Synthesis, characterization, and biological activity of substituted thiazole-5-carboxaldehydes and their ylidenenitriles derivatives

Article abstract of DOI:10.1080/10426500802583520

The Vilsmeier-Haack reaction of 2-amino -4-(4-substituted phenyl)-thiazoles 1, in the presence of micellar media, gives formylated derivatives 2, which upon hydrolysis afforded thiazole-5-carboxaldehydes 3. Microwave-assisted Knoevenagel condensation of 3 with active methylene compounds, in the presence of piperidine as catalyst, gives excellent yields of ylidenenitrile compounds 4. The structures of the newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR, and ¹³C NMR spectral analysis. All newly synthesized compounds were screened for antibacterial activity using two Gram-positive and one Gram-negative bacterial species and their antifungal activity was screened using two fungal species. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500802583520

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Phosphorus, Sulfur, and Silicon
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Synthesis, Characterization,
and Biological Activity of
Substituted Thiazole-5-
carboxaldehydes and Their
Ylidenenitriles Derivatives
Nilesh J. Thumar a & Manish P. Patel a
a Department of Chemistry , Sardar Patel
University , Gujarat, India
Published online: 21 Sep 2009.
To cite this article: Nilesh J. Thumar & Manish P. Patel (2009) Synthesis,
Characterization, and Biological Activity of Substituted Thiazole-5-carboxaldehydes
and Their Ylidenenitriles Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:10, 2720-2732, DOI: 10.1080/10426500802583520
To link to this article: http://dx.doi.org/10.1080/10426500802583520
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Phosphorus, Sulfur, and Silicon, 184:2720–2732, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802583520
Synthesis, Characterization, and Biological Activity of
Substituted Thiazole-5-carboxaldehydes and Their
Ylidenenitriles Derivatives
Nilesh J. Thumar and Manish P. Patel
Department of Chemistry, Sardar Patel University, Gujarat, India
The Vilsmeier–Haack reaction of 2-amino -4-(4-substituted phenyl)-thiazoles 1, in
the presence of micellar media, gives formylated derivatives 2, which upon hy-
drolysis afforded thiazole-5-carboxaldehydes 3. Microwave-assisted Knoevenagel
condensation of 3 with active methylene compounds, in the presence of piperidine
as catalyst, gives excellent yields of ylidenenitrile compounds 4. The structures
of the newly synthesized compounds were established on the basis of elemental
analysis, IR, 1H NMR, and 13C NMR spectral analysis. All newly synthesized com-
pounds were screened for antibacterial activity using two Gram-positive and one
Gram-negative bacterial species and their antifungal activity was screened using
two fungal species.
Keywords Arylaminothiazole; biological activity; Knoevenagel condensation; micelles;
Vilsmeier–Haack reaction
INTRODUCTION
Thiazoles are a familiar group of heterocyclic compounds that possess
a wide variety of biological activities, and their utility as medicines is
well-established.1–4 The thiazole nucleus is also an integral part of all
the available penicillins, which have revolutionized the therapy of bac-
terial diseases.5–10 A detailed literature survey11,12 reveals that a large
number of thiazole derivatives containing other heterocyclic systems
have been designed, synthesized, and evaluated for their antimicrobial
activity involving several strains of bacteria, fungi, and viruses.13–17
The Vilsmeier–Haack reaction in micellar media18,19 plays an impor-
tant role for synthesizing a variety of aromatic and biologically active
Received 8 July 2008; accepted 27 October 2008.
One of the authors is thankful to the Gujarat Government, India, for the Gujarat Gov-
ernment Research Fellowship, and Department of Chemistry, Sardar Patel University,
for providing research facilities.
Address correspondence to Manish P. Patel, Department of Chemistry, Sardar
Patel University, Vallabh Vidyanagar-388 120, Gujarat, India. E-mail: patelman-
ish1069@yahoo.com
2720

Substituted Thiazole-5-carboxaldehydes
2721
heterocyclic compounds in good yield with improved reaction time. Mi-
celles by their solubilization capacity increase the reactant concentra-
tion within the hydrophilic or hydrophobic micellar regions facilitating
the reactions. They act as microreactors, by which rate and selectiv-
ity of the reaction increases. Sodium dodecyl sulfate (SDS) is one of
the inexpensive, nontoxic, and readily available micelles used in the
Vilsmeier–Haack reaction.
Ylidenenitriles have increasing applications20 in industry, medicine,
agriculture, and biological sciences; are useful substrates for cycload-
dition reactions; and are precursors to heterocyclic compounds with
potential pharmacologically active heterocycles.
In continuation of our work21,22 in synthesizing sulfur-containing
biologically active heterocyclic compounds, and in view of the bio-
logical significance of the aminothiazole derivatives, we report the
Vilsmeier–Haack reaction of substituted amino thiazole in the pres-
ence of SDS to obtain formylated derivatives, which upon Knoeve-
nagel condensation with active methylene compounds, give ylidenen-
itrile derivatives. The structures of the synthesized derivatives were
1
well characterized by their elemental analysis, IR, H NMR, and 13C
NMR spectral data, and were screened for their biological activity using
Gram-positive and Gram-negative bacterial species and their antifun-
gal activity was screened using fungal species.
RESULTS AND DISCUSSION
4-(4-substituted phenyl)-2-aminothiazoles 1 was prepared by the solid
phase reaction of thiourea, substituted acetophenones, and iodine. The
Vilsmeier–Haack reaction of 4-(4-substituted phenyl)-2-aminothiazoles
1, in the presence of SDS, afforded intermediates 2. It is observed that
the reaction time decreased from 4–5 h to 1–1.5 h by using an equimolar
amount of SDS in the reaction media. The IR spectrum of the interme-
diates 2 showed an absorption band in the region of 1730–1690 cm−1
(C O) and 1385–1340 cm−1 (-N (CH3)2), whereas the band due to –NH2
was absent. The 1H NMR (CDCl3) spectra of intermediates 2 exhibited
the signal around 9.81–9.88 δ (1H, s, -CHO-), which confirms the formy-
lation and the presence of signal around 3.21–3.87 δ (6H, s, -N (CH3)2),
8.38–8.50 δ (1H, s, -N CH-N = ), and the absence of a signal due to
–NH2 indicates the conversion of –NH2 to –N CH-N (CH3)2. There
are reports in the literature23 where such a conversion of the –NH2
group has taken place upon Vilsmeier–Haack adduct. In addition, the
13C NMR (CDCl3) spectra of intermediates 2 shows a peak around
178.43–180.78 δ (C O), 41.57–47.10 δ (-N (CH3)2), and 150.26–153.24

2722
N. J. Thumar and M. P. Patel
δ (-N CH-N (CH3)2), and also confirms formylation and blocking of the
amino group. The hydrolysis of intermediates 2 using NaOH afforded
2-amino-4-(4-substituted phenyl) 1, 3-thiazole-5-carboxaldehyde 3. The
IR spectrum of 3 showed a band in the region of the 3500–3200 cm−1(-
NH2); the 1H NMR (DMSO-d6) spectra of product 3 exhibited the signal
around 8.25–8.42 δ (-NH2); the disappearance of peaks due to -N (CH3)2
and -N CH-N = group indicates the deblocking of the -NH2 group upon
hydrolysis; and the 13C-NMR (DMSO-d6) spectra of 3 indicates the ab-
sence of peaks due to -N (CH3)2 and -N CH-N = group, which confirms
the hydrolysis. The microwave-assisted Knoevenagel condensation of
thiazole-5-carboxaldehydes 3 with active methylene compounds in the
presence of piperidine as catalyst afforded ylidenenitrile compounds 4,
which were confirmed by the disappearance of band for the aldehyde
(C O) and appearance of band at 2250–2180 cm−1 (CN) in the IR; the
absence of peak due to the –CHO group and the presence of a sig-
1
nal around 7.20–7.35 δ (–CH C (CN)2) in the H NMR spectrum; and
also the 13C-NMR (DMSO-d6) spectra of the ylidenenitrile compounds
4 shows the 20.10–23.09(COOCH2CH3), 64.18–65.82(-COOCH2CH3),
and 111.63–114.15 δ (-CN), which supports the Knoevenagel condensa-
tion (Scheme 1).
Antimicrobial Activity
Twenty synthesized compounds were screened in vitro for their an-
timicrobial activities against two strains of Gram-positive bacterial
species, namely Bacillus subtilis and Staphylococcus aureus; one strain
of Gram-negative bacterial species, namely Escherichia coli, and two
strains of fungi, namely Aspergillus niger and Rhizopus nigricans, by
the disc diffusion method.24 Nutrient agar and potato dextrose agars
were used to culture the bacteria and fungi, respectively. The agar me-
dia were inoculated with different microorganisms and culture tested.
The compounds were tested at 1000 ppm in DMF solution. DMF was
used as control. The inhibition zones of microbial growth surrounding
the disc were measured in millimeters at the end of 24 h incubation
period at 30◦C for bacteria and 48 h of incubation period at 35◦C for
fungi. All the compounds were screened with reference to the standard
drugs Ampicillin and Ciprofloxacin for antibacterial and Grisofulvine
for antifungal activities, respectively. The antimicrobial activity of syn-
thesized compounds 2a–e, 3a–e, and 4a–j were tested, and the protocols
are summarized in Table I.
The antibacterial evaluation of the synthesized compounds revealed
that only compounds 2a and 2c are moderately active against Gram-
positive bacterial species B. subtilis, and compounds 2a, 2d, and 2e are

Substituted Thiazole-5-carboxaldehydes
2723
Compd.
R
Compd.
R
Compd.
R
R1
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
H
Br
Cl
OCH3
CH3
H
Br
Cl
OCH3
CH3
3a
3b
3c
3d
3e
H
Br
Cl
OCH3
CH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Br
Cl
OCH3
CH3
H
Br
Cl
OCH3
CH3
CN
CN
CN
CN
CN
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
4j
SCHEME 1
moderately to fairly active against Gram-positive bacterial species S.
aureus, whereas all other compounds are inactive. On the other hand, it
was found that the compounds 2b and 3e showed good activity against
Gram-negative bacterial species E. coli, whereas all other compounds
showed moderate to fair activity.
The investigation of fungicidal screening data revealed that the com-
pounds 2b, 4h, and 4i exhibited good activity against the fungal strain
A. niger, whereas all other compounds had a moderate inhibitory effect.
Moreover, the compounds 3a and 4e exhibited a moderate inhibitory
effect, whereas all other compounds showed lower inhibition against
the fungal strain R. nigricans.

2724
N. J. Thumar and M. P. Patel
TABLE I Antimicrobial Screening Results of the Compounds
2a–e, 3a–e, and 4a–j
Antibacterial activity Zone of
inhibition (in mm)
Antifungal activity Zone of
inhibition (in mm)
Compd.
B. subtilis S. aureus
E. coli
A. Niger
Rhizopus n.
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
14
–
22
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
20
–
–
18
13
–
–
–
–
–
–
–
–
–
–
–
–
–
25
28
26
25
26
26
24
18
23
27
22
21
17
20
25
20
20
21
20
20
31
35
–
17
23
14
19
18
16
15
12
12
13
19
17
16
18
15
17
12
21
20
16
–
17
16
15
15
20
22
20
15
16
15
19
21
16
19
23
21
16
17
18
19
–
4g
4h
4i
4j
–
–
33
37
–
–
–
33
34
–
Ampicillin
Ciprofloxacin
Griseofulvin
–
25
–
28
CONCLUSION
Some new 2-[(1E)-1-aza-2-(dimethylamino)vinyl]-4-(4-substituted
phenyl)-1,3-thiazole-5-carboxaldehydes (2a–e), 2-amino-4-(4-
substituted phenyl)-1,3-thiazole-5-carboxaldehydes (3a–e), [(2-
amino-4-(4-substituted phenyl)-1,3-thiazol-5-yl)methylene]methane-
1,1-dicarbonitriles (4a–e), and ethyl(2E)-3-[2-amino-4-(4-substituted
phenyl)(1,3-thiazol-5-yl)]-2-cyanoprop-2-enoates (4f–j) were synthe-
sized and screened for their antibacterial and antifungal activities.
The antimicrobial study revealed that compounds have moderate to
fair activity against the tested organisms Escherichia coli, Aspergillus
niger, and Rhizopus nigricans. Most of the synthesized compounds
are inactive against the species Bacillus subtilis and Staphylococcus
aureus.

Substituted Thiazole-5-carboxaldehydes
2725
EXPERIMENTAL
All melting points were taken in open capillaries and are uncorrected.
The IR spectra were recorded in KBr on a Nicolet 400D spectrophotome-
1
ter, and only the characteristic peaks are reported. H NMR and 13C
NMR were recorded in CDCl3/DMSO-d6 on a Bruker Avance 400F (400
MHz) using TMS as an internal standard. Chemical shifts are reported
in parts per million (ppm). Purity of the compounds was checked by thin
layer chromatography (TLC) on silica gel plates using a toluene:ethyl
acetate (7:3) solvent system. UV radiation and iodine were used as the
visualizing agents.
General Synthesis Procedure: 2-[(1E)-1-Aza-2-(dimethylamino)
vinyl]-4-(4-substituted phenyl)-1,3-thiazole-5-carboxaldehyde
(2a–e)
To a solution of DMF (7.7 mL, 10 mmol) cooled to 0◦C, POCl3 (9.3 mL,
10 mmol) was added, and the mixture was stirred for 30 min at 0◦C.
Sodium dodecyl sulfate (2.88 g, 10 mmol) and 1a–e (10 mmol) was
added to the above pre-cooled Vilsmeier complex in one portion. The
temperature of the reaction mixture was gradually raised to 90◦C and
maintained for 1 h. The reaction mixture was gradually run into well-
stirred chilled water (25 mL). The pH was adjusted to 8 by the addition
of Na2CO3 (∼10 g). The separated solid product thus obtained was
filtered, washed thoroughly with water, dried, and crystallized from
methanol to give compounds 2a–e.
Analytical and spectroscopic characterization data of the synthe-
sized compounds 2a–e are given below:
2-[(1E)-1-Aza-2-(dimethylamino)vinyl]-4-phenyl-1,3-thiazole-5-
carboxaldehyde (2a)
Mp 130–131◦C25, Rf 0.425 (toluene:ethyl acetate, 7:3), Yield 93%,
anal. calcd. for C13H13N3OS: C 60.21, H 5.05, N 16.20; found C
60.05, H 5.00, N 16.29. 1H-NMR δH (CDCl3, 400 MHz): 3.21(6H,
s, -N(CH3)2), 7.35–7.50(5H, m, Ar-H), 8.48(1H, s, -N CH-N(CH3)2),
9.81(1H, s, -CHO). IR: νmax (KBr, cm−1): 3075(CH-arom.str.), 1690(C O
str.), 1579(C C arom. str.), 1381 & 1374(-N (CH3)2 str.), 1154(C =
S str.). 13C-NMR δc (CDCl3): 46.09(-N(CH3)2), 118.54, 124.18, 123.13,
128.76, 129.15, 131.15(aromatic), 151.50(-N CH-N (CH3)2), 160.87(-
C C-N = ), 175.23(-S-C N-), 180.54(Ar-CHO).
2-[(1E)-1-Aza-2-(dimethylamino)
vinyl]-4-(4-bromophenyl)-1,3-thiazole-5-carboxaldehyde (2b)
Mp 149–150◦C, Rf 0.350 (toluene:ethyl acetate, 7:3), Yield 88%,
anal. calcd. for C13H12BrN3O3S: C 46.17, H 3.58, N 12.42; found C

2726
N. J. Thumar and M. P. Patel
1
46.23, H 3.49, N 12.32. H-NMR δH (CDCl3, 400 MHz): 3.27(6H, s,
-N(CH3)2), 7.31(2H, d, J = 8.4 Hz, Ar-H), 7.46(2H, d, J = 8.4 Hz, Ar-
H), 8.41(1H, s, -N CH-N(CH3)2), 9.87(1H, s, -CHO). IR: νmax (KBr,
cm−1): 3086(CH-arom. str.), 1710(C ; O str.), 1582(C C arom. str.), 1364
& 1343(-N (CH3)2 str.), 1218(C = S str.), 554(C-Br str.). 13C-NMR δc
(CDCl3): 44.23(-N(CH3)2), 122.23, 125.86, 128.20, 130.16, 131.24(aro-
matic), 153.24(-N CH-N (CH3)2), 161.65(-C C-N = ), 175.69(-S-C N-
), 180.78(Ar-CHO).
2-[(1E)-1-Aza-2-(dimethylamino) vinyl]-4-(4-chlorophenyl)-
1,3-thiazole-5-carboxaldehyde (2c)
Mp 144–145◦C, Rf 0.325 (toluene:ethyl acetate, 7:3), Yield 89%, anal.
calcd. for C13H12ClN3OS: C 53.15, H 4.12, N 14.30; found C 53.05, H
1
4.17, N 14.17. H-NMR δH (CDCl3, 400 MHz): 3.36 (6H, s, -N(CH3)2),
7.30(2H, d, J = 8.8 Hz, Ar-H), 7.39(2H, d, J = 8.8 Hz, Ar-H), 8.38(1H,
s, -N CH-N(CH3)2), 9.84(1H, s, -CHO). IR: νmax (KBr, cm−1): 3094(CH-
arom. str.), 1720(C O str.), 1592(C C arom. str.), 1379 & 1360(-N
(CH3)2 str.), 1312(C = S str.), 895(C-Cl str.). 13C-NMR δc (CDCl3): 45.05(-
N(CH3)2), 122.29, 125.94, 128.56, 130.58, 131.54(aromatic), 151.54(-
N CH-N (CH3)2), 159.98(-C C-N = ), 176.45(-S-C N-), 181.68(Ar-
CHO).
2-[(1E)-1-Aza-2-(dimethylamino)vinyl]-4-(4-methoxyphenyl)-
1,3-thiazole-5-carboxaldehyde (2d)
Mp 154–155◦C, Rf 0.350 (toluene:ethyl acetate, 7:3), Yield 85%, anal.
calcd. for C14H15N3O2S: C 58.11, H 5.23, N 14.52; found C 58.05, H 5.13,
1
N 14.43. H-NMR δH (CDCl3, 400 MHz): 3.49(3H, s, -OCH3), 3.87(6H,
s, -N(CH3)2), 7.41(2H, d, J = 8.0 Hz, Ar-H), 7.53(2H, d, J = 8.0 Hz,
Ar-H), 8.45(1H, s, -N CH-N(CH3)2), 9.85(1H, s, -CHO). IR: νmax (KBr,
cm−1): 3025(CH-arom. str.), 1680(C O str.), 1609(C C arom. str.), 1380
& 1369(-N (CH3)2 str.), 1230(C = S str.). 13CNMR δc (CDCl3): 41.57(-
N(CH3)2), 56.65(Ar-OCH3), 121.40, 123.09, 128.02, 129.14, 131.26(aro-
matic), 152.59(-N CH-N (CH3)2), 159.89(-C C-N = ), 174.35(-S-C N-
), 178.43(Ar-CHO).
2-[(1E)-1-Aza-2-(dimethylamino)vinyl]-4-(4-methylphenyl)-1,3-
thiazole-5-carboxaldehyde (2e)
Mp 136–137◦C, Rf 0.400 (toluene:ethyl acetate, 7:3), Yield 87%, anal.
calcd. for C14H15N3OS: C 61.51, H 5.53, N 15.37; found C 61.60, H 5.44,
1
N 15.49. H-NMR δH (CDCl3, 400 MHz): 1.90(3H, s, -CH3), 3.23(6H,
s, -N(CH3)2), 7.33(2H, d, J = 8.0 Hz, Ar-H), 7.47(2H, d, J = 8.0 Hz,
Ar-H), 8.50(1H, s, -N CH-N(CH3)2), 9.88(1H, s, -CHO). IR: νmax (KBr,

Substituted Thiazole-5-carboxaldehydes
2727
cm−1): 3050(CH-arom. str.), 1721(C O str.), 1533(C C arom. str.), 1372
& 1358(-N (CH3)2 str.), 1172(C = S str.). 13C-NMR δc (CDCl3): 20.08(Ar-
CH3), 47.10(-N (CH3)2), 120.83, 123.25, 128.47, 129.88, 131.26(aro-
matic), 150.26(-N CH-N (CH3)2), 160.08(-C C-N = ), 175.79(-S-C N-
), 180.68(Ar-CHO).
2-Amino-4-(4-substituted phenyl)-1,3-
thiazole-5-carboxaldehyde (3a–e)
The compound 2a–e (10 mmol), 10 mL ethanol, and NaOH (0.04 g, 10
mmol) were charged in a 100 mL round bottom flask, and the mixture
was refluxed for 4–5 h. The reaction mixture was cooled and poured
onto crushed ice. The solid thus separated was filtered, washed thor-
oughly with water, dried, and crystallized from ethyl acetate to give
compounds 3a–e. Analytical and spectroscopic characterization data of
the synthesized compounds 3a–e are given below:
2-Amino-4-phenyl-1,3-thiazole-5-carboxaldehyde (3a)
Mp 212–214◦C25, Rf 0.500 (toluene:ethyl acetate, 7:3), Yield 87%,
anal. calcd. for C10H8N2OS: C 58.50, H 3.95, N 13.72; found C 58.43,
H 3.89, N 13.66. 1H-NMR δH (DMSO-d6, 400 MHz): 7.30–7.61(5H,
m, Ar-H), 8.30(2H, s, -NH2) 9.61(1H, s, -CHO). IR: νmax (KBr, cm−1):
3430–3250(NH2), 3090(CH-arom. str.), 1723(C O str.), 1612(C C
arom. str.), 1235(C = S str.). 13CNMR δc (DMSO-d6): 122.67, 129.66,
129.85, 131.09, 140.06(aromatic), 163.95(-C C-N = ), 173.11(-S-C N-
), 181.86(Ar-CHO).
2-Amino-4-(4-bromophenyl)-1,3-thiazole-5-carboxaldehyde
(3b)
Mp 224–226◦C, Rf 0.425 (toluene:ethyl acetate, 7:3), Yield 85%, anal.
calcd. for C10H7BrN2OS: C 42.42, H 2.49, N 9.89; found C 42.33, H 2.33,
N 9.76. 1H-NMR δH (DMSO-d6, 400 MHz): 7.32(2H, d, J = 8.4 Hz, Ar-H),
7.57(2H, d, J = 8.4 Hz, Ar-H), 8.41(2H, s, -NH2) 9.54(1H, s, -CHO). IR:
νmax (KBr, cm−1): 3490–3350(NH2 str.), 3034(CH-arom. str.), 1685(C O
str.), 1545(C C arom. str.), 1185(C = S str.), 555(C-Br str.). 13CNMR δc
(DMSO-d6): 122.42, 129.62, 130.22, 131.37, 140.63(aromatic), 164.58(-
C C-N = ), 172.74(-S-C N-), 182.66(Ar-CHO).
2-Amino-4-(4-chlorophenyl)-1,3-thiazole-5-carboxaldehyde (3c)
Mp 209–210◦C, Rf 0.450 (toluene:ethyl acetate, 7:3), Yield 86%, anal.
calcd. for C10H7ClN2OS: C 50.20, H 2.81, N 11.90; found C 50.42, H
1
2.61, N 11.60. H-NMR δH (DMSO-d6, 400 MHz): 7.54(2H, d, J = 8.4

2728
N. J. Thumar and M. P. Patel
Hz, Ar-H), 7.73(2H, d, J = 8.8 Hz, Ar-H), 8.37(2H, s, -NH2), 9.66(1H, s,
-CHO). IR: νmax (KBr, cm−1): 3420–3220(NH2 str.), 3076(CH-arom. str.),
1672(C O str.), 1529(C C arom. str.), 1293(C = S str.), 770(C-Cl str.).
13C-NMR δc (DMSO-d6): 123.29, 123.15, 131.64, 132.62, 135.05(aro-
matic), 162.12(-C C-N = ), 173.18(-S-C N-), 181.79(Ar-CHO).
2-Amino-4-(4-methoxyphenyl)-1,3-thiazole-5-carboxaldehyde
(3d)
Mp 231–233◦C, Rf 0.475 (toluene:ethyl acetate, 7:3), Yield 84%, anal.
calcd. for C11H10N2O2S: C 56.40, H 4.30, N 11.96; found C 56.28, H
1
4.27, N 11.99. H-NMR δH (DMSO-d6, 400 MHz): 3.62(3H, s, -OCH3),
7.25(2H, d, J = 8.4 Hz, Ar-H), 7.62(2H, d, J = 8.0 Hz, Ar-H), 8.42(2H, s,
-NH2) 9.42(1H, s, -CHO). IR: νmax (KBr, cm−1): 3460–3200(NH2 str.),
3049(CH-arom. str.), 1720(C O str.), 1525(C C arom. str.), 1315(C
= S str.). 13C-NMR δc (DMSO-d6): 54.9(Ar-OCH3), 123.15, 129.72,
130.37, 131.93, 141.34(aromatic), 162.41(-C C-N = ), 171.43(-S-C N-),
182.16(Ar-CHO).
2-Amino-4-(4-methylphenyl)-1,3-thiazole-5-carboxaldehyde
(3e)
Mp 217–218◦C, Rf 0.500 (toluene:ethyl acetate, 7:3), Yield 82%, anal.
calcd. for C11H10N2OS: C 60.53, H 4.62, N 12.83; found C 60.42, H 4.50,
N 12.97. 1H-NMR δH (DMSO-d6, 400 MHz): 2.15(3H, s, -CH3), 7.29(2H,
d, J = 8.0 Hz, Ar-H), 7.59(2H, d, J = 8.0 Hz, Ar-H), 8.25(2H, s, -NH2)
9.71(1H, s, -CHO). IR: νmax (KBr, cm−1): 3450–3250(NH2 str.), 3071(CH-
arom. str.), 1725(C O str.), 1540(C C arom. str.), 1290(C = S str.).
13C-NMR δc (DMSO-d6): 21.38(Ar-CH3), 122.67, 129.66, 129.85, 131.09,
140.06(aromatic), 163.95(-C C-N = ), 173.11(-S-C N-), 181.86(Ar-
CHO).
[(2-Amino-4-(4-substituted phenyl)-1,3-thiazol-5-yl)
methylene]methane-1,1-dicarbonitrile (4a–e) and Ethyl
(2E)-3-[2-Amino-4-(4-substituted phenyl)
(1,3-Thiazol-5-yl)]-2-cyanoprop-2-enoate (4f–j)
To a solution of 3a–e (10mmol) in 5 mL ethanol, malononitrile or cyano
ethyl acetate (10 mmol) and piperidine was added as catalyst. The re-
action mixture was then irradiated in the microwave oven for 5–7 min.
The cooled mixture was filtered, repeatedly washed with ethanol, dried,
and crystallized from ethyl acetate to give compounds 4a–j. Analytical
and spectroscopic characterization data of the synthesized compounds
4a–j are given below:

Substituted Thiazole-5-carboxaldehydes
2729
[(2-Amino-4-phenyl-1,3-thiazol-5-yl)methylene]methane-1,1-
dicarbonitrile (4a)
Mp 228–230◦C, Rf 0.550 (toluene:ethyl acetate, 7:3), Yield 89%,
anal. calcd. for C13H8N4S: C 61.89, H 3.20, N 22.20; found C 61.76,
H 3.05, N 22.07. 1H-NMR δH (DMSO-d6, 400 MHz): 7.23(1H, s,
–CH C(CN)2), 7.62–7.89(5H, m, Ar-H), 8.12(2H, s, -NH2). IR: νmax
(KBr, cm−1): 3350–3200 (NH2 str.), 3090(CH-arom. str.), 2210 &
2200(CN str.), 1520(C C arom. str.), 1350(C = S str.). 13C-NMR
δc (DMSO-d6): 84.37(Ar-CH = C(CN)2), 111.63(-CN), 122.02, 123.09,
124.69, 128.82, 131.59(aromatic), 141.56(Ar-CH = C(CN)2), 153.72(-
C C-N = ), 173.56(-S-C N-).
[(2-Amino-4-(4-bromophenyl)-1,3-thiazol-5-yl)methylene]
methane-1,1-dicarbonitrile (4b)
Mp 236–238◦C, Rf 0.500 (toluene:ethyl acetate, 7:3), Yield 86%,
anal. calcd. for C13H7BrN4OS: C 47.15, H 2.13, N 16.92; found C
1
47.22, H 2.19, N 16.81. H-NMR δH (DMSO-d6, 400 MHz): 7.31(1H,
s, –CH C(CN)2), 7.57(2H, d, J = 8.4 Hz, Ar-H), 7.88(2H, d, J = 8.4
Hz, Ar-H), 8.21(2H, s, -NH2). IR: νmax (KBr, cm−1): 3410–3270(NH2
str.), 3054(CH-arom. str.), 2252 & 2225(CN str.), 1555(C C arom. str.),
1275(C = S str.), 559(C-Br str.). 13C-NMR δc (DMSO-d6): 84.20(Ar-CH =
C(CN)2), 111.12(-CN), 122.28, 123.59, 124.23, 128.12, 131.13(aromatic),
142.72(Ar-CH = C(CN)2), 153.83(-C C-N = ), 173.57(-S-C N-).
[(2-Amino-4-(4-chlorophenyl)-1,3-thiazol-5-yl)methylene]
methane-1,1-dicarbonitrile (4c)
Mp 240–241◦C, Rf 0.550 (toluene:ethyl acetate, 7:3), Yield 87%, anal.
calcd. for C13H4ClOS: C 54.45, H 2.46, N 19.54; found C 54.33, H 2.57,
N 19.62. 1H-NMR δH (DMSO-d6, 400 MHz): 7.25(1H, s, –CH C(CN)2),
7.50(2H, d, J = 8.4 Hz, Ar-H), 7.82(2H, d, J = 8.0 Hz, Ar-H), 8.31(2H, s,
-NH2). IR: νmax (KBr, cm−1): 3495–3210(NH2 str.), 3065(CH-arom. str.),
2215 & 2208(CN str.), 1575(C C arom. str.), 1180(C = S str.), 795(C-
Cl str.). 13C-NMR δc (DMSO-d6): 85.02(Ar-CH = C(CN)2), 112.67(-
CN), 123.05, 123.68, 124.34, 127.63, 131.25(aromatic), 141.67(Ar-CH
= C(CN)2), 155.78(-C C-N = ), 174.87(-S-C N-).
[(2-Amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl)methylene]
methane-1,1-dicarbonitrile (4d)
Mp 224–226◦C, Rf 0.575 (toluene:ethyl acetate, 7:3), Yield 83%, anal.
calcd. for C14H10N4OS: C 59.56, H 3.57, N 19.85; found C 59.41., H
1
3.42, N 19.91. H-NMR δH (DMSO-d6, 400 MHz): 3.55(3H, s, -OCH3),
7.29(1H, s, –CH C(CN)2), 7.42(2H, d, J = 8.0 Hz, Ar-H), 7.69(2H, d, J =

2730
N. J. Thumar and M. P. Patel
8.0 Hz, Ar-H), 8.10(2H, s, -NH2). IR: νmax (KBr, cm−1): 3540–3280(NH2
str.), 3045(CH-arom. str.), 2192 & 2180(CN str.), 1595(C C arom. str.),
1345(C = S str.). 13C-NMR δc (DMSO-d6): 54.13(Ar-OCH3), 87.48(Ar-
CH = C(CN)2), 113.15(-CN), 121.56, 123.10, 124.46, 127.74, 130.90(aro-
matic), 141.30(Ar-CH = C(CN)2), 155.82(-C C-N = ), 175.91(-S-C N-).
[(2-Amino-4-(4-methylphenyl)-1,3-thiazol-5-yl)methylene]
methane-1,1-dicarbonitrile (4e)
Mp 234–236◦C, Rf 0.575 (toluene:ethyl acetate, 7:3), Yield 84%,
anal. calcd. for C14H10N4S: C 63.14, H 3.79, N 21.04; found C 63.43,
H 3.63, N 21.15. 1H-NMR δH (DMSO-d6, 400 MHz): 1.95(3H, s, -
CH3), 7.35(1H, s, –CH C(CN)2), 7.37(2H, d, J = 8.4 Hz, Ar-H),
7.65(2H, d, J = 8.4 Hz, Ar-H), 8.33(2H, s, -NH2). IR: νmax (KBr,
cm−1): 3560–3190(NH2 str.), 3010(CH-arom. str.), 2240 & 2225 (CN
str.), 1585(C C arom. str.), 1320(C = S str.). 13C-NMR δc (DMSO-d6):
23.45(Ar-CH3), 85.11(Ar-CH = C(CN)2), 114.15(-CN), 120.53, 124.11,
124.45, 128.37, 131.91(aromatic),142.14(Ar-CH = C(CN)2), 155.28(-
C C-N = ), 174.89(-S-C N-).
Ethyl (2E)-3-(2-Amino-4-phenyl(1,3-thiazol-5-yl))-2-cyanoprop-
2-enoate (4f)
Mp 230–231◦C, Rf 0.550 (toluene:ethyl acetate, 7:3), Yield 88%,
anal. calcd. for C15H13N3O2S: C 60.19, H 4.38, N 14.04; found
C 60.11, H 4.50, N 14.15. 1H-NMR δH (DMSO-d6, 400 MHz):
1.92–2.18(3H, t, -CH2-CH3), 3.61–3.74(2H, q, -CH2-CH3), 7.20(1H, s,
–CH C(CN)2), 7.63–7.89(5H, m, Ar-H), 8.12(2H, s, -NH2). IR: νmax
(KBr, cm−1): 3490–3250(NH2 str.), 3080(CH-arom. str.), 2198 (CN
str.), (C O str.), 1578(C C arom. str.), 1255(C = S str.). 13C-NMR δc
(DMSO-d6): 20.37(COOCH2CH3), 64.18(-COOCH2CH3), 95.63(EtOOC-
C-CN), 113.18(-CN), 123.13, 125.60, 128.76, 129.15, 131.50(aromatic),
139.87(Ar-CH = C(CN)2), 147.24(-C C-N = ), 163.11(-COOCH2CH3),
173.95(-S-C N-).
Ethyl (2E)-3-[2-Amino-4-(4-bromophenyl) (1,3-Thiazol-
5-yl)]-2-cyanoprop-2-enoate (4g)
Mp 220–222◦C, Rf 0.525 (toluene:ethyl acetate, 7:3), Yield 86%, anal.
calcd. for C15H12BrN3O2S: C 47.63, H 3.20, N 11.11; found C 47.51, H
3.05, N 11.27. 1H-NMR δH (DMSO-d6, 400 MHz): 1.77–1.94(3H, t, -CH2-
CH3), 3.63–3.91(2H, q, -CH2-CH3), 7.29(1H, s, –CH C(CN)2), 7.31(2H,
d, J = 7.6 Hz, Ar-H), 7.51(2H, d, J = 8.0 Hz, Ar-H), 8.19(2H, s, -NH2). IR:
νmax (KBr, cm−1): 3420–3140(NH2 str.), 3030(CH-arom. str.), 2220 (CN
str.), 1600(C C arom. str.), 1372(C = S str.), 566(C-Br str.). 13C-NMR δc

Substituted Thiazole-5-carboxaldehydes
2731
(DMSO-d6): 21.24(COOCH2CH3), 65.82(-COOCH2CH3), 95.60(EtOOC-
C-CN), 113.48(-CN), 123.41, 125.18, 128.344, 129.62, 131.36(aromatic),
138.60 (Ar-CH = C(CN)2), 147.70 (-C C-N = ), 164.74 (-COOCH2CH3),
174.65(-S-C N-).
Ethyl (2E)-3-[2-Amino-4-(4-chlorophenyl)
(1,3-Thiazol-5-yl)]-2-cyanoprop-2-enoate (4h)
Mp 242–243◦C, Rf 0.500 (toluene:ethyl acetate, 7:3), Yield 84%, anal.
calcd. for C15H12ClN3O2S: C 53.97, H 3.62, N 12.59; found C 53.75, H
3.51, N 12.73. 1H-NMR δH (DMSO-d6, 400 MHz): 1.72–2.08(3H, t,-CH2-
CH3), 3.48–3.62(2H, q, -CH2-CH3), 7.23(1H, s, –CH C(CN)2), 7.26(2H,
d, J = 7.6 Hz, Ar-H), 7.41(2H, d, J = 7.6 Hz, Ar-H), 8.25(2H, s, -NH2). IR:
νmax (KBr, cm−1): 3350–3190(NH2 str.), 3085(CH-arom. str.), 2195 (CN
str.), 1546(C C arom. str.), 1285(C = S str.), 790(C-Cl str.). 13C-NMR δc
(DMSO-d6): 20.10(COOCH2CH3), 65.38(-COOCH2CH3), 95.77(EtOOC-
C-CN), 113.93(-CN), 123.9, 125.01, 128.44, 128.55, 131.64(aromatic),
139.83(Ar-CH = C(CN)2), 147.56(-C C-N = ), 165.23(-COOCH2CH3),
174.94(-S-C N-).
Ethyl (2E)-3-[2-Amino-4-(4-methoxyphenyl)
(1,3-Thiazol-5-yl)]-2-cyanoprop-2-enoate (4i)
Mp 237–239◦C, Rf 0.600(toluene:ethyl acetate, 7:3), Yield 82%, anal.
calcd. for C16H15N3O3S: C 58.35, H 4.59, N 12.76; found C 58.22, H
1
4.51, N 12.88. H-NMR δH (DMSO-d6, 400 MHz): 1.67–2.02(3H, t, -
CH2-CH3), 3.51–3.62(2H, q, -CH2-CH3), 3.81(3H, s, -OCH3), 7.28(1H,
s, –CH C(CN)2), 7.51(2H, d, J = 8.0 Hz, Ar-H), 7.76(2H, d, J = 8.0
Hz, Ar-H), 8.34(2H, s, -NH2). IR: νmax (KBr, cm−1): 3560–3200(NH2
str.), 3025(CH-arom. str.), 2188 (CN str.), 1620(C C arom. str.),
1156(C = S str.). 13C-NMR δc (DMSO-d6): 22.70(COOCH2CH3),
55.78(Ar-OCH3), 64.58(-COOCH2CH3), 94.19(EtOOC-C-CN), 112.36(-
CN), 122.37, 124.96 127.26, 130.15, 132.51(aromatic), 138.64(Ar-CH =
C(CN)2), 148.16(-C C-N = ), 164.37(-COOCH2CH3), 174.16(-S-C N-).
Ethyl (2E)-3-[2-Amino-4-(4-methylphenyl)
(1,3-Thiazol-5-yl)]-2-cyanoprop-2-enoate (4j)
Mp 230–232◦C, Rf 0.625 (toluene:ethyl acetate, 7:3), Yield 88%,
anal. calcd. for C16H15N3O2S: C 61.32, H 4.83, N 13.41; found
C 61.42, H 4.77, N 13.33. 1H-NMR δH (DMSO-d6, 400 MHz):
1.60(3H, s, -CH3)1.88–2.12(3H, t, -CH2-CH3), 3.52–3.68(2H, q, -CH2-
CH3), 7.22(1H, s, –CH C(CN)2), 7.45(2H, d, J = 8.4 Hz, Ar-H),
7.70(2H, d, J = 8.4 Hz, Ar-H), 8.23(2H, s, -NH2). IR: νmax (KBr,
cm−1): 3495–3210(NH2 str.), 3075(CH-arom. str.), 2208 (CN str.),

2732
N. J. Thumar and M. P. Patel
1535(C C arom. str.), 1295(C = S str.). 13C-NMR δc (DMSO-d6): 21.86
(Ar-CH3), 23.09(COOCH2CH3), 65.46(-COOCH2CH3), 95.65(EtOOC-C-
CN), 112.13(-CN), 122.13, 123.18, 127.32, 130.24, 132.72(aromatic),
134.23(Ar-CH = C(CN)2), 140.41(-C C-N = ), 162.42(-COOCH2CH3),
175.76(-S-C N-).
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