One-pot synthesis of 4,6-diaryl-3-cyanopyridine-2(1H)-thiones and their transformation to substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines

Article abstract of DOI:10.1023/B:RUCB.0000011879.89900.1f

4,6-Diaryl-3-cyanopyridine-2(1H)-thiones were synthesized in one step by the reaction of elemental sulfur, malononitrile, and 2-aryl-1-aroylethylenes in the presence of excess triethylamine. The products were used in one-pot syntheses of substituted thien

Full text of DOI:10.1023/B:RUCB.0000011879.89900.1f

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2203—2206, October, 2003
2203
Oneꢀpot synthesis of 4,6ꢀdiarylꢀ3ꢀcyanopyridineꢀ2(1H )ꢀthiones
and their transformation to substituted thieno[2,3ꢀb;4,5ꢀb]dipyridines
and pyrido[3´,2´:4,5]thieno[3,2ꢀd ]pyrimidines
A. M. Shestopalov,ꢀ K. G. Nikishin, A. V. Gromova, and L. A. Rodinovskaya
N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: shchem@dol.ru
4,6ꢀDiarylꢀ3ꢀcyanopyridineꢀ2(1H )ꢀthiones were synthesized in one step by the reaction of
elemental sulfur, malononitrile, and 2ꢀarylꢀ1ꢀaroylethylenes in the presence of excess triethylꢀ
amine. The products were used in oneꢀpot syntheses of substituted thieno[2,3ꢀb;4,5ꢀb]diꢀ
pyridines and pyrido[3´,2´:4,5]thieno[3,2ꢀd]pyrimidines.
Key words: malononitrile, α,βꢀunsaturated ketones, elemental sulfur, pyridineꢀ2(1H )ꢀ
thiones, thienodipyridines, pyridothienopyrimidines.
4,6ꢀDiarylꢀ3ꢀcyanopyridineꢀ2(1H )ꢀthiones are used
for the synthesis of antioxidants, biocides, dyes, and other
practically valuable substances.1—3 In most cases, pyriꢀ
dinethiones are prepared by condensation of cyanothioꢀ
acetamide with α,βꢀunsaturated ketones, 1,3ꢀdiketones,
and 1,3ꢀketoenamines; by the reaction of elemental sulꢀ
fur with 1,4ꢀketonitriles; or by replacement of the haloꢀ
gen atom in 2ꢀhalopyridines by sulfur.1,4—6 The main
drawback of these methods is the fact that they require
preliminary synthesis of rather complex starting comꢀ
pounds. Moreover, the reactions are not always regioꢀ
selective and often give target products in relatively low
yields.
This study is devoted to the development of an imꢀ
proved oneꢀpot method for the synthesis of 4,6ꢀdiarylꢀ
3ꢀcyanopyridineꢀ2(1H )ꢀthiones starting from simple
and readily available chemicals, namely, elemental sulꢀ
fur, malononitrile, and α,βꢀunsaturated ketones. The reꢀ
sulting pyridineꢀ2(1H )ꢀthiones served as the starting
compounds in oneꢀpot methods for the synthesis of
annelated heterocycles, namely, thienodipyridines and
pyridothienopyrimidines, difficult to obtain by other
methods.
The strategy used to prepare pyridineꢀ2(1H )ꢀthiones
is as follows: first, finely ground sulfur is refluxed in ethaꢀ
nol in the presence of a slight excess of triethylamine to
cleave the S8 ring giving betaine 1; then a mixture of
α,βꢀunsaturated ketone 2a—n and malononitrile (3) is
added to the hot solution (Scheme 1). Apparently, under
the action of excess base, ketonitrile 4 is formed, which is
then thiolated at the C(2)—H bond to afford interꢀ
mediate 5. The subsequent transformation of intermediꢀ
ate 5 can follow two pathways. The first pathway includes
elimination of hydrogen sulfide, which then adds to a
nitrile group of unsaturated nitrile 6 to yield unsaturated
thioamide 7, whose intramolecular condensation leads to
pyridineꢀ2(1H )ꢀthiones 8a—n. The other reaction pathꢀ
way does not include elimination of hydrogen sulfide but
goes through thiirene ring 9 and also gives rise to comꢀ
pounds 8a—n.
This reaction scheme is confirmed to a certain extent
by earlier experimental data. Cyclic sulfur is known to
react with organic bases to give betaines 1.7 The high
probability of the formation of ketonitriles 4 in the reacꢀ
tion medium is confirmed by the fact that these comꢀ
pounds and elemental sulfur have already been used to
synthesize pyridineꢀ2(1H )ꢀthiones.4,6 Thiolation of the
C—H bond giving intermediate 5 is also probable, as
3ꢀcyanoꢀ4,6ꢀdiphenylpyridineꢀ2(1H )ꢀthione has previꢀ
ously been prepared by the reaction of 1ꢀbromoꢀ1,1ꢀ
dicyanoꢀ2,4ꢀdiphenylbutanꢀ4ꢀone with sodium hydrogen
sulfide.
The structure of pyridineꢀ2(1H )ꢀthiones 8a—n obꢀ
tained in this way was confirmed by instrumental methꢀ
ods and by comparing their IR spectra and melting points
with those of known pyridineꢀ2(1H )ꢀthiones (Table 1,
Experimental).
Substituted pyridineꢀ2(1H )ꢀthiones 8b,l,m were used
in oneꢀpot syntheses of thienobipyridines 10a—c. The
products were obtained in 46—73% yields by refluxing
the corresponding pyridineꢀ2(1H )ꢀthiones 8 with ethyl
4ꢀchloroacetoacetate (11) in ethanol in the presence of
excess sodium ethoxide (in 1 : 2.5 ratio). Compounds 10
are produced (after acidification of the reaction mixture)
in a domino reaction or cascade heterocyclization acꢀ
cording to a previously reported pattern.8
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2087—2090, October, 2003.
1066ꢀ5285/03/5210ꢀ2203 $25.00 © 2003 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Shestopalov et al.
Scheme 1
pyridothienopyrimidines (13). Heating of pyridinethiones
8a,b,e,n with urethane 12 in a ethanol—dimethylformꢀ
amide (1 : 1) mixture in the presence of excess sodium
ethoxide gave compounds 13a—d in one step (Scheme 2).
Scheme 2
i. 1) 11, 2.5 M EtONa, EtOH, ∆; 2) HCl.
ii. 1) 12, 2.5 M EtONa, EtOH/DMF, ∆; 2) HCl.
Comꢀ
10
13
pound
Ar1
Ar2
Ar1
Ph
4ꢀFC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
Ar2
a
b
c
d
4ꢀClC6H4
4ꢀFC6H4
2ꢀMeOC6H4
—
Ph
Ph
Ph
—
Ph
Ph
Ph
2ꢀThienyl
These products are apparently formed via a sequence
of nucleophilic substitution (SN2) and the Thorpe—Ziegler
and Guareschi—Thorpe reactions, similar to the sequence
involved in the previously studied reactions between viciꢀ
nal mercaptonitriles and ethyl 4ꢀchloroacetoacetate or
Nꢀcyanochloroacetamidine.8,9
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ar1
Ar2
4ꢀMeOC6H4
4ꢀFꢀC6H4
2ꢀThienyl
2ꢀThienyl
4ꢀMeOC6H4
3,4ꢀ(MeO)2C6H3
3ꢀThienyl
Ph
4ꢀFC6H4
Ph
4ꢀClC6H4
4ꢀClC6H4
2ꢀMeOC6H4
Ph
Ph
Ph
The structures of compounds 10 and 13 were conꢀ
firmed by the data of elemental analysis and IR and NMR
spectroscopy (Table 2). The absorption bands in the IR
spectra and the chemical shifts in the 1H NMR spectra of
thienodipyridines 10 were assigned by analogy with known
data.8 It is noteworthy that the IR spectra of compounds
4ꢀFC6H4
4ꢀMeOC6H4
2ꢀThienyl
2ꢀThienyl
2ꢀThienyl
2ꢀFuryl
2ꢀThienyl
4ꢀMeOC6H4
2ꢀThienyl
Ph
13c,d exhibit a narrow absorption band at 3580 cm–1
typical of compounds containing an OH group.10
,
Ph
Ph
Experimental
By using Nꢀ(ethoxycarbonyl)chloroacetamide (chloroꢀ
acetourethane) (12) in the reaction with pyridineꢀ
thiones 8, we developed a new oneꢀpot synthetic route to
IR spectra were recorded on a Specord Mꢀ82 instrument
in KBr pellets. 1H and 13C NMR spectra were recorded on a
Bruker WMꢀ250 instrument (250 and 63 МHz, respectively)

Oneꢀpot synthesis of substituted thiones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2205
Table 1. 3ꢀCyanopyridineꢀ2(1H )ꢀthiones 8
Comꢀ Yield M.p.
Molecular
formula
Found
Calculated
IR,
1H NMR, δ
(%)
N
poꢀ
(%) /°C
ν/cm–1
und
C
H
СS
CN
Ar1
Ar2
C(5)H NH
(s, 1 H)
8c
8d
8e
93 202—203 C16H9FN2S2 61.29 2.87 8.85 1205 2230 7.10 (t, 1 H,
61.54 2.88 8.97 J = 3.9, J = 4.6);
7.60 (m, 2 H);
7.74 (m, 2 H)
7.05 14.26
7.93 (br.s, 1 H);
8.12 (d, 1 H, J = 4.6)
89 214—216 C17H12N2OS2 62.71 3.67 8.58 1202 2224 7.08 (t, 1 H, J = 3.9,
3.85 (s, 3 H, OMe); 7.04 14.18
7.44 (d, 2 H,
J = 8.5); 7.68
(d, 2 H, J = 8.5)
7.02 (t, 1 H,
J = 3.7, J = 4.8);
7.84 (d, 1 H,
J = 3.7); 8.02
(d, 1 H, J = 4.8)
62.96 3.70 8.64
J = 4.6); 7.95 (d,
1 H, J = 3.9); 8.10
(d, 1 H, J = 4.6)
92 234—236 C17H12N2OS2 63.05 3.68 8.56 1205 2225 3.87 (s, 3 H, OMe);
7.02 14.09
7.06 14.04
62.96 3.70 8.64
7.40 (d, J = 8.5);
7.57 (d, J = 8.5)
8f
84 238—240 C18H14N2O2S2 60.83 3.94 7.52 1204 2226 3.72 (s, 3 H, 3ꢀOMe); 7.08 (t, 1 H,
61.02 3.95 7.61
3.83 (s, 3 H, 4ꢀOMe); J = 3.9, J = 5.2);
7.12 (s, 1 H);
7.82 (d, 1 H,
7.38 (d, J = 8.4);
7.52 (d, J = 8.4)
J = 3.9); 8.04
(d, 1 H, J = 5.2)
8g
8h
8i
90 245—246 C14H8N2S3
55.66 2.65 9.26 1195 2220
56.00 2.67 9.33
7.03—8.14
7.08* 14.30
7.06* 14.02
7.01 14.32
(m, 6 H)
6.98—7.98
(m, 6 H)
93 224—226 C16H10N2OS 68.61 3.59 10.00 1204 2228
69.06 3.60 10.07
82 203—205 C16H9FN2S2 62.01 2.87 8.86 1200 2217 7.48 (m, 2 H);
7.22 (t, 1 H,
61.52 2.90 8.97
7.60 (m, 2 H)
J = 3.7, J = 4.9);
7.89 (d, 1 H,
J = 3.7); 8.13
(d, 1 H, J = 4.9)
7.18 (t, 1 H,
8k
94 220—222 C16H9FN2S2 58.92 2.71 8.64 1204 2213 7.42 (d, 2 H,
6.96 14.29
58.44 2.76 8.52
J = 8.5); 7.50
(d, 2 H, J = 8.5)
J = 4.3, J = 4.8);
7.73 (d, 1 H,
J = 4.3); 8.12
(d, 1 H, J = 4.8)
* The proton signals overlap.
Note. The physicochemical characteristics of compounds 8a,b,j,l—n were reported previously.5,6
Table 2. 4ꢀHydroxyꢀ1Hꢀthieno[2,3ꢀb;4,5ꢀb]dipyridinꢀ2ꢀones 10 and pyrido[3´,2´:4,5]thieno[3,2ꢀd]pyrimidinꢀ2,4ꢀdiols (13)
Comꢀ Yield
Molecular
formula
Found
Calculated
IR,
1H NMR, δ
(%)
N
poꢀ
(%)
ν/cm–1
Ar1
Ar2
C(8)H C(3)H NH
(ОН)
und
CONH, OH
C
H
(s, 1 H)
10a 54.32
C
22H13ClN2O2S 65.04 3.15 6.70
65.26 3.24 6.92
1632, 3384, 7.61 (d, 2 H, J = 8.1); 7.52 (m, 3 H); 7.90 6.10 11.66
3408, 3464 7.76 (d, 2 H, J = 8.1)
8.25 (d, 2 H,
J = 7.4)
10b 46.15 C22H13FN2O2S 67.87 3.21 7.08
1628, 3400, 7.39 (t, 2 H, J = 8.8); 7.53 (m, 3 H); 7.90 6.10 11.71
68.03 3.37 7.21
3468
7.78 (m, 2 H)
8.26 (d, 2 H,
J = 6.6)
(to be continued)

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Shestopalov et al.
Table 2 (continued)
Comꢀ Yield
Molecular
formula
Found
Calculated
IR,
1H NMR, δ
(%)
N
poꢀ
(%)
ν/cm–1
Ar1
Ar2
C(8)H C(3)H NH
(ОН)
und
CONH, OH
C
H
(s, 1 H)
10c 72.50 C23H16N2O3S
68.73 3.92 6.83
68.98 4.03 7.00
1632, 3388, 2.50 (s, 1 H, Me);
3408, 3468 7.21 (t, 1 H, J = 7.4);
7.31 (d, 1 H, J = 8.1);
7.55 (m, 1 H);
7.51 (m, 3 H); 7.91 5.90 11.71
8.23 (d, 2 H,
J = 5.9)
7.63 (t, 1 H, J = 7.4,
J = 8.1)
13a 62.10 C21H13N3O2S
68.12 3.68 11.54 1642, 1704
67.91 3.53 11.31 sh, 3408
7.44—7.80 (m, 6 H);
8.17—8.35 (m, 4 H)
7.54 (m, 3 H); 7.87
J = 8.5); 7.76 (t, 2 H, 8.25 (d, 2 H,
8.01
—
—
11.64
13b 54.36 C21H12FN3O2S 64.95 3.36 10.92 1668, 1702 7.35 (t, 2 H, J = 7.5,
64.77 3.11 10.79 sh, 3408
9.94
(br.s)
J = 7.2, J = 5.9)
J = 6.6)
13c 85.41 C22H15N3O3S
65.64 3.54 10.24 1644,
65.82 3.77 10.47 1704 sh,
3.87 (s, 3 H, MeO);
7.01 (d, 2 H, J = 8.1); 8.21 (d, 2 H,
7.51 (m, 3 H); 7.68*
—
—
9.67
(br.s)
3404, 3580 7.66* (d, 2 H, J = 8.1) J = 7.4)
13d 81.48 C20H13N3O3S2 58.67 3.17 10.02 1640,
58.95 3.22 10.31 1684 sh,
3.86 (s, 3 H, Me);
7.01 (d, 2 H, J = 8.1);
7.18 (t, 1 H,
7.63*
9.49
(br.s)
J = 4.4); 7.68
3400, 3580 7.62* (d, 2 H, J = 8.1) (d, 1 H,
J = 5.2); 7.94
(br.s, 1 H)
* The proton signals overlap. The melting points of compounds 10 and 13 are higher than 300 °C.
in DMSOꢀd6. Elemental analysis was carried out on a
Perkin—Elmer C,H,Nꢀanalyzer.
2. V. P. Litvinov, Usp. Khimii, 1999, 68, 817 [Russ. Chem. Rev.,
1999, 68 (Engl. Transl.)].
4,6ꢀDiarylꢀ3ꢀcyanopyridineꢀ2(1H )ꢀthiones 8a—n (general
procedure). A mixture of finely dispersed sulfur (3.5 g, 0.11 mol)
and morpholine (8.7 g, 0.1 mol) in 100 mL of ethanol
was refluxed for 20 min. Malononitrile (6.6 g, 0.1 mol) and
α,βꢀunsaturated ketone 2 (0.1 mol) were added and the mixture
was refluxed for 2 h. Then the mixture was cooled to ∼20 °C, and
10% HCl was added to reach pH 5—6. The precipitate was
filtered off and washed with water. The product was recrystalꢀ
lized from ethanol.
4ꢀHydroxyꢀ1Hꢀthieno[2,3ꢀb;4,5ꢀb]dipyridinꢀ2ꢀones 10a—c
(general procedure). A mixture of the required pyridineꢀ2(1H )ꢀ
thione 8 (10 mmol), sodium ethoxide (25 mmol), and ethyl
4ꢀchloroacetoacetate (10 mmol) in 50 mL of ethanol was reꢀ
fluxed for 0.5 h, cooled to 20 °C, and acidified with 2.5 mL of
10% HCl. The precipitate was filtered off and washed with waꢀ
ter, ethanol, and hexane.
3. K. G. Nikishin, Ph.D. Thesis, Moscow, 2001, 131 pp. (in
Russian).
4. Yu. A. Sharanin, V. K. Promonenkov, and A. M.
Shestopalov, Zh. Org. Khim., 1982, 18, 630 [J. Org. Chem.
USSR, 1982, 18, 557 (Engl. Transl.)].
5. A. A. Krauze, Z. A. Bomika, A. M. Shestopalov, L. A.
Rodinovskaya, Yu. E. Pelcher, G. Ya. Dubur, Yu. A.
Sharanin, and V. K. Promonenkov, Khimiya Geterotsikl.
Soedinen., 1981, 377 [Chem. Heterocycl. Compd., 1981, 17,
279 (Engl. Transl.)].
6. A. M. Shestopalov, V. K. Promonenkov, Yu. A. Sharanin,
L. A. Rodinovskaya, and S. Yu. Sharanin, Zh. Org. Khim.,
1984, 20, 1517 [J. Org. Chem. USSR, 1984, 20, 1382 (Engl.
Transl.)].
7. S. Oae, Organic Chemistry of Sulfur, Plenum Press, New
York, 1977.
Pyrido[3´,2´:4,5]thieno[3,2ꢀd]pyrimidineꢀ2,4ꢀdiols (13a—d)
(general procedure). The required pyridineꢀ2(1H )ꢀthione 8
(10 mmol), Nꢀethoxycarbonylchloroacetamide (10 mmol), and
sodium ethoxide (25 mmol) were placed in a solvent mixture
consisting of 25 mL of ethanol and 25 mL of DMF. The reaction
mixture was refluxed for 2 h, cooled to 20 °C, and acidified with
2.5 mL of 10% HCl. The precipitate was filtered off and washed
with water, ethanol, and hexane.
8. L. A. Rodinovskaya, and A. M. Shestopalov, Izv. Akad. Nauk,
Ser. Khim., 2000, 347 [Russ. Chem. Bull., Int. Ed., 2000, 49,
348 (Engl. Transl.)].
9. V. A. Artyomov, L. A. Rodinovskaya, A. M. Shestopalov,
and V. P. Litvinov, Tetrahedron, 1996, 52, 101.
10. The Infraꢀred Spectra of Complex Molecules, by L. J. Bellamy,
London, Methuen and Co.Ltd, New York, John Wiley and
Sons, Inc.
References
1. V. P. Litvinov, L. A. Rodinovskaya, Yu. A. Sharanin, A. M.
Received March 6, 2003;
Shestopalov, and A. Senning, Sulfur Rep., 1992, 13, 1.
in revised form June 11, 2003