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Published in final edited form as: Tetrahedron Lett. 2012 Jul 3;53(37):4921–4924. doi: 10.1016/j.tetlet.2012.06.116

Microwave-assisted Hantzsch thiazole synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and thioureas

Sukanta Kamila 1, Kimberly Mendoza 1, Edward R Biehl 1,*
PMCID: PMC3501130  NIHMSID: NIHMS391318  PMID: 23175584

Abstract

N-Phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a-q) have been synthesized by the Hantzsch thiazole reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a-e) with suitably substituted thioureas using microwave heating. The ethanones (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with chloroacetylchloride in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.

Keywords: microwave irradiation, (6-phenylimidazo[2, 1-b]thiazol-5-yl)thiazol-2-amine 2-chloro-1-(6-phenylimidazo[2, 1-b]thiazol-5-yl)ethanones, 6-phenylimidazo[2, 1-b]thiazoles

1. Introduction

Many natural products and biologically active compounds containing imidazo[2,1-b]thiazole moieties have been synthesized and shown to exhibit potent biological activity.1 As shown in Figure 1, tetramisole (A) is a strong anthelmintic in the treatment of many nematodes.2 Thieno[3,2-d]pyrimidinone (B)3 and 5,6-diarylimidazo[2,1-b][1,3]thiazoles (C),4 are excellent antibacterial agents and C-2 aryl-substituted pilicides [thiazole ring-fused 2-pyridones (D)]5 exhibit anti-coccidial behavior. 11C-labeled imidazo[2,1-b]benzothiazole (E)6 has been shown to be a superb fluoroprobe in PET analysis of Alzheimer’s disease. Milne et al.7 have prepared compound (F) which possesses an imidazo[2,1-b]benzothiazole ring. Compound F, although unrelated in structure to resveratrol, showed a 1000-fold greater affinity toward SIRT1 than resveratrol. These workers also demonstrated that compound F binds to the SIRT1 enzyme–peptide substrate complex at an allosteric amino terminal site to the catalytic domain resulting in lower Michaelis constant for acetylated substrates. Compound G (Figure 1) inhibits binding of radio labeled TARC (Thymus and Activation Regulated Chemokine) and MDC (Macrophase-derived Chemokine) to CCR4 receptors on the surface of CEM8 and also inhibits the in vitro migration of CEM cells mediated by TARC.8 Subsequently another research group identified hydrazone derivatives of imidazo[2,1-b]benzothiazoles as a potent antitumor agent.9 It also been reported that imidazo[2,1-b]benzothiazole system acts as a scaffold endowing dihydropyridines with selective cardiodepressant activities.10

Figure 1.

Figure 1

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Imidazo[2,1-b]thiazoles and 2-aminothiazoles

For the past few years, our group has, also, been preparing biologically important heterocycles using microwave irradiation11a–g Of particular importance to this report, is our preparation of novel bis (2-thioxothiazolidin-4-one) derivatives,11a several of which possess strong neuroprotecting activities against Alzheimer’s and Parkinson’s diseases. We have now extended our research to the microwave-assisted synthesis of potentially biologically active N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2 amine derivatives (6a-p) in which imidazo[2,1-b]thiazole core moieties are attached to a variety of 2-aminothiazoles, and report the results herein. We were attracted to the Hantzsch synthesis since it has been one of the methods of choice for preparing aminothiazoles.12 Most of these syntheses involve extended conventional heating and give aminothiazoles in mediocre yields. For example, N-thiazoyl α-amino acids were prepared in yields generally ranging from 18–55% in a one-pot, two-step, 7–15 hours Hantzsch reaction.13 There are only a few reports on microwave-assisted Hantzsch reactions.14a–d Thus this study should add to the increasing importance of microwave-assisted reactions in heterocyclic chemistry.15

2. Results and Discussion

Scheme 1 outlines the synthesis of 6a-p. Optimum conditions for carrying out the Hantzsch microwave-assisted reactions were ascertained by carrying out a series of reactions of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a) with N-phenylthiourea. The results, which are summarized in Table 1, showed that maximum yield of 6a (95%) were obtained by heating at 90 °C for 30 min in methanol.

Scheme 1.

Scheme 1

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Schematic representation for the synthesis of compounds 6a-p.

Table 1.

Screening of solvents, reaction time, and temperature for synthesis of 6a

Condition Temp (°C) Time (min) Yield (%)
No solvent 90–120 15 trace
Ethanol 90–120 15 79
Ethanol 90–120 30 85
Methanol 90 15 71
Methanol 90 30 95
Acetonitrile 90–100 15–30 55
Water 90–120 30–45 trace
THF 70–100 30–45 trace
n-Butanol 90–110 30–45 trace
DME 90–110 30–45 trace
Sulfonale 90–130 30–45 trace
Benzene/Toluene 90–110 30–45 trace
DMF 90–110 30–45 trace
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Reaction condition: microwave irradiation using 4a: 5a (1:1 equiv) and 1 mmol of 4a, solvent (2 mL) under 250 psi pressure in a capped specially designed microwave test tube.

The results for the reactions of 6a-p are shown in Table 2. Compounds 6a-p were obtained in 89–95% yields and most of them are powder-like solids. They are insoluble in usual organic solvents such as, dichloromethane, ethyl acetate, THF, ethanol or methanol but soluble in DMF or DMSO. The proposed structures of 6a-p were confirmed, in part, by the presence of C=N signals around δ 164 ppm (indicative of an 2-aminothiazole ring) in the 13C NMR spectra. The 1H NMR spectra of these compounds showed a broad singlet (equivalent to 1H) around δ 11 ppm which corresponds to NH functionality. The starting 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a-e) were prepared by refluxing 2.5 equivalent of chloroacetylchloride and 1 equivalent of 6-phenylimidazo[2,1-b]thiazoles (3a-e) in refluxing 1,4-dioxane. Although we tried other solvents, 1,4-dioxane proved to be superior. The structures of 4a-e were confirmed by the presence of C=O signals aound δ 180 ppm and the CH2 signal around δ 47 ppm. The 1H NMR spectra of 4a-e showed characteristic singlets (equivalent to 2H) around δ 4 ppm which corresponds to -CH2 functionality. The starting 6-phenylimidazo[2,1-b]thiazoles (3a-e) were synthesized according to a literature16 procedure. All compounds were characterized by 1H NMR, 13C NMR, DEPT-135 and HRMS analysis.

Table 2.

The synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a-p) by the microwave-assisted Hantzsch reaction of ethanone derivatives (4a-e) with substituted thioureas (5a-d).

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Entry graphic file with name nihms391318u2.jpg
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6 		Yielda,b Yielda,c
1 4a, R1 = H 5a, R2 = R3 = R4 = H 6a, R1 = R2 = R3 = R4 = H 98 65
2 4b, R1 = OCH3 5a, R2 = R3 = R4 = H 6b, R1 = OCH3, R2 = R3 = R4 = 96 45
3 4c, R1 = CH3 5a, R2 = R3 = R4 = H 6c, R1 = CH3, R2 = R3 = R4 = H 92 69
4 4d, R1 = CN 5a, R2 = R3 = R4 = H 6d, R1 = CN, R2 = R3 = R4 = H 90 60
5 4e, R1 = Br 5a, R2 = R3 = R4 = H 6e, R1 = Br, R2 = R3 = R4 = H 95 78
6 4a, R1 = H 5b, R2 = R4 = H, R3 = Cl 6f, R1 = H, R2 = R4 = H, R3 = Cl 93 74
7 4a, R1 = H 5c, R2 = R4 = Cl, R3 = H 6g, R1 = H, R2 = R4 = Cl, R3 = H 99 88
8 4a, R1 = H 5d, R2 = R4 = H, R3 = OCH3 6h, R1 = H, R2 = R4 = H, R3 = OCH3 90 53
9 4c, R1 = CH3 5d, R2 = R4 = H, R3 = OCH3 6i, R1 = CH3, R2 = R4 = H, R3 = OCH3 89 47
10 4e, R1 = Br 5c, R2 = R4 = Cl, R3 = H 6j, R1 = Br, R2 = R4 = Cl, R3= H 98 67
11 4c, R1 = CH3 5b, R2 = R4 = H, R3 = Cl 6k, R1 = CH3, R2 = R4 = H, R3 = Cl 93 81
12 4c, R1 = CH3 5c, R2 = R4 = Cl, R3 = H 6l, R1 = CH3, R2 = R4 = Cl, R3 = H 96 80
13 4e, R1 = Br 5b, R2 = R4 = H, R3 = Cl 6m, R1 = Br, R2 = R4 = H, R3 = Cl 89 55
14 4e, R1 = Br 5d, R2 = R4 = H, R3 = OCH3 6n, R1 = Br, R2 = R4 = H, R3 = OCH3 91 58
15 4d, R1 = CN 5c, R2 = R4 = Cl, R3 = H 6o, R1 = CN, R2 = R4 = Cl, R3 = H 98 67
16 4b, R1 = OCH3 5c, R2 = R4 = Cl, R3 = H 6p, R1 = OCH3, R2 = R4 = Cl, R3 = H 96 70
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a

Isolated yield, all compounds were characterized by 1H NMR, 13C NMR, IR and HRMS analysis.

b

MW, 30 min, 90° C.1mmol:06mmol 4:5/2 mL MeOH

c

Conventional heating 8 h at 90°C; 0.1mmol:06mmol 4:5/2 mL MeOH d. 3.6mmol:23.4mmol/10 mL MeOH

Interestingly, the same reactions carried out under conventional reflux conditions using methanol as a solvent gave 6a-p in lower yields (Table 2), required longer reaction time (8 h) and/or the products required rigorous purification. However, the microwave reactions provided 6a-p in higher yields in faster reaction times (usually less than 30 min) and the pure products were obtained by simple washing of the crude products with cold ethanol. Our method compares favorably to that reported for the microwave-assisted synthesis of functionalized simple 2-aminothiazoles14a with respect to yield and reaction time. However a higher temperature was needed in our procedure presumably due to the more complex nature of the phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amine products.

In conclusion, we have successfully developed an easy practical access to novel series of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amine derivatives. Thus, the mild reaction condition, easy work up procedure, good to excellent yields, and readily available starting materials make this reaction an attractive method for the preparation of titled compounds. To the best of our knowledge, there has been no reported example of synthesis of this type of biologically important molecule. Efforts directed toward the synthesis of other important drug molecule with imidazo[2,1-b]thiazol-5-yl)thiazol moieties by microwave irradiation are ongoing in our laboratory. Also work is in progress to obtain biological activity (antibacterial, antifungal, anticancer, antitumor and neuroprotective kinase inhibitory activity) of these important compounds. Results in these studies will be presented in due course.

Supplementary Material

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Acknowledgments

The authors are grateful to NIH (IRC2NS064950) for generous financial support.

Footnotes

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