Synthesis and reactions of 4-trifluoromethyl-3-cyano pyridine-2(1H)-thione/ one derivatives

Article abstract of DOI:10.1080/17415993.2011.628994

4,4,4-Trifluoro-1-(thiophen-2-yl)butane-1,3-dione was reacted by grinding with cyanothioacetamide and cyanoacetamide under solvent-free conditions at 25°C to give pyridine-2(1H)thione/one derivatives in excellent yields. These compounds were further reacted by grinding with different halogenated reagents to give 2-S/O-alkyl pyridine derivatives. The latter compounds were utilized for the synthesis of thieno[2,3-b]pyridine, pyrazolopyridine, pyridothienopyrimidine and pyridothienooxazinone derivatives.

Full text of DOI:10.1080/17415993.2011.628994

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Synthesis and reactions of
4-trifluoromethyl-3-cyano
pyridine-2(1H)-thione/one derivatives
Nora M. Rateb a
a Department of Chemistry, Faculty of science, Cairo University,
Giza, 12136, Egypt
Version of record first published: 02 Nov 2011.
To cite this article: Nora M. Rateb (2011): Synthesis and reactions of 4-trifluoromethyl-3-cyano
pyridine-2(1H)-thione/one derivatives, Journal of Sulfur Chemistry, 32:6, 611-622
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Journal of Sulfur Chemistry
Vol. 32, No. 6, December 2011, 611–622
Synthesis and reactions of 4-trifluoromethyl-3-cyano
pyridine-2(1H)-thione/one derivatives
Nora M. Rateb*
Department of Chemistry, Faculty of science, Cairo University, Giza 12136, Egypt
(Received 26 August 2011; final version received 29 September 2011)
4,4,4-Trifluoro-1-(thiophen-2-yl)butane-1,3-dione was reacted by grinding with cyanothioacetamide and
cyanoacetamide under solvent-free conditions at 25 ◦C to give pyridine-2(1H)thione/one derivatives in
excellent yields. These compounds were further reacted by grinding with different halogenated reagents to
give 2-S/O-alkyl pyridine derivatives. The latter compounds were utilized for the synthesis of thieno[2,3-
b]pyridine, pyrazolopyridine, pyridothienopyrimidine and pyridothienooxazinone derivatives.
CF3
CF3
NH2
CN
XCH2Y
Y
N
H
S
S
N
S
S
MeI/NH2NH2
CF3
HCOOH/HCONH2
NH2
CF3
N
N
N
N
N
z
S
N
H
S
S
Keywords: Green synthesis; grinding; 3-cyanopyridine-2(1H)thione/one; thieno[2,3-b]pyridine; pyri-
dothienopyrimidine; pyrazolopyridine; pyridothienooxazinone
1. Introduction
At present, developing green chemical protocols is one of the most important efforts in organic
synthesis. Moreover, improving the efficiency of organic synthesis, lowering the consumption of
chemicals, and obtaining polycyclic molecules from simple starting materials are fundamental
*Email: nonaratb@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2011.628994
http://www.tandfonline.com

612 N.M. Rateb
goals in organic synthesis. Grinding the reactants together constitutes the simplest green chemistry
protocol. It has proven to be an efficient, economical and environmentally benign process (1–5).
On the other hand, interest in the development of synthetic approaches for preparation of 3-cyano-
2(1H)-pyridinethiones is related to their use as versatile precursors in the preparation of dyes,
herbicides, bactericides, and other biologically active compounds (6–9). Moreover, pyridine-3-
carbonitriles were used as cardiotonic (10, 11) and antiviral agents (12). Also, S-alkyl pyridines
possess neurotropic activity (13) and they are used as adenosine receptor ligands (14, 15) and
also have cardiovascular activity (16). Moreover, thieno[2,3-b]pyridines are of special impor-
tance due to their reported biological activities such as antibacterial (17–20), antihypertensive
(21), and anti-inflammatory (22). Furthermore, pyridothienopyrimidines were reported to have
antiallergic (23), antiprotozoals (24), antianaphylatic (25, 26), and antimicrobial (21, 27) prop-
erties. Thus, in continuation of previous work together with our interest in developing a green
protocol for the synthesis of organic compounds (1, 28) we report herein a convenient synthesis
of 4-trifluoromethyl-3-cyano-2(1H)pyridinethione/one compounds.
2. Results and discussion
Reaction of 4,4,4-trifluoro-1-thiophen-2-yl-butane-1,3-dione (1) with 2-cyanothioacetamide (2a)
was investigated under different basic conditions. Thus, pyridinethione 3a was prepared in excel-
lent yield (95%) by grinding equivalent amounts of 1 and 2a in the presence of solid potassium
hydroxide in a porcelain mortar under solvent-free conditions. Grinding for about 1–5 min led to
a colored solid mass that proved to be the target pyridinethione 3a (m.p. according to the literature
(29)). When the same reaction was carried out in ethanolic triethylamine solution under reflux,
compound 3a was also obtained (m.p., mixed m.p. and TLC) (29). On the other hand, when the
reaction was carried out in ethoxide solution, it gave a mixture of two compounds as revealed by
TLC. These compounds were separated by crystallization from different solvents. One of these
two compounds was found to be identical with compound 3a (m.p., mixed m.p., TLC).
Examination of 19F NMR spectra of the two compounds showed signals at different positions
for the trifluoromethyl groups. The 19F NMR δ, ppm (DMSO-d6) spectra of 3a showed a signal
at 69.87 while its isomer 3aꢀ (m.p. >300 ◦C) showed a signal at 64.23.
S
CF3
CN
CN
N
H
S
CF3
N
H
S
S
3a`
3a
Thus, compound 3a was assigned as 4-(trifluoromethyl)-1,2-dihydro-6-(thiophen-2yl)-2-
thioxopyridine-3-carbonitrile (3a) (29) while its isomer was assigned as 6-(trifluoromethyl)-
1,2-dihydro-4-(thiophen-2-yl)-2-thioxopyridine-3-carbonitrile (3aꢀ). These data are in agreement
with those of the earlier work which reported stereoselective synthesis of 6-methyl-1,2-dihydro-4-
(trifluoromethyl)-2-thioxopyridine-3-carbonitrile and 4-methyl-1,2-dihydro-6-(trifluoromethyl)-
2-thioxopyridine-3-carbonitrile (30, 31).
Similarly, a mixture of 4,4,4-trifluoro-1-thiophen-2-yl-butane-1,3-dione (1) was ground with
2-cyanoacetamide (2b) under solvent-free condition to afford 4-trifluoromethyl-1,2-dihydro-
2-oxo-6-(thiophen-2-yl)pyridine-3-carbonitrile (3b) (96%). This method of preparation of

Journal of Sulfur Chemistry 613
Table 1. Yield comparison between solvent-free preparation of
compounds 3–7a and b and the classical conditions.
Yield (%)
Compound
Method A
Method B
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
95
96
96
75
89
80
92
85
93
79
80
92
93
53
85
65
80
75
89
56
Notes: A: Grinding; B: Classical conditions.
pyridinethionones is simple and effective in terms of short reaction time and excellent yields
compared with the classical methods of preparations (29, 32, 33) (Table 1).
Structure 3b was supported by its elemental analysis and spectral data. The IR spectrum of
3b revealed absorption bands at 2221, 3097, and 1665 cm−1 for cyano, NH, and CO groups,
1
respectively. Its H NMR spectrum showed signals at δ = 7.29 (dd, 1H, 4-H of thienyl), 7.66
(s, 1H, 5-H of pyridinyl), 7.93 (d, 1H, 3-H of thienyl), 8.20 (d, 1H, 5-H of thienyl), 13.89 (s,
1H, NH) and its mass spectrum showed a peak corresponding to the molecular ion at m/z 270.
Compounds 3a and b were reacted with methyliodide, chloroacetonitrile, ethyl bromoacetate,
and chloroacetone by grinding in the presence of KOH, in a porcelain mortar; under solvent-free
conditions, to give 4a and b, 5a and b, 6a and b, and7a and b derivatives, respectively, which
can be also obtained by the reaction of compounds 3a and b with the same alkylating agents in
DMF/KOH (Scheme 1).
X
CF
3
S
H2N
CH2CN
+
1
O
O
a, X=S
b, X=O
2
Grinding
KOH
CF
CF
3
CF3
3
CN
CN
CN
ClCH2Y
MeI
Grinding
Grinding
XCH2Y
N
H
X
N
XCH3
S
S
S
5a, X = S, Y = CN
5b, X = O, Y = CN
3a,b
4 a,b
6a, X = S, Y = COOC2H5
6b, X = O, Y = COOC2H5
7a, X = S, Y = COCH3
7b, X = O, Y = COCH3
Scheme 1. Reaction of 3a and b with different alkylating agents.
1
The IR spectrum of 4b revealed absorption band at 2223 cm−1 for the cyano group. Its H
NMR spectrum showed a signal at δ = 4.18 (s, 3H, CH3), 7.27 (dd, 1H, 4-H of thienyl), 7.50
(s, 1H, 5-H of pyridinyl), 7.60 (d, 1H, 3-H of thienyl), and 7.79 (d, 1H, 5-H of thienyl).

614 N.M. Rateb
The IR spectrum of 5b revealed the presence of two absorption bands at 2227 and 2268 cm−1
for the two cyano groups. Its 1H NMR spectrum showed signals at δ = 5.20 (s, 2H, CH2), 7.24
(dd, 1H, 4-H of thienyl), 7.27 (s, 1H, 5-H of pyridinyl), 7.67 (d, 1H, 3-H of thienyl), and 7.86 (d,
1H, 5-H of thienyl).
The structures of compounds 4a,5a, 6a and b, and 7a and b were also confirmed based on
elemental analysis and spectral data.
Compounds 5a, 6a, and 7a were converted to the corresponding thienopyridine derivatives by
refluxing in sodium ethoxide solution to give 8, 9, and 10, respectively (Scheme 2). The reaction
proceeded via intramolecular cyclocondensation to give the substituted thieno[2,3-b] pyridine
derivatives in good yield.
CF3
CF3
NH2
CN
NaOEt
Y
N
SCH2Y
S
N
S
S
8
9
Y=CN
5a, Y=CN
Y= COOC2H5
6a, Y=COOC2H5
7a, Y=COCH3
10 Y=COCH3
Scheme 2. Conversion of S-alkyl derivative to thienopyridines.
The absence of cyano group absorption in the IR spectrum of compounds 8–10 and the appear-
ance of absorption bands in the region 3050–3400 cm−1 for the amino group confirmed the
1
proposed structures. Furthermore, the H NMR spectrum of 10 showed signals at δ = 2.52 (s,
3H, CH3), 7.17 (dd, 1H, 4-H of thienyl), 7.27 (s, 1H, 5-H of pyridinyl), 7.55 (d, 1H, 3-H of
thienyl), 7.78 (d, 1H, 5-H of thienyl), and 14.00 (b, 2H, NH2) and the disappearance of the sig-
nal at δ 4.01 (s, 2H, CH2). Based on these facts, the structure of compound 10 was assigned as
1-(3-amino-4-(trifluoromethyl)-6-(thiophen-2-yl)thieno[2,3-b]pyridine-2-yl)ethanone.
On the other hand, treatment of 4a with hydrazine hydrate under reflux for 12 h gave com-
pound 12 in almost quantitative yield (Scheme 3), which was also prepared by the reaction of 11
with hydrazine hydrate under the same conditions. The IR spectrum of compound 12 revealed
Scheme 3. Preparation of pyrazolopyridine derivative.

Journal of Sulfur Chemistry 615
absorption bands at 3330 and 3225 cm−1 for the amino group and no absorption was detected for
the cyano group.
Compound 8 as a typical enaminonitrile reacted with formic acid upon heating for several
hours to yield 7-thiophen-2-yl-9-trifluoromethyl-3-H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-
one (13) (Scheme 4). The absence of cyano absorption and the appearance of the NH and carbonyl
absorption bands at 3046 and 1668 cm−1 in the IR spectrum confirmed the proposed structure 13.
Its mass spectrum showed a peak at m/z 353 (M+). Compound 13 was alternatively obtained by
heating compound 9 in formamide under reflux for 7 h (Scheme 4).
CF3
CF3
N
NH2
N
N
N
CONHNH2
S
S
S
S
Cl
14
15
POCl3
NH2NH2
CF3
N
HCONH2
HCOOH
N
H
9
8
N
S
S
O
13
PhNCS
AC2O
CF3
CF3
H
CH3
S
N
N
O
N
N
N
S
S
S
S
O
O
16
17
Scheme 4. Synthesis of some new polycyclic compounds.
4-Chloro-7-thiophen-2-yl-9-trifluoromethyl-pyrido[3ꢀ,2ꢀ:4,5]thieno [3,2-d]pyrimidine (14)
was obtained by the reaction of 13 with POCl3 under reflux for 1 h. Finally, compound 9 reacted
with hydrazine hydrate, acetic anhydride and phenylisothiocyanate to give the corresponding com-
pounds 15, 16, and 17, respectively. Structures of compounds 15,16, and 17 have been determined
by their elemental analyses and spectral data.
3. Conclusion
In summary, we developed a new approach for the synthesis and reactions of heterocyclic
compounds that has proven to be simple, efficient, environmentally benign, and cost-effective
compared with the classical synthetic methods. In the process, we investigated the

616 N.M. Rateb
regioselective synthesis of 4-(trifluoromethyl)-1,2-dihydro-6-(thiophen-2-yl)-2-thioxopyridine -
3-carbonitrileunder different basic conditions and we isolated the two possible regioisomers, 4-
and 6-trifluoromethyl-3-cyano-2(1H)-pyridinethiones.
4. Experimental
Melting points were measured on an Electrothermal melting point apparatus and are uncorrected.
1
IR spectra were recorded on a Shimadzu FT-IR 8101 PC infrared spectrophotometer. The H
NMR spectra were determined in DMSO-d6 at 300 MHz on a Varian mercury VX 300 NMR
spectrometer using TMS as an internal standard. Mass spectra were measured on a GCMS-
QP1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the Microanalytical
Center of Cairo University.
4.1. Synthesis of 3a and b
Method A. A mixture of 1 (3 mmol), 2-cyanothioacetamide (2a) or 2-cyanoacetamide (2b)
(0.3 g/0.25, 3 mmol), and KOH (4 mmol) was thoroughly ground with a pestle in an open mortar
at 25 ◦C for 3–5 min until the mixture turned into a melt. The initial syrupy reaction mixture
solidified within 4–6 min. Grinding continued for 5–15 min and the reaction was monitored by
TLC. The solid was washed with water and recrystallized from the proper solvent to give 3a and
b, respectively.
Method B. A mixture of 1 (11.1 g, 50 mmol) and 2-cyanothioacetamide or 2-cyanoacetamide
2a and b (5 g, 4.2 g, 50 mmol) was heated under reflux in ethanolic triethylamine solution for
15 min. The reaction mixture was cooled; the so-formed solid was filtered and recrystallized from
the proper solvent to give 3a and b, respectively.
4.1.1. 4-(Trifluoromethyl)-1,2-dihydro-2-oxo-6-(thiophen-2-yl) pyridine-3-carbonitrile (3b)
Yellow crystals from ethanol, m.p. 300–302 ◦C; IR (KBr, cm−1) υ 3197 (NH), υ 2225 (CN),
1
υ 1665 (CO). H NMR (DMSO-d6): δ = 7.29 (dd, 1H, 4-H of thienyl), 7.66 (s, 1H, 5-H of
pyridinyl), 7.93 (d, 1H, 3-H of thienyl), 8.20 (d, 1H, 5-H of thienyl), 13.89 (s, 1H, NH). MS
(70 eV) m/z = 270 (M+). Anal. for C11H5F3N2OS: C, 48.89; H, 1.86.; N, 10.37; S, 11.87%.
Found: C, 49.00; H, 1.95.; N, 10.35; S, 11.85%.
4.2. Synthesis of 4a and b, 5a and b, 6a and b, and 7a and b
Method A.A mixture of 3a and b (3 mmol), methyl iodide, chloroacetonitrile, ethyl bromoacetate,
chloroacetone(3 mmol), andKOH(4 mmol)wasthoroughlygroundwithapestleinanopenmortar
at 25 ◦C for 3–5 min until the mixture turned into a melt. The initial syrupy reaction mixture
solidified within 4–6 min. Grinding continued for 5–15 min and the reaction was monitored by
TLC. The solid was washed with water and recrystallized from the proper solvent to give 4a and
b,5a and b,6a and b, and 7a and b, respectively.
Method B. A mixture of 3a andb (2.86, 2.70, 10 mmol) and potassium hydroxide (0.62,
11 mmol) in N,N-dimethylformamide (10 ml) was stirred for 2 h at room temperature. Methyl
iodide, chloroacetonitrile, ethyl bromoacetate, and chloroacetone (10 mmol each) were then added
and stirring was continued for 2 h to give a solid that was collected and recrystallized from the
proper solvent to give 4a and b, 5a and b, 6a and b, and 7a,b respectively.

Journal of Sulfur Chemistry 617
4.2.1. 4-(Trifluoromethyl)-2-(methylthio)-6-(thiophen-2-yl)pyridine-3-carbonitrile (4a)
1
Light brown crystals from ethanol, m.p. 142–145 ◦C; IR (KBr, cm−1) υ 2218 (CN). H NMR
(DMSO-d6): δ = 7.24 (dd, 1H, 4-H of thienyl), 7.26 (s, 1H, 5-H of pyridinyl), 7.58 (d, 1H, 3-H
of thienyl), 7.76 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 300 (M+). Anal. for C12H7F3N2S2:
C, 47.99; H, 2.35; N, 9.33; S, 21.35%. Found: C, 48.00; H, 2.25; N, 9.20; S, 20.99%.
4.2.2. 4-(Trifluoromethyl)-2-(methxoy)-6-(thiophen-2-yl)pyridine-3-carbonitrile (4b)
Yellow crystals from ethanol; m.p. 108–110 ◦C; IR (KBr, cm−1) υ 2223 (CN). 1H NMR (DMSO-
d6): δ = 4.18 (s, 3H, CH3), 7.27 (dd, 1H, 4-H of thienyl), 7.50 (s, 1H, 5-H of pyridinyl), 7.60
(d, 1H, 3-H of thienyl), 7.79 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 284 (M+). Anal. for
C12H7F3N2OS: C, 50.70; H, 2.48; N, 9.85; S, 11.28%. Found: C, 50.90; H, 2.45; N, 10.00;
S, 11.12%.
4.2.3. 2-(Cyanomethylthio)-4-(trifluoromethyl)-6-(thiophen-2-yl)pyridine-3-carbonitrile (5a)
1
Pale yellow crystals from DMF, m.p. 235 ◦C; IR (KBr, cm−1) υ 2223, 2251 (2 CN). H NMR
(DMSO-d6): δ = 4.45 (s, 2H, CH2), 7.31 (dd, 1H, 4-H of thienyl), 8.01 (d, 1H, 3-H of thienyl),
8.29 (s, 1H, 5-H of pyridinyl), 8.34 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 325 (M+). Anal.
for C13H6F3N3S2: C, 47.99; H, 1.86; N, 12.92; S, 19.71%. Found: C, 48.10; H, 1.80; N, 13.00;
S, 19.99%.
4.2.4. 2-(Cyanomethoxy)-4-(trifluoromethyl)-6-(thiophen-2-yl)pyridine-3-carbonitrile (5b)
Yellow crystals from ethanol; m.p. 188–190 ◦C; IR (KBr, cm−1) υ 2227, 2268 (2 CN). 1H NMR
(DMSO-d6): δ = 5.20 (s, 2H, CH2), 7.21 (dd, 1H, 4-H of thienyl), 7.27 (s, 1H, 5-H of pyridinyl),
7.67 (d, 1H, 3-H of thienyl), 7.86 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 309 (M+). Anal.
for C13H6F3N3OS: C, 50.49; H, 1.96; N, 13.59; S, 10.37. Found: C, 50.10; H, 1.90; N, 13.50;
S, 10.35%.
4.2.5. Ethyl 2- (3-cyano-4-(trifluoromethyl)-6-(thiophen-2-yl)(pyridine-2-ylthio) acetate (6a)
Yellow crystals from acetic acid; m. p. 148–150 ◦C; IR (KBr, cm−1) υ 2218 (CN), υ 1733 (CO
ester). 1H NMR (DMSO-d6): δ = 1.30 (t, 3H, CH3, J = 7 Hz), 4.01 (s, 2H, CH2), 4.27 (q, 2H,
CH2CH3, J = 7 Hz), 7.26 (dd, 1H, 4-H of thienyl), 7.35 (s, 1H, 5-H of pyridinyl), 7.58 (d, 1H, 3-H
of thienyl), 7.79 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 372 (M+).Anal. for C15H11F3N2O2S2:
C, 48.38; H, 2.98; N, 7.52; S, 17.22%. Found: C, 48.00; H, 2.95, N, 7.50; S, 17.00%.
4.2.6. Ethyl 2-(3-cyano-4-(trifluoromethyl)-6-(thiophen-2-yl)pyridine-2-yloxy) acetate (6b)
Yellow crystal from ethanol; m.p. 227–230 ◦C; IR (KBr, cm−1) υ 2226 (CN), υ 1756 (CO ester).
1H NMR (DMSO-d6): δ = 1.23 (t, 3H, CH3, J = 7 Hz), 4.22 (q, 2H, CH2CH3, J = 7 Hz), 5.14
(s, 2H, CH2) 7.28 (dd, 1H, 4-H of thienyl), 7.95 (s, 1H, 5-H of pyridinyl) 8.19 (d, 1H, 3-H of
thienyl), 8.26 (d, 1H, 5-H of thienyl). MS (70 eV) m/z = 356 (M+). Anal. for C15H11F3N2O3S:
C, 50.56; H, 3.11; N, 7.86; S, 9.00%. Found: C, 50.45; H, 3.00; N, 7.76; S, 9.00%.

618 N.M. Rateb
4.2.7. 2-(2-Oxopropylthio)-4-(trifluoromethyl)-6-(thiophen-2-yl)pyridine-3-carbonitrile (7a)
Brown crystals from ethanol/DMF; m.p. 176–181 ◦C; IR (KBr, cm−1) υ 2221 (CN), υ 1717 (CO).
1H NMR (DMSO-d6): δ = 2.41 (s, 3H, CH3), 4.15 (s, 2H, CH2), 7.21 (dd, 1H, 4-H of thienyl),
7.27 (s, 1H, 5-H of pyridinyl) 7.60 (d, 1H, 3-H of thienyl), 7.75 (d, 1H, 5-H of thienyl). MS
(70 eV) m/z = 342 (M+). Anal. for C14H9F3N2OS2: C, 49.12; H, 2.65; N, 8.18; S, 18.73. Found:
C, 49.00; H, 2.45; N, 8.00; S, 18.55%.
4.2.8. 2-(2-Oxopropoxy)-4-(trifluoromethyl)-6-(thiophen-2-yl)pyridine-3-carbonitrile (7b)
Yellow crystals from ethanol, m.p. 143–145 ◦C; IR (KBr, cm−1) υ 2226 (CN), υ 1669 (CO). 1H
NMR (DMSO-d6): δ = 2.32 (s, 3H, CH3), 5.08 (s, 2H, CH2), 7.21 (dd, 1H, 4-H of thienyl), 7.27
(s, 1H, 5-H of pyridinyl), 7.60 (d, 1H, 3-H of thienyl), 7.75 (d, 1H, 5-H of thienyl). MS (70 eV)
m/z = 326 (M+). Anal. for C14H9F3N2O2S: C, 51.53; H, 2.78; N, 8.59; S, 9.83%. Found: C,
51.25; H, 2.58; N, 8.35; S, 9.75%.
4.3. Synthesis of 8–10
Generalprocedure. Compounds5a (3.25g, 10 mmol), 6a (3.7 g, 10 mmol)and 7a (3.4 g, 10 mmol)
were refluxed in sodium ethoxide solution (0.23 g, 10 ml) for 3 h. The so-formed solid was
collected by filtration and recrystallized from the proper solvent to give 8, 9, and 10, respectively.
4.3.1. 3-Amino-4-(trifluoromethyl)-6-(thiophen-2-yl)thieno[2,3-b]pyridine-2-carbonitrile (8)
Orange crystals from ethanol (84%), m.p. 253–255 ◦C; IR (KBr, cm−1) υ 3460, υ 3313 (NH2)
υ 2206 (CN). 1H NMR (DMSO-d6): δ = 6.67 (b, 2H, NH2), 7.47 (dd, 1H, 4-H of thienyl), 7.82
(s, 1H, 5-H of pyridinyl), 8.18 (d, 1H, 3-H of thienyl), 8.26 (d, 1H, 5-H of thienyl). MS (70 eV)
m/z = 325 (M+). Anal. for C13H6F3N3S2: C, 47.99; H, 1.86; N, 12.92; S, 19.71%. Found: C,
48.00; H, 1.90; N, 13.00; S, 19.50% (literature 237 ◦C (29)).
4.3.2. Ethyl 3-amino-4-(trifluoromethyl)-6-(thiophen-2-yl)thieno[2,3-b]pyridine-2-
carboxylate (9)
Yellow crystals from ethanol/DMF (86%), m.p. 175–179 ◦C; IR (KBr, cm−1) υ 3479, 3371 (NH2),
1
υ 1685 (CO). H NMR (DMSO-d6): δ = 1.47 (t, 3H, CH3, J = 7 Hz), 4.44 (q, 2H, CH2CH3,
J = 7 Hz), 6.35 (b, 2H, NH2), 7.21 (dd, 1H, 4-H of thienyl), 7.53 (s, 1H, 5-H of pyridinyl), 7.56
(d, 1H, 3-H of thienyl), 7.90 (d, 1H, 5-H of thienyl). 13C NMR: δ = 14.1 (CH3), 60.9 (CH2),
118.8 (CH), 122.0 (C), 125.3 (CH), 125.5 (CH), 125.6 (CH), 125.9 (CH), 128 (C), 134 (C), 140.0
+
=
(C), 147.7 (C), 152.4 (C), 156.0 (C), 160.6 (C O ester). MS (70 eV) m/z = 372 (M ). Anal. for
7.50% (literature 182 ◦C (29)).
C15H11F3N2O2S2: C, 48.38; H, 2.98; N, 7.52; S, 17.22%. Found: C, 48.38; H, 2.88; N, 7.50; S,
4.3.3. 1-(3-Amino-4-(trifluoromethyl)-6-(thiophen-yl)thieno[2,3-b]pyridine-2-yl)
ethanone (10)
Orange crystals form ethanol (80%), m.p. 165–167 ◦C; IR (KBr, cm−1) υ 3527, 3307 (NH2), υ
1
1718 (CO). H NMR (DMSO-d6): δ = 2.52 (s, 3H, CH3), 7.27 (s, 1H, 5-H of pyridinyl) 7.55
(d, 1H, 3-H of thienyl), 7.78 (b, 2H, NH2), 7.87 (dd, 1H, 4-H of thienyl), 7.90 (d, 1H, 5-H of
thienyl). 13C NMR: δ = 27.8 (CH3), 122.0 (C), 125.3 (CH), 125.5 (CH), 125.6 (CH), 125.9 (CH),

Journal of Sulfur Chemistry 619
=
128 (C), 133 (C), 140.0 (C), 146 (C) 147.7 (C), 152.4 (C), 156.8 (C), 190.5 (C O). MS (70 eV)
m/z = 342 (M+). Anal. for C14H9F3N2OS2: C, 48.38; H, 2.98; N, 8.18; S, 18.73%. Found: C,
48.38; H, 2.88; N, 8.00; S, 18.74%.
4.4. Synthesis of 11
To a stirred mixture of 4a (1.5 g, 5 mmol) in glacial acetic acid (10 ml) was added 30% H2O2
solution (15 ml) and the mixture was heated under reflux for 3 h. After cooling, the solid that
formed was collected and recrystallized from ethanol to give 11.
4.4.1. 4-(Trifluoromethyl)-2-(methylsulfonyl)-6-(thiophen-2-yl)pyridine-3-carbonitrile (11)
1
Green crystals from ethanol (65%), m.p. 208–210 ◦C; IR (KBr, cm−1) υ 2219 (CN). H NMR
(DMSO-d6): δ = 3.40 (s, 3H, CH3), 7.01 (dd, 1H, 4-H of thienyl), 7.20 (d, 1H, 5-H of thienyl),
7.55 (d, 1H, 3-H of thienyl), 8.00 (s, 1H, 5-H of pyridinyl). MS (70 eV) m/z = 332 (M+). Anal.
for C12H7F3N2O2S2: C, 43.37; H, 2.12; N, 8.43; S, 19.30%. Found: C, 43.43; H, 2.01; N, 8.50;
S, 19.72%.
4.5. Synthesis of 12
Method A. A mixture of 4a (1.5 g, 5 mmol) and excess of hydrazine hydrate was refluxed for 6h.
The reaction mixture was cooled, and the solid that formed was filtered, dried, and recrystallized
from ethanol to give 12.
Method B. A mixture of 11 (1 g, 3 mmol) and excess of hydrazine hydrate was refluxed for 3h.
The reaction mixture was cooled, and the solid that formed was filtered, dried, and recrystallized
from ethanol to give 12.
4.5.1. 4-(Trifluoromethyl)-6-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine (12)
Yellow crystals from ethanol (90%), m.p. 229–230 ◦C; IR (KBr, cm−1) υ 3450, υ 3330, υ 3225
(NH2, NH). 1H NMR (DMSO-d6): δ = 7.55 (d, 1H, 3-H of thienyl), 7.60 (s, 1H, 5-H of pyridinyl),
7.78 (b, 2H, NH2), 7.87 (dd, 1H, 4-H of thienyl), 7.90 (d, 1H, 5-H of thienyl), 13.7 (s, 1H, NH).
MS (70 eV) m/z = 284 (M+). Anal. for C11H7F3N4S: C, 46.48; H, 2.48; N, 19.71; S, 11.28%.
Found: C, 46.43; H, 2.50; N, 19.70; S, 11.30%.
4.6. Synthesis of 13
Method A. A mixture of 8 (1.8 g, 5 mmol) and formic acid (20 ml) was heated under reflux for
7 h. After cooling, the reaction mixture was poured on ice and the solid that formed was collected
and recrystallized from DMF to give 13.
Method B. Compound 9 (2 g, 5 mmol) was heated under reflux with formamide (20 ml) for 2 h.
After cooling, the reaction mixture was poured on ice and the solid that formed was collected and
recrystallized from DMF to give 13.

620 N.M. Rateb
4.6.1. 7-Thiophen-2-yl-9-trifluoromethyl-3H-pyrido[3ꢀ ,2ꢀ :4,5]thieno[3,2-d]pyrimidin-
4-one (13)
Dark brown crystals from DMF (75%), m.p. >300 ◦C; IR (KBr, cm−1) υ 3450 (NH), υ 1668
1
(CO). H NMR (DMSO-d6): δ = 7.24–7.64 (m, 4H, Ar-H), 7.50 (s, 1H, 2-H of pyrimidinyl),
7.55 (d, 1H, 3-H of thienyl), 7.60 (s, 1H, 5-H of pyridinyl), 7.87 (dd, 1H, 4-H of thienyl), 7.90 (d,
1H, 5-H of thienyl). MS (70 eV) m/z = 353 (M+). Anal. for C14H6F3N3OS2: C, 47.59; H, 1.71;
N, 11.89; S, 18.15%. Found: C, 47.50; H, 1.90; N, 12.00; S, 18.35%.
4.7. Synthesis of 14
Compound 13 (1.1 g, 3 mmol) reacted with POCl3 (20 ml) under reflux for 1 h. The reaction
mixture was poured over ice, and the resulting solid was collected by filtration and recrystallization
from DMF to give 14.
4.7.1. 4-Chloro-7-thiophen-2-yl-9-trifluoromethyl-pyrido[3ꢀ, 2ꢀ:4,5]thieno[3,2-d]
pyrimidine (14)
Dark brown crystals from DMF (75%), m.p. >300 ◦C; 1H NMR (DMSO-d6): δ = 7.55 (d, 1H, 3-H
ofthienyl), 7.60(s, 1H, 5-Hofpyridinyl), 7.87(dd, 1H, 4-Hofthienyl), 7.90(d, 1H, 5-Hofthienyl),
9.46 (s, 1H, 2-H of pyrimidinyl). MS (70 eV) m/z = 371 (M+). Anal. for C14H5ClF3N3S2: C,
45.23; H, 1.36; N, 11.30; S, 17.25%. Found: C, 45.50; H, 1.46; N, 11.00; S, 17.30%.
4.8. Synthesis of 15
A mixture of 9 (4.0 g, 10 mmol) and hydrazine hydrate (4 ml, 85% solution, 4 mmol) in absolute
ethanol(20 ml)for24 hwasheatedunderreflux.Thereactionmixturewascooled, andtheresulting
solid was collected and recrystallized from ethanol to give 15.
4.8.1. 3-Amino-6-thiophen-2-yl-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid
hydrazide (15)
Yellow crystals from ethanol/DMF (65%), 294–297 ◦C; IR (KBr, cm−1) υ 3346, υ 3319 (NH2,
NH), υ 1650, (CO). MS (70 eV) m/z = 358 (M+). Anal. Calcd for C13H9F3N4OS2: C, 43.57; H,
2.53, N, 15.63; S, 17.89%. Found: C, 43.50; H, 2.50; N, 15.50; S, 17.90%.
4.9. Synthesis of 16
A mixture of 9 (4.0 g, 10 mmol) and acetic anhydride (10 ml) in was heated under reflux for 5 h.
The reaction mixture was cooled, and the resulting solid was collected and recrystallized from
acetic acid to give 16.
4.9.1. 2-Methyl-7-thiophen-2-yl-9-trifluoromethylpyrido[3ꢀ, 2ꢀ
:4,5]thieno[3,2-d][1,3]oxazin-4-one (16)
1
Yellow crystals from acetic acid (80%), m.p. 255 ◦C; IR (KBr, cm−1) υ 1743 (CO). H NMR
(DMSO-d6): δ = 2.59 (s, 3H, CH3), 7.27 (dd, 1H, 4-H of thienyl), 7.85 (d, 1H, 3-H of thienyl),
7.87 (d, 1H, 5-H of thienyl), 8.06 (s, 1H, 5-H of pyridinyl). MS (70 eV) m/z = 368 (M+). Anal.

Journal of Sulfur Chemistry 621
for C15H7F3N2O2S2: C, 48.91; H, 1.92; N, 7.60; S, 17.41%. Found: C, 48.98; H, 1.88; N, 7.70;
S, 17.50%.
4.10. Synthesis of 17
A mixture of 9 (4.0 g, 10 mmol) and the phenyl isothiocyanate (1.35 g, 10 mmol) in acetoni-
trile (30 ml) was heated under reflux for 15 h in the presence of anhydrous potassium carbonate
(1.4 g). The reaction mixture was cooled, filtered, dilute with water (10 ml), and neutralized with
hydrochloric acid (2M). The resulting solid was collected, washed with water, and recrystallized
from ethanol to give 17.
4.10.1. 3-Phenyl-7-thiophen-2-yl-2-thioxo-9-trifluoromethyl-2,3-dihydro-1H-pyrido[3ꢀ, 2ꢀ
:4,5]thieno[3,2-d]pyrimidine (17)
Yellow crystals from ethanol (75%), m.p. 183–185 ◦C; IR (KBr, cm−1) υ 3337 (NH), υ 1674
1
(CO). H NMR (DMSO-d6): δ = 7.24–7.64 (m, 4H, Ar-H), 7.55 (d, 1H, 3-H of thienyl), 7.60
(s, 1H, 5-H of pyridinyl), 7.87 (dd, 1H, 4-H of thienyl), 7.90 (d, 1H, 5-H of thienyl). 13C NMR:
δ = 121.6 (2 CH), 124.4 (CH), 125.3 (CH), 125.5 (CH), 125.6 (CH), 125.9 (CH), 129 (2 CH), 129
(2 C), 132.8 (C), 133.4 (C), 140.0 (C), 147.7 (C), 152.4 (C), 156.8 (C), 165.2 (C9O amide), 177.0
(C9S). MS (70 eV) m/z = 461 (M+). Anal. for C20H10F3N3OS3: C, 52.05; H, 2.18; N, 9.10; S,
20.84% Found: C, 52.12; H, 2.20; N, 8.99; S, 20.50%.
References
(1) (a) Rateb, N.M.; Zohdi, H.F. Synth. Commun. 2009, 39, 2784–2789. (b) Nadia, H.; Metwally, N.H.; Rateb, N.M.;
Zohdi, H.F. Green Chem. Lett. Rev. 2011, 4, 225–228.
(2) Rong, L.; Li, X.; Wang, H.; Shi, D.; Tu, Sh.; Zhuang, Q. Synth. Commun. 2006, 36, 2407–2412.
(3) Tannaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074.
(4) Villemin, D.; Martin, B. Synth. Commun. 1995, 25, 3135–3136.
(5) Lonpy, A.; Song, S.J.; Sohn, S.M.; Lee, Y.M.; Kwon, T.W. J. Chem. Soc., Perkin Trans 1 2001, 1220–1222.
(6) Kislyi, V.P.; Nikishin, K.G.; Kruglova, E.Ya.; Shestopalov, A.M.; Semenov, V.V.; Gakh, A.A.; Buchanan, A.C.
Tetrahedron 1996, 52, 10841–10848.
(7) Litvinov, V.P.; Rodinovskaya, L.A.; Sharanin, Yu.A.; Shestopalov, A.M.; Senning, A. Sulfur Rep. 1992, 13, 1–155.
(8) Shestopalov, A.M.; Promomenkov, V.K.; Sharanin,Yu.A.; Rodinovskaya, L.A.; Sharnin, S.Yu. Zh. Org. Khim. 1984,
20, 1571–1586.
(9) Litvinov, V.P.; Promomenkov, V.K.; Sharanin, Yu.A.; Shestopalov, A.M. In Organicheskaya Khimiya; Kabachnic,
M.I., Ed.; VINITI: Moscow, 1989; Vol. 17, 72–156 and references therein.
(10) Bekhit, A.A.; Baraka, A.M. Eur J Med Chem. 2005, 40, 1405–1413.
(11) Krauze, A.; Vitolina, R.; Garaliene, V.; Stile, L.; Klusa, V.; Dubrus, G. Eur J Med Chem. 2005, 40, 1163–1167.
(12) Attaby, F.A.; Ali, M.A.; Elghandour, A.H.H.; Ibrahem, Y.M. Phosphorus Sulfur Silicon 2006, 181, 1–14.
(13) Krause, A.; Germane, S.; Eberlins, O.; Sturms, I.; Klusa, V.; Dubrus, G. Eur J Med Chem. 1999, 34, 301–310.
(14) Rosentreter, U.; Henning, R.; Bauser, M.; Kraemer, T.; Vaupel, A.; Huebsch, W.; Dembowsky, K.; Schraufstaetter,
O.S.; Stasch, P.J.; Krahn, T.; Perzbon, E. PCT Int. Appl. WO 01 25, 210, 1999; Chem. Abstracts 2001, 134, 295744e.
(15) Rosentreter, U.; Kraemer, T.; Vaupel, A.; Huebsch, W.; Diedrichs, N.; Krahn, T.; Dembowsky, K.; Stasch, P.J. PCT
Int. Appl. WO 02, 70, 485, 2002; Chem. Abstracts 2002, 137, 216880g.
(16) Rosentreter, U.; Kraemer, T.; Vaupel, A.; Huebsch, W.; Diedrichs, N.; Krahn, T.; Dembowsky, K.; Stasch, P.J.;
Shimida, M. PCT Int. Appl. WO 02, 79, 195, 2002; CA 2002, 137, 279099e.
(17) Attaby, F.A.; Abdel-Fattah, A.M. Phosphorus Sulfur Silicon 1999, 155, 253–270.
(18) Shraideh, Z.; Salla, A.K. Biomed. Lett. 1997, 54, 233–238.
(19) Bompart, J.; Giral, I.; Malicone, G.; Puyarenier, M. Eur. J. Med. Chem. 1987, 22, 139–145.
(20) Abdel-Rahman, A.E.; Bakhite, E.A.; Al-Taifi, E.A. J. Chin. Chem. Soc. 2002, 49, 223–231.
(21) Eldin, S.M. Z. Naturforsch. 1999, 54b, 674–680.
(22) Moloney, G.P. Molecules 2001, 6, M203.
(23) Quintela, J.M.; Peinador, C.; Veiga, C.; Gonzales, L.; Botana, L. M.; Alfonso, A.; Riguera, R. Bioorg. Med. Chem.
1998, 6, 1911–1925.
(24) Quintela, J.M.; Peinador, C.; Gonzales, L.; Iglesias, R.; Parama, A.; Alvares, F.; Sanmartin, M.L.; Riguera, R. Eur.
J. Med. Chem. 2003, 38, 365–370.

622 N.M. Rateb
(25) Wagner, G.; Leistner, S.; Vieweg, H.; Krasselt, U.; Prantz, J. Pharmazie 1993, 48, 342–346.
(26) Boehm, N.; Krasselt, U.; Leistner, S.; Wagner, G. Pharmazie 1992, 47, 897–901.
(27) Hussin, A.M.; Abu-Shanab, F.A.; Ishak, E.A. Phosphorus Sulfur Silicon 2000, 159, 55–68.
(28) Rateb, N.M. Phosphorus Sulfur Silicon 2007, 182, 2393–2407.
(29) Ho, Y.W.; Yao, W.H. Dyes and Pigments 2006, 70, 60–69.
(30) Shestopalov, A.M.; Litvinov, V.P.; Rodinovskaya, L.A.; Sharanin, Yu.A. Synthesis 1991, 5, 402–404.
(31) Shestopalov,A.M.; Bogomolova, O.P.; Rodinovskaya, L.A.; Litvinov,V.P.; Bujnicki, B.; Mikolajchyk, M.; Nesterov,
V.N.; Struchkov, Yu.T. Heteroat. Chem. 1993, 4, 593–602.
(32) Rodinovskaya, L.A.; Shestopalov, A.M.; Gromova, A.V.; Shestopalov, A.A. J. Comb. Chem. 2008, 10 (2), 313–322.
(33) Salem, M.A.; Thabet, H.K.; Ismail, M.A.; Ammar, Y.A., Chem. Sci. J. 2011, 36, 1–11.