INTRODUCTION:

Five-membered heterocyclic are not only found in numerous natural products, but also are widely used as valuable scaffolds in medicinal chemistry and combinatorial chemistry [1]. Thiazole and its derivatives are very useful compounds in various fields of chemistry including medicine and agriculture. For example, the thiazolium ring present in vitamin B1 serves as an electron sink, and its coenzyme form is important for the decarboxylation of α-keto acids [2]. This heterocyclic system has found broad application in drug development for the treatment of inflammation[3], hypertension [4], bacterial [5] HIV infections [6]. Aminothiazoles are known to be ligands of estrogen receptors [7] as well as a novel class of adenosine receptor antagonists [8]. Other analogues are used as fungicides, inhibiting in vivo growth of Xanthomonas, as an ingredient of herbicides or as schistosomicidal and anthelmintic drugs. In addition, thiazoles are also synthetic intermediates and common substructures in numerous biologically active compounds. The thiazole ring unit is a common structural feature in various bioactive molecules [9]. This heterocyclic system has been employed in the preparation of different important drugs required for treatment of inflammation [10] hypertensionbact[11] erial[12]HIV infections. Thus the thiazole nucleus has been much studied in the field of organic and medicinal chemistry. 2-iminothiazoline derivatives are important classes of 5-membered heterocyclic compounds, because of their wide utilities [13].

They are not only seen as building blocks in natural products, but are also considered to be extraordinarily useful scaffolds, especially in combinatorial and medicinal chemistry [14, 15]. Furthermore, thiazolines have interesting applications in agriculture as acaricides, insecticides, and plant growth regulators [16]. Although several procedures have been developed for the synthesis of 2-iminothiazoles, it can be easily synthesized from α-halocarbonyls and N,N-dialkylthiourea, and has an additional advantage over 2-aminothiazole that there are four derivatizable positions in it. some methods for the preparation of 2-iminothiazolines are effective, the drawbacks associated with most of the procedures reported in literature are, hazardous preparation of precursor substrates, difficulties in work up and isolation, the need for critical reaction conditions, low yields and longer reaction time. The use of lachrymatory α- haloketones is unavoidable for methods using thioureas as starting materials. There are only two reports on one-pot procedure for the synthesis of 2-iminothiazoline involving N,N’-dialkylthiourea and in situ generated α-bromo ketones which is limited to only symmetrical thioureas and few selected ketones thus lacking regioselectivity in 2- iminothiazoline formation[17].

RESULTS AND DISCUSSION:

In general the syntheses of 2-iminothiazoline derivatives were achieved by the reaction thiourea derivatives with various substituted α-bromoketone in the presence of suitable base. Here also we adopted the similar reaction procedure for the synthesis of 4-amino-2-iminothiazoline derivatives from the reaction of various arylthiourea derivatives with a variety of bromobenzyl cyanides. In order to improve the yield of the desired product, we have screened several reaction conditions. Firstly, we screened various solvents like acetonitrile, chloroform, dichloromethane and ethanol for this reaction; we found the reaction was efficient in acetonitrile compared to the other solvents tested which is described in Table 1. As it was known from the literature that diisopropyl amine work as best base for this kind of transformation, we also used the same base in our method. The thiourea derivatives were synthesised using the previous standard procedure. We obtained the best results when benzoylthiourea, bromobenzylcyanide and triethylamine were taken in the ratio of 1:1.1:1.5 equivalents respectively and the reaction should e performed at room temperature, drop-wise addition of bromobenzylcyanide to the mixture of thiourea derivatives and diisopropyl amine. Under these conditions, we obtained the desired product in 92 % along with trace of unidentified product which was washed out with hexane. The product was fully characterized using all spectroscopic analysis (IR, ¹HNMR, ¹³C NMR and Mass). In the IR spectrum, the characteristic peak for NH₂was observed at 3340-3222 cm^-1 and C=N was observed at 1590-1550 cm^-1.In ¹H NMR, NH₂appeared as broad singlet at δ 3.5 ppm.

Table 1: Thiazole derivatives under different solvent systems

S.No	Solvent	Time	Yield^a
1	CH₃CN	3h	45
2	CHCl₃	3h	75
3	DCM	3.5h	92
4	EtOH	4h	65

The NH proton present between carbonyl and a thiocarbonyl is sufficiently more acidic and its deprotonation by diisopropyl amine is feasible and is essential as it enhances the nucleophilicity of the sulphur towards the attack on bromo benzyl cyanide forming stable imine derivative. The lone pair on phenyl attached nitrogen attacks nitrile carbon, to form five membered thiazol derivatives containing unstable imine, which further gives the desired amines by the tertiary proton.

EXPERIMENTAL:

General procedure

To 10 m mol of thiourea derivative in dichloromethane, added diisopropyl amine(10.5 moles) and stirred at room temperature (25-30 ⁰C) for ten minutes then solution turns pale yellow. To that 10.10 mmol of bromobenzylcyanide (which was dissolved in 1 ml dichloromethane) was added drop-wise for ten minutes. After 15 mins yellow precipitate was observed. Solvent was concentrated under reduced pressure, solid material was filtered and washed with hexane to get rid of the excess of diisopropyl amine. A yellow colored crystalline compound was observed. It was purified and characterized by advanced spectroscopy.

N-(4-Amino-3, 5-diphenyl-3H-thiazol-2-ylidene)-benzamide (A)

M.P:78-80°C; IR(KBr):3220, 1670, 1598, 1560, 1219cm^-1; ¹HNMR (CDCl₃400MHz)δ 6.0(S, 2H, NH₂), 6.98.0(m, 15H, aromatic). ¹³ C NMR (CDCl₃100-MHz) δ 95.3, 124.1, 126.7, 127.2, 129.8, 131.2, 133.7, 135.5, 136.8, 137.6, 167.0, 174.4, 178.5. EI (m/z):371.1

N-(4-Amino-3-(2-chloro-phenyl)-5-phenyl-3-H-thiazol-ylidene)-benzamide (B)

M.P:113-115°C; IR(KBr):3322, 3058, 1623, 1590, 1560, 1219, 1132cm¹; ¹HNMR(CDCl₃400MHz)δ 3.7(S, 2H, NH₂), 7.1-7.9(m, 14H, aromatic); ¹³CNMR (CDCl₃100MHz)δ95.8, 126.8, 127.3, 128.8, 129.2, 129.4, 130.0, 130.7, 131.4, 131.9, 133 4, 135.3, 136.4, 166.7, 174.5.; EI (m/z):405.1.

N-(4-Amino-3-(4-methoxy-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-2-chloro-benzamide (C)

M. P: 108-110°C; IR (KBr):3337, 3063, 1673, 1585, 1554, 1304, 1247, 1173 cm^-1; ¹H NMR (CDCl₃ 400 MHz)δ 3.6(S, 2H, NH₂), 3.8(S, 3H, OCH₃), 6.9-7.7(m, 13H, aromatic); ¹³ C NMR (CDCl₃100MHz)δ 55.6, 95.2, 115.0, 126.1, 127.1, 129.1, 129.4, 130.7, 131.7, 132.1, 133.4, 134.6, 160.4, 166.9, 174.0. EI (m/z):439.0.

Furan-2-carboxylicacid(4-amino-3-(3-chloro-phenyl)-5-phenyl-3H-thiazol-2-ylidene) amide (D)

M.P:201-203°C; IR(KBr):3290, 3056, 1638, 1590, 1556, 1218, 1130cm^-1; ¹HNMR(CDCl₃400MHz)δ3.8(S, 2H, NH₂), 6.37.6(m, 12H, aromatic); ¹³CNMR(CDCl₃100MHz)δ96.0, 111.4, 115.6, 126.8, 127.4, 128.8, 129.4, 129.4, 130.0, 131.7, 133.3, 135.3, 136.2, 145.3, 151.6, 166.2.; EI(m/z):395.0.

N-(4-Amino-3-(2-nitro-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-benzamide (E)

M.P:138-140°C; IR(KBr): 3291, 1597, 1555, 1169 cm¹; ¹HNMR(CDCl₃400MHz)δ 4.0(S, 2H, NH₂), 7.27.4(m, 12H, aromatic), 7.6(d, 1H, J=8Hz), 8.2(d, 1H, J=8Hz); ¹³CNMR (CDCl₃ 100 MHz)δ97.6, 125.7, 127.1, 127.9, 128.6, 128.8, 129.2, 129.4, 131.0, 133.3, 134.5, 136.3, 146.8, 166.1, 174.3.; EI (m/z):416.1.

N-(4-Amino-3-(4-fluoro-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-benzamide (F)

M.P:143-145°C; IR(KBr):3344, 1622, 1590, 1550, 1224 cm^-1; ¹HNMR(CDCl₃400MHz)δ3.9(S, 2H, NH₂), 7.26-7.55(m, 12H, aromatic), 8.0(2H, d, J=7.2Hz); ¹³CNMR(CDCl₃100-MHz)δ 95.5, 116.8, 117.0, 26.8, 127.2, 127.5, 129.2, 130.4, 130.5, 131.4, 133.9, 136.7, 166.9, 174.9; EI (m/z): (M+1)390(100%), 217(25%), 239(25%), 391(29%).

N-(4-Amino-3-(4-bromo-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-2-chloro-benzamide (G)

M.P:148-150°C; IR(KBr): 3349, 2938, 1626, 1593, 1233, 1173 cm^-1; ¹HNMR(CDCl₃400MHz)δ 3.9(S, 2H, NH₂), 7.71(2H, d, J=7.2Hz), 7.7(d, 1H, J=7.6Hz), 7.17-7.8(m, 9H, aromatic); ¹³CNMR(CDCl₃100-MHz)δ 96.0, 123.9, 125.5, 126.2, 126.9, 127.2, 129.3, 129.4, 130.5, 130.7, 131.7, 133.0, 133.3, 134.2, 166.5, 174.0; EI (m/z): 285(100%), 217(49%), 239(50%), 484(27%), (M+2)486(37%, 488(15%).

N-(4-Amino-3-(2-nitro-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-2-chloro-benzamide (H)

M. P: 123-125 °C; IR (KBr): 3384, 1647, 1585, 1526, 1253, 1166 cm^-1; ¹HNMR(CDCl₃400MHz)δ 3.88(S, 2H, NH₂), 7.17.8(m, 9H, aromatic), 8.1(d, 1H, J=8.4Hz), 8.2(d, 2H, J=8.Hz), 8.4(d, 1H, J=8.4Hz); ¹³CNMR (CDCl₃100-MHz)δ 98.6, 125.2, 126.9, 127.9, 128.1, 129.1, 130.7, 131.1, 131.2, 131.7, 133.4, 133.5, 134.5, 135.7, 146.8, 166.4, 174.0, 188.1; EI (m/):218(15%), 230(35%), 270(90%), 451(50%), M+2, 453(18%).

N-(4-Amino-3-(3-chloro-phenyl)-5-phenyl-3H-thiazol-2-ylidene)-2-chloro-benzamide (I)

M. P:160-162°C; IR (KBr):3311, 1627, 1592, 1535, 1316, 1160 cm^-1; ¹HNMR(CDCl₃400MHz)δ 3.9(S, 2H, NH₂), 7.17.8(m, 13H, aromatic); ¹³CNMR(CDCl₃100MHz) 96.1, 122.1, 124.0, 126.2, 126.9, 127.2, 128.6, 129.2, 130.1, 130.7, 131.8, 133.4, 133.7, 134.4, 135.3, 136.0, 138.6, 166.6, 177.9; EI (m/z) :( M+1)440(20%), (M+2)442(18%), 217(30%), 239(70%), 283(95%), 2859100%).

N-(4-Amino-3, 5-bis-(4-chloro-phenyl)-3H-thiazol-2-ylidene)-benzamine (J)

M.P:190-192°C; IR (KBr)cm^-1:3300, 3061, 1631, 1597, 1564, 1327, 601; ¹H NMR (CDCl₃400MHz)δ 3.8(S, 2H, NH₂), 7.2-7.4(m, 7H, aromatic), 7.6(d, d, 2H, J=8 Hz), 7.6(d, d, 2H, J=4 Hz), 8.0 (d, 2H, J=8 Hz); ¹³CNMR (CDCl₃100-MHz) δ 94.7, 128.1, 128.6, 129.4, 129.7, 130.0, 130.3, 130.6, 131.7, 132.8, 134.0, 136.6, 166.6, 174.7. EI (m/z):439.0.

CONCLUSION:

2-iminothiazoline derivatives were achieved by the reaction thiourea derivatives with various substituted α-bromoketone in the presence of suitable base. Here also we adopted the similar reaction procedure for the synthesis of 4-amino-2-iminothiazoline derivatives from the reaction of various arylthiourea derivatives with a variety of bromo benzyl cyanides.

ACKNOWLEDGEMENT:

We thank Chandra shekar reddy, Managing Director, Enanthi Pharmaceuticals Ltd., for his encouragement and support.

REFERENCES:

1. (a) Jin, Z. Nat. Prod. Rep., 2009, 26, 382. (b) Huffman, J.; and Padgett, L. Curr. Med. Chem.,2005, 12, 1395. (c) Forte, B.; Malgesini, B.; Piutti, C.; Quartieri, F.; Scolaro, A.; and Papeo, G. Mar. Drugs.,2009, 7, 705. (d) Zhang, J.; Polishchuk, E.; Chen, J.; and Ciufolini, M. J. Org. Chem.,2009, 74, 9140. (e) Schmuck, C.; Rupprecht, D. Synthesis.,2007. 3095.

2. Breslow, R. J. Am. Chem. Soc.,1958, 80, 3719.

3. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.; and Carter, G. W. J. Med. Chem.,1988, 31, 1719.

4. Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor, D. G. Jr.; Connolly, C. J. C.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud, C. A.; Rapundalo, S. T.; Michniewicz, B. M.; and Olson, S. C. J. J. Med. Chem.,1992, 35, 2562.

5. Tsuji, K.; and Ishikawa, H. Bioorg. Med. Chem. Lett.,1994, 4, 1601.

6. Bell, F. W.; Cantrell, A. S.; Hoegberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordon, C. L.; Kinnick, M. D.; Lind, P.; Morin, J. M., Jr.; Noreen, R.; O berg, B.; Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; and Zhou. J. Med. Chem.,1995, 38, 4929.

7. Fink, B. A.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; and Katzenellenbogen, J. A. Chem. Biol.,1999, 6, 205.

8. Van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R. C.;Von Drabbe Kunzel, J. F; De Groote, M.; Visser, S.; and Ijzerman,A. P. J. Med. Chem.,2001, 44, 749.

9. Lewis, J.R. Nat. Prod. Rep.,1999, 16, 389.

10. Clemence, F.; Marter, O.L., Delevalle, F.; Benzoni, J.; Jouanen, A.; Jouquey, S.; Mouren, M.; and Deraedt, R. J. Med. Chem.,1988, 31,1453.

11. Patt, W.C.; Hamilton, H.W.; Taylor, M.D.; Ryan, M.J.; Taylor Jr, D.J.; Connolly, C.J.C.; Doharty, A.M.; Flutchko, S.R.; Sircar, I.; Steinbaugh, B.A.; Bately, B.L., Painchand, C.A.; Rapundalo, S.T.; Michniewicz, B.M.; and Olzon, S.C.J. J. Med. Chem.,1992, 35, 2562.

12. Tsuji, K.; and Ishikawa, H. Biorg. Med. Chem. Lett.,1944, 4, 1601.

13. Dondoni, A.; and Merino, P. In Comprehe. Heterocycl. Chem. II., 1996, 3, Chapter 3.06.

14. Lewis, J. R. Nat. Prod. Res.,1999, 16, 389.

15. (a) Mang, S.; Jakupovic, S.; Schunk,H.D.; Ambrosi, O.; and Jakupovic, J. J. Comb. Chem.,2006, 8,268. (b) Lin, R.; Connolly, P.; Huang, S.; Wetter, S. K.; Lu,Y.; Murray, W.; Emanuel, S. L.; Gruninger, R. H.; Fuentes-Pesquera, A. R.; Rugg, C. A.; Middleton, S. A.; and Jolliffe, L. K. J. Med. Chem.,2005, 48, 4208. (c) Borzilleri, R. M.; Bhide, R. S.; Barrish, J. C.; D. Arienzo, C. J.; Derbin, G. M.; Fargnoli, J.; Hunt, J. T.; Jeyaseelan, R. Sr.; Kamath, A.; Kukral, D. W.; Marathe, P.; Mortillo, S.; Qian, L.; Tokarski, J. S.; Wautlet, B. S.; Zheng, X.; and Lombardo, L. J. J. Med. Chem.,2006, 49, 3766. (d) Furet, P.; Bold, G.; Meyer, T.; Roesel, J.; and Guagnano, V. J. Med.Chem.,2006, 49, 4451–4454.

16. (a) Nagasaki, F.; Yamada, T.; Takahashi, E.; Kitagawa, Y.; and Hatano, R. Jpn. Kokai Tokkyo Koho JP 63250371, 18/10/1988; Chem.Abstr.,1989, 110, 192810. (b) Hoelzel, H.; Creuzburg, D.; Stohr, P.; Dehne, H.; Teller, J.; Kranz, L.; Luthardt, H.; Roethling, T.; and Kaestner, A. Ger., DD 258168, 13/07/1988; Chem. Abstr., 1989, 111, 2681g.

17. (a) Bijev, A.; and Prodanova, P. Synth. Commun. 2006, 3095. (b) Dash, B.C.; and Nandi, B.B. J. Indian. Chem. Soc.,1979, 56, 70.

Received on 15.12.2013 Modified on 14.01.2014

Asian J. Research Chem. 7(3): March 2014; Page 335-338