288 °C; 1H NMR δ 6.70–7.18 (m, 9H), 8.23 (s, 18 Z.-T. Zhang, Y. Liang, Y.-Q. Ma, D. Xue and J.-L. Yang,
1H), 10.03 (s, 1H), 12.70 (s, 1H); 13C NMR δ 116.1, 117.0, 119.1,
J. Comb. Chem., 2010, 12, 600.
127.3, 128.7, 129.2, 131.1, 131.6, 136.9, 151.2, 155.6, 160.3; IR 19 D. A. Berry, PCT Int. Appl., 2011097092, 2011.
ν (cm−1) 3237, 3012, 2826, 2223, 1635, 1586, 1204, 1116, 950, 20 M. Varga, S. Batori, K.-R. Maria, P.-N. Ildiko,
856; HRMS m/z calcd for [C18H12N2OS + Na]+ 327.0568, found
V.-M. Magdolna, Z. Bocskey, S. Bokotey, K. Simon and
327.0565.
I. Hermecz, Eur. J. Org. Chem., 2001, 3911.
2038 | Org. Biomol. Chem., 2013, 11, 2034–2038
This journal is © The Royal Society of Chemistry 2013