An efficient synthesis of thiazol-2-imine derivatives via a one-pot, three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2011.11.017

A simple and highly efficient one-pot, three-component procedure for the synthesis of thiazol-2-imines, via the reaction of aromatic α- bromoketones, primary amines, and phenyl isothiocyanate in the presence of a catalytic amount of triethylamine, is desc

Full text of DOI:10.1016/j.tetlet.2011.11.017

Tetrahedron Letters 53 (2012) 392–394
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An efficient synthesis of thiazol-2-imine derivatives via a one-pot,
three-component reaction
⇑
Majid M. Heravi , Setareh Moghimi
Department of Chemistry, School of Science, Alzahra University, PO Box 1993891176, Vanak, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and highly efficient one-pot, three-component procedure for the synthesis of thiazol-2-imines,
Received 29 August 2011
Revised 22 October 2011
Accepted 4 November 2011
Available online 17 November 2011
via the reaction of aromatic
of a catalytic amount of triethylamine, is described.
a-bromoketones, primary amines, and phenyl isothiocyanate in the presence
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reaction
Thiazol-2-imine
One-pot
Triethylamine
As a result of the convergent character of multi-component reac-
tions (MCRs), several molecules are assembled into the product in
one reaction step. Atom economy, simplicity, and time-saving fea-
tures are the advantages of MCRs for the synthesis of biologically
active compounds such as drugs and agricultural chemicals. For
these reasons MCRs are important in research.1,2
Heterocyclic compounds demonstrate various biological activi-
ties in particular, thiazoline derivatives have been applied in agri-
culture as acricides, insecticides, and plant growth regulators.3 The
thiazol-2-imine ring system has attracted considerable attention
due to its presence in several drug candidates with different bio-
logical activities4 such as anti-inflammatory, analgesic and kinase
(CDK1, CDK5, and GSK3) inhibition,5 antifungal,6 melanin-reducing
activity (skin whitening agent),7 and as platelet GPIIb/IIIa receptor
antagonists.8
Several alternative methods have been devised, which include
copper-catalyzed N-phenylation of 2-aminobenzothiazole deriva-
tives,14 condensation of thiazol-2(3H)-imines with 4-chloro and
4-isothiocyanato acridines,5 cycloaddition of 5-imino-1,2,4-thiaz-
olidin-3-ones with both electrophilic and nucleophilic unsaturated
compounds such as enamines and ester enolates,15 condensation
of (2-bromo-1-phenylethylidene)malononitrile and monoalkylated
thioureas,16 ring expansion of 1-aryl methyl-2-(thiocyanatometh-
yl)aziridine with an acyl chloride in the presence of TiCl4,17 reac-
tion of N-propargylaniline with acylisothiocyanates,18 potassium
thiocyanate with an a
-bromoketimine,19 phenylamino acetonitrile
and alkyl isothiocyanate,20 and many one-pot procedures for the
preparation of 2-acylimino thiazoline derivatives.21
Due to the biological activity of thiazol-2-imines and our contin-
uing interest in the development of new strategies toward the
synthesisof heterocyclic compounds,22–24 we report a regioselective
The Hantzsch condensation reaction was the first method
employed for the synthesis of 2-aminothiazole moiety using an
three-component reaction, between aromatic
a-bromoketones 1,
a
-haloketone and thiourea as starting materials.9 N-alkylated
imino-thiazolines could be obtained by replacing thioureas with
mono and N,N-disubstituted thioureas under different reaction
conditions10 such as in aqueous media catalyzed by diammonium
hydrogen phosphate or DABCO,11 and basic alumina under MW
Ph
N
O
R2
Br
irradiation.12 Instead of using
a-bromoketones in this procedure
N
S
EtOH, Et3N
+
R2 NH2
+
PhNCS
as one of the starting materials, Murru et al.13 reported the one-
pot reaction of 1,10-(ethane-1,2-diyl) dipyridinium bistribromide
(EDPBT), as a brominating agent, enolizable ketones, and disubsti-
tuted thioureas.
R1
reflux
7-15 min
1
3
2
4
R1
65-82%
R1 = H, Cl, Me
R2 = C6H5, C6H5CH2
⇑
Corresponding author. Tel.: +98 21 88044051; fax: +98 21 88041344.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
Scheme 1. Three component synthesis of thiazole-2-imines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.017

M. M. Heravi, S. Moghimi / Tetrahedron Letters 53 (2012) 392–394
393
Table 1
References and notes
Reaction of aromatic a-bromoketones, phenyl isothiocyanate and primary amines
1. Zhu, J.; Bienyame, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
2. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3220.
3. (a) Nagasaki, F.; Yamada, T.; Takahashi, E.; Kitagawa, Y.; Hatano, R. Jpn. Kokai
Tokyo Koho JP 63250371, 1988; Chem. Abstr. 1989, 110, 192810.; (b) Hoelzel,
H.; Creuzburg, D.; Stohr, P.; Dehne, H.; Teller, J.; Kranz, L.; Luthardt, H.;
Roethling, T.; Kaestner, A. Ger. DD 258168, 1988; Chem. Abstr. 1989, 111, 2681g.
4. (a) Ivanov, Y. Y.; Tkachenko, S. E.; Proshin, A. N.; Bachurin, S. O. Biomed. Khim.
2003, 49, 92–95; (b) Baumann, R. J.; Mayer, G. D.; Fite, L. D.; Gill, L. M.; Harrison,
B. L. Chemotherapy 1991, 37, 157–165; (c) Webel, L. M.; Degman, M. B.; Harger,
G. F.; Capps, D. B.; Islip, P. J.; Closier, M. D. J. Med. Chem. 1972, 15, 955–963; (d)
Beyer, H.; Ruhlig, G. Chem. Ber. 1956, 89, 107–114.
Entry
R1
R2
Product
Time (min)
Yielda (%)
1
2
3
4
5
6
H
H
Cl
Cl
Me
Me
C6H5
C6H5CH2
C6H5
C6H5CH2
C6H5
C6H5CH2
4a
4b
4c
4d
4e
4f
9
13
10
7
7
12
79
82
70
65
77
72
a
Isolated yield.
5. Sondhi, S. M.; Singh, N.; Lahoti, A. M.; Bajaj, K.; Kumar, A.; Lazach, O.; Meijer, L.
Bioorg. Med. Chem. 2005, 13, 4291–4299.
6. Bae, S.; Hahn, H. G.; Dai Nam, K. J. Comb. Chem. 2005, 7, 7–9.
7. Kim, D. S.; Jeong, Y. M.; Park, I. K.; Hahn, H. G.; Lee, H. K.; Kwon, S. B.; Jeong, J.
H.; Yang, S. J.; Sohn, U. D.; Park, K. C. Biol. Pharm. Bull. 2007, 30, 180–183.
8. Manaka, A.; Sato, M.; Aoki, M.; Tanaka, M.; Ikeda, T.; Toda, Y.; Yamang, Y.;
Nakaike, S. Bioorg. Med. Chem. Lett. 2001, 11, 1031–1035.
R2
S
HN
N
1
O
Ph
2 +
3
NHR2
PhHN
S
Et3N
9. (a) Hantzsch, A.; Weber, J. H. Chem. Ber. 1887, 20, 3118–3132; (b) Traumann, V.
Liebigs Ann. Chem. 1888, 31–53.
R1
5
10. (a) Vernin, G. In Thiazole and its Derivatives; Metzger, J. V., Ed.; John Wiley and
Sons: New York, NY, 1979. Part 1, Chapter 4; (b) Bramley, S. E.; Dupplin, V.;
Goberdhan, D. G.; Meakins, G. D. J. Chem. Soc., Perkin Trans. 1 1987, 639–644.
11. Balalaie, S.; Nikoo, S.; Haddadi, S. Synth. Commun. 2008, 38, 2521–2528.
12. Kasmi, S.; Hamelin, J.; Benhaoua, H. Tetrahedron Lett. 1998, 39, 8093–8096.
13. Murru, S.; Singh, C. B.; Kavala, V.; Patel, B. K. Tetrahedron 2008, 64, 1931–
1942.
6
Ph
N
R2
-H2O
4
S
N
14. Miloudi, A.; El-Abed, D.; Boyer, G.; Finet, J.; Galy, J.; Siri, D. Eur. J. Org. Chem.
2004, 1509–1516.
HO
15. Tittelbach, F.; Vieth, S.; Schneider, M. Eur. J. Org. Chem. 1998, 515–520.
16. Svetlik, J. J. Org. Chem. 1990, 55, 4740–4744.
7
R1
17. Dhooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org. Chem. 2005, 70, 227–232.
18. Sanemitsu, Y.; Kawamura, S.; Satoh, J.; Katayama, T.; Hashimoto, S. J. Pestic. Sci.
2006, 31, 305–310.
Scheme 2. Plausible mechanism for the formation of thiazole-2-imines.
19. De Kimpe, N.; Boelens, M.; Declereq, J.-P. Tetrahedron 1993, 49, 3411–3424.
20. Ingle, S. T.; Kapley, S. M.; Chande, M. S. Proc. Indian Acad. Sci., Chem. Sci. 1980,
89, 295–301.
21. (a) Wang, X.; Wang, F.; Quan, Z.; Zhang, Z.; Wang, M. Synth. Commun. 2006, 36,
2453–2460; (b) Xia, M.; Lu, Y.-D. Synth. Commun. 2006, 36, 1637–1643; (c)
Manaka, A.; Ishii, T.; Takahashi, K.; Sato, M. Tetrahedron Lett. 2005, 46, 419–422.
22. Saeedi, M.; Heravi, M. M.; Beheshtiha, Y. S.; Oskooie, H. A. Tetrahedron 2010, 66,
5345–5348.
23. Heravi, M. M.; Saeedi, M.; Beheshtiha, Y. S.; Oskooie, H. A. Heterocycles 2011, 83,
535–545.
24. Saeedi, M.; Beheshtiha, Y. S.; Heravi, M. M.; Oskooie, H. A. Heterocycles 2011, 83,
1831–1841.
primary amines 2 and phenyl isothiocyanate 3 in the presence of tri-
ethylamine, which leads to thiazol-2-imines 4 in good to excellent
yields (Scheme 1). 25
As summarized in Table 1, the reactions proceed in short times
and afford pure products in good to excellent yields, without the
need for tedious purification procedures. The structures of the syn-
thesized compounds were fully supported by IR, 1H, and 13C NMR
spectroscopy, mass spectrometry, and elemental analysis. The pre-
viously reported X-ray crystal structure13 of thiazol-2-imine also
confirmed that they have syn stereochemistry due to the steric hin-
drance between the R2 and N-Ph groups.
A proposed mechanism for the reaction is outlined in Scheme 2.
Addition of the primary amine to phenyl isothiocyanate affords
intermediate 5. The carbon of the bromomethyl group of 1 is at-
tacked by sulfur to produce 6, which is facilitated by abstraction
of the NH proton. Cyclization and dehydration result in product
4. The reaction proceeds regioselectively because of the higher
acidity of the NH proton flanked by a phenyl group.
25. General procedure for the synthesis of N-(3,4-diphenylthiazol-2(3H)-
ylidene)phenylamine (4a): To
a mixture of aniline (1 mmol) and phenyl
isothiocyanate (1 mmol) in EtOH (3 ml) under reflux, was added phenacyl
bromide (1 mmol) and Et3N (0.2 mmol). After heating for the time shown in
Table 1 (completion of the reaction was monitored by TLC), the mixture was
cooled and the resulting solid filtered and dried to give 4a as a white powder
without further purification (0.26 g, 79%): mp = 189–192 °C. lit.13 196–197 °C.
IR (KBr) cmꢀ1 1616, 1576, 1486, 1361, 1246, 1141, 766, 696. 1H NMR
:
(500.1 MHz, CDCl3) d: 5.97 (1H, s, @CH), 7.04 (2H, d, J = 7.7, H-Ar), 7.11 (2H, d,
J = 7.1, H-Ar), 7.18–7.24 (4H, m, H-Ar), 7.27–7.28 (3H, m, H-Ar), 7.30–7.38 (4H,
m, H-Ar). 13C NMR (125.7 MHz, CDCl3) d: 97.1, 121.6, 123.2, 127.2, 128.0, 128.6,
128.8, 129.1, 129.8, 130.5, 137.4, 137.9, 139.5, 151.7, 159.9. MS m/z: 328 (M+,
16), 180 (34), 149 (79), 77 (66), 69 (67), 57 (85), 43 (100). Anal. Calcd for
A previous mechanistic study13 suggested that the tertiary hy-
droxyl in the intermediate from ring closure, is protonated prior
to elimination; under our conditions the Et3N (20 mol %) cannot
neutralize all the HBr produced and thus we suggest that acid-cat-
alyzed elimination of water also occurs under our conditions. The
reaction was also studied using one equivalent of Et3N: after cool-
ing the reaction mixture, triethylamine hydrobromide separated
and was dissolved in H2O, however the desired product was ob-
tained in only a low yield.
In conclusion we have described a simple and efficient route for
the synthesis of new thiazol-2-imine derivatives via a one-pot,
three-component reaction. Short reaction times, good to excellent
yields, and the simple experimental procedure are the advantages
of this method in comparison to other routes.
C
21H16N2S: C, 76.80; H, 4.91; N, 8.53. Found: C, 76.75; H, 4.98; N, 8.39.
Compound characterization Data. N-(3-Benzyl-4-phenylthiazol-2(3H)-
ylidene)phenylamine (4b): white powder (0.28 g, 82%): mp = 156–157 °C. IR
(KBr) cmꢀ1 1618, 1583, 1488, 1321, 1234, 1123, 793, 700. 1H NMR
:
(400.2 MHz, CDCl3) d: 5.13 (2H, s, CH2), 5.83 (1H, s, @CH), 7.07–7.14 (5H, m,
H-Ar), 7.25–7.30 (5H, m, H-Ar) 7.36–7.45 (5H, m, H-Ar). 13C NMR (100.6 MHz,
CDCl3) d: 48.5, 95.9, 121.5, 123.0, 127.1, 127.2, 128.3, 128.6, 129.0, 129.1,
129.4, 131.6, 137.5, 140.4, 151.5, 159.9. MS m/z: 342 (M+, 11), 251 (24), 167
(100), 149 (32), 134 (91), 91 (56). Anal. Calcd for C22H18N2S: C, 77.16; H, 5.30;
N, 8.18. Found: C, 77.24; H, 5.23; N, 8.30.
N-[4-(4-Chlorophenyl)-3-phenylthiazol-2(3H)-ylidene]-phenylamine (4c): white
powder (0.25 g, 70%): mp = 277–279 °C. IR (KBr) cmꢀ1: 1606, 1564, 1485, 1349,
1143, 1082, 810, 756, 693.1H NMR (400.2 MHz, CDCl3) d: 6.01 (1H, s, @CH),
7.05–7.10 (5H, m, H-Ar), 7.19–7.21 (2H, d, J = 8.4, H-Ar), 7.28–7.33 (4H, m, H-
Ar), 7.35–7.40 (3H, m, H-Ar). 13C NMR (100.6 MHz, CDCl3) d: 97.9, 121.6, 123.4,
127.8, 128.5, 128.8, 129.1, 129.3, 129.4, 130.0, 134.3, 137.7, 138.8, 151.6, 159.9.
MS m/z: 364 (M+, 37Cl, 9), 362 (M+, 35Cl, 32), 214 (93), 167 (75), 149 (100), 113
(36), 77 (60), 57 (91). Anal. Calcd for C21H15ClN2S: C, 69.51; H, 4.17; N, 7.72.
Found: C, 69.52; H, 4.25; N, 7.63.
N-[3-Benzyl-4-(4-chlorophenyl)thiazol-2(3H)-ylidene]-phenylamine (4d): white
powder (0.24 g, 65%): mp = 154 °C. IR (KBr) cmꢀ1: 1614, 1582, 1486, 1321,
1231, 1125, 1086, 841, 769, 693. 1H NMR (400.2 MHz, CDCl3) d: 5.10 (2H, s,
CH2), 5.83 (1H, s, @CH), 7.08–7.18 (7H, m, H-Ar), 7.24–7.40 (7H, m, H-Ar).
13C NMR (100.6 MHz, CDCl3) d: 48.6, 96.6, 121.5, 123.2, 127.0, 127.2, 128.5,
Acknowledgments
M.M.H. is grateful for partial financial support from Alzahra
University.

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M. M. Heravi, S. Moghimi / Tetrahedron Letters 53 (2012) 392–394
128.8, 129.5, 130.0, 130.2, 135.3, 137.3, 139.3, 151.3, 159.8. MS m/z: 378
77.16; H, 5.30; N, 8.18. Found: C, 77.25; H, 5.34; N, 8.09.
N-(3-Benzyl-4-p-tolylthiazol-2(3H)-ylidene)phenylamine (4f): white powder
(M+, 37Cl, 9), 376 (M+, 35Cl, 25), 285 (28), 167 (100), 149 (36), 91 (92). Anal.
Calcd for C22H17ClN2S: C, 70.11; H, 4.55; N 7.43. Found: C, 70.13; H, 4.57; N,
7.39.
(0.26 g, 72%): mp = 106–108 °C. IR (KBr) cmꢀ1
: 1614, 1577, 1451, 1379,
1232, 1119, 1025, 875, 727, 696.1H NMR (400.2 MHz, CDCl3) d: 2.41 (3H, s,
CH3), 5.17 (2H, s, CH2), 5.83 (1H, s, @CH), 7.07–7.20 (9H, m, H-Ar), 7.22–7.30
(3H, m, H-Ar), 7.37 (2H, t, J = 7.6, H-Ar). 13C NMR (100.6 MHz, CDCl3) d: 21.4,
48.6, 95.8, 121.6, 123.2, 127.1, 127.2, 128.4, 128.6, 128.9, 129.3, 129.5,
137.5, 139.3, 140.7, 151.1, 160.3. MS m/z: 356 (M+, 10), 265 (18), 167 (100),
148 (71), 101 (27), 86 (93). Anal. Calcd for C23H20N2S: C, 77.49; H, 5.65; N,
7.86. Found: C, 77.56; H, 5.57; N, 7.87.
N-(3-Phenyl-4-p-tolylthiazol-2(3H)-ylidene)phenylamine (4e): white powder
(0.26 g, 77%): mp = 153 °C. IR (KBr) cmꢀ1: 1598, 1549, 1487, 1362, 1171,
1065, 846, 767, 693. 1H NMR (400.2 MHz, CDCl3) d: 2.32 (3H, s, CH3), 5.96
(1H, s, @CH), 7.03–7.08 (7H, m, H-Ar), 7.26–7.39 (7H, m, H-Ar). 13C NMR
(100.6 MHz, CDCl3) d: 21.2, 96.6, 121.7, 123.2, 127.5, 128.1, 128.81, 128.89,
128.9, 129.0, 129.4, 138.1, 138.2, 140.0, 151.9, 160.3. MS m/z: 342 (M+, 25),
194 (96), 167 (67), 149 (100), 91 (33), 77 (55). Anal. Calcd for C22H18N2S: C,