Synthesis of some novel fused azole derivatives

Article abstract of DOI:10.1080/00397911.2011.566462

(Chemical Equation Presented) A novel synthesis of pyrazolopyrimidine derivatives was reported wherein 5-amino- 1-benzoyl-3-(methylthio)-1H-pyrazole- 4-carbonitrile was treated with formic acid, formamide, thioacetamide, carbon disulfide, and phenylisocyanate and phenylisothiocyanate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.566462

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Synthesis of Some Novel Fused Azole
Derivatives
A. M. Soliman a , A. A. Sultan a , M. A. A. El Remaily a & H. Abdel-
Ghany a
a Chemistry Department, Faculty of Science, Sohag University, Egypt
Accepted author version posted online: 31 Oct 2011.
To cite this article: A. M. Soliman , A. A. Sultan , M. A. A. El Remaily & H. Abdel-Ghany (2012):
Synthesis of Some Novel Fused Azole Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 42:18, 2748-2762
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Synthetic Communications1, 42: 2748–2762, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.566462
SYNTHESIS OF SOME NOVEL FUSED AZOLE
DERIVATIVES
A. M. Soliman, A. A. Sultan, M. A. A. El Remaily, and
H. Abdel-Ghany
Chemistry Department, Faculty of Science, Sohag University, Egypt
GRAPHICAL ABSTRACT
Abstract A novel synthesis of pyrazolopyrimidine derivatives was reported wherein 5-amino-
1-benzoyl-3-(methylthio)-1H-pyrazole-4-carbonitrile was treated with formic acid, forma-
mide, thioacetamide, carbon disulfide, and phenylisocyanate and phenylisothiocyanate.
Keywords Isocyanate; phenylisothiocyanate; pyrazolopyridine; pyrazolopyrimidine
INTRODUCTION
Pyrazole derivatives have attracted particular interest because they are used as the
core structure in many drug substances covering a wide range of pharmacological appli-
cations,[1–6] such as antibacterials, antifungals, anticonvulsants,[6] hypertensives,[7] antide-
pressants,[8] analgesics, antiinflammatories,[9] and neuroprotectives.[10] Also, pyrazole
derivatives are used as antianemic agents,[11] novel legands for estrogen receptor,[12]
claimed and nitrification inhibitors with the use of fertilizers.[13] Pyrazolopyrimidines
and related fused heterocycles are of interest as potential bioactive molecules. They are
known to exhibit pharmacological activities such as CNS depressive,[14] neuroleptic,[15]
and tuberculostatic[16] activities. In connection with our efforts directed toward the syn-
thesis of heterocyclic ring systems,[14–19] our target in this study was the synthesis of some
new heterocyclic compounds with an expected wide spectrum of potential applications.
RESULTS AND DISCUSSION
Our first attempts to prepare the key precursor 5-amino-1-benzoyl-3-
(methylthio)-1H-pyrazole-4-carbonitrile 2[20] led us to obtain a product that has a
Received January 11, 2011.
Address correspondence to M. A. A. El Remaily, Chemistry Department, Faculty of Science,
Sohag University, Sohag, Egypt. E-mail: msremaily@yahoo.com
2748

FUSED AZOLE DERIVATIVES
2749
melting point of 220 ꢀC, different from the melting point reported (290 ꢀC). The lack
of the reported analytical data prompted us to investigate this reaction. So,we pre-
pared the compound 2 via either the previously reported procedure or by refluxing
in ethanol. In both cases, we obtained the same product with melting point
218–220 ꢀC. The structure of compound 2 was established through analytical data
1
(IR, H NMR, and mass spectra). IR: 3382, 3291 (NH2), 3223 (NH), 2209 (CN),
1
1681 (CO) cmꢁ1; HNMR: 8.2 (s, 2H, NH2), 8.00–7.52(m, 5H, phenyl), 2.50(s, 3H,
SCH3); MS: m=z (100%): 258 (Mþ, 10.5%); 105 (100%); 77 (73%). Compound 2
was reacted with formic acid to give 1-benzoyl-3-(methylthio)-1,5-dihydro-4H-pyra-
zolo[3,4-d]pyrimidin-4-one 4. The formation of compound 4 was assumed to proceed
via the amide formation, followed by an intramolecular cyclization with formic acid
to furnish the desired product.[21]
Also, compound 2 was cyclocondensed with formamide, thio-acetamide, car-
bon disulfide, and phenyl isocyanate or phenyl isothiocyanate to give 1-benzoyl-3-
(methylthio)-1H-pyrazolo[3,4-d] pyrimidin-4-amine 5, 1-benzoyl-6-methyl-3-(methyl
thio)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4-thione 6, 1-benzoyl-3-(methyl
thio)-1H-pyrazolo[3,4-d]pyramidine-4,6-(5H,7H)-dithione 7, 1-benzoyl-4-imino-3-
(methylthio)-5-phenyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-d]pyrimidin-6-one 8a,1-
benzoyl-4-imino-3-(methylthio)-5-phenyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-d]pyri-
midine-6-thione 8b respectively (Scheme 1).
Compound 2 was treated with ethyl cyanoacetate, 2,5-dimethoxy- tetrahydro-
furan or Lawesson’s reagent (LR) to give 4-amino-1-benzoyl-3-(methylthio)-6-oxo-6,
7-dihydro-1H-pyrazolo [3,4-b] pyridine-5-carbonitrile 9, 1-benzoyl-3-(methylthio)-
5-(1H-pyrrol-1-yl)-1H-pyrazole-4-carbonitrile 10, and 2-(4-methoxyphenyl)-5-(meth-
yllthio)-7-[(phenyl-k4-sulf-anylidyne)methyl]-1,2,3,7-tetra-hydro-4H-pyrazolo[3,4-d]
[1,3,2]diazaphosphinine-4-thione 2-sulfide 11 respectively (Scheme 2).
When compound 2 was allowed to react with hydrazine, only the substitution
reaction occurred, and the replacement of 3-methoxythio group with hydrazine led
to 5-amino-1-benzoyl-3-hydrazino-1H-pyrazole-4-carbonitrile 12 and did not give
the cyclic compound as we expected. We tried to interpret why the attachment hydra-
zine group did not add to the cyano group by studying this reaction through minimized
energy structure of compound 12 by MM2 and AM1, and we noticed that the hydrazo
group is out of plane with the cyano group (Fig. 1).
N-[1-Benzoyl-4-cyano-3-(methylthio)-1H-pyrazol-5-yl]-3-oxo-3-phenyl propa-
namid 13 was yielded on treating compound 2 with ethyl benzoylacetate in either pyri-
dine, dimethylformamide (DMF), or fusion and did not give the expected cyclized
product even when the isolated compound 13 was refluxed in ethanol with sodium
ethoxid as a catalyst for 6 h. Compound 2 was easily acylated with acetic anhydride
or acetyl chloride to give N-[1-benzoyl-4-cyano-3-(methylthio)-1H-pyrazol-5-yl]

2750
A. M. SOLIMAN ET AL.
Scheme 1. Synthesis of pyrazolopyrimidine derivatives (2–8).
acetamide 14 and also with triethylorthoformate to give ethyl[1-benzoyl-4-cyano-
3-(methylthio)-1H-pyrazol-5-yl] imidoformate 15. Compound 15 was allowed to react
with hydrazine or phenylhydrazine and gave the starting compound 2 (Scheme 3). For
the same reason mentioned previously when we studied this reaction through the
minimized energy structure of compound 15 with hydrazine or phenylhydrazine by
MM2 and AM1, we deduced that the imidoformate group is out of plane with the
cyano group (Fig. 2).
Ethyl 5-amino-1-benzoyl-3-(methylthio)-1H-pyrazole-4-carboxylate 3[20] was
treated with malononitril to give 6-amino-1-benzoyl-4-hydroxy-3-(methylthio)-1H-
pyrazo-lo[3,4-b]pyridine-5-carbonitrile 16. On the other hand, when compound 3
was treated with formamide it gave the same compound 4 and this confirmed the

FUSED AZOLE DERIVATIVES
2751
Scheme 2. Preparation of pyrazole derivatives (9–11).
Figure 1. Minimized energy structure of 12 by MM2 and AM1. Optimization was done using semiempirical
calculation with MM2 and AM1 force fields. The optimization done for 50,000 steps. Calculations were
performed using ChemOffice software developed by Cambridge Soft. (Figure is provided in color online.)

2752
A. M. SOLIMAN ET AL.
reaction pathway, which was assumed to proceed via hydrolysis of the cyano
group.[21]
Also,
1-benzoyl-3-(methylthio)-5-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6
(5H, 7H) dione 17 was obtained via treatment of compound 3 with phenylisocyanate
(Scheme 4).
When compound 3 was treated with phenylisothiocyanate under the same
reaction conditions, the reaction gave the open product identified on the basis
of microanalysis and spectral data as ethyl-1-benzoyl-3-(methylthio)-5-
[(phenylcarbamothioyl)amino]-1H-pyrazole-4-carboxylate 18, 1H-NMR spectrum
showed clear two beaks at d4.2 (q, 2H, CH2) and d 1.22 (t, 3H, CH3) corresponding
to the ethyl group. The reaction of compound 3 with ethyl cyanoacetate, ethyl
Scheme 3. Synthesis of unexpected open chain products (12–15).

FUSED AZOLE DERIVATIVES
2753
Figure 2. Minimized energy structure of 15 by MM2 and AM1. (Figure is provided in color online.)
benzoylacetate, acetyl chloride, or acetic anhydride occurred on the amino function
to give the open products, namely ethyl 1-benzoyl-5-[(cyanoacetyl)amino]-3-(methyl-
lthio)-1H-pyrazole-4-carboxy-late 19, ethyl 5-(3-oxo-3-phenyl-propanamido)-1-
benzoyl-3-(methylthio)-1H-pyrazole-4-carboxylate 20, and ethyl 5-acetamido-1-ben-
zoyl-3-(methylthio)-1H-pyraz-ole-4-carboxylate 21 respectively (Scheme 5).
The only substitution reaction occurred via the replacement of 3-methylthio
with hydrazine when compound 3 was refluxed with hydrazine to give ethyl 5-
amino-1-benzoyl-3-hydrazino-1H-pyrazole-4-carboxylate 22, and this was confirmed
by the spectral studies. Also, when we studied this reaction through minimized energy
Scheme 4. Preparation of pyrazolopyridine and pyrazolopyrimidine derivatives (16,17).

2754
A. M. SOLIMAN ET AL.
Scheme 5. Synthesis of N-substituted pyrazole derivatives (18–21).
structure of compound 22 by MM2 and AM1, we noticed that the hydrazo group is
out of plane with the ester group as in compound 22 (Fig. 3).
Ethyl-1-benzoyl-3-(methylthio)-5-(1H-pyrrol-1-yl)-1H-pyra-zole-4-carboxylate
23 was yielded when compound 3 was reacted with 2,5-dimethoxytetrahydrofuran.
When ethyl 1-benzoyl-5-f[(1E)-ethoxymethylene]aminog-3-(methylthio)-1H-pyra-
zole-4-carboxylate 24, which was yielded from the reaction of triethylorthoformat
with compound 3, was reacted with hydrazine or phenylhydrazine, it underwent
the same behavior as the previous reactions of compound 2 with hydrazine or
phenyl-hydrazine, and we also separated the starting compound 3 (Scheme 6).
The third case was the same as we deduced, that the imidoformate lies out of
plan, with the ester group (Fig. 4).
EXPERIMENTAL
Pyrazolopyrimidine Derivatives 4 and 5
Compound 2 (0.004 mol, 1 g) and excess formic acid or formamide (10 ml)
were heated under reflux for 10 h. The mixture was left to cool and poured onto

FUSED AZOLE DERIVATIVES
2755
Figure 3. Minimized energy structure of 22 by MM2 and AM1. (Figure is provided in color online.)
Scheme 6. Preparation of pyrazole derivatives (22–24).

2756
A. M. SOLIMAN ET AL.
Figure 4. Minimized energy structure of 24 by MM2 and AM1. (Figure is provided in color online.)
ice-cold water. The obtained solid product was filtered off, washed with water, and
crystallized from ethanol.
1-Benzoyl-3-(methylthio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-
one (4).
Method A. Yield 2.2 g, 77%, Buff, mp 305 ꢀC; IR: cmꢁ1 3161 (NH), 1680
1
(2CO); H NMR: d 10.50 (s, 1H, NH), 8.25 (s, 1H, CH pyrimidine), 7.94–7.55 (m,
5H, arom), 2.50 (s, 3H, SCH3); 13C NMR (DMSO-d), TMS, d (ppm) 161.97,
151.20, 150.57, 142.12, 134.48, 130.57, 129.64, 110.08, 12.02. Anal. calc. for C13
H10N4O2S (286.31): C, 54.54; H, 3.52; N, 19.57; S, 11.20. Found: C, 54.12; H,
3.15; N, 19.92; S, 11.01.
Method B. Compound 3 (0.003 mol, 1 g) and excess formamide (10 ml) were
heated under reflux for 10 h. The mixture was left to cool and poured onto ice-cold
water. The obtained solid product was filtered, washed with water, and crystallized
from ethanol.
1-Benzoyl-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin -4-amine (5). Yield
2.1 g, 74%, pale yellow, mp 250 ꢀC; IR: cmꢁ1 3217, 3105 (NH2), 1662 (CO); 1H NMR:
8.11 (s, 1H, CH pyrimidine), 7.83–7.55 (m, 5H, arom), 6.43 (s, 2H, NH2), 2.50 (s, 3H,
SCH3); 13C NMR (DMSO-d), TMS, d (ppm) 161.76, 154.94, 154.63, 154.13, 146.87,
134.06, 129.34, 128.88, 102.34, 12.34. Anal. calc. for C13H11N5OS (285.32): C,
54.72; H, 3.89; N, 24.55; S, 11.24. Found: C, 54.44; H, 3.65; N, 24.92; S, 11.46.
1-Benzoyl-6-methyl-3-(methylthio)-1,5-dihydro-4H-pyrazolo
[3,4-d]pyrimidine-4-thione (6)
Compound 2 (0.004 mol, 1 g) and thioacetamide (0.004 mol, 0.4 g) in trifluoro-
acetic acid (5 ml) were heated under reflux for 24 h. The mixture was left to cool and
poured onto ice-cold water. The obtained solid product was filtered, washed witꢁh
water and crystallized from ethanol. Yield 2.8 g, 88%, brown, mp 245 ꢀC; IR: cm
1
1
3172 (NH), 1660 (CO); H NMR: d 11.50 (s, 1H, NH), 7.95–7.50 (m, 5H, arom),
2.50 (s, 3H, SCH3), 2.48 (s, 3H, CH3); 13C NMR (DMSO-d), TMS, d (ppm) 193.23,
164.52, 158.83, 157. 31, 146.13, 134.48, 131.08, 129.36, 115.03, 20.35, 10.47. Anal.

FUSED AZOLE DERIVATIVES
2757
calc. for C14 H12N4O S2 (316.40): C, 53.14; H, 3.82; N, 17.71; S, 20.27. Found: C,
53.44; H, 3.55; N, 17.42; S, 20.45.
Pyrazolopyrimidine and Pyridine Derivatives 7–8a,b
Compound 2 (0.004 mol, 1 g) and carbon disulfide, phenyl isocyanate, pheny-
lisothiocyanate, or ethyl cyanoacetate (0.004 mol) in pyridine (15 ml) were heated
under reflux for 12 h. The mixture was left to cool and poured onto ice cold water.
The obtained solid product was filtered, washed with water, and crystallized from
ethanol.
1-Benzoyl-3-(methylthio)-1H-pyrazolo[3,4-d]pyramid-dine-4,6(5H,7H)-
dithione (7). Yield 3 g, 90%, yellowish white, mp 320 ꢀC; IR: cmꢁ1 3223 (2NH),
1
1662 (CO); H NMR: d 11.19 (s, 1H, NH), 8.19 (s, 1H, NH), 8.01–7.52 (m, 5H,
arom), 2.51 (s, 3H, SCH3); 13C NMR (DMSO-d), TMS, d (ppm) 197. 32, 167.50,
163.38, 153.31, 150.27, 134.85, 134.48, 129.32, 127.98, 112.14, 10.37. Anal. calc.
For C13H10 N4OS3 (334.44): C, 46.69; H, 3.01; N, 16.75; S, 28.76. Found: C,
46.34; H, 3.45; N, 16.42; S, 28.43.
1-Benzoyl-4-imino-3-(methylthio)-5-phenyl-1,4,5,7-tetrahydro-6H-pyra-
zolo[3,4-d]pyrimidin-6-one (8a). Yield 2.9 g 77%, Yellowish white, mp 140 ꢀC;
1
IR: cmꢁ1 3351, (2NH), 1668 (2CO); H NMR: d 13.90 (s, 1H, NH), 10.24 (s, 1H,
NH), 7.97–7.10 (m, 10H, arom), 2.50 (s,3H, SCH3); 13C NMR (DMSO-d), TMS,
d (ppm)) 164.59, 150.34, 143.83, 142. 61, 134.13, 130.80, 130.08, 128.98, 125.03,
95.15, 10.68. Anal. calc. for C19H15N5O2S (377.42): C, 60.46; H, 4.01; N, 18.56; S,
8.50. Found: C, 60.13; H, 3.75; N, 18.86; S, 8.23.
1-Benzoyl-4-imino-3-(methylthio)-5-phenyl-1,4,5,7-tetrahydro-6H-pyra-
zolo[3,4-d]pyrimidine-6-thione (8b). Yield 3.2 g 81%, yellowish white, mp 250 ꢀC;
IR: cmꢁ1 3206 (2NH), 1687 (CO); 1H NMR: d 13.80 (s, 1H, NH), 8.56 (s, 1H, NH),
7.72–7.01 (m,10H, arom), 2.51 (s,3H, SCH3); Anal. calc. for C19 H15N5OS2 (393.48):
C, 58.00; H, 3.84; N, 17.80; S, 16.30. Found: C, 58.44; H, 3.55; N, 17.42; S, 16.54.
4-Amino-1-benzoyl-3-(methylthio)-6-oxo-6,7-dihydro-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile (9)
Yield 2.5 g, 77%, yellowish white, mp 230 ꢀC; IR: cmꢁ1 3384, 3286, 3228 (NH,
1
NH2), 2223 (CN), 1667 (2CO); H NMR:d 9.76 (s, 1H, NH), 7.83 (s, 2H, NH2),
7.67–7.43 (m, 5H, arom), 2.50 (s, 3H, SCH3); 13C NMR (DMSO-d), TMS, d
(ppm) 167.47, 165.44, 154.24, 149. 53, 139.01, 134.48, 130.01, 128.98, 128.43,
89.18, 77.58, 10.73. Anal. calc. for C15 H11N5O2S (325.34): C, 55.38; H, 3.41; N,
21.53; S, 9.86. Found: C, 55.54; H, 3.75; N, 21.85; S, 9.55.
1-Benzoyl-3-(methylthio)-5-(1H-pyrrol-1-yl)-1H-pyrazole-4-
carbonitrile (10)
An equimolar ratio of compound 2 (0.004 mol, 1 g) and 2,5-dimethoxytetrahy-
dro-furan (0.7 ml) in 15 ml of glacial acetic acid were heated under reflux for 1 h, left
to cool, and then poured onto ice-cold water. The precipitated solid was filtered off,

2758
A. M. SOLIMAN ET AL.
washed well with water, dried, and crystallized from ethanol. Yield 2.7 g, 87%,
1
brown, mp 250 ꢀC; IR: cmꢁ1 2220 (CN), 1669 (CO); H NMR: d 8.25–7.58 (br,
7H, arom þ pyrrolyl), 7.37 (d, 2H, pyrrolyl); 2.50 (s, 3H, SCH3); MS m=z (%):
Mþ 308 (21.2), 258 (7.3), 105 (100), 77 (833); 13C NMR (DMSO-d), TMS, d
(ppm) 163.59, 148.04, 143.73, 135. 61, 134.43, 130.60, 128.28, 120.89, 116.93,
113.15, 79.08, 11.78. Anal. calc. for C16H12N4OS (308.36): C, 62.32; H, 3.92; N,
18.17; S, 10.40. Found: C, 62.00; H, 3.65; N, 18.52; S, 10.64.
2-(4-Methoxyphenyl)-5-(methylthio)-7-[(phenyl-k4-sulfanylidyne)
methyl]-1,2,3,7-tetrahydro-4H-pyrazolo[3,4-d][1,3,2]
diazaphosphinine-4-thione 2-sulfide (11)
A mixture of compound 2 (0.004 mol, 1 g) and Lawesson’s reagent (0.004 mol,
1.3 g) in dry p-xylene (20 ml) was heated under reflux for 6 h. The solvent was
removed under reduced pressure, and the obtained residue was triturated with cold
methanol (20 ml). The precipitate was filtered off and ꢁc1rystallized from dioxane.
Yield 3.4 g, 71%, Reddish brown, mp 120ꢀC; IR: cm 3435, 3287 (2NH); 1H
NMR: d 10.50 (s, 2H, 2NH), 7.67–6.26 (m, 9H, arom), 3.78 (s, 3H, OCH3), 2.50
(s, 3H, SCH3); 13C NMR (DMSO-d), TMS, d (ppm) 188.90, 188.54, 161.63, 161.
51, 152.16, 143.62, 140.40, 140.08, 139.88, 132.00, 131.77, 128.15, 127.71, 126.58,
103.97, 103.77, 55.30, 10.88. Anal. calc. for C19 H17N4OPS4 (476.60): C, 47.88; H,
3.60; N, 11.76; S, 26.91. Found: C, 47.44; H, 3.25; N, 12.10; S, 26.77.
5-Amino-1-benzoyl-3-hydrazino-1H-pyraz-ole-4-carbonitrile (12)
Compound 2 (0.004 mol, 1 g) and excess of hydrazine hydrate (5 ml) in absolute
ethanol (15 ml) were heated under reflux for 7 h. The reaction mixture was concen-
trated and left to cool. The obtained solꢁid1 filtered and crystallized from ethanol. Yield
1.8 g, 74%, brown, mp 110 ꢀC; IR: cm 3386, 3285, 3210, 3135 (NH, 2NH2), 2219
1
(CN), 1664 (CO); H NMR: d 9.76 (s, 1H, NH), 8.25 (s, 2H, NH2), 7.83–7.43 (m,
5H, arom), 6.43 (s, 2H, NH2); 13C NMR (DMSO-d), TMS, d (ppm) 163.09, 154.54,
149.83, 134. 48, 132.43, 130.55, 128.58, 118.18, 77.03. Anal. calc. for C11H10N6O
(242.24): C, 54.54; H, 4.16; N, 34.69. Found: C, 54.84; H,3.85; N, 34.92.
N-[1-Benzoyl-4-cyano-3-(Methylthio)-1H-pyrazol-5-yl]-3-oxo-3-
phenylpropanamide (13)
Compound 2 (0.004 mol, 1 g) and excess ethyl benzoylacetate (10 ml) were
heated at 200 ꢀC. solid products began to form after 15–20 min. The heating was
continued for 1 h. The solid products was filtered, washed with ethanol and crystal-
lized from ethanol. Yield 3.1 g, 77%, yellow, mp 270 ꢀC; IR: cmꢁ1 3280 (NH), 2228
1
(CN), 1694–1673 (3CO); H NMR: d 10.24(s, 1H, NH), 7.97–7.10, 7.10 (m, 10H,
arom), 4.10 (s, 2H, CH2) 2.50 (s, 3H, SCH3); Anal. calc. for C21H16N4O3S
(404.44): C, 62.36; H, 3.99; N, 13.85; S, 7.93. Found: C, 62.02; H, 3.65; N, 13.45;
S, 7.73.

FUSED AZOLE DERIVATIVES
2759
N-[1-Benzoyl-4-cyano-3-(methylthio)-1H-pyrazol-5-yl]acetamide (14)
Compound 2 (0.004 mol, 1 g) in DMF (15 ml) and acetyl chloride (0.004 mol,
0.3 ml) or acetic anhydride (10 ml) were stirred at room temperature for 30 min and
then heated under reflux for 3 h. The reaction mixture was allowed to cool. The pre-
cipitated solid was filtered and crystallized from ethanol. Yield 2.5 g, 83%, yellowish
white, mp 265 ꢀC; IR: cmꢁ1 3290 (NH), 2225,(CN), 1687 (2CO); 1H NMR: d 10.20 (s,
1H, NH), 7.96–7.50 (m, 5H, arom), 2.50 (s, 3H, SCH3), 2.30 (s, 3H, CH3); Anal. calc.
for C14H12N4O2S (300.34): C, 55.99; H, 4.03; N, 18.65; S, 10.68. Found: C, 55.59; H,
3.75; N, 18.92; S, 10.87.
Ethyl [1-Benzoyl-4-cyano-3-(methylthio)-1H-pyrazol-5-yl]imido-
formate (15)
A mixture of compound 2 (0.004 mol, 1 g), triethyl orthoformate (3 ml), and
acetic anhydride (10 ml) was heated under reflux for 6 h. The reaction mixture was
concentrated and poured onto ice-cold water. The separated solid was filtered and
crystallized from ethanol. Yield 2.5 g, 80%, yellowish white, mp 170 ꢀC; IR: cmꢁ1
1
2225 (CN), 1694 (CO); H NMR: d 7.82–7.33 (m, 5H, arom), 7.22 (s, 1H, CH),
3.33 (q, 2H, CH2), 2.50 (s, 3H, SCH3), 1.80 (t, 3H, CH3); 13C NMR (DMSO-d),
TMS, d (ppm)) 166.24, 164.64, 149.77, 134.47, 132.83, 132.19, 129.88, 112.95,
95.35, 61.70, 14.28, 10.37. Anal. calc. for C15H14N4O2S (314.36): C, 57.31; H, 4.49;
N, 17.82; S, 10.20. Found: C, 57.02; H, 4.12; N, 17.50; S, 10.41.
1-Benzoyl-4-hydroxy-6-imino-3-(methyl-thio)-6,7-dihydro-1H-
pyrazolo[3,4-b]pyridine-5-carbo-nitrile (16)
Compound 3 (0.003 mol, 1 g) and malononitrile (0.003 mol) in pyridine (15 ml)
were heated under reflux for 12 h. The mixture was left to cool and poured onto
ice-cold water. The obtained solid product was filtered, washed with water, and crys-
tallized from ethanol. Yield 2.2 g, 74%, buff, mp 240 ꢀC; IR: cmꢁ1 3447 (OH), 3323,
1
3187 (2NH), 2213 (CN), 1671 (CO); H NMR: d 10.50 (s, 1H, OH), 9.76 (s, 2H,
2NH), 7.95–7.50 (m, 5H, arom), 2.5 (s, 3H, SCH3); 13C NMR (DMSO-d), TMS, d
(ppm) 165.61, 163.14, 155.46, 151. 37, 141.97, 134.50, 134.44, 128.88, 127.78,
121.65, 101.87, 59.61, 10.72. Anal. calc. for C15 H11N5O2S (325.34): C, 55.38; H,
3.41; N, 21.53; S, 9.86. Found: C, 55.69; H, 3.05; N, 21.93; S, 9.64.
1-Benzoyl-3-(methylthio)-5-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,
6(5H,7H)-dione (17)
Compound 3 (0.003mol, 1 g) and phenylisocyanate (0.003 mol) in pyridine
(15 ml) were heated under reflux for 12h. The mixture was left to cool and poured onto
ice-cold water. The obtained solid product was filtered, washed with water and crystal-
lized from ethanol. Yield 3.0 g, 79%, white, mp 160 ꢀC; IR: cmꢁ1 3335 (NH), 1682-1660
(3CO); 1H NMR: d 10.34 (s, 1H, NH), 8.07–7.05 (m, 10H, arom), 2.59 (s, 3H, SCH3);
MS m=z (%): Mþ 378 (34), 197 (11.1), 105 (96.5), 77 (100). Anal. calc. for C19H14N4O3S
(378.40): C, 60.31; H, 3.73; N, 14.81; S, 8.47. Found: C, 60.64; H, 3.38; N, 14.42; S, 8.69.

2760
A. M. SOLIMAN ET AL.
Ethyl 1-Benzoyl-3-(methylthio)-5-[(phenyl-carbamothioyl)amino]-
1H-pyrazole-4-carboxylate (18)
Compound 3 (0.003 mol, 1 g) and phenylisothiocyanate (0.003 mol) in pyridine
(15 ml) were heated under reflux for 12 h. The mixture was left to cool and poured
onto ice-cold water. The obtained solid product was filtered, washed with water,
and crystallized from ethanol. Yield 3.6 g, 82%, white, mp 190 ꢀC; IR: cmꢁ1 3279
1
(2NH), 1666 (2CO); H NMR: d 10.43 (s, 1H, NH), 10.23 (s, 1H, NH), 7.97–6.65
(m, 10H, arom), 4.16 (q, 2H, CH2), 2.50 (s, 3H, SCH3), 1.24 (t, 3H, CH3). Anal. calc.
for C21H20N4O3S2 (440.54): C, 57.25; H, 4.58; N, 12.72; S, 14.56. Found: C, 57.66;
H, 4.18; N, 13.03; S, 14.39.
Ethyl 1-Benzoyl-5-[(cyanoacetyl)amino]-3-(methylthio)-1H-pyrazole-
4-carboxylate (19)
Compound 3 (0.003 mol, 1 g) and ethyl cyanoacetate (0.003 mol) in pyridine
(15 ml) were heated under reflux for 12 h. The mixture was left to cool and poured
onto ice-cold water. The obtained solid product was filtered, washed with water
and crystallized from ethanol. Yield 2.8 g, 75%, yellowish green, mp 140 ꢀC; IR:
1
cmꢁ1 3203 (NH), 2222 (CN), 1687–1663 (3CO); H NMR: d 7.90 (s, 1H, NH),
7.60–7.00 (m, 5H, arom), 4.20 (q, 2H, CH2), 3.80 (s, 2H, CH2) 2.50 (s, 3H,
SCH3), 1.20 (t, 3H, CH3). Anal. calc. for C17H16N4O4S (372.40): C, 54.83; H,
4.33; N, 15.04; S, 8.61. Found: C, 54.44; H, 4.00; N, 15.42; S, 8.85.
Ethyl 5-(3-Oxo-3-phenylpropanamido)-1-benzoyl-3-(methylthio)-1H-
pyrazole-4-carboxylate (20)
Compound 3 (0.003 mol, 1 g) and excess ethyl benzoylacetate (10 ml) were
heated at 200 ꢀC; solid products were began formed after 15–20 min. The heating
was continued for 1 h. The solid products were filtered, and washed with ethanol.
Yield 3.4 g 75%, pale yellow, mp 260 ꢀC; IR: cmꢁ1 3234, (NH), 1689–1659 (4CO);
1HNMR: d 7.90 (s, 1H, NH), 7.67–7.00 (m,10H, arom), 4.16 (q, 2H, CH2), 3.95 (s,
2H, CH2), 2.50 (s, 3H, SCH3), 1.24 (t, 3H, CH3). Anal. calc. for C23 H21N3O5S
(451.50): C, 61.18; H, 4.69; N, 9.31; S, 7.10. Found: C, 61.51; H, 4.25; N, 9.72; S, 7.23.
Ethyl 5-Acetamido-1-benzoyl-3-(methylthio)-1H-pyrazole-4-
carboxylate (21)
Compound 3 (0.003 mol, 1 g) in DMF (15 ml) and acetyl chloride (0.003 mol,
0.3 ml) or acetic anhydride (10 ml) were stirred at room temperature for 30 min
and then heated under reflux for 3 h. The reaction mixture was allowed to cool.
The precipitated solid wasꢁfi1ltered and crystallized from ethanol. Yield 2.7 g, 78%,
1
white, mp 120 ꢀC; IR: cm 3329 (NH), 1696–1678 (3CO); H NMR: d 8.76 (s,
1H, NH), 7.87–7.00 (m, 5H, arom), 4.10 (q, 2H, CH2), 2.50 (s, 3H, SCH3), 2.30
(s, 3H, CH3), 1.20 (t, 3H, CH3). Anal. calc. for C16H17N3 O4S (347.39): C, 55.32;
H, 4.93; N, 12.10; S, 9.23. Found: C, 55.73; H, 4.55; N, 12.54; S, 9.01.

FUSED AZOLE DERIVATIVES
2761
Ethyl 5-Amino-1-benzoyl-3-hydrazino-1H-pyrazole-4-carboxylate (22)
Compound 3 (0.003 mol, 1 g) and excess hydrazine hydrate (5 ml) in absolute
ethanol (15 ml) was heated under reflux for 7 h. The reaction mixture was left to cool
and the obtained solid was filtered and crystallized from ethanol. Yield 2.2 g, 76%,
1
buff, mp 150 ꢀC; IR: cmꢁ1 3485, 3389, 3331 (NH, 2NH2), 1682 (2CO); H NMR: d
9.76 (s, 1H, NH), 7.83–7.40 (m, 5H, arom), 6.00 (s, 4H, 2NH2), 4.16 (q, 2H, CH2),
1.23 (t, 3H, CH3); 13C NMR (DMSO-d), TMS, d (ppm) 167.59, 164.94, 154.43,
150.61, 134.43, 132.30, 129.08, 128.88, 97. 30, 58.75, 14.18. Anal. calc. for
C13H15N5O3 (289.30): C, 53.97; H, 5.23; N, 24.21. Found: C, 53.54; H, 4.85; N, 24.62.
Ethyl 1-Benzoyl-3-(methylthio)-5-(1H-pyrrol-1-yl)-1H-
pyrazole-4-carboxylate (23)
An equimolar ratio of compound 3 (0.003 mol, 1 g) and 2,5-dimethoxytetrahy-
drofuran (0.6 ml) in 15 ml of glacial acetic acid was heated under reflux for 1 h, left to
cool and then poured onto ice-cold water. The precipitated solid was filtered off,
washed well with water, dꢁri1ed, and crystallized from ethanol. Yield 3.0 g, 85%,
1
brown, mp 163 ꢀC; IR: cm 1695 (2CO); H NMR: d 8.10–7.40 (m, 5H, arom),
7.00 (d, 2H, pyrrolyl) 6.61 (d, 2H, pyrrolyl), 4.20 (q, 2H, CH2), 2.50 (s, 3H,
SCH3), 1.20 (t, 3H, CH3). Anal. calc. for C18H17N3O3S (355.41): C, 60.83; H,
4.82; N, 11.82; S, 9.02. Found: C, 60.42; H, 4.55; N, 11.41; S, 9.22.
Ethyl 1-Benzoyl-5-f[(1E)-ethoxymethylene]aminog-3-(Methylthio)-
1H-pyrazole-4-carboxylate (24)
A mixture of compound 3 (0.003 mol, 1 g), triethyl orthoformate (3 ml), and
acetic anhydride (10 ml) was heated under reflux for 6 h. The reaction mixture was
concentrated and poured onto ice-cold water. The solid product was filtered and
crystallized from ethanol. Yield 3.0 g, 83%, White, mp 118–120 ꢀC; IR: cmꢁ1
1
1701–1690 (2CO); H NMR: d 7.80–7.35 (m, 5H, arom), 7.19 (s, 1H, CH), 4.20
(q, 4H, 2CH2), 2.50 (s, 3H, SCH3), 1.20 (t, 6H, 2CH3); 13C NMR (DMSO-d),
TMS, d (ppm) 164.39, 160.74, 160.40, 157. 19, 149.63, 134.47, 132.78, 130.40,
129.63, 110.65, 61.70, 58.73, 14.20, 14.18, 10.36. Anal. calc. for C17H19 N3O4S
(361.42): C, 56.50; H, 5.30; N, 11.63; S, 8.87. Found: C, 56.22; H, 4.93; N, 11.98;
S, 8.65.
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