Cyanothioacetamide in heterocyclic synthesis: A novel synthesis of styrylpyridinethione, styrylthieno[2,3-b]pyridine, styrylpyrazolo[3,4-b] pyridine, pyrido[2′,3′:3,4]pyrazolo[5,1-a]pyrimidine, pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine and pyrido[3′, 2′:4,5]thieno[3,2-d]-1,2,3-triazin-4-one derivatives

Article abstract of DOI:10.1080/713744557

Synthesis of 6-styrylpyridinethione 6a-d, 6-styrylthienopyridine 11a-d, 15a-d, pyrido[2′,3′:3,4]pyrazolo[5,1-a]pyrimidine 25, 29, pyrido[3′, 2′:4,5]thieno[3,2-d]pyrimidine 34, and pyrido[3′,2′:4,5]thieno[3,2-d]-1,2,3-triazin-4-one 35 derivatives by the reaction of 4a,b, 6a-d, 22, 33, with 5a,b, 9, 13, 23, 27, acetic anhydride and nitrous acid respectively.

Full text of DOI:10.1080/713744557

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Phosphorus, Sulfur, and Silicon and the Related
Elements
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Cyanothioacetamide in Heterocyclic Synthesis: A Novel
Synthesis of Styrylpyridinethione, Styrylthieno[2,3-
b]pyridine, Styrylpyrazolo[3,4-b]pyridine,
Pyrido[2′,3′:3,4]pyrazolo[5,1-a]pyrimidine,
Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine and
Pyrido[3′,2′:4,5]thieno[3,2-d]-1,2,3-triazin-4-one
Derivatives
Mohamed A. A. Elneairy a
a Cairo University , Giza, Egypt
Published online: 27 Oct 2010.
To cite this article: Mohamed A. A. Elneairy (2003) Cyanothioacetamide in Heterocyclic Synthesis: A Novel Synthesis of
Styrylpyridinethione, Styrylthieno[2,3-b]pyridine, Styrylpyrazolo[3,4-b]pyridine, Pyrido[2′,3′:3,4]pyrazolo[5,1-a]pyrimidine,
Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine and Pyrido[3′,2′:4,5]thieno[3,2-d]-1,2,3-triazin-4-one Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 178:10, 2201-2214, DOI: 10.1080/713744557
To link to this article: http://dx.doi.org/10.1080/713744557
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Phosphorus, Sulfur, and Silicon, 178:2201–2214, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390234498
CYANOTHIOACETAMIDE IN HETEROCYCLIC
SYNTHESIS: A NOVEL SYNTHESIS OF
STYRYLPYRIDINETHIONE,
STYRYLTHIENO[2,3-b]PYRIDINE,
STYRYLPYRAZOLO[3,4-b]PYRIDINE,
PYRIDO[2ꢀ,3ꢀ:3,4]PYRAZOLO[5,1-a]PYRIMIDINE,
PYRIDO[3ꢀ,2ꢀ:4,5]THIENO[3,2-d]PYRIMIDINE AND
PYRIDO[3ꢀ,2ꢀ:4,5]THIENO[3,2-d]-1,2,3-TRIAZIN-4-ONE
DERIVATIVES
Mohamed A. A. Elneairy
Cairo University, Giza, Egypt
(Received December 2, 2002; accepted May 16, 2003)
Synthesis of 6-styrylpyridinethione 6a–d, 6-styrylthienopyridine 11a–
d, 15a–d, pyrido[2ꢁ,3ꢁ:3,4]pyrazolo[5,1-a]pyrimidine 25, 29, pyrido[3ꢁ,
2ꢁ:4,5]thieno[3,2-d]pyrimidine 34, and pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]-
1,2,3-triazin-4-one 35 derivatives by the reaction of 4a,b, 6a–d, 22, 33,
with 5a,b, 9, 13, 23, 27, acetic anhydride and nitrous acid respectively.
Keywords: Cyanothioacetamide; pyridopyrazolopyrimidine; pyridoth-
Ienotriazinone; styrylpyrazoloopyridine; styrylthienopyridine
The reactivity of 2- and 4-alkylpyridine was studied.1−3 This phe-
nomenon has found extensive applications.4−7 In the last decades much
attention have been devoted to the construction of new pyridine-2-
thione and annelated derivatives on account of their reported bio-
logical activities.8−20 Various series of substituted pyridine-2-thione
and their annelated derivatives are reported to have diverse biolog-
ical activities as antibiotic,21,22 antiarteriosclerotic,23 antibacterial,24
antihyperglycemic,25 antifungal,26 agents and as inhibitors of the blood
coagulation factor.27 Also, thienopyridine derivatives have been re-
ported to be useful as antibiotic,28−31 drug intermediates32 against
endoparasiticides33 and as antianaphylactics compounds.34,35 Moreover
Address correspondence to Mohamed A. A. Elneairy, Chemistry Department, Faculty
of Science, Cairo University, Giza, Egypt. E-mail: elneairy@hotmail.com
2201

2202
M. A. A. Elneairy
some substituted thienopyridine have been reported to inhibit
acetyl CoA-cholesterol O-acetyltransferase36 the release of cerebal
glutamate37 smooth muscle cells proliferation38 and the pressor re-
sponse of angiotensin in rats.39
RESULTS AND DISCUSSION
It has been found that compound 1a,b reacted with acetylacetone (2)
to give the final isolable reaction products 4a,b. Compounds 4a,b could
be formed through the non-isolable intermediates 3a,b via the Micheal
addition of the methylene group of 2 to the double bond of 1a,b and
elimination of one molecule of water and one molecule of hydrogen un-
der the experimental reaction conditions to give the cyclized products
4a,b (cf. Scheme 1). The IR spectrum of 4a showed the absorption bands
of OH, NH, CN, and C O groups. Moreover its mass spectrum gave the
molecular ion peak at 284 which is exactly molecular weight of 4a. From
the above data compound 4a could be formulated as 5-acetyl-3-cyano-4-
(4-hydroxyphenyl)-6-methylpyridine-2-thione (4a) (cf. Scheme 1). Due
to the reactivity of methyl group at 6 position in pyridine and presence
of more than one active site, compounds 4a,b were taking as starting
materials for the present work to synthesis a new heterocyclic deriva-
tives with expected biological activity. It has been found that the com-
pound 4a reacted with benzaldehyde (5a) and p-chlorobenzaldehyde
(5b) to afford the reaction products 6a,b and not 7a–d.1−3 The IR spec-
tra of 6a,b showed the absorption bands of nitrile at 2222, carbonyl at
1681. The 1H-NMR of 6a,b revealed the signals of styryl and aromatic
protons at 6.83–7.65. Compounds 6a,b could be formed via the con-
densation reaction between carbonyl group of aldehyde and methyl at
pyridine1−3 ring to give the final isolable reaction product corresponding
to 6-styrylpyridine-2-thione derivatives 6a,b (cf. Scheme 1 and Experi-
mental). In the same manner compound 4b reacted with 5a,b to afford
the corresponding 6-styrylpyridinethione 6c,d. These reaction products
could be formulated based on the elemental analyses and spectral data
as 6a,b previously prepared, all trials to cyclize the compounds 6a–d
into quinolinone-2-thione derivatives 8a–d are failed. The structure of
compounds 6a–d were confirmed via the reaction of 6a–d with halo-
genated compounds such as α-chloroacetone (9) and α-chloroacetamide
(13). It has been found that compound 6a reacted with chloroacetone
(9) to yield the corresponding 6-styrylthieno[2,3-b]pyridine derivative
11a. The IR of 11a showed the absorption bands at 3201, 3101, and
1697 corresponding to NH2 and C O groups at pyridine ring and didn’t
show any absorption band for nitrile function. Compound 11a could

Cyanothioacetamide in Heterocyclic Synthesis
2203
SCHEME 1

2204
M. A. A. Elneairy
be formed via the addition of methylene group to the nitrile function
of 10a. Based on the above data compound 11a could be formulated
as 2,5-diacetyl-3-amino-6-styrylthieno[2,3-b]pyridine derivative. In the
same manner compounds 6b–d reacted with 9 to give the corresponding
6-styrylthieno[2,3-b]pyridine derivatives 11b–d in respective manner.
On the other hand compounds 6a–d reacted with chloroacetamide (13).
It has been found that compound 6a reacted with 13 to give the cor-
responding 6-styrylthieno[2,3-b]pyridine derivative 15a. The IR spec-
trum of 15a showed the absorption bands of two amino groups at 3373,
3327, 3256, 3192. Moreover it’s H-NMR spectrum revealed the signal
corresponding to two amino, methyl, aromatic and styryl protons (cf. Ex-
perimental Part). In the same manner compounds 6b–d reacted with
13 and gave the corresponding 6-styrylthieno[2,3-b]pyridine derivative
15b–d respectively. Compounds 15a–d were confirmed based on the
elemental analyses and spectral data (cf. Scheme I and Experimen-
tal). Compounds 6a–d were further reacted with hydrazine hydrate
to give 18a–d. It has been found that compound 6a reacted with hy-
drazine hydrate to afford sulfur free compound corresponding to 6-
styrylpyrazolo[3,4–b]pyridine derivative 18a. The latter reaction prod-
uct could be formed via the addition of hydrazino group of 17a to the ni-
trile function. The IR spectrum of 18a didn’t show any absorption band
corresponded to the nitrile function and show the newly born amino
group. In the same manner compounds 6b–d reacted with hydrazine hy-
drate to give the corresponding 6-styrylpyrazolo[3,4-b]pyridine deriva-
tives 18b–d respectively. Compounds 18b–d could be confirmed based
on the elemental analyses and spectral data (cf. Scheme 1 and Ex-
perimental). All trials to cyclize 11a–d, 15a–d, and 18a–d to the
corresponding thieno[2,3-b]qunolinone derivatives and pyrazolo[3,4-b]-
quinolinone derivatives 12a–d, 16a–d and 19a–d were unsuccessful.
The work was extended to prepare a new heterocyclic derivatives. It
has been found that compounds 4a,b reacted with hydrazine hydrate
to give the corresponding pyrazolo[3,4-b]pyridine derivatives 21a,b.
Compound 21b was taking as starting material for synthesis new het-
erocyclic moiety via the reaction with dimethylformamide dimethylac-
etal (DMF-DMA). It has been found that compound 21b reacted with
dimethylformamide dimethylacetal (DMF-DMA) in dry xylene to af-
ford 3-(N,N-dimethylmethyleneamino)pyrazolo[3,4-b]pyridine deriva-
tive 22 (cf. Scheme 2). The IR spectrum of the latter reaction prod-
uct showed a band at 3179 which corresponded to the NH group in
pyrazole ring and didn’t show any absorption band corresponding to
the amino group which consumed in the reaction to give the imino
group. Moreover it’s H-NMR spectrum didn’t reveal any signal cor-
responding to the amino group (cf. Scheme 2). Further elucidation of

Cyanothioacetamide in Heterocyclic Synthesis
2205
SCHEME 2
compound 22 via the reaction with different active methylene contain-
ing compounds such as malononitrile (23), cyanothioacetamide (26)
and ethyl cyanoacetate (27). It has been found that compound 22 re-
acted with 23 to give the corresponding pyrido[2ꢁ,3ꢁ:3,4]pyrazolo[5,1-a]-
pyrimidine derivative 25 via a) loss of one molecule of dimethylamine
and b) addition of NH group of pyrazole to the nitrile function in 24.
The IR spectrum of 25 showed the newly born of amino group. Com-
pound 25 could be also prepared via another route by the reaction of
22 with cyanothioacetamide (26) to afford the corresponding pyrido-
[2ꢁ,3ꢁ:3,4]pyrazolo[5,1-a]pyrimidine derivative 25 via loss one molecule
of dimethylamine and one molecule of hydrogen sulphide. Compound 25
which prepared via this route was found to be identical as 25 previous

2206
M. A. A. Elneairy
prepared in all aspects (melting point and mixed melting point) (cf.
Scheme 2 and Experimental).
A third elucidation of compound 22 via its reaction with ethyl
cyanoacetate (27) to give the corresponding pyrido[2ꢁ,3ꢁ:3,4]pyrazolo-
[5,1-a]pyrimidine derivative 29. Compound 29 could be confirmed based
on the elemental analysis and spectral data (cf. Scheme 2 and Ex-
perimental). The work was extended to prepare a new thieno[2,3-b]-
pyridine, pyrido[3ꢁ2ꢁ:4,5]thieno[3,2-d]pyrimidine and pyrido-[3ꢁ,2ꢁ:4,
5]thieno[3,2-d]-1,2,3-triazin-4-one derivatives. It has been found that
compound 4a reacted with 9 to give the corresponding thieno[2,3-
b]pyridine derivative 31. The IR spectrum of 31 showed the absorp-
tion bands at 3468, 3341 which corresponded to the amino group.
Moreover it’s H-NMR revealed the signal corresponded to the amino
protons. Based on the above data compound 31 could be formulated as
thieno[2,3-b]pyridine derivative (cf. Scheme 3 and Experimental).
SCHEME 3
On the other hand compound 4a reacted with 13 to yield the 2-S-
carbamoylmethylpyridine derivative 32 which could be cyclized via it’s
boiling with alcoholic potassium hydroxide solution into thieno[2,3-
b]pyridine derivative 33. Compound 33 could be confirmed via the

Cyanothioacetamide in Heterocyclic Synthesis
2207
reaction with acetic anhydride and nitrous acid to give the correspond-
ing pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]pyrimidine and pyrido[3ꢁ,2ꢁ:4,5]thieno-
[3,2-d]-1,2,3-triazin-4-one derivatives 34 and 35 in respective manner.
The structures of compounds 34 and 35 were confirmed based on the
elemental analyses and spectral data (cf. Scheme 3 and Experimental).
Compound 34 could be synthesized via another route by the reac-
tion of 32 with acetic anhydride to give pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]-
pyrimidine derivative 34. Compound 34 was formed via this route
was found to be identical as 34 previously prepared (cf. Scheme 3 and
Experimental).
EXPERIMENTAL
All melting points were measured on a Gallenkamp electrothermal
melting point apparatus and are uncorrected. The infrared spectra were
recorded in potassium bromide on a Pye Unicam SP 3-300 infrared and
1
FT-IR 8101PC Schimadzu spectrophotometers. The H NMR spectra
were recorded in deuterated chloroform or dimethyl sulphoxide on a
Varian Gemini 200 NMR and varian Mercury 300 MHz spectrometer
using tetramethysilane(TMS) as an internal reference; mass spectra
were recorded on a GCMS-QP 1000 EX Shimadzu mass spectrumeter
at 70 eV. Elemental analysis were carried out at the Microanalytical
Center of Cairo University, Giza, Egypt.
Compounds 1a,b,40 4b13 and 21b13 were prepared according to the
literature procedure.
Synthesis of Compounds 4a, 6a–d, 25, and 29
General Procedure
A solution of each of 1a, 4a,b, 22 (0.01 mmol) and 2, 5a,b, 23 (26),
27 (0.01 mmol) in ethanol (30 ml) and piperidine (0.5 ml) were heated
under reflux for 5 h. The excess of the ethanol was evaporated in vacuo.
The solids obtained were collected by filtration and crystallized from
the proper solvent to give 4a, 6a–d, 25 and 29 respectively.
5-Acetyl-3-cyano-4-(4-hydroxyphenyl)-6-methylpyridine-2(1H)-thione
(4a). Yellow crystals (75%, ethanol), m.p. 294–296◦C; IR (cm−1) ν 3244
(OH), 3101 (NH), 2229 (CN) and 1658 (CO). MS (M = 89.7%, M-
15 = 100%). Anal. for C15H12N2O2S (284) Calcd: C, 63.36, H, 4.25; N,
9.85; S, 11.28. Found: C, 63.00; H, 4.00; N, 9.60; S, 11.60.
5-Acetyl-3-cyano-4-(4-hydroxyphenyl)-6-styrylpyridine-2(1H)-thione
(6a). Yellow crystals (75% ethanol), m.p. 226–228◦C; IR (cm−1) ν 3425

2208
M. A. A. Elneairy
(OH), 3417 (NH), 2222 (CN), 1682 (C O). Anal. for C22H16N2O2S
(372.45) Calcd: C, 70.95; H, 4.33; N, 7.52; S, 8.61. Found: C, 71.10; H,
4.10; N, 7.90; S, 8.70.
5-Acetyl-3-cyano-4-(4-hydroxyphenyl)-6-(4-chlorostyryl)pyridine-2-
(1H)-thione (6b). Yellow crystals (80%, ethanol), m.p. 182–184◦C; IR
(cm−1) ν 3420 (OH), 3209 (NH), 2206 (CN), 1682 (C O); 1H NMR
(DMSO) δ 1.78 (s, 3H, CH3), 4.36 (brs, 1H, NH), 6.83–7.65 (m, 10H,
ArH’s and CH CH) and 7.73 (s, 1H, OH). Anal. for C22H15N2O2SCl
(406.89) Calcd: C, 64.94; H, 3.72; N, 6.88; S, 7.88; Cl, 8.71. Found: C,
64.60; H, 3.90; N, 6.70; S, 8.10.
5-Acetyl-3-cyano-4-(4-N,N-dimethylaminophenyl)-6-styrylpyridine-
2(1H)-thione (6c). Yellow crystals (75%, ethanol), m.p. 234–236◦C;
IR (cm−1) ν 3230, (NH), 2210 (CN); 1678 (C O); MS (M = 100%,
M-15 = 31.1%). Anal. for C24H21N3OS (399.52) Calcd: C, 72.15; H, 5.30;
N, 10.52; S, 8.03. Found: C, 72.40; H, 4.10; N, 10.50; S, 7.90.
5-Acetyl-3-cyano-4-(4-N,N-dimethylaminophenyl)-6-(4-chlorostyryl)-
pyridine-2(1H)-thione (6d). Brown crystals (80%, ethanol), m.p. 282–
284◦C; IR (cm−1) ν 3417 (NH), 2214 (CN), 1697 (C O). Anal. for
C24H20N3OSCl (433.96) Calcd: C, 66.43; H, 4.65; N, 9.68; S, 3.69; Cl,
8.17. Found: C, 66.30; H, 4.80; N, 9.90; S, 3.80; Cl, 8.30.
9-Acetyl-4-amino-8-methyl-10-(4-N,N-dimethylaminophenyl)pyrido-
[2ꢁ,3ꢁ:3,4]pyrazolo-[5,1-a]pyrimidine-3-carbonitrile
(25). Pale-green
crystals (75%, ethanol), m.p. >350◦C; IR (cm−1) ν 3433, 3271 (NH2),
2214 (CN); 1682 (C O); MS (M = 98.04%, M-15 = 100%). Anal. for
C21H19N7O. (385.43) Calcd: C, 65.44; H, 4.97; N, 25.44. Found: C, 65.30;
H, 4.80; N, 25.70.
Ethyl-9-acetyl-4-amino-8-methyl-10-(4-N,N-dimethylaminophenyl)-
pyrido[2ꢁ,3ꢁ:3,4]-pyrazolo[5,1-a]pyrimidine-3-carboxylate (29). Yellow
crystals (75%, ethanol), m.p. 308–310◦C; IR (cm−1) ν 3402, 3232 (NH2),
1
1689 (C O); HNMR (CDCl3) d 1.37–1.44 (t, 3H, OCH2CH3), 1.64 (s,
2H, NH2), 1.98 (s, 3H, CH3 at pyridine), 2.70 (s, 3H, COCH3), 3.07 (s,
6H, N(Me)2), 4.37–4.48 (q, 2H, OCH2CH3) 6.78–7.53 (m, 4H, ArH’s)
and 8.91 (s, 1H, CH at pyrimidine). Anal. for C23H24N6O3 (432.00)
Calcd: C, 63.88; H, 5.59; N, 19.43. Found: C, 63.60; H, 5.80; N, 19.50.
Synthesis of Compounds 11a–d and 31
General Procedure
A solution of each of 6a–d and 4a (0.01 mmol) in sodium ethoxide
(0.01 mmol) prepared from 0.01 mmol sodium metal in 30 ml ethanol)
and chloroacetone (9) (0.01 mmol) was heated under reflux for 5 h. Cool

Cyanothioacetamide in Heterocyclic Synthesis
2209
poured on to ice bath, then acidified with hydrochloric acid. The solid
products were collected by filtration, washed with water and crystal-
lized from the proper solvent to give 11a–d and 31 respectively.
2,5-Diacetyl-3-amino-4-(4-hydroxyphenyl)-6-styrylthieno[2,3-b]pyrid-
ine (11a). White crystals (60% ethanol/DMF), m.p. >330◦C; IR (cm−1
)
ν 3417 (OH), 3201, 3101 (NH2), 1705, 1674 (two C O). Anal. for
C25H20N2O3S (428.51) Calcd: C, 70.07; H, 4.70; N, 6.54; S, 7.48. Found:
C, 70.20; H, 4.50; N, 6.40; S, 7.20.
2,5-Diacetyl-3-amino-4-(4-hydroxyphenyl)-6-(4-chlorostyryl)thieno[2,
3-b]pyridine (11b). Yellow crystal (60% ethanol), m.p. 308–310◦C; IR
1
(cm−1) ν 3471 (OH), 3310, 3125 (NH2), 1705 (C O). H NMR (DMSO)
δ 2.1 (s, 3H, COCH3 at pyridine), 2.38 (s, 3H, COCH3 at thiophene),
3.58 (s, 2H, NH2), 6.95–7.99 (m, 10H, ArH’s and CH CH) and 10.1 (s,
1H, OH). Anal. for C25H19N2O3SCl (462.96) Calcd: C, 64.86; H, 4.14;
N, 6.05; S, 6.93; Cl, 7.66. Found: C, 64.70; H, 4.30; N, 6.3; S, 7.10; Cl,
7.30.
2,5-Diacetyl-3-amino-4-(4-N,N-dimethylaminophenyl)-6-styrylthieno-
[2,3-b]pyridine (11c). Orange crystals (55% ethanol), m.p. 281–283◦C;
1
IR (cm−1) 3464, 3320 (NH2), 1705 (C O); H NMR (DMSO) δ 2.1 (s,
3H, COCH3 at pyridine), 2.38 (s, 3H, COCH3 at thiophene), 3.37 (s,
6H, N(CH3)2), 6.51 (brs, 2H, NH2) and 6.85–8.00 (m, 11H, ArH’s and
CH CH). Anal. for C27H25N3O2S (455.58) Calcd: C, 71.18; H, 5.53; N,
9.22; S, 7.04. Found: C, 71.20; H, 5.30; N, 9.5; S, 7.30.
2,5-Diacetyl-3-amino-4-(4-N,N-dimethylaminophenyl)-6-(4-chlorost-
yryl)thieno[2,3-b]pyridine (11d). Brown crystals (60% ethanol), m.p.
>340◦C; IR (cm−1) ν 3425, 3351 (NH2), 1702 (C O). Anal. for
C27H24N3O2SCl (490.03) Calcd: C, 66.18; H, 4.94; N, 8.58; S, 6.54; Cl,
7.23. Found: C, 66.30; H, 4.70; N, 8.70; S, 6.80; Cl, 6.90.
2,5-Diacetyl-3-amino-4-(4-hydroxyphenyl)-6-methylthieno[2,3-b]pyri-
dine (31). Yellow crystals (60% ethanol), m.p. 308–310◦C; IR (cm−1) ν
3500 (OH), 3468, 3341 (NH2), 1697, 1632 (two C O). 1H NMR (DMSO)
δ 2.00 (s, 3H, COCH3 at pyridine), 2.35 (s, 3H, COCH3 at thiophene),
6.46 (brs, 2H, NH2) 6.97–7.21 (m, 4H, ArH’s) and 10.34 (s, 1H, OH).
Anal. For. C18H16N2O3S (340.40) Calcd: C, 63.51; H, 4.74; N, 8.23; S,
942. Found: C, 63.40; H, 4.90; N 8.50; S, 9.20.
Synthesis of 15a–d and 32
General Procedure
A solution of each of 6a–d and 4a (0.01 mmol) in sodium ethoxide
(0.01 mmol prepared from 0.01 mmol sodium metal in 30 ml ethanol)

2210
M. A. A. Elneairy
and chloroacetamide (13) (0.01 mmol) was heated under reflux for 5 h.
It was cooled by being poured into an ice-bath, then acidified with hy-
drochloric acid. The solid products were collected by filtration, washed
with water, and crystallized from the proper solvent to give 15a–d and
32 respectively.
5-Acetyl-3-amino-2-carbamoyl-4-(4-hydroxypyenyl)-6-styrylthieno[2,
3-b]pyridine (15a). Yellow crystals (65%, ethanol), m.p. 256–258◦C;
IR (cm−1) ν 3483 (OH), 3373, 3327, 3250, 3192 (two NH2), 1697, 1654
(two C O); 1H NMR (DMSO) δ 2.01 (s, 3H, COCH3), 4.1 (s , 2H, NH2),
6.94-8.22 (m, 13H, ArH’s, NH2 and CH CH) and 7.88 (s, 1H, OH).
MS (M = 80.2%, M-18 = 30.9%, M-44 = 100%). Anal. for C24H19N3O3S
(429.50) Calcd: C, 67.12; H, 4.46; N, 9.78; S, 7.47. Found: C, 67.1; H,
4.2; N, 10.00; S, 7.40.
5-Acetyl-3-amino-2-carbamoyl-4-(4-hydroxypyenyl)-6-(4-chlorostyryl)-
thieno[2,3-b]pyridine (15b). Brown crystals (55%, ethanol), m.p. 319–
321◦C; IR (cm−1) ν 3483 (OH), 3373, 3327, 3250, 3192 (two NH2), 1697,
1654 (two C O). Anal. for C24H18N3O3SCl (463.95) Calcd: C, 62.13; H,
3.91; N, 9.06; S, 6.91; Cl, 7.64. Found: C, 62.30; H, 4.00; N, 9.20; S, 6.70;
Cl, 7.30.
5-Acetyl-3-amino-2-carbamoyl-4-(4-N,N-dimethylaminopyenyl)-6-
styrylthieno[2,3-b]pyridine (15c). Yellow crystals (65%, ethanol), m.p.
312–314◦C; IR (cm−1) ν 3472, 3356, 3210, 3180 (two NH2), 1690 (C O);
1H NMR (CDCl3) δ 1.95 (s, 3H, COCH3), 3.96 (s , 2H, NH2), 3.05 (s,
6H, N(Me)2) and 6.74–8.16 (m, 13H, ArH’s, NH2 and CH CH). Anal.
for C26H24N4O2S (456.57) Calcd: C, 68.40; H, 5.30; N, 12.27; S, 7.02.
Found: C, 68.10; H, 5.6; N, 13.00; S, 7.30.
5-Acetyl-3-amino-2-carbamoyl-4-(4-N,N-dimethylaminophyenyl)-6-
(4-chlorostyryl)thieno[2,3-b]pyridine (15d). Brown crystals (60%,
ethanol), m.p. >330◦C; IR (cm−1) ν 3460, 3350, 3220, 3190 (two NH2)
1688 (two C O). Anal. for C26H23N4O2SCl (491.02) Calcd: C, 63.60; H,
4.72; N, 11.41; S, 6.53; Cl, 7.22. Found: C, 63.50; H, 4.50; N, 11.20; S,
6.20; Cl, 7.00.
5-Acetyl-2-carbamoylmethylthio-3-cyano-4-(4-hydroxyphenyl)-6-met-
hylpyridine (32). Yellow crystals (70%, ethanol), m.p. 226–228◦C; IR
(cm−1) ν 3456 (OH), 3364, 3295 (NH2), 2222 (CN), 1682 (C O); 1H
NMR (DMSO) δ 1.98 (s, 3H, CH3), 2.53 (s, 3H, COCH3), 4.1 (s, 2H,
SCH2CONH2), 6.98–7.28 (m, 4H, ArH’s), 7.77 (s, 1H, OH), 10.2
(brs, 4H, two NH2). Anal. for C17H15N3O3S (341.39) Calcd: C, 59.81;
H, 4.43; N, 12.31; S, 9.39. Found: C, 59.00; H, 4.70; N, 12.20; S,
9.50.

Cyanothioacetamide in Heterocyclic Synthesis
2211
Synthesis of 18a–d and 21a
A solution of each of 6a–d and 4a (0.01 mmol) in hydrazine hydrate
(5 ml) and ethanol (20 ml) was heated under reflux for 5 h. The solid
products that formed were collected by filtration and crystallized from
the proper solvent to give 18a–d and 21a respectively.
5-Acetyl-3-amino-4-(4-hydroxyphenyl)-6-styrylpyrazolo[3,4-b]pyridine
(18a). Brown crystals (70%, dilute ethanol), m.p. 201–203◦C; IR (cm−1
)
ν 3460 (OH), 3364, 3294, 3217 (NH2 and NH), 1690 (C O). Anal. for
C22H18N4O2 (370.41) Calcd; C, 71.34; H, 4.90; N, 15.13. Found: C,
71.50, H, 4.80; N, 15.3.
5-Acetyl-3-amino-4-(4-hydroxyphenyl)-6-(4-chlorostyryl)pyrazolo[3,4-
b]pyridine (18b). Brown (70%, dilute ethanol), m.p. 203–205◦C; IR
1
(cm−1) ν 3460 (OH), 3430, 3294, 3194 (NH2 and NH), 1682 (C O). H
NMR (DMSO) δ 1.58 (s, 2H, NH2), 1.93 (s, 3H, COCH3), 6.71–7.23 (m,
10H, ArH’s and CH CH), 7.44 (s, 1H, OH) and 9.54 (s, 1H, NH). Anal.
for C22H17N4O2Cl (404.86) Calcd: C, 65.27; H, 4.23; N, 13.84; Cl, 8.76.
Found: C, 65.50; H, 4.50; N, 14.00; Cl, 8.60.
5-Acetyl-3-amino-4-(4-N,N-dimethylaminophenyl)-6-styrylpyrazolo-
[3,4-b]pyridine (18c). Yellow crystals (70%, ethanol), m.p. 276–278◦C,
1
IR (cm−1) ν 3425, 3310, 3140 (NH2 and NH) (C O). H NMR (CDCl3)
δ 1.78 (s, 3H, COCH3), 2.98 (s, 6H, N(Me)2), 5.79 (brs, 1H, NH), 6.71–
7.39 (m, 13H, ArH’s, NH2 and CH CH). Anal. for C24H23N5O (397.48)
Calcd: C, 72.52; H, 5.83; N, 17.62. Found: C, 72.50; H, 6.00; N, 17.90.
5-Acetyl-3-amino-4-(4-N,N-dimethylaminophenyl)-6-(4-chlorostyryl)-
pyrazolo[3,4-b]pyridine (18d). Yellow (70%, dilute ethanol), m.p. 280–
1
282◦C; IR (cm−1) ν 3456, 3302, 3194 (NH2 and NH) (1689 (C O). H
NMR (DMSO) δ 1.94 (s, 3H, COCH3), 3.00 (s, 6H, NMe2), 4.45 (s, 2H,
NH2), 6.85–7.21 (m, 10H, ArH’s and CH CH) and 12.21 (s, 1H, NH).
Anal. for C24H22N5OCl (431.93) Calcd: C, 66.74; H, 5.13; N, 16.21; Cl,
8.21. Found: C, 66.50; H, 4.80; N, 15.90; Cl, 8.50.
5-Acetyl-3-amino-4-(4-hydroxyphenyl)-6-methylpyrazolo[3,4-b]pyrid-
ine (21a). Yellow (70%, ethanol), m.p. 310–312◦C; IR (cm−1) ν 3460
(OH), 3294, 3194 (NH2 and NH), 1683 (C O). Anal. for C15H14N4O2
(282.3) Calcd: C, 63.82 H, 5.00; N, 19.85. Found: C, 63.50, H, 4.80; N,
20.00.
Synthesis of 22
A solution of 4b (0.01 mmol) and dimethylformamide dimethylacetal
(DMF-DMA 0.01 mmol) in dry xylene (30 ml) was heated under reflux

2212
M. A. A. Elneairy
for 4 h. The excess of xylene evaporated in vacuo. The residue was tritu-
rated with petroleum ether the solid obtained was collected by filtration
and crystallized from ethanol to give 22.
5-Acetyl-4-(4-N,N-dimethylaminophenyl)-6-methyl-3-(N,N-dimethyl-
aminomethyleneamino)pyrazolo[3,4-b]pyridine (22). Yellow (70%,
ethanol), m.p. 248–250◦C; IR (cm−1) ν 3179 (NH) 1690 (C O); 1H
NMR (DMSO) δ 1.90 (s, 3H, CH3), 2.72 (s, 3H, COCH3), 2.93 (s, 6H,
NMe2), 2.97 (s, 6H, NMe2), 6.74–7.23 (m, 4H, ArH’s), 7.72 (s, 1H,
N = CH NMe2) and 12.60 (s, 1H, NH) Anal. for C20H24N6O (364.45)
Calcd: C, 65.91 H, 6.64; N, 23.06. Found: C, 66.00; H, 6.40; N, 22.90.
Synthesis of 33
A solution of 32 (1 mmol), potassium hydroxide (2 mmol) and ethanol
(30 ml) was heated under reflux for 4 h. It was cooled and acidified
with concentrated hydrochloric acid. The solid obtained was collected
by filtration and crystallized from ethanol to give 33.
5-Acetyl-3-amino-2-carbmoyl-4-(4-hydroxyphenyl)-6-methylthieno[2,
3-b]pyridine (33). Yellow crystals (75% ethanol), m.p. 255–257◦C; IR
(cm−1) ν OH (3417), 3390, 3280 (two NH2), 1682, 1643 (two C O).
Anal. For. C17H15N3O3S (341.39) Calcd: C, 59.81; H, 4.43; N, 12.31; S,
9.39. Found: C, 60.00; H, 4.70; N, 12.20; S, 9.50.
Synthesis of 34
A solution of 32 or 33 (0.01 mmol) in acetic anhydride (20 ml) was
heated under reflux for 4 h. The solid obtained was collected by filtration
and crystallized from acetic acid to give 34.
8-Acetyl-2,7-dimethyl-9-(4-hydroxyphenyl)pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-
d]pyrimidin-4-one (34). White crystals (55%, acetic acid), m.p. 328–
330◦C; IR (cm−1) ν 3448 (OH), 3385 (NH), 1705, 1651 (two C O).
Anal. for C19H15N3O3S (365) Calcd: C, 62.45; H, 4.14; N, 11.50; S, 8.77.
Found: C, 62.40; H, 3.90; N, 11.20; S, 9.90.
Synthesis of 35
To a stirred cold solution (0–5◦C) of 33 (1 mmol) in water (10 ml) and
concentrated hydrochloric acid (5 ml), a solution of sodium nitrite (0.23 g
in 5 ml of water) was added during 30 min. Stirring was continued
for 40 min at −5◦C. The reaction mixture was then allowed to stand
at 0–5◦C for 3 h. The solid obtained was collected by filtration and
crystallized from ethanol to give 35.

Cyanothioacetamide in Heterocyclic Synthesis
2213
7-Acetyl-8-methyl-9-(4-hydroxyphenyl)pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]-
1,2,3-triazin-4-one (35). Yellow crystals (55%, ethanol), m.p. >320◦C;
IR (cm−1) ν 3418 (OH), 3320 (NH), 1697, 1651 (two C O). Anal. for
C17H12N4O3S (352.37) Calcd: C, 57.95; H, 3.43; N, 15.90; S, 9.10.
Found: C, 58.10; H, 3.70; N,16.10; S, 8.90.
REFERENCES
[1] A. R. Kataritzky, Handbook of Heterocyclic Chemistry (Pergamon Press, Oxford,
1985).
[2] J. A. Joule and G. F. Smith, Heterocyclic Chemistry (Van Nostrand Reinhhold Com-
pany Ltd., London, 1978), p. 42.
[3] S. A. S. Ghozlan, Sulfur Letters, 13, 27 (1991).
[4] S. A. S. Ghozlan, M. H. Mohamed, A. Y. Soliman, and H. Bakeer, Gazz. Chem. Ital.,
119 (1989).
[5] R. Merkx, Bull. Soc. Chem. Belg., 58, 460 (1949).
[6] A. J. Boulton and A. McKillp, Comprehensive Heterocyclic Chemistry, edited by A. R.
Katritzky and R. Rees (Pergamon Press, Oxford, 1984), vol. 2, p. 50.
[7] M. H. Elnagdi, F. M. Abdel-Razik, N. S. Ibrahim, and A. W. Erian, Tetrahedron, 45,
3597 (1989).
[8] F. A. Attaby, S. M. Eldin, W. M. Basyouni, and M. A. A. Elneairy, Phosphorus, Sulfur
and Silicon, 108, 31 (1996).
[9] F. A. Attaby, S M. Eldin, W. M. Basyouni, and M. A. A. Elneairy, Phosphorus, Sulfur
and Silicon, 119, 1 (1996).
[10] F. A. Attaby, S. M. Eldin, and M. A. A. Elneairy, J. Chem. Res. (M), 10, 632; (S), 10,
2754 (1998).
[11] S. M. Eldin, F. A. Attaby, and M. A. A. Elneairy, Heteroatom Chem., 9, 571 (1998).
[12] M. A. A. Elneairy, T. M. Abdel-Rahman, and A. M. Hammmad, J. Chem. Res., (M),
11, 2834; (S) 11, 684 (1998).
[13] M. A. A. Elneairy, Phosphorus, Sulfur, and Silicon, 148, 189 (1999).
[14] F. A. Attaby, M. A. A. Elneairy, and M. S. Elsayed, Phosphorus, Sulfur and Silicon,
149, 49 (1999).
[15] M. A. A. Elneairy, F. A. Attaby, and M. S. Elsayed, Phosphorus, Sulfur and Silicon,
167, 161 (2000).
[16] M. A. A. Elneairy and A. M. Abdel-Fattah, Phosphorus, Sulfur and Silicon, 175, 15
(2001).
[17] M. A. A. Elneairy, S. M. Eldin, F. A. Attaby, and A. K. K. El-Louh, Phosphorus,
Sulfur and Silicon, 167, 289 (2000).
[18] S. M. Eldin, M. A. A. Elneairy, F. A. Attaby, and A. K. K. El-Louh; Phosphorus,
Sulfur and Silicon, 176, 49 (2001).
[19] A. A. Abbas, M. A. A Elneairy, and Y. N. Mabkhot, J. Chem. Res. (M), 411; (S), 124
(2001).
[20] F. A. Attaby, M. A. A. Elneairy, S. M. Eldin, and A. K. K. El-Louh, J. Chem. Chinese,
48, 893 (2001).
[21] K. Hirai, Y. Iwano, T. Nishi, A. Youshida, K. Oda, and H. Koyama, U.S. Pat. 5. 541,
317; C.A., 125, 167960 (1996).
[22] Y. Momose and H. Odaka, PCT Int. Appl. WO 97 36,882; Chem. Abstr., 117, 331478
(1997).
[23] A. Youshida, H. Kogen, I. Hayakawa, et al., JP 09,292,775; C.A., 127, 234181 (1997).

2214
M. A. A. Elneairy
[24] J. K. Hinks, A. K. Takel, and E. Hunt, PCT Int. Appl. WO 9725,309; C.A., 127,
161997 (1997).
[25] J. Wrobel, Z. Li, A. Dietrich, et al., J. Med. Chem., 41, 1084 (1998).
[26] L. Muthusubramanian, R. B. Mitra, S. Rajkumar, and V. S. S. Rao, J. Chem. Technol.
Biotechnol., 72, 164 (1998).
[27] S. I. Klein, M. Czekaj, C. J. Gardner, et al., J. Med. Chem., 41, 437 (1998).
[28] A. Taaia, M. H. Abo-Ghalia, and O. I. Abd El-Salam, Pharmazia, 50, 455 (1995),
C.A., 123, 313812 (1995).
[29] J. Aszodi, A. Bonnet, and J. F. Chantot, EP 315, 518; C.A., 112, 2118535 (1990).
[30] J. Aszodi, A. Bonnet, and D. S. Gouin, EP 462, 009; C.A., 116, 128504 (1992).
[31] J. F. Chantot, D. S. Gouin, D. Humbert, and J. G. Teutsch, EP 520, 880; C.A., 119,
138972 (1993).
[32] H. Schaefer, K. Gewald, H. Mueller, and T. Jeschke, Ger. Pat. 285, 356; C.A., 114,
228888 (1991).
[33] N. Mueller, W. Hallenbach, and A. Harder, Eur. Pat. Appl., EP 403 (1990); C.A., 114,
157181 (1991).
[34] G. Wanger, S. Leistner, H. Vieweg, and U. Krasselt, J. Prantz. Pharmazia, 48, 342
(1993).
[35] N. Biowiss, U. Krasselt, S. Leistner, and G. Wanger, Pharmazia, 47, 897 (1992).
[36] K. Meguro. H. Tawada, and H. Ikeda, Eur. Pat. Appl. EP 472 (1990), C.A., 116,
214482 (1992).
[37] M. Ueda, T. Gemba, M. Eigyo, and I. Adachi, EP 519, 602; C.A., 118, 94335 (1993).
[38] Y. Saito, M. Kitabara, M.Sakashita, K. Toyoda, and T. Shibazaki; Eur. Pat. Appl.
EP 533 (1993), C.A., 119, 117112 (1993).
[39] A. Morimoto, K. Nishikawa, and T. Naka, EP 443, 568; C.A., 115, 232279 (1991).
[40] J. S. A. Brunskill, A. De, and D. F. Ewing, J. Chem. Soc., Perkin Trans I, 629 (1978).