Regioselective synthesis of new 2-(E)-cyano(thiazolidin-2-ylidene)thiazoles

Article abstract of DOI:10.3390/molecules14114849

Cyclocondensation of 2-[bis(methylthio)methylene]malononitrile (1) and cysteamine (2) afforded 2-(thiazolidin-2-ylidene)malononitrile (3). This compound on treatment with NaSH gave the corresponding thioamide derivative 4a in a regioselective manner on th

Full text of DOI:10.3390/molecules14114849

Molecules 2009, 14, 4849-4857; doi:10.3390/molecules14114849
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Regioselective Synthesis of New 2-(E)-Cyano(thiazolidin-2-
ylidene)thiazoles
Mehdi Bakavoli 1,*, Hamid Beyzaie 1, Mohammad Rahimizadeh 1, Hossein Eshghi 1 and
Reza Takjoo 2
1
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436
Mashhad, Iran; E-Mails: hamidchem@yahoo.com (H.B.); rahimizh@yahoo.com (M.R.);
heshghi@ferdowsi.um.ac.ir (H.E.)
2
Department of Chemistry, School of Science, Islamic Azad University, Mashhad Branch, Mashhad,
Iran; E-Mail: rezatakjoo@yahoo.com
* Author to whom correspondence should be addressed; E-Mail: mbakavoli@um.ac.ir.
Received: 8 October 2009; in revised form: 4 November 2009 / Accepted: 25 November 2009 /
Published: 25 November 2009
Abstract: Cyclocondensation of 2-[bis(methylthio)methylene]malononitrile (1) and
cysteamine (2) afforded 2-(thiazolidin-2-ylidene)malononitrile (3). This compound on
treatment with NaSH gave the corresponding thioamide derivative 4a in a regioselective
manner on the basis of its single crystal X-ray diffraction analysis. Reaction of this
compound with several α-bromocarbonyl compounds gave new 2-(E)-cyano(thiazolidin-2-
ylidene)thiazoles 5a-g.
Keywords: thiazole; thiazolidine; Hantzsch’s synthesis; heterocyclization; regioselective
synthesis; X-ray crystallography
Introduction
Thiazole is an important scaffold in heterocyclic chemistry and 1,3-thiazole ring is present in many
pharmacologically active substances [1]. For example thiazole-5-ylacetic acid derivatives possess
strong anti-inflammatory activity [2]. Other compounds containing the thiazole ring have been
reported as being histamine H3 antagonists [3], with herbicidal [4], antitumoral [5] and selective
cardiodepressant activities [6].

Molecules 2009, 14
4850
Several methods for the synthesis of thiazole derivatives have been developed [7-11], the most
widely used method being the Hantzsch’s synthesis utilizing thioamides and α-halocarbonyl
compounds as the starting materials [12]. The preparation of thioamides has been reviewed elsewhere
[13]. One procedure involves nitriles which can be converted to thioamides through treatment with
elemental sulfur, S8 [14,15], gaseous hydrogen sulfide in the presence of anion exchange resin (Dowex
1X8, SH- from) at room temperature [16], sodium hydrosulfide hydrate and magnesium chloride
hexahydrate in DMF or methanol [17], ammonium sulfide in methanol [18] and phosphorus
pentasulfide [19].
Our interest in the synthesis of heterocyclic compounds of biologically importance has encouraged
us to study the synthesis of some new functionalized thiazoles. In this context we wish to report on the
reactions and single crystal X-ray diffraction analysis of a newly synthesized thioamide which on
treatment with various α-bromocarbonyl compounds afforded some new 2-(E)-cyano(thiazolidin-2-
ylidene)thiazoles.
Results and Discussion
2-(E)-Cyano(thiazolidin-2-ylidene)thiazoles 5a-g were prepared in a three-step procedure starting
from the dinitrile 3 (Scheme 1). Cyclocondensation of 2-[bis(methylthio)methylene]malononitrile (1)
and cysteamine (2) in ethanol afforded thiazolidine 3, which was filtered off and thionated by sodium
hydrosulfide hydrate in water to give 2-cyano-2-(thiazolidin-2-ylidene)ethanethioamide (4) that can
form either E and/or Z geometric isomers 4a,b.
Scheme 1. Synthesis of 2-(E)-cyano(thiazolidin-2-ylidene)thiazoles 5a-g. For substituents
R1 and R2 see Table 1.
NH2
NH2
NC
S
CN
NH
NC
CN
NC
S
NC
HN
i)
ii)
S
S
HS
+
or
NH2
MeS
SMe
NH
S
1
2
3
4a
4b
R1
S
O
R2
R1
NC
i) EtOH
ii) H2O, NaSH (68%)
iii) DMF, NaHCO3
N
R2
NH2
S
Br
S
NH
S
NC
S
iii)
+
5a-f
NH
O
O
NC
S
N
Br
4a
EtO
NH
5g

Molecules 2009, 14
Table 1. Results of reaction 4a and α-bromocarbonyl compounds in DMF at room temperature.
4851
Entry R1
R2
Substrate α-Bromocarbonyl
Time, h
Yield, %
1
2
3
4
5
6
7
H
H
H
H
CO2Et
CH3
5a
5b
5c
5d
5e
5f
Ethyl bromopyruvate
Bromoacetone
2
2
2
2
2
2
8
71
73
79
82
77
77
75
C6H5
Phenacyl bromide
p-NO2C6H4
p-Nitrobromoacetophenone
3-Bromo acetylacetone
Ethyl 2-bromoacetoacetate
Ethyl bromoacetate
COCH3 CH3
CO2Et
-
CH3
-
5g
For exact determination of these geometric isomers 4a,b, single crystal X-ray analysis would seem
to be preferable to other available techniques but all our efforts to prepare a suitable single crystal from
compound 4 were unsuccessful, but instead we obtained a single crystal from the derivative ethyl 2-
(E)-cyano(thiazolidin-2-ylidene)methyl)thiazole-4-carboxylate (5a). X-ray quality crystals were grown
from ethanol with slow evaporation. A crystal structure was determined for product 5a and is shown in
Figure 1. The molecule exists in the E geometric form with respect to C1-C4 bond. This observation
clearly indicates that compound 4 must have the E isomeric structure 4a. The packing diagram of 5a
shows that there is intermolecular hydrogen bonding between the hydrogen atom on the N1 and the N2
atom. Another intramolecular interaction is Van der Waals interaction between molecules. The high
contact interaction between S1…S1 (3.777 Å) and O1…H9A (2.709 Å) gives rise to crystal growth
expansion along b axis (see Figure 2).
Figure 1. Molecular plot of 5a with the thermal ellipsoids representing 50% probability.

Molecules 2009, 14
Figure 2. Molecular packing of 5a showing Van der Waals as dashed lines along b axis.
4852
The bond lengths of five-membered ring C5S2C7C6N2 are shorter than that ring C1S1C3C2N1,
confirming the aromacity of the former ring. In this compound the C4C11N3 bond and the aromatic
ring are in the same plane.
The thioamide 4a was treated with α-bromocarbonyl compounds in DMF to afford the new 2-(E)-
cyano(thiazolidin-2-ylidene)thiazoles 5a-g (Table 1). The structures of compounds 3, 4a and 5a-g were
deduced from their elemental analyses and 1H-NMR spectral data. The 1H-NMR spectra of compounds
3, 4a and 5a-g showed triplet signals at 3.47-3.63 ppm and 3.99-4.32 ppm (J ~ 7.6 Hz) due to the two
methylene groups of the thiazolidine rings, and broad signals due to the NH group at 6.84-12.17 ppm.
The 13C-NMR spectrum of 4a showed signals due to nitile and thiocarbonyl groups at 119.42 ppm and
189.56 ppm. IR spectroscopy also confirmed the structure of products.
Experimental
General
All of the melting points are uncorrected and were recorded on an Electrothermal type 9100 melting
point apparatus. The mass spectra observed on a Varian Mat CH-7 at 70 ev. The infrared spectra were
determined on 4300 Shimadzu spectrometer and only noteworthy absorptions are listed. The 1H-NMR
13
spectra were recorded on a Bruker AC 100 spectrometer. The C-NMR spectrum was recorded on a
Bruker Avance DRX-500 Fourier transform spectrometer. Chemical shifts are reported in ppm
downfield from TMS as internal standard. All solvents and chemicals were of research grade and were
used as obtain from Merck. Elemental analyses were performed on a Thermo Finnigan Flash EA
microanalyzer. Compound 1 was prepared according to the procedure reported in the literature [20].
Synthesis of 2-(thiazolidin-2-ylidene)malononitrile (3)
A suspension of 2-[bis(methylthio)methylene]malononitrile 1 (3.4 g, 0.02 mol) and cysteamine 2
(1.54 g, 0.02 mol) in ethanol (96%) (40 mL) was stirred at room temperature for 4 h. The white

Molecules 2009, 14
4853
powder of 3 that precipitated was collected by suction filtration, washed with ethanol (2 × 10 mL), and
1
dried in air to give 2.2 g (73%) of 3, mp 209-212 °C; IR (KBr): 3,195, 2,207, 1,571 cm-1; H-NMR
(CDCl3) δ 3.48 (t, J = 6.9 Hz, 2H, SCH2), 3.99 (t, J = 6.9 Hz, 2H, NCH2), 6.84 (s, 1H, NH); MS (70
eV) m/z: 151 (M+); Anal. Calcd. for C6H5N3S: C, 47.66; H, 3.34; N, 27.79; S, 21.21. Found: C, 47.56;
H, 3.43; N, 27.71; S, 21.30.
Synthesis of (E)-2-cyano-2-(thiazolidin-2-ylidene)ethanethioamide (4a)
A solution of thiazolidine 3 (1.5 g, 0.01 mol) and sodium hydrosulfide hydrate (68%) (1.65 g,
0.02 mol) in water (10 mL) was heated at 50 °C for 22 h. The reaction mixture was cooled to room
temperature and the product was precipitated by addition of acetic acid. The precipitate was collected
by suction filtration, washed with ethanol (2 × 5 mL), dried in air, and recrystallized from CH3CN, to
give 1.21g (65%) of 4a as white needles, mp 217-219 °C; IR (KBr): 3,435, 3,320, 2,182, 1,613, 1,570
cm-1; 1H-NMR (acetone-d6) δ: 3.61 (t, J = 7.1 Hz, 2H, SCH2), 4.32 (t, J = 7.1 Hz, 2H, NCH2), 7.50 (s,
13
2H, NH2), 12.17 (1H, s, NH); C-NMR (DMSO-d6) δ: 30.28, 52.86, 75.45, 119.42, 175.53, 189.56;
MS (70 eV) m/z: 185 (M+); Anal. Calcd. for C6H7N3S2: C, 38.90; H, 3.81; N, 22.68; S, 34.61. Found:
C, 38.95; H, 3.74; N, 22.76; S, 34.55.
General procedure for the synthesis of 2- (E)-cyano(thiazolidin-2-ylidene)thiazoles 5a-g
A suspension of thioamide 4a (1.85 g, 1 mmol), the appropriate α-bromocarbonyl (1 mmol) and
sodium bicarbonate (0.84 g, 1 mmol) in DMF (1 mL) was stirred at room temperature for 2-8 h. After
dilution with water (5 mL), the solid obtained was filtered off, washed with water (1 × 5 mL) and
ethanol (1 × 5 mL), dried in air, and recrystallized from CH3CN, to give 5a-g in 71–82% yield.
Ethyl 2-[(E)-cyano(thiazolidin-2-ylidene)methyl]thiazole-4-carboxylate (5a): mp 264-267 °C; IR
(KBr): 3,430, 2,186, 1,597, 1,561 cm-1; 1H-NMR (DMSO-d6) δ: 1.34 (t, J = 6.6 Hz, 3H, CH3), 3.52 (t,
J = 7.2 Hz, 2H, SCH2), 4.12 (t, J = 7.2 Hz, 2H, NCH2), 4.31 (q, J = 6.6 Hz, 2H, OCH2), 8.24 (s, 1H,
C=C-H), 9.93 (s, 1H, NH); MS (70 eV) m/z: 281 (M+); Anal. Calcd. for C11H11N3O2S2: C, 46.96; H,
3.94; N, 14.94; S, 22.79. Found: C, 47.07; H, 4.02; N, 14.90; S, 22.63.
(E)-2-(4-Methylthiazol-2-yl)-2-(thiazolidin-2-ylidene)acetonitrile (5b): mp 166-168 °C; IR (KBr):
1
3,438, 2,180, 1,563 cm-1; H-NMR (DMSO-d6) δ: 2.32 (s, 3H, CH3), 3.47 (t, J = 7.7 Hz, 2H, SCH2),
4.01 (t, J = 7.7 Hz, 2H, NCH2), 6.91 (s, 1H, C=C-H), 9.94 (s, 1H, NH); MS (70 eV) m/z: 223 (M+);
Anal. Calcd. for C9H9N3S2: C, 48.41; H, 4.06; N, 18.82; S, 28.71. Found: C, 48.40; H, 4.10; N, 18.74;
S, 28.76.
(E)-2-(4-Phenylthiazol-2-yl)-2-(thiazolidin-2-ylidene)acetonitrile (5c): mp 181-184 °C; IR (KBr):
1
3,438, 2,187, 1,563 cm-1; H-NMR (DMSO-d6) δ: 3.53 (t, J = 7.9 Hz, 2H, SCH2), 4.12 (t, J = 7.9 Hz,
2H, NCH2), 7.41, 8.05 (5H, Ph), 7.85 (s, 1H, C=C-H), 9.81 (s, 1H, NH); MS (70 eV) m/z: 285 (M+);
Anal. Calcd. for C14H11N3S2: C, 58.92; H, 3.88; N, 14.73; S, 22.47. Found: C, 58.94; H, 3.77; N,
14.41; S, 22.78.

Molecules 2009, 14
4854
(E)-2-(4-(4-Nitrophenyl)thiazol-2-yl)-2-(thiazolidin-2-ylidene)acetonitrile (5d): mp 264-267 °C; IR
1
(KBr): 3,433, 2,193, 1,569 cm-1; H NMR (DMSO-d6) δ: 3.62 (t, J = 7.8 Hz, 2H, SCH2), 4.13 (t,
J = 7.8 Hz, 2H, NCH2), 8.15 (s, 1H, C=C-H), 8.31 (s, 4H, Ph), 9.65 (s, 1H, NH); MS (70 eV) m/z: 330
(M+); Anal. Calcd. for C14H10N4O2S2: C, 50.90; H, 3.05; N, 16.96; S, 19.41. Found: C, 51.12; H, 2.97;
N, 17.02; S, 19.56.
(E)-2-(5-Acetyl-4-methylthiazol-2-yl)-2-(thiazolidin-2-ylidene)acetonitrile (5e): mp 255-257 °C; IR
1
(KBr): 3,421, 2,191, 1,648, 1,557 cm-1; H-NMR (DMSO-d6) δ: 2.52 (s, 3H, COCH3), 2.65 (s, 3H,
CH3), 3.52 (t, J = 7.7 Hz, 2H, SCH2), 4.12 (t, J = 7.7 Hz, 2H, NCH2), 10.13 (s, 1H, NH); MS (70 eV)
m/z: 265 (M+); Anal. Calcd. for C11H11N3OS2: C, 49.79; H, 4.18; N, 15.84; S, 24.16. Found: C, 49.68;
H, 4.02; N, 15.60; S, 24.42.
Ethyl 2-((E)-cyano(thiazolidin-2-ylidene)methyl)-4-methylthiazole-5 carboxylate (5f): mp 253-255 °C;
IR (KBr): 3,443, 2,190, 1,706, 1,562 cm-1; 1H-NMR (DMSO-d6) δ: 1.26 (t, J = 7.1 Hz, 3H, CH2CH3),
2.60 (s, 3H, CH3), 3.57 (t, J = 7.6 Hz, 2H, SCH2), 4.06 (t, J = 7.6 Hz, 2H, NCH2), 4.16 (q, J = 7.1 Hz,
2H, OCH2), 10.13 (s, 1H, NH); MS (70 eV) m/z: 295 (M+); Anal. Calcd. for C12H13N3O2S2: C, 48.80;
H, 4.44; N, 14.23; S, 21.71. Found: C, 48.76; H, 4.27; N, 14.05; S, 21.77.
(2E)-2-(4,5-Dihydro-4-oxothiazol-2-yl)-2-(thiazolidin-2-ylidene)acetonitrile (5g): mp 248-252 °C; IR
1
(KBr): 3,422, 2,193, 1,688, 1,573 cm-1; H-NMR (DMSO-d6) δ: 3.63 (t, J = 7.8 Hz, 2H, SCH2), 4.01
(s, 2H, COCH2), 4.12 (t, J = 7.8 Hz, 2H, NCH2), 10.53 (s, 1H, NH); MS (70 eV) m/z: 225 (M+); Anal.
Calcd. for C8H7N3OS2: C, 42.65; H, 3.13; N, 18.65; S, 28.46. Found: C, 42.74; H, 3.00; N, 18.46; S,
28.68.
Crystal data for 5a
Crystallographic data and details of 5a are presented in Tables 2 and 3. The X-ray diffraction data
for crystals of 5a were collected on Bruker AXS Smart Apex II CCD diffractometer at 100 K. The raw
intensity data frames were integrated with the SAINT program, which also applied corrections [21].
Data were corrected for absorption effects by the SADABS procedure [22]. The software package
SHELXTL v6.12 was used for the space group determination, structure solution and refinement. The
structures were solved by direct methods (SHELXS-97) [23], completed with difference Fourier
syntheses and refined with full-matrix least-squares using SHELXL-97 minimizing w
2
2
=1/[σ2(Fo )+(0.0440P)2+0.8400P] where P=(Fo +2Fc2)/3. CCDC 711896 contains the supplementary
crystallographic data for this article. These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/conts/retrieving.html.
Table 2. Crystallographic data for compound 5a.
Empirical formula
Formula weight
Temperature
C11H11N3O2S2
281.35
100(2) K
Crystal system
Crystal size
Monoclinic
0.30 × 0.08 × 0.04 mm
3

Molecules 2009, 14
4855
Table 2. Cont.
P21/n
Space group
a
14.9127(16) Å
b
c
β
V
Z
Dcalc
µ
4.6129(5) Å
18.658(2) Å
106.175(2)°
1232.7(2) Å3
4
1.516 Mgm-3
-1
0.429 mm
584
F(000)
θ range
Index ranges
Reflections collected
Data/restraints/parameters
Goodness-of-fit on F
Radiation
Independent reflections
Completeness to theta = 30.66°
Absorption correction
Refinement method
Final R indices [for 4865 rfln. with I>2σ(I)]
R indices (all data)
Largest diff. peak and hole
1.55 to 30.66°
-21<=h<=21, -6<=k<=6, -26<=l<=26
15302
3802/0/164
1.006
Mo Kα 0.71073 (λ, Å)
3802 [R(int) = 0.0473]
99.2 %
2
Semi-empirical from equivalents
2
Full-matrix least-squares on F
R1 = 0.0419, wR2 = 0.0947
R1 = 0.0588, wR2 = 0.1022
-3
0.368 and -0.257 e.Å
Table 3. Selected bond lengths [Å] and angles [°] for compound 5a.
S(1)-C(1)
S(1)-C(3)
S(2)-C(7)
S(2)-C(5)
O(1)-C(8)
O(2)-C(8)
O(2)-C(9)
N(1)-C(1)
N(1)-C(2)
N(2)-C(5)
N(2)-C(6)
N(3)-C(11)
C(1)-C(4)
C(2)-C(3)
C(4)-C(11)
C(4)-C(5)
C(6)-C(7)
C(6)-C(8)
C(9)-C(10)
1.7507(17)
1.8222(19)
1.7141(18)
1.7459(17)
1.207(2)
1.342(2)
1.462(2)
1.333(2)
1.463(2)
1.315(2)
1.382(2)
1.153(2)
1.385(2)
1.522(3)
1.418(2)
1.443(2)
1.358(2)
1.484(2)
1.506(3)
C(1)-S(1)-C(3)
C(7)-S(2)-C(5)
C(8)-O(2)-C(9)
C(1)-N(1)-C(2)
C(5)-N(2)-C(6)
N(1)-C(1)-C(4)
N(1)-C(1)-S(1)
C(4)-C(1)-S(1)
N(1)-C(2)-C(3)
C(2)-C(3)-S(1)
C(1)-C(4)-C(11)
C(1)-C(4)-C(5)
C(11)-C(4)-C(5)
N(2)-C(5)-C(4)
N(2)-C(5)-S(2)
C(4)-C(5)-S(2)
C(7)-C(6)-N(2)
C(7)-C(6)-C(8)
N(2)-C(6)-C(8)
C(6)-C(7)-S(2)
O(1)-C(8)-O(2)
O(1)-C(8)-C(6)
O(2)-C(8)-C(6)
90.58(8)
89.28(8)
115.60(14)
115.26(14)
110.17(14)
125.56(15)
112.39(12)
122.04(13)
104.77(14)
104.89(12)
119.36(15)
121.88(15)
118.75(15)
125.14(15)
114.32(12)
120.53(13)
116.01(16)
125.49(16)
118.41(15)
110.22(13)
124.65(16)
124.04(16)
111.30(15)
O(2)-C(9)-C(10) 107.40(15)
N(3)-C(11)-C(4) 179.5(2)

Molecules 2009, 14
4856
Conclusions
We have reported synthesis of novel 2-(E)-cyano(thiazolidin-2ylidine)thiazoles from dinitrile 3 as a
starting material. Application of these compounds to the synthesis of other heterocyclic ring systems is
currently under investigation and the results will be published in due course.
References and Notes
1. Masquelin, T.; Obrecht, D. A new general three component solution-phase synthesis of 2-amino-
1,3-thiazole and 2,4-diamino-1,3-thiazole combinatorial libraries. Tetrahedron 2001, 6, 153–156.
2. Hirai, K.; Sugimoto, H.; Ishiba, T. Heterocyclic cation systems. 14. Synthesis of thieno[3,2-
e][1,4]diazepine, thiazolo[4,5-e][1,4]diazepine, and s-triazolo[3,4-c]thiazolo[4,5-e][1,4]diazepine.
J. Org. Chem. 1980, 45, 253–260.
3. Walczynski, K.; Zuiderveld, O.P.; Timmerman, H. Non-imidazole histamine H3 ligands. Part III.
New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists. Eur. J. Med. Chem. 2005,
40, 15–23.
4. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Andreani, F.; Gehret, J.C. Synthesis of
imidazo[2,1-b]thiazoles as herbicides. Pharm. Acta Helv. 1996, 71, 247–252.
5. Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.;
Varoli, L.; Calonghi, N.; Cappadone, C.; Farruggia, G.; Zini, M.; Stefanelli, C.; Masotti, L.;
Radin, N.S.; Shoemaker, R.H. New antitumor imidazo[2,1-b]thiazole guanylhydrazones and
analogues. J. Med. Chem. 2008, 51, 809–816.
6. Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M.P.; Andreani, A.; Di
Toro, R.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.; Chiarini, A. Imidazo[2,1-
b]thiazole system: A scaffold endowing dihydropyridines with selective cardiodepressant activity.
J. Med. Chem. 2008, 51, 1592–1600.
7. Anandan, S.K.; Ward, J.S.; Brokx, R.D.; Denny, T.; Bray, M.R.; Patel, D.V.; Xiao, X.Y. Design
and synthesis of thiazole-5-hydroxamic acids as novel histone deacetylase inhibitors. Bioorg.
Med. Chem. Lett. 2007, 17, 5995–5999.
8. Potewar, T.M.; Ingale, S.A.; Srinivasan, K.V. Efficient synthesis of 2,4-disubstituted thiazoles
using ionic liquid under ambient conditions: A practical approach towards the synthesis of
Fanetizole. Tetrahedron 2007, 63, 11066–11069.
9. Zambon, A.; Borsato, G.; Brussolo, S.; Frascella, P.; Lucchini, V. Efficient access to 5-substituted
thiazoles by a novel metallotropic rearrangement. Tetrahedron Lett. 2008, 49, 66–69.
10. Franklin, P.X.; Pillai, A.D.; Rathod, P.D.; Yerande, S.; Nivsarkar, M.; Padh, H.; Vasu, K.K.;
Sudarsanam, V. 2-Amino-5-thiazolyl motif: A novel scaffold for designing anti-inflammatory
agents of diverse structures. Eur. J. Med. Chem. 2008, 43, 129–134.
11. Karegoudar, P.; Karthikeyan, M.S.; Prasad, D.J.; Mahalinga, M.; Holla, B.S.; Kumari, N.S.
Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents. Eur. J. Med.
Chem. 2008, 43, 261–267.
12. Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.W. Synthesis of 2,4-disubstituted
thiazoles from (Z)-(2-acetoxyvinyl)phenyl-λ3-iodanes: Nucleophilic substitution of λ3-iodanyl
ketones with thioureas and thioamides. J. Org. Chem. 2003, 68, 7887–7888.

Molecules 2009, 14
4857
13. Koketsu, M.; Ishihara, H. Synthesis and applications of chalcogenoamide: Thio-, seleno- and
telluroamides. Curr. Org. Synth. 2007, 4, 15–29.
14. Moghaddam, F.M.; Hojabri, L.; Dohendou, M. Microwave-assisted conversion of nitriles to
thioamides in solvent-free condition. Syn. Commun. 2003, 33, 4279–4284.
15. Poupaert, J.; Duarte, S.; Colacino, E.; Depreux, P.; McCurdy, C.; Lambert, D. Willgerodt-
kindler's microwave-enhanced synthesis of thioamide derivatives. Phosphor. Sulfur Silicon 2004,
179, 1959–1973.
16. Liboska, R.; Zyka, D.; Bobek, M. Synthesis of primary thioamides from nitriles and hydrogen
sulfide catalyzed by anion-exchange resin. Synthesis 2002, 1649–1651.
17. Manaka, A.; Sato, M. Synthesis of aromatic thioamide from nitrile without handling of gaseous
hydrogen sulfide. Syn. Commun. 2005, 35, 761–764.
18. Begley, M.C.; Chapaneri, K.; Eleanor, G.; Merritt, A. Simple microwave-assisted method for the
synthesis of primary thioamides from nitriles. Synlett 2004, 2615–2617.
19. Kaboudin, B.; Elhamifar, D. Phosphorus pentasulfide: A mild and versatile reagent for the
preparation of thioamides from nitriles. Synthesis 2006, 224–226.
20. Wang, X.J.; Huang, Z.T. Synthesis and spectral and structural characteristics of cyano substituted
heterocyclic ketene aminals. Acta. Chim. Sin. 1989, 47, 890–895.
21. SAINTPlus v6.2—Data Reduction and Correction Program; Bruker AXS, Inc.: Madison, WI,
USA, 2001.
22. Sheldrick, G.M. SADABS v2.03—Bruker/Siemens Area Detector Absorption Correction Program;
Bruker AXS, Inc.: Madison, WI, USA, 2003.
23. Sheldrick, G.M. SHELXTL v6.12—Structure Determination Software Suite; Bruker AXS, Inc.:
Madison, WI, USA, 2001.
Sample Availability: Not available.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).