The first catalyst and solvent-free synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles: a comparative assessment of greenness

Abstract

A concise and efficient one pot synthesis of bicyclic imidazo[2,1-b][1,3,4]thiadiazoles via the three component Groebke–Blackburn–Bienaymé (GBB) reaction utilizing 5-aryl-1,3,4-thiadiazol-2-amines, aromatic aldehydes and isonitriles has been developed. The reactions were carried out under microwave irradiation and ultimate green conditions excluding both catalysts and solvents. Furthermore, the “greenness” of the protocol was evaluated within the ambits of green metrics and the method exhibited an excellent score in the defined parameters such as atom economy, E-factor, reaction mass efficiency, process mass intensity and carbon efficiency. This environmentally benign GBB methodology paves easy access towards the synthesis of pharmacologically significant scaffolds.

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Introduction

Fused heterocyclic structures over the last few decades have presented enormous opportunities in the fields of drug design and therapeutics.^1,2 The bicyclic core of imidazo[2,1-b][1,3,4]thiadiazoles³ is one such scaffold widely manifested in an array of pharmacophoric activities⁴ such as antihyperlipidemic,⁵ antitubercular,⁶ antitumor⁷ and antimicrobial activities.⁸ Some representative members of this class are displayed in Fig. 1 e.g., 5,6-diarylsubstituted thiazolotriazole (I) acts as a COX-2 inhibitor,⁹ compound 2-trifluoromethyl-5,6-(4′,4′′-dimethoxyphenyl)imidazo [2,1-b][1,3,4]thiadiazole (II) as an antitubercular, 5-formyl-6-aryl-imidazo[2,1-b][1,3,4]thiadiazole sulphonamide derivatives (III) and 2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1,3,4]thiadiazole (IV) as potent anti-cancer agents.

Fig. 1 Structures of pharmaceutically important imidazo[2,1-b][1,3,4]thiadiazoles.

From a synthetic point of view, to date, the routes for the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles are rather limited. In literature, this core was mainly synthesized by employing classical methods involving substituted 1,3,4-thiadiazol-2-amines and their reaction with a variety of reagents e.g. functionalized α-haloketones,^10,11 α-haloacetic acid,¹² chloroacetyl chloride,¹³ acetophenones¹⁴ and N,N-dimethylformamide dimethyl acetal.¹⁵ These classical methodologies possess several disadvantages, including the use of organic solvents, detrimental reagents, long reaction time, cumbersome work up procedures and moderate yields. Moreover, these methodologies are not well suited for a diversity oriented synthesis of imidazo[2,1-b][1,3,4]thiadiazole scaffolds.

In the past decade, Microwave-Assisted Organic Synthesis (MAOS) has gained prominence, particularly in developing sustainable catalyst-free and solvent-free versions of tedious reactions (CFR & SFR). Moreover and quite frequently, these approaches result in pollutant reduction, drastic reduction in reaction times, and formation of relatively pure products thereby avoiding tedious column chromatography. Hence, it represents a powerful green alternative to conventional synthesis.¹⁶

In this context, microwave-assisted multi-component Groebke–Blackburn–Bienaymé (GBB)¹⁷ can be a promising approach towards synthesis of imidazo[2,1-b][1,3,4]thiadiazoles. With this, we had hoped to harvest some of the benefits associated with MAOS as stated above.

Surprisingly, there are only couple of reports for syntheses of imidazo[2,1-b][1,3,4]thiadiazoles through GBB route. First in the seminal report by Bienaymé et al.,¹⁸ where a single example of N-tert-butyl-6-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-5-amine was generated using perchloric acid as catalyst in trifluoroethanol, and second by Krasavin et al.,¹⁹ where 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines were synthesized using trimethylsilyl chloride as a promoter in acetonitrile (Scheme 1). Hence there is a sufficient scope for improvement of this reaction in terms of scope, reactions conditions and environment friendliness.

Scheme 1 One pot three-component synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles.

In continuation with our constant quest aimed at utilizing known isocyanide-based MCRs for creating libraries in a combinatorial fashion,²⁰ we herein propose a straightforward, catalyst-free and solvent-less method that can easily access diversity-oriented imidazo[2,1-b][1,3,4]thiadiazoles via successive cyclisation of 5-aryl-1,3,4-thiadiazol-2-amines, aromatic aldehydes, and isonitriles under microwave irradiation (Scheme 1).

Moreover, most of the products were crystallized out from the crude reaction mixture in high yields and purity.

Results and discussion

In a pursuit to develop a catalyst and solvent-free approach for the synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles (Scheme 2).

Scheme 2 A microwave assisted protocol for the synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles.

We started our investigation with the optimization of three-component GBB reaction using 5-phenyl-1,3,4-thiadiazol-2-amines 1a (0.25 mmol), benzaldehyde 2a (0.27 mmol) and N-tert-butyl isonitrile 3a (0.30 mmol) as model substrates (Table 1) under microwave irradiation. Initially, the reaction was carried out at a mild temperature of 40 °C for 30 minutes in a sealed vial excluding solvent and catalyst (Table 1, entry 1). The reaction did not proceed at all and the starting materials remained completely unconsumed. However, by increasing the temperature to 80 °C, the desired product 4a was formed in moderate yields (61%) with still some unreacted starting material.

Table 1 Optimization of the reaction conditions for the synthesis of N-tert-butyl-2,6-diphenylimidazo[2,1-b][1,3,4]thiadiazol-5-amine 4a^a

Entry	Temperature^b (°C)	Time (min)	Yield^c (%)
a General condition: 5-phenyl-1,3,4-thiadiazol-2-amines 1a (0.25 mmol); benzaldehyde 2a (0.27 mmol); N-tert-butyl isonitrile 3a (0.3 mmol).b Anton Paar Monowave 300 reactor. Irradiation power: 850 W; ramp time: 1 min. 60 °C.c Isolated yield by recrystallization.d No reaction.
1	40	10	nr^d
2	80	10	61
3	100	10	73
4	120	10	98
5	140	10	85
6	160	10	87
7	120	5	98
8	120	2	90

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Next, the reaction was conducted at various temperatures viz. 120 °C, 140 °C and 160 °C for 10 min, furnishing the products in 98%, 85% and 87% yields, respectively (Table 1, entries 4–6). Furthermore, to reduce the reaction time, the reaction mixture was irradiated at 5 and 2 minutes interval which furnished the product in 98% and 90% yield, respectively (Table 1, entries 7 and 8). Following this examination, the best result was obtained at 120 °C, which yielded the product 4a in 98% yield under 5 minutes of microwave irradiation (Table 1, entry 7). It is particularly advantageous; since the reaction is selective and quantitative, the product form exclusively and no column purification is required in most of the cases. The optimization of reaction yield versus the reaction temperature is mentioned in Fig. 2.

Fig. 2 Reaction temperature vs. reaction yield (%) for the synthesis of N-tert-butyl-2,6-diphenylimidazo[2,1-b][1,3,4]thiadiazol-5-amine 4a.

After corroborating the feasibility of the reaction, the scope and robustness of this one-pot three-component domino 2-arylimidazo[2,1-b][1,3,4]thiadiazoles synthesis was evaluated by employing a diverse range of 5-aryl-1,3,4-thiadiazol-2-amines, aldehydes and isocyanides (Table 2). To see the effect of heteroatom on the amine functionality towards the reaction efficiency, we attempted the reaction with 5-aryl-1,3,4-oxadiazol-2-amine and observed that it failed to provide the respective product 4s (0%) and only starting material was recovered.

Table 2 Library of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles via the one-pot GBB condensation

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The electronic nature of the 5-substituted-1,3,4-thiadiazol-2-amines and aldehydes had an impact on the reaction efficiency. It was found that a variety of 5-aryl-1,3,4-thiadiazol-2-amines derived from benzoic acid containing both electron-donating and electron-withdrawing groups on the phenyl ring were employed and were well tolerated under the optimal reaction conditions. 5-Aryl-1,3,4-thiadiazol-2-amines having electron-donating groups e.g., methoxy 4o (85%) & 4p (87%) and chloro 4c (91%) & 4d (91%), etc. resulted in good yields of the product. On the contrary, electron-withdrawing groups on the amine functionality e.g., nitro 4g (85%) & 4l (85%) yielded slightly lower yields.

Diverse aromatic aldehydes (electron-donating as well as electron-withdrawing) were also well accommodated. It is worth mentioning that aromatic aldehydes with an electron-withdrawing group viz. nitro 4d (91%), 4p (87%) and fluoro 4q (89%) & 4r (86%) etc. resulted in good yields of the product as expected. However, aromatic aldehydes bearing electron-donating substituents e.g. methoxy 4b (90%), 4h (85%) etc. also well accepted. Therefore, the present methodology works well with both activated and deactivated systems. It is worth mentioning that deactivating systems containing e.g. nitro & fluoro also gave excellent yields without adding any catalyst or promoters as utilized in Krasavin et al. method¹⁹ and in this context, it scores over it.

Similarly, the reaction seemed well tolerant to a range of isocyanides e.g. aliphatic (N-tert-butyl), alicyclic (cyclohexyl) and aromatic (2,6-dimethylphenyl) isocyanides. From the results, it seemed that the reaction worked efficiently and smoothly with N-tert-butyl and 2,6-dimethylphenyl isocyanides resulting in crystallization of the pure products. However, reactions employing cyclohexyl isocyanide 4f (90%), 4i (89%), 4k (91%) & 4m (86%) required column chromatography to isolate the pure products, albeit in excellent yields.

The structure of all the newly synthesized imidazo[2,1-b][1,3,4]thiadiazoles were deduced by their satisfactory spectral data (¹H, ¹³C NMR and HRMS). By taking the entire experimental outcome into consideration, a plausible mechanistic pathway for the synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles is outlined in Scheme 3. The first step is believed to be the imine (I) formation by the reaction of 5-aryl-1,3,4-thiadiazol-2-amines 1a–d and aldehyde 2a–h, followed by trapping of the imine carbon by isocyanides 3a–c through [4 + 1] cycloaddition, yields nitrilium ion intermediate (II), which upon aromatization forms 2-arylimidazo[2,1-b][1,3,4]thiadiazoles (4a–r).

Scheme 3 Tentative reaction mechanism for the synthesis of 2-arylimidazo[2,1-b][1,3,4]thiadiazoles.

From the standpoint of green chemistry, it would be imperative to evaluate our chemical process as environmentally benign, for which quantification of sustainable practices such as measuring the “greenness” of our method would be essential.^21–24 Several green metrics such as Atom Economy (AE), E-factor, Process Mass Intensity (PMI), Reaction Mass Efficiency (RME) and Carbon Efficiency (CE) has been developed which enables us to evaluate chemical processes in terms of waste, energy usage and carbon efficiency. Table 3 provides the calculation of the illustrative metrics for all the synthesized compounds.

Table 3 Summary of green metrics for the synthesized 2-arylimidazo[2,1-b][1,3,4]thiadiazoles

S. no.	Yield (%)	%AE	%CE	E-factor	%RME	PMI
4a	98	95.08	89.65	0.153	86.05	1.153
4b	90	95.45	82.85	0.252	79.74	1.252
4c	91	95.50	83.83	0.228	81.39	1.228
4d	91	95.96	82.91	0.240	80.73	1.240
4e	87	95.65	78.61	0.308	76.43	1.308
4f	90	90.35	82.15	0.261	79.32	1.261
4g	85	96.33	78.34	0.308	76.40	1.308
4h	85	96.24	76.99	0.324	75.51	1.324
4i	89	96.09	83.98	0.219	82.02	1.219
4j	92	95.92	84.70	0.209	82.66	1.209
4k	91	95.78	83.07	0.235	81.01	1.235
4l	85	96.43	76.80	0.316	75.76	1.316
4m	86	96.05	78.49	0.305	76.05	1.305
4n	93	95.82	85.47	0.201	83.26	1.201
4o	85	95.45	78.63	0.317	76.31	1.317
4p	87	95.92	80.48	0.284	77.85	1.284
4q	89	95.39	81.91	0.268	78.84	1.268
4r	86	95.72	79.26	0.299	76.98	1.299

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The higher environmental compatibility factors such as smaller E-factor, higher atom economy make the present methodology an ideal green and sustainable process. Furthermore, we evaluated the greenness of our protocol with respect to existing literature reports for the synthesis of fused imidazo[2,1-b][1,3,4]thiadiazoles (Fig. 3), the results are collected and tabulated in Table 4. These results corroborates that our protocol for synthesis of imidazo[2,1-b][1,3,4]thiadiazoles has a greener profile over published traditional procedures when identical chemistries of reactions are compared. The detailed calculations are explained in the ESI.†

Fig. 3 E-factor and PMI profiles showing individual contributions for the synthesis of fused imidazo[2,1-b][1,3,4]thiadiazoles.

Table 4 A comparison of efficiency between present and reported methods for the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles^a

Entry	Solvent/reaction conditions	Temp. (°C)	Time	Yield (%)	E-factor	PMI
a Calculations upto the crude product in all cases.
1.	5 mol% HClO4, TFE^18	25	18 h	76	13.36	14.46
2.	TMSCl, ACN/DCM^19	70	12 h	84	4.23	5.23
3.	No solvent, no catalyst	120	5 min	98	0.153	1.153

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In summary, we report a simple and straightforward one-pot three-component catalyst and solvent free integrated protocol for the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles in good yields under microwave irradiation. This convergent and versatile method presents broad substrate scope and excellent functionality tolerance. This approach enables the rapid assembly of diverse imidazo[2,1-b][1,3,4]thiadiazoles based frameworks utilizing all the three components efficiently. More importantly, the methodology works well for both activating and deactivating starting material. This methodology therefore exemplifies the reconciliation of structural complexity and operational simplicity in an environmentally benign manner. In all the cases, but a few ones, the isolation and purification of compounds were done by mere filtration and ethanol washing which makes the process tailor made for automation in a high throughput synthetic platform. Furthermore, a variety of green metrics have been explored and our method exemplary fit in this grid.

Experimental section

General procedure for the synthesis of imidazo[2,1-b][1,3,4]thiadiazole fused heterocycles (4a–r)

5-Aryl-1,3,4-thiadiazol-2-amines 1a (0.25 mmol), aromatic aldehyde 2a (0.27 mmol) and isocyanide 3a (0.3 mmol) were taken in G-10 glass vial capped with Teflon septum. After a pre-stirring of 1 or 2 minutes at RT, the vial was subjected to microwave irradiation with the initial ramp time of 1 minute at 60 °C. The temperature was then raised to 120 °C with the holding time of 5 minutes. The products were recrystallized using EtOH. Some of the viscous products (4f, 4i, 4k, 4m) were purified by silica gel column chromatography (ethyl acetate/hexane). All compounds were fully characterized by Mp, IR, NMR, mass spectral data.

N-tert-Butyl-2,6-diphenylimidazo[2,1-b][1,3,4]thiazol-5 amine (4a)

Yellow solid (98%), Mp 174–176 °C, IR (4000–600 cm⁻¹): ν_max = 3431 (stretch NH), 1642 (stretch C=N), 1559 (bend NH), 1412, 1339 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.10–8.15 (m, 2H), 7.85–7.92 (m, 2H), 7.47–7.55 (m, 3H), 7.40 (m, 2H), 7.22–7.28 (m, 1H), 3.16 (brs, NH), 1.20 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 167.1, 160.5, 140.8, 138.4, 135.1, 133.6, 131.5, 130.7, 130.4, 129.3, 128.2, 127.7, 126.9, 56.3, 30.3. HR-MS (ESI) for C₂₀H₂₀N₄S m/z calcd: 349.1481; found: 349.1516 [M + H]⁺.

N-tert-Butyl-6(4-methoxyphenyl)-2-phenylimidazo[2,1-b][1,3,4]thiazol-5-amine (4b)

Yellow solid (90%), Mp 212–213 °C, IR (4000–600 cm⁻¹): ν_max = 3411 (stretch NH), 1645 (stretch C=N), 1562 (bend NH), 1509, 1406, 1339 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.06 (d, 2H, J = 8.5 Hz), 7.83–7.91 (m, 2H), 7.46–7.54 (m, 3H), 6.94 (d, 2H, J = 8 Hz), 3.85 (s, 3H), 3.10 (brs, 1H), 2.17 (brs, enaminic proton), 1.19 (s, 9H). ¹³C NMR (CDCl₃, 125 MHz): δ_C (ppm) 160.0, 158.5, 140.6, 138.3, 131.4, 130.7, 129.2, 128.1, 127.8, 126.7, 125.8, 113.6, 56.1, 55.2, 30.3. HR-MS (ESI) for C₂₁H₂₂N₄OS m/z calcd: 379.1587; found: 379.1580 [M + H]⁺.

N-tert-Butyl-2-(4-chlorophenyl)-6-phenylimidazo[2,1-b][1,3,4]thiazol-5-amine (4c)

Yellow solid (91%), Mp 219–221 °C, IR (4000–600 cm⁻¹): ν_max = 3437 (stretch NH), 1639 (stretch C=N), 1559 (bend NH), 1409, 1336 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.11 (d, 2H, J = 10 Hz), 7.82 (d, 2H, J = 10 Hz), 7.48 (d, 2H, J = 10 Hz), 7.40 (t, 2H, J = 10 Hz), 7.24–7.29 (m, 1H), 3.15 (brs, NH), 2.17 (brs, enaminic proton), 1.19 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 159.2, 138.7, 137.7, 135.0, 129.6, 129.1, 128.3, 128.0, 127.0, 126.9, 126.81, 126.80, 56.4, 30.3. HR-MS (ESI) for C₂₀H₁₉ClN₄S m/z calcd: 383.1091; found: 383.1125 [M + H]⁺.

N-tert-Butyl-2(4-chlorophenyl)-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiazol-5-amine (4d)

Yellow solid (90%), Mp 221–222 °C, IR (4000–600 cm⁻¹): ν_max = 3434 (stretch NH), 2952 (sp²-CH), 2919 (sp³-CH), 1592 (stretch C=N), 1509 (asymm. stretch NO₂), 1468 (symm. stretch NO₂), 1327 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.42 (d, 2H, J = 12 Hz), 8.24 (d, 2H, J = 8 Hz), 7.82 (d, 2H, J = 8 Hz), 7.51 (d, 2H, J = 12 Hz), 3.15 (brs, NH), 1.10 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 160.4, 160.4, 146.2, 141.6, 141.6, 138.2, 129.8, 128.7, 128.1, 127.0, 123.7, 57.0, 30.4. HR-MS (ESI) for C₂₀H₁₈ClN₅O₂S m/z calcd: 450.0761; found: 450.0750 [M + Na]⁺.

N-(2,6-Dimethylphenyl)-2,6-diphenylimidazo[2,1-b][1,3,4]thiazol-5-amine (4e)

Yellow solid (87%), Mp 194–195 °C, IR (4000–600 cm⁻¹): ν_max = 3417 (stretch NH), 1642 (stretch C=N), 1559 (bend NH), 1409 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.02 (d, 2H, J = 8 Hz), 7.69 (d, 2H, J = 7 Hz), 7.41–7.51 (m, 3H), 7.36 (t, 2H, J = 7.5 Hz), 7.22–7.27 (m, 1H), 6.99 (d, 2H, J = 7.5 Hz), 6.853 (t, 1H, J = 7.5 Hz), 5.29 (brs, NH), 2.17 (s, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 161.0, 140.7, 140.5, 136.2, 133.9, 131.5, 130.3, 129.1, 129.1, 128.3, 128.1, 126.9, 126.7, 126.1, 124.7, 122.1, 18.6. HR-MS (ESI) for C₂₄H₂₀N₄S m/z calcd: 397.1481; found: 397.1473 [M + H]⁺.

N-Cyclohexyl-2,6-diphenylimidazo[2,1-b][1,3,4]thiazol-5-amine (4f)

Yellow solid (90%), Mp 211–213 °C, IR (4000–600 cm⁻¹): ν_max = 3437 (stretch NH), 1639 (stretch C=N), 1556 (bend NH), 1412, 1339 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.04 (d, 2H, J = 8 Hz), 7.86–7.92 (m, 2H), 7.48–7.54 (m, 3H), 7.42 (t, 2H, J = 8 Hz), 7.24–7.28 (m, 1H) (merge with CDCl₃ region (7.260)), 3.24–3.40 (m, 2H), 1.92–2.05 (m, 2H), 1.68–1.78 (m, 2H), 1.58–1.62 (m, 1H), 1.15–1.36 (m, 5H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 160.9, 160.8, 134.8, 134.0, 131.6, 130.7, 129.3, 128.7, 128.6, 126.9, 126.6, 125.9, 56.8, 34.2, 25.9, 25.0. HR-MS (ESI) for C₂₂H₂₂N₄S m/z calcd: 375.1637; found: 375.1648 [M + H]⁺.

N-tert-Butyl-6-(2-chloro-5-nitrophenyl)-2-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-amine (4g)

Orange solid (85%), Mp 210–211 °C, IR (4000–600 cm⁻¹): ν_max = 3428 (stretch NH), 1642 (stretch C=N), 1559 (bend NH), 1412 (asymm. Stretch NO₂), 1341 (symm. stretch NO₂). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.55 (d, 1H, J = 2.4 Hz), 8.39 (dt, 2H, J = 8 Hz, J = 4 Hz), 8.17 (dd, 1H, J = 8 Hz, J = 4 Hz), 8.11 (dt, 2H, J = 8 Hz, J = 4 Hz), 7.65 (d, 1H, J = 8.8 Hz), 3.28 (brs, NH), 2.17 (brs, enaminic proton), 1.06 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 158.9, 149.6, 139.6, 135.9, 135.5, 135.4, 135.3, 131.0, 129.2, 127.8, 127.6, 124.7, 123.7, 56.0, 30.0. HR-MS (ESI) for C₂₀H₁₇ClN₆O₄S m/z calcd: 495.0612; found: 473.0590 [M + Na]⁺.

2-(4-Chlorophenyl)-N-(2,6-dimethylphenyl)-6-(4-methoxy phenyl)imidazo[2,1-b][1,3,4]thiazol-5-amine (4h)

Yellow solid (85%), Mp 197–198 °C, IR (4000–600 cm⁻¹): ν_max = 3414 (stretch NH), 1642 (stretch C=N), 1559 (bend NH), 1412, 1339 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 7.96 (d, 2H, J = 8 Hz), 7.62 (dt, 2H, J = 8 Hz, J = 4 Hz), 7.41 (dt, 2H, J = 8 Hz, J = 4 Hz), 6.99 (d, 2H, J = 8 Hz), 6.90 (d, 2H, J = 8 Hz), 6.84 (t, 1H, J = 8 Hz), 5.24 (brs, NH), 3.82 (s, 3H), 2.15 (s, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 158.9, 137.7, 129.5, 129.3, 129.0, 127.9, 127.9, 127.9, 127.5, 122.1, 113.9, 55.3, 18.7. HR-MS (ESI) for C₂₅H₂₁ClN₄OS m/z calcd: 461.1197; found: 461.1210 [M + H]⁺.

2,6-Bis(4-chlorophenyl)-N-cyclohexylimidazo[2,1-b][1,3,4]thiadiazol-5-amine (4i)

Yellow solid (92%), Mp 223–224 °C, IR (4000–600 cm⁻¹): ν_max = 3437 (stretch NH), 1639 (stretch C=N), 1559 (bend NH), 1409, 1336 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.02 (d, 2H, J = 8.5 Hz), 7.82 (d, 2H, J = 8 Hz), 7.49 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 3.15–3.30 (m, 2H), 1.87–2.00 (m, 2H), 1.68–1.80 (m, 2H), 1.50–1.68 (m, 1H), 1.13–1.40 (m, 5H). ¹³C NMR (CDCl₃, 125 MHz): δ_C (ppm) 159.7, 139.7, 137.7, 133.6, 133.1, 132.2, 126.6, 128.9, 128.6, 128.0, 127.1, 56.8, 33.9, 25.8, 24.8. HR-MS (ESI) for C₂₂H₂₀Cl₂N₄S m/z calcd: 465.0677; found: 465.0653 [M + Na]⁺.

N-tert-Butyl-6-(4-methoxyphenyl)-2-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-amine (4j)

Red solid (92%), Mp 210–211 °C, IR (4000–600 cm⁻¹): ν_max = 3431 (stretch NH), 1645 (stretch C=N), 1562 (asymm. stretch NO₂), 1415 (symm. stretch NO₂), 1338 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.34–8.38 (m, 2H), 8.03–8.08 (m, 4H), 6.92–6.97 (m, 2H), 3.85 (s, 3H), 3.11 (brs, NH), 2.17 (brs, 1H), 1.20 (s, 9H). ¹³C NMR (CDCl₃, 125 MHz): δ_C (ppm) 158.9, 157.2, 149.2, 140.6, 139.4, 136.4, 128.2, 127.5, 127.3, 126.1, 124.6, 113.7, 56.3, 55.3, 30.4. HR-MS (ESI) for C₂₁H₂₁N₅O₃S m/z calcd: 424.1438; found: 424.1463 [M + H]⁺.

2-(4-Chlorophenyl)-N-cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiazol-5-amine (4k)

Yellow solid (91%), Mp 201–202 °C, IR (4000–600 cm⁻¹): ν_max = 3423 (stretch NH), 1642 (stretch C=N), 1559 (bend NH), 1415, 1336 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.03 (d, 2H, J = 7.5 Hz), 7.83 (d, 2H, J = 8.5 Hz), 7.49 (d, 2H, J = 8.5 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.24–7.28 (m, 1H), 3.23–3.36 (m, 2H), 2.170 (s, enaminic proton), 1.91–2.02 (m, 2H), 1.69–1.77 (m, 2H), 1.15–1.35 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 169.7, 169.6, 134.7, 129.6, 129.1, 129.1, 128.9, 128.0, 126.7, 125.9, 125.9, 125.9, 56.8, 51.0, 34.2, 25.8, 24.8. HR-MS (ESI) for C₂₂H₂₁ClN₄S m/z calcd: 409.1248; found = 409.1225 [M + H]⁺.

N-(2,6-Dimethylphenyl)-2,6-bis(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiazol-5-amine (4l)

Brown solid (85%), Mp 180–181 °C, IR (4000–600 cm⁻¹): ν_max = 3434 (stretch NH), 1639 (stretch CN), 1553 (asymm. stretch NO₂), 1409 (symm. stretch NO₂), 1341 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 8.32 (d, 2H, J = 8.4 Hz), 8.21 (d, 2H, J = 8.8 Hz), 8.17 (d, 2H, J = 8.6 Hz), 7.85 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 7.4 Hz), 6.94 (t, 1H, J = 7.3 Hz), 5.41 (brs, NH), 2.17 (s, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 149.5, 146.2, 140.7, 140.1, 139.4, 139.4, 135.6, 129.3, 129.3, 127.6, 127.6, 126.3, 124.6, 123.9, 123.7, 18.7. Anal. calcd for C₂₄H₁₈N₆O₄S; C, 59.25; H, 3.73; N, 17.27. Found: C, 59.29; H, 3.81; N, 17.31.

2-(4-Chlorophenyl)-N-cyclohexyl-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiazol-5-amine (4m)

Yellow solid (86%), Mp 208–209 °C, IR (4000–600 cm⁻¹): ν_max = 3428 (stretch NH), 1636 (stretch C=N), 1565 (bend NH), 1409 (stretch C–N). ¹H NMR (CDCl₃, 500 MHz): δ_H (ppm) 7.98 (d, 2H, J = 9 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.48 (d, 2H, J = 8.5 Hz), 6.97 (d, 2H, J = 9 Hz), 3.85 (s, 3H), 3.18–3.27 (bm, 2H), 1.92–1.98 (m, 2H), 1.71–1.78 (m, 2H), 1.17–1.33 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 177.8, 177.8, 177.5, 161.6, 157.3, 142.0, 129.5, 127.9, 127.2, 113.9, 113.9, 113.9, 55.3, 55.3, 34.0, 25.8, 24.8. HR-MS (ESI) for C₂₃H₂₃ClN₄OS m/z calcd: 461.1173; found: 461.1136 [M + Na]⁺.

N-tert-Butyl-2-(4-chlorophenyl)-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiazol-5-amine (4n)

Off white solid (85%), Mp 209–210 °C, IR (4000–600 cm⁻¹): ν_max = 3428 (stretch NH), 1642 (stretch C=N), 1562 (bend NH), 1415, 1336 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.05 (dt, 2H, J = 8 Hz, J = 4 Hz), 7.81 (dt, 2H, J = 8 Hz, J = 4 Hz), 7.48 (dt, 2H, J = 8 Hz, J = 4 Hz), 6.94 (dt, 2H, J = 8 Hz, J = 4 Hz), 3.85 (s, 3H), 3.09 (brs, NH), 2.18 (brs, enaminic proton), 1.19 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 158.7, 137.5, 137.5, 129.6, 129.2, 128.1, 127.9, 127.7, 127.7, 113.7, 56.2, 55.3, 30.4. Anal. calcd for C₂₁H₂₁ClN₄OS; C, 61.08; H, 5.13; N, 13.57. Found: C, 61.13; H, 5.18; N, 13.63.

N-tert-Butyl-2(4-methoxyphenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-amine (4o)

Off white solid (85%), Mp 204–204.5 °C, IR (4000–600 cm⁻¹): ν_max = 3443 (stretch NH), 1640 (stretch C=N), 1563 (bend NH), 1467 (stretch C–N), 1414 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.10 (d, 2H, J = 8 Hz), 7.80 (d, 2H, J = 8.8 Hz), 7.38 (t, 2H, J = 8 Hz), 7.22–7.26 (m, 1H), 6.99 (d, 2H, J = 8.8 Hz), 3.87 (s, 3H), 3.13 (brs, NH), 1.18 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 162.3, 160.4, 135.2, 135.2, 128.4, 128.2, 128.2, 126.8, 126.8, 126.8, 123.3, 114.7, 56.3, 55.6, 30.3. Anal. calcd for C₂₁H₂₂N₄OS; C, 66.64; H, 5.86; N, 14.80. Found: C, 66.70; H, 5.80; N, 14.86.

N-tert-Butyl-2(4-methoxyphenyl)-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-amine (4p)

Yellow solid (87%), Mp 227–227.5 °C, IR (4000–600 cm⁻¹): ν_max = 3447 (stretch NH), 1643 (stretch C=N), 1567 (bend NH), 1412 (stretch C–N), 1340 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.40 (d, 2H, J = 8 Hz), 8.22 (d, 2H, J = 8 Hz), 7.80 (d, 2H, J = 8 Hz), 7.00 (d, 2H, J = 8 Hz), 3.88 (s, 3H), 3.14 (brs, NH), 2.16 (s, enaminic proton), 1.20 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 162.6, 146.0, 141.9, 136.0, 128.6, 128.5, 126.8, 123.7, 122.8, 122.8, 114.8, 57.0, 55.7, 30.4. Anal. calcd for C₂₁H₂₁N₅O₃S; C, 59.56; H, 5.00; N, 16.54. Found: C, 59.65; H, 5.08; N, 16.61.

N-tert-Butyl-6-(4-fluorophenyl)-2-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-amine (4q)

Yellow solid (89%), Mp 233.7–233.9 °C, IR (4000–600 cm⁻¹): ν_max = 3446 (stretch NH), 1639 (stretch C=N), 1559 (bend NH), 1360 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.09–8.16 (m, 2H), 7.83–7.90 (m, 2H), 7.46–7.53 (m, 3H), 7.06 (t, 2H, J = 8 Hz), 3.07 (brs, NH), 2.16 (s, enaminic proton), 1.17 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 163.1, 160.7, 160.6, 131.6, 131.2, 131.2, 130.6, 130.2, 129.3, 129.1, 128.6, 128.5, 127.1, 126.8, 115.2, 115.0, 56.3, 30.3. Anal. calcd for C₂₀H₁₉FN₄S; C, 65.55; H, 5.23; N, 15.29. Found: C, 65.62; H, 5.32; N, 15.35.

N-tert-Butyl-2-(4-chlorophenyl)-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-amine (4r)

Yellow solid (86%), Mp 229.0–229.2 °C, IR (4000–600 cm⁻¹): ν_max = 3431 (stretch NH), 1648 (stretch C=N), 1564 (bend NH), 1349 (stretch C–N). ¹H NMR (CDCl₃, 400 MHz): δ_H (ppm) 8.09–8.15 (m, 2H), 7.80 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.07 (t, 2H, J = 8.8 Hz), 3.07 (brs, NH), 2.17 (s, enaminic proton), 1.18 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ_C (ppm) 163.2, 160.7, 159.3, 140.7, 137.7, 131.1, 131.1, 129.6, 129.1, 128.6, 128.5, 128.0, 115.2, 115.0, 56.4, 30.3. Anal. calcd for C₂₀H₁₈ClFN₄S; C, 59.92; H, 4.53; N, 13.98. Found: C, 59.99; H, 4.62; N, 14.06.

Acknowledgements

We gratefully acknowledge the Department of Science and Technology (DST), Govt. of India for financial support (Grant no. SR/FT/CS-55/2011). The authors P. W. and T. K. thank MHRD for the award of JRF and Post-Doctoral Fellowship, respectively.

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Footnote

† Electronic supplementary information (ESI) available: Representative ¹H, ¹³C NMR and HRMS spectra. See DOI: 10.1039/c5ra06747b

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