Chemoselective route for synthesis of N-aryl-3-oxochromeno[2,3-c]pyrazole- 2(3H)-carbothioamide derivatives

Article abstract of DOI:10.1002/hlca.201300388

A chemoselective route for the synthesis of chromeno[2,3-c]pyrazole-2(3H)- carbothioamide derivatives by a five-component reaction of salicylaldehyde, malononitrile, NH₂NH₂·H₂O, aryl isothiocyanate, and H₂O in EtOH/AcOH mixture is reported. This new protocol has the advantages of high yields, short reaction times, ease of operation, and simple purification. All structures were confirmed by IR, ¹H- and ¹³C-NMR, and MS analyses. A plausible mechanism for this type of reaction is proposed (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201300388

Helvetica Chimica Acta – Vol. 97 (2014)
895
Chemoselective Route for Synthesis of N-Aryl-3-oxochromeno[2,3-c]-
pyrazole-2(3H)-carbothioamide Derivatives
by Abdolali Alizadeh* and Rashid Ghanbaripour
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: aalizadeh@modares.ac.ir,
abdol_alizad@yahoo.com)
A chemoselective route for the synthesis of chromeno[2,3-c]pyrazole-2(3H)-carbothioamide
derivatives by a five-component reaction of salicylaldehyde, malononitrile, NH2NH2 · H2O, aryl
isothiocyanate, and H2O in EtOH/AcOH mixture is reported. This new protocol has the advantages
of high yields, short reaction times, ease of operation, and simple purification. All structures were
confirmed by IR, 1H- and 13C-NMR, and MS analyses. A plausible mechanism for this type of reaction is
proposed (Scheme 2).
Introduction. – The development of new approaches for the efficient construction
of specific heterocycles continues to be essential to access to natural products and their
structural analogs. According to the report of Volmajer and co-workers [1], and in the
course of our research program on design of new routes for synthesis of new heterocylic
compounds [2 – 5], herein, we report the synthesis of chromeno[2,3-c]pyrazole-2(3H)-
carbothioamides via five-component reactions.
Results and Discussion. – Our new synthetic route is outlined in Scheme 1. First, to
achieve suitable conditions for the synthesis of 3-oxo-N-phenylchromeno[2,3-c]pyr-
azole-2(3H)-carbothioamide (3a), the reaction of salicylaldehyde, malononitrile,
NH2NH2 · H2O, and phenyl isothiocyanate has been selected as a model.
Different solvents and amounts of NH4OAc for the model reaction were explored.
As compiled in Table 1, the best results were obtained on reflux in EtOH/AcOH 1:1 in
the presence of 1 equiv. NH4OAc to yield product 3a in good yield (Table 1, Entry 8).
Further experiments were carried out by using more than 1 mmol of NH4OAc to
compare the catalytic activities under similar conditions. The results were the same
(Table 1, Entries 9 and 10). To explore the generality of the reaction, we extended our
study to different salicylaldehydes and aryl isothiocyanates. The results are collected in
Table 2.
Scheme 1. Synthesis of Chromeno[2,3-c]pyrazole-2(3H)-carbothioamide Derivatives 3
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Table 1. Optimization of the Reaction Conditions for the Formation of 3a
Entry
Solvent
Catalyst (mmol)
Yield [%]
1
2
MeCN
EtOH
–
–
–
–
3
4
5
6
7
8
9
10
EtOH/AcOH 1 : 1
EtOH
EtOH/AcOH 1 : 1
MeCN
EtOH/AcOH 1 : 1
EtOH/AcOH 1 : 1
EtOH/AcOH 1 : 1
EtOH/AcOH 1 : 1
–
–
–
NH4OAc (0.5)
NH4OAc (0.5)
NH4OAc (0.5)
NH4OAc (0.75)
NH4OAc (1)
NH4OAc (1.25)
NH4OAc (1.5)
40
–
55
89
89
89
Table 2. Prepared N-Aryl-3-oxochromeno[2,3-c]pyrazole-2(3H)-carbothioamides 3
Compound
R
Ar
Yield [%]
3a
3b
3c
3d
3e
3f
3g
H
Br
Br
NO2
H
Ph
Ph
89
83
92
79
87
75
80
4-FꢀC6H4
Ph
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
Br
MeO
The structures of compounds 3a – 3g were deduced from their elemental analysis,
1
IR, and high-field H- and 13C-NMR spectra. The mass spectrum of 3a displayed the
molecular-ion peak at m/z 321, which is in agreement with the proposed structure. The
IR spectrum of 3a showed absorption bands due to the NH stretching frequency at
3339 cmꢀ1, and absorption bands at 1724, 1607, and 1566 cmꢀ1 were assigned to the CO
1
and C¼C groups. The H-NMR spectrum of 3a showed four triplets (d(H) 7.02 (J ¼
8.6), 7.36 (J ¼ 8.6), 7.43 (J ¼ 8.6), and 7.69 (J ¼ 8.6)), three doublets (d(H) 7.50 (J ¼
8.6), 7.64 (J ¼ 8.6), and 7.97 (J ¼ 8.6)) for aromatic H-atoms, and also two singlets
(8.96 and 10.52) for CH of the chromene ring and NH, respectively. The 1H-decoupled
13C-NMR spectrum of 3a exhibited 15 distinct resonances in agreement with the
suggested structure. Although we have not established the mechanism of the reaction
experimentally, a proposal is presented in Scheme 2.
It is conceivable that initially the salicylaldehyde 1 undergoes an NH4OAc
promoted Knoevenagel condensation and cyclization with malononitrile to give
iminochromene-carbonitrile 4, which has two electrophilic sites, namely a conjugated
C¼C bond (as a Michael acceptor) and an imino function. Next, arylthiosemicarbazide
5 is formed by addition of NH2NH2 · H2O to phenyl isothiocyanate 2. At this stage,
considering the previous reports, we would normally expect 5 to undergo Michael-type
addition via attack at the C¼C bond to give the desired product 6 (Path A) or
condensation with the imino group to give intermediate 7 (Path B). However, on the
1
basis of IR, and H- and 13C-NMR spectra, product 6 was not formed, but another
remarkable reaction took place. In fact, at this stage, the chemoselective condensation

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897
Scheme 2. Proposed Mechanism for the Formation of the Products 3a – 3g
of the NH2 group of 5 with the C¼NH bond leads to intermediate 7. Then, N-cyclization
provides intermediate 8. Finally, hydrolysis of 8 gives the title compounds 3 (Path B).
To confirm this proposal, the intermediates 4 [1] and 5 were synthesized separately. The
reaction of these intermediates in the presence of NH4OAc led to compounds 3. In
another attempt, when we reacted compound 4 and 5 in the absence of NH4OAc, no
product 3 was observed. So, there is a clear evidence that NH4OAc is also necessary at
this stage of the reaction sequence.
In summary, we have disclosed a concise approach to the synthesis of new
chromenopyrazole derivatives by one-pot reaction between salicylaldehyde, malono-
nitrile, NH2NH2 · H2O, arylisothiocyanate, and H2O. These types of heterocycles
contain a number of functional groups that may lead to biological activity. Excellent
yields of the products, fairly short reaction times, simple purifications, and the use of
simple and inexpensive starting materials characterize this method. The simplicity of
the present procedure renders it an interesting alternative to complex multistep
approaches.
Experimental Part
General. All starting materials were obtained from Merck (Germany) and Fluka (Switzerland) and
were used without further purification. M.p.: Electrothermal 9100 apparatus. IR Spectra: in KBr on a
Shimadzu IR-460 spectrometer. 1H- and 13C-NMR spectra: at 400 and 100 MHz, resp., on a Bruker DRX
400-AVANCE FT-NMR instrument, in CDCl3 if not otherwise stated. MS: Finnigan-MAT 8430 mass

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spectrometer, at an ionization potential of 70 eV. Elemental analyses for C, H, and N: Heraeus
CHNꢀOꢀRapid analyzer.
General Procedure (exemplified for 3a). A soln. of phenyl isothiocyanate (0.135 g, 1 mmol) and
NH2NH2 · H2O (80%; 0.040 g, 1 mmol) in EtOH (3 ml) was magnetically stirred for 1 h at r.t. Then,
malononitrile (0.066 g, 1 mmol), salicylaldehyde (0.122 g, 1 mmol), NH4OAc (0.077 g, 1 mmol), and
AcOH (3 ml) were added, and the mixture was stirred at reflux for 2 h. After completion, the hot mixture
was filtered, and the precipitate was washed with EtOH to afford the pure product 3a.
3-Oxo-N-phenylchromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3a). Yield: 268 mg (89%). Yel-
low powder. M.p. > 3008 (dec.). IR: 3339 (NH), 1724 (C¼O), 1607, 1566, 1498 (Ar), 1427 (C¼S), 1211
(CꢀO). 1H-NMR: 7.02 (t, J ¼ 7.3, Hp of Ph); 7.36 (t, J ¼ 7.4, 2 Hm of Ph); 7.43 (t, J ¼ 7.4, HꢀC(6)); 7.50 (d,
J ¼ 8.2, HꢀC(8)); 7.63 (d, J ¼ 6.1, 2 Ho of Ph); 7.69 (t, J ¼ 7.5, HꢀC(7)); 7.97 (d, J ¼ 7.4, HꢀC(5)); 8.96 (s,
HꢀC(4)); 10.52 (s, NH). 13C-NMR: 115.9; 117.6; 117.9; 118.8; 122.1; 125.2; 129.1; 129.6; 132.9; 138.8;
140.5; 149.3; 153.0; 159.4; 166.7. EI-MS (70 eV): 321 (90, Mþ), 320 (23), 236 (16), 150 (83), 123 (26), 114
(32), 97 (49), 83 (56), 69 (75), 57 (100). Anal. calc. for C17H11N3O2S (321.35): C 63.54, H 3.45, N 13.08;
found: C 63.61, H 3.50, N 13.10.
6-Bromo-3-oxo-N-phenylchromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3b). Yield: 332 mg
(83%). Orange powder. M.p. > 3008 (dec.). IR: 3323 (NH), 1706 (C¼O), 1602, 1547, 1488 (Ar), 1442
1
(C¼S), 1210 (CꢀO). H-NMR: 7.00 (t, J ¼ 7.3, Hp of Ph); 7.34 (t, J ¼ 7.4, 2 Hm of Ph); 7.44 (d, J ¼ 6.6,
HꢀC(8)); 7.60 (d, J ¼ 6.1, 2 Ho of Ph); 7.79 (d, J ¼ 8.4, HꢀC(7)); 8.21 (s, HꢀC(5)); 8.88 (s, HꢀC(4)); 10.55
(s, NH). 13C-NMR: 117.2; 118.1; 119.0; 119.5; 121.3; 122.6; 129.7; 131.9; 135.5; 137.7; 140.9; 149.5; 152.5;
159.5; 167.3. EI-MS (70 eV): 401 (10, [M þ 2]þ), 399 (10, Mþ), 368 (49), 268 (100), 251 (27), 236 (30), 150
(40), 135 (36), 93 (50). Anal. calc. for C17H10BrN3O2S (400.25): C 51.02, H 2.52, N 10.50; found: C 51.10,
H 2.59, N 10.40.
6-Bromo-N-(4-fluorophenyl)-3-oxochromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3c). Yield:
385 mg (92%). Orange powder. M.p. > 3008 (dec.). IR: 3338 (NH), 1706 (C¼O), 1555, 1508 (Ar),
1435 (C¼S), 1223 (CꢀO). 1H-NMR: 7.19 – 7.22 (m, 2 arom. H); 7.47 (d, J ¼ 8.8, HꢀC(8)); 7.63 – 7.67 (m,
2 arom. H); 7.82 (dd, J ¼ 8.8, 2.3, HꢀC(7)); 8.24 (d, J ¼ 2.3, HꢀC(5)); 8.91 (s, HꢀC(4)); 10.53 (s, NH).
2
13C-NMR: 115.7 (d, J ¼ 22.3); 116.8; 118.5; 119.0; 119.4 (d, J(C,F) ¼ 109.8); 120.8; 131.5; 135.1; 136.9;
137.3; 149.1; 152.1; 157.4 (d, 1J(C,F) ¼ 239.2); 159.0; 167.0. EI-MS (70 eV): 368 (31), 304 (100), 251 (75),
223 (36), 194 (27), 152 (47), 111 (96), 83 (53), 57 (43). Anal. calc. for C17H9BrFN3O2S (418.24): C 48.82,
H 2.17, N, 10.05; found: C 48.65, H 2.29, N 10.14.
6-Nitro-3-oxo-N-phenylchromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3d). Yield: 289 mg
(79%). Orange powder. M.p. > 3008 (dec.). IR: 3210 (NH), 1718 (C¼O), 1610, 1493 (Ar), 1537, 1344
(NO2), 1449 (C¼S), 1195 (CꢀO). 1H-NMR: 7.04 (t, J ¼ 7.2, Hp of Ph); 7.38 (t, J ¼ 7.6, 2 Hm of Ph); 7.65 (d,
J ¼ 7.6, 2 Ho of Ph); 7.73 (d, J ¼ 9.2, HꢀC(8)); 8.46 (dd, J ¼ 9.2, 2.8, HꢀC(7)); 9.00 (d, J ¼ 2.8, HꢀC(5));
9.13 (s, HꢀC(4)); 10.63 (s, NH). 13C-NMR: 117.6; 117.8; 119.4; 119.8; 122.2; 125.3; 127.0; 129.2; 137.3;
140.3; 144.0; 148.7; 156.4; 158.7; 166.9. EI-MS (70 eV): 268 (37), 209 (100), 167 (14), 150 (34), 135 (72),
118 (12), 104 (29), 93 (30), 77 (45). Anal. calc. for C17H10N4O4S (366.35): C 55.74, H 2.75, N 15.29; found:
C 55.86, H 2.69, N 15.40.
N-(4-Chlorophenyl)-3-oxochromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3e). Yield: 308 mg
(87%). Yellow powder. M.p. > 3008 (dec.). IR: 3313 (NH), 1683 (C¼O), 1607, 1555 (Ar), 1492
(C¼S), 1209 (CꢀO). 1H-NMR: 7.38 (t, J ¼ 7.5, HꢀC(6)); 7.42 (d, J ¼ 8.6, 2 arom. H); 7.44 (t, J ¼ 7.5,
HꢀC(7)); 7.52 (d, J ¼ 8.3, HꢀC(8)); 7.69 (d, J ¼ 8.6, 2 arom. H); 7.96 (d, J ¼ 7.4, HꢀC(5)); 8.98 (s,
HꢀC(4)); 10.67 (s, NH). 13C-NMR: 116.7; 118.2; 119.3; 119.5; 125.7; 125.9; 129.4; 130.2; 133.5; 139.4;
139.8; 150.3; 153.5; 159.9; 166.7. EI-MS (70 eV): 357 (36, [M þ 2]þ), 355 (89, Mþ), 236 (30), 201 (22), 184
(38), 171 (56), 169 (100), 127 (61), 111 (28). Anal. calc. for C17H10ClN3O2S (355.80): C 57.39, H 2.83, N
11.81; found: C 57.35, H 2.72, N 11.99.
6-Bromo-N-(4-chlorophenyl)-3-oxochromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3f). Yield:
326 mg (75%). Orange powder. M.p. > 3008 (dec.). IR: 3329 (NH), 1704 (C¼O), 1601, 1542 (Ar),
1490 (C¼S), 1199 (CꢀO). 1H-NMR: 7.39 (d, J ¼ 8.7, 2 arom. H); 7.45 (d, J ¼ 8.8, HꢀC(8)); 7.66 (d, J ¼ 8.7,
2 arom. H); 7.80 (dd, J ¼ 8.9, 2.0, HꢀC(7)); 8.22 (d, J ¼ 2.0, HꢀC(5)); 8.89 (s, HꢀC(4)); 10.65 (s, NH).
13C-NMR: 116.8; 118.5; 118.8; 119.1; 120.7; 125.5; 128.9; 131.5; 135.1; 137.4; 139.3; 149.5; 152.0; 159.0;
166.5. EI-MS (70 eV): 436 (1, [M þ 4]þ), 434 (8, [M þ 2]þ), 432 (6, Mþ), 368 (21), 313 (8), 264 (8), 236

Helvetica Chimica Acta – Vol. 97 (2014)
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(18), 201 (20), 169 (100), 127 (43), 96 (11). Anal. calc. for C17H9BrClN3O2S (434.69): C 46.97, H 2.09, N
9.67; found: C 46.92, H 2.18, N 9.78.
N-(4-Chlorophenyl)-6-methoxy-3-oxochromeno[2,3-c]pyrazole-2(3H)-carbothioamide (3g). Yield:
308 mg (80%). Yellow powder. M.p. > 3008 (dec.). IR: 3432 (NH), 1724 (C¼O), 1568, 1493 (Ar), 1446
(C¼S), 1285, 1190 (CꢀO). 1H-NMR: 3.80 (s, MeO); 7.37 – 7.40 (m, 3 arom. H); 7.51 – 7.52 (m, 1 arom. H);
7.65 – 7.68 (m, 3 arom. H); 8.88 (s, HꢀC(4)); 10.64 (s, NH). 13C-NMR: 56.3; 111.8; 117.8; 118.3; 119.5;
119.7; 121.3; 125.9; 129.4; 139.1; 139.8; 148.0; 150.3; 156.5; 160.0; 166.7. EI-MS (70 eV): 201 (100), 186
(59), 173 (28), 158 (82), 143 (8), 130 (36), 114 (5), 102 (40), 76 (25). Anal. calc. for C18H12ClN3O3S
(385.82): C 56.04, H 3.13, N 10.89; found: C 56.22, H 3.21, N 10.84.
REFERENCES
[1] J. Volmajer, R. Toplak, I. Leban, A. M. Le Marechal, Tetrahedron 2005, 61, 7012.
[2] A. Alizadeh, M. Babaki, N. Zohreh, Tetrahedron 2009, 65, 1704.
[3] A. Alizadeh, R. Ghanbaripour, L.-G. Zhu, Synth. Commun. 2013, 43, 2575.
[4] A. Alizadeh, R. Ghanbaripour, Helv. Chim. Acta 2013, 96, 473.
[5] A. Alizadeh, R. Ghanbaripour, L.-G. Zhu, Synlett 2013, 24, 2124.
Received November 2, 2013