One-Pot Synthesis of Imidazo[2,1-b]thiazole via Groebke–Blackburn–Bienaymé Reaction under Free Catalyts ^†

Abstract

The imidazo[2,1-b]thiazole scaffold is widely present in natural and synthetic compounds with important properties or biological activities, such as anti-inflammatory, anti-bacterial, anti-tuberculosis, cytotoxic, anthelmintic, anti-hypertensive, or herbicidal properties. The isocyanide multicomponent reaction (I-MCR) process is a greener alternative and efficient synthetic tool. Herein, we describe a novel methodology, one-pot synthesis for the synthesis of imidazo[2,1-b]thiazole by Groebke–Blackburn–Bienaymé reaction (GBBR) using little-explored 3-formylchromone.

1. Introduction

Many natural and synthetic products are based on the imidazo[2,1-b]thiazole framework. The fused five-membered heterocyclic rings containing bridgehead nitrogen and a sulfur atom are the core of molecules exhibiting important biological activities such as anthelmintic, anti-alzheimer, anti-hypertensive, and herbicidal properties (Figure 1) [1,2,3,4].

As the imidazo[2,1-b]thiazole scaffolds have significant applications, a large number of routes for their synthesis have been developed. However, the classical methods imply stepwise synthesis, resulting in long time reactions, high temperatures, limited scope, low yields, and metal-catalyzed processes [5,6,7].

The isocyanide-based multicomponent reactions (I-MCR) have been used as an alternative to overcome this problem. The Groebke–Blackburn–Bienaymé reaction (GBBR) provides simplicity in a one-pot reaction and high atom economy. However, there are few reports of GBBR regarding imidazo[2,1-b]thiazoles compared with imidazo[1,2-a]pyridines [8].

As far as our survey of the literature is concerned, few reports of the synthesis of imidazo[2,1-b]thiazoles by I-MCR processes have been reported (Scheme 1) [9].

Chromone derivatives are abundant in nature and exhibit a wide range of pharmacological activities [10]. Herein, we report the synthesis of imidazo[2,1-b]thiazoles holding chromone moiety by GBBR, increasing the diversity of isocyanides.

2. Results and Discussion

The optimization of the reactions was conducted by 3-formylchromone (1), 2-aminothiazole (2), and tert-butyl isocyanide (3). Initially, the GBBR was performed by stirring in methanol at 85 °C without a catalyst (

Table 1. Screening conditions for the synthesis of 4a.

Entry	Solvent	Time (min)	Temp °C	Yield
1	MeOH	60	85	33
2	MeCN	60	85	40
3	PhMe	60	85	68
4	PhMe	30	100	78

, entry 1), giving the desired product at a 33% yield. To perform the reaction again acetonitrile was chosen, but a similar yield was obtained (entry 2); then, the reaction was carried out by employing toluene, affording the product in 68% of yield (entry 3). Finally, carrying out the reaction in the same conditions with toluene and with an increase in temperature to 100 °C improved the yield to 78% and decreased the reaction time to 30 min (entry 4).

After optimizing the conditions, we explored the versatility of the methodology through variations of isocyanide reagents. The respective imidazo[2,1-b]thiazoles products 4a–e (Scheme 2) were obtained in moderate yields (74–78%), synthesized under the optimized conditions (Table 1, entry 4).

3. Experimental Section

3.1. General Information, Instrumentation, and Chemicals

¹H and ¹³C NMR spectra were acquired on Bruker Advance III spectrometers (500 MHz). The solvent CDCl₃ was used for NMR samples. Chemical shifts are reported in parts per million (δ/ppm). The internal reference for NMR spectra was TMS at 0.00 ppm. Coupling constants are reported in Hertz (J/Hz). Multiplicities of the signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). NMR spectra were analyzed using the Mestre Nova software (version 6.0.2-5475). IR spectra were recorded on a Perkin Elmer 100 spectrometer (PerkinElmer Inc. Waltham, MA, USA) by using the ATR method employing neat compounds. The wavelengths are reported in reciprocal centimeters (_Vmax/cm⁻¹). FT-IR spectra were analyzed using the Report Builder software (Rev. 2.01). HRMS spectra were acquired using a Maxis-Impact ESI(+)-QqTOF Bruker mass spectrometer (Bruker, Billerica, MA, USA). HRMS spectra were analyzed using the data analysis software (Bruker, version 4.1). Microwave-assisted reactions were performed in closed-vessel mode using a monomodal CEM Discover unit (CEM Corporation, Matthews, NC, USA). The reaction progress was monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Flash column chromatography was performed using silica gel (230–400 mesh) and mixtures of hexanes with AcOEt (7:3; v/v) as the mobile phase. Melting points were determined using a Fisher-Johns apparatus and are uncorrected. Commercially available starting materials were used without further purification. The solvents were distilled and dried according to standard procedures. Commercially available reagents were purchased from Sigma-Aldrich and were used without further purification. Structure names and drawings were performed using the ChemBioDraw Ultra software (version 13.0.0.3015).

3.2. General Procedure (GP)

In a flask with a magnetic stirring bar, amine (1.0 equiv.) and isocyanide (1.0 equiv.) were added sequentially to a 0.5 M solution of aldehyde (1.0 equiv.) in anhydrous toluene [0.5 M], and the reaction mixture was heated (100 °C) for 30 min. Then, the solvent was removed to the point of dryness and the crude was immediately purified by using silica gel column chromatography employing a mixture of hexanes with ethyl acetate (7/3; v/v) to afford the corresponding products 4a–4e.

3.3. Spectral Data

3.3.1. Synthesis and Characterization of the 3-(5-(tert-butylamino)imidazo[2,1-b]thiazol-6-yl)-4H-chromen-4-one (4a)

• According to the GP, 3-formylchromone (44.8 mg, 1 mmol), 2-aminothiazole (25.8 mg, 1 mmol), and tert-butyl isocyanide (27.9 μL, 1 mmol) were reacted together in anhydrous toluene (0.5 mL) to afford the product 4a (66 mg, 78%) as orange solid; mp = 228 °C; R_f = 0.38 (hexanes–AcOEt = 7/3; v/v). ¹H NMR (500 MHz; CDCl₃; TMS): δ 8.66 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.73–7.69 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 4.5 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 4.5 Hz, 1H), 4.90 (s, 1H), 1.05 (s, 9H); ¹³C NMR (126 MHz, CDCl₃; TMS): δ 176.0, 156.0, 155.6, 145.6, 133.6, 130.4, 130.3, 126.4, 125.3, 124.2, 121.4, 118.3, 118.2, 111.1, 55.6, 29.7; FT-IR (ATR) _Vmax/cm⁻¹ 3286 (N-H), 1629 (C=O); HRMS (ESI⁺): m/z calcd. for C₁₈H₁₈N₃O₂S⁺ 340.1114, found to be 340.1118.

3.3.2. Synthesis and Characterization of the 3-(5-(Cyclohexylamino)imidazo[2,1-b]thiazol-6-yl)-4H-chromen-4-one (4b)

• According to the GP, 3-formylchromone (44.8 mg, 1 mmol), 2-aminothiazole (25.8 mg, 1 mmol), and cyclohexyl isocyanide (31.7 µL, 1.0 mmol) were reacted together in anhydrous toluene (0.5 mL) to afford the product 4b (70 mg, 77%) as brown solid; mp = 170 °C; R_f = 0.31 (hexanes–AcOEt = 7/3; v/v). ¹H NMR (500 MHz; CDCl₃; TMS): δ 8.70 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47–7.43 (m, 1H), 7.38 (d, J = 4.5 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 2.76–2.69 (m, 1H), 1.87–1.80 (m, 2H), 1.70–1.64 (m, 2H), 1.55–1.50 (m, 1H), 1.18–1.07 (m, 5H); ¹³C NMR (126 MHz, CDCl₃; TMS): δ 176.2, 156.1, 155.3, 144.9, 133.7, 132.1, 126.8, 126.5, 125.3, 124.3, 121.0, 118.3, 117.5, 111.6, 57.8, 34.1, 25.8, 25.2; FT-IR (ATR) _Vmax/cm⁻¹ 3291 (N-H), 1638 (C-O); HRMS (ESI): m/z calcd. for C₂₀H₂₀N₃O₂S⁺ 366.1270, found to be 366.1271.

3.3.3. Synthesis and Characterization of the 3-(5-(Benzylamino)imidazo[2,1-b]thiazol-6-yl)-4H-chromen-4-one (4c)

• According to the GP, 3-formylchromone (44.8 mg, 1 mmol), 2-aminothiazole (25.8 mg, 1.0 mmol), and benzyl isocyanide (31.1 µL, 1.0 mmol) were reacted together in anhydrous toluene (0.5 mL) to afford the product 4c (71 mg, 76%) as orange solid; mp = 124 °C; R_f = 0.32 (hexanes–AcOEt = 1/3; v/v). ¹H NMR (500 MHz; CDCl₃; TMS): δ 8.45 (s, 1H), 8.27 (dd, J = 8.0, 1.4 Hz, 1H), 7.71–7.67 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45–7.41 (m, 1H), 7.27–7.25 (m, 1H), 7.13–7.10 (m, 2H), 7.09–7.06 (m, 3H), 6.71 (d, J = 4.5 Hz, 1H), 5.69 (s, 1H), 4.06 (s, 1H); ¹³C NMR (126 MHz, CDCl₃; TMS): δ 176.3, 156.0, 155.1, 139.5, 133.6, 132.2, 128.5, 128.4, 127.2, 126.4, 125.3, 124.2, 118.2, 117.3, 111.8, 53.6; FT-IR (ATR) _Vmax/cm⁻¹ 3282 (N-H), 1631(C-O); HRMS (ESI): m/z calcd. for C₂₁H₁₆N₃O₂S⁺ 374.0957, found to be 374.0963.

3.3.4. Synthesis and Characterization of the 3-(5-((4-Methoxybenzyl)amino)imidazo[2,1-b]thiazol-6-yl)-4H-chromen-4-one (4d)

• According to the GP, 3-formylchromone (44.8 mg, 1.0 mmol), 2-aminothiazole (25.8 mg, 1.0 mmol), and 4-methoxybenzyl isocyanide (37.5 mg, 1.0 mmol) were reacted together in anhydrous toluene (1.0 mL) to afford the product 4d (74 mg, 74%) as pale yellow oil; R_f = 0.11 (hexanes–AcOEt = 7/3; v/v). ¹H NMR (500 MHz; CDCl₃; TMS): δ 8.42 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.71–7.67 (m, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.46–7.42 (m, 1H), 7.30 (d, J = 3.9 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.8 Hz, 1H),6.54 (d, J = 7.8 Hz, 2H), 5.51 (s, 1H), 3.97 (s, 2H), 3.61 (s, 3H); ¹³C NMR (126 MHz, CDCl₃; TMS): δ 176.1, 158.9, 155.9, 155.1, 133.6, 132.0, 131.6, 129.9, 129.0, 127.4, 126.4, 125.3, 124.2, 118.2, 117.3, 114.3, 113.7, 111.8, 55.2, 53.1; FT-IR (ATR) _Vmax/cm⁻¹ 3282 (N-H), 1638 (C=O); HRMS (ESI): m/z calcd. for C₂₂H₁₈N₃O₃S⁺ 404.1063, found to be 404.1083.

3.3.5. Synthesis and Characterization of the 3-(5-((3,4-Dimethoxyphenethyl)amino)imidazo[2,1-b]thiazol-6-yl)-4H-chromen-4-one (4e)

• According to the GP, 3-formylchromone (44.8 mg, 1.0 mmol), 2-aminothiazole (25.8 mg, 1.0 mmol), and 3,4-dimethoxyphenethyl isocyanide (50 mg, 1.0 mmol) were reacted together in anhydrous toluene (1.0 mL) to afford the product 4e (84 mg, 75%) as pale brown solid; mp = 152.8 °C; R_f = 0.30 (hexanes–AcOEt = 7/3; v/v). ¹H NMR (500 MHz; CDCl₃; TMS): δ 8.65 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.74–7.69 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.47–7.43 (m, 1H), 7.27 (s, 1H), 7.25–7.22 (m, 1H), 6.77–6.75 (m, 1H), 6.70–6.66 (m, 2H), 4.12 (s, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.28–3.24 (m, 2H), 2.74–2.70 (m, 2H); ¹³C NMR (126 MHz, CDCl₃; TMS): δ 176.0, 155.9, 155.0, 148.8, 147.4, 144.8, 133.6, 132.6, 131.7, 126.3, 125.2, 123.9, 120.6, 120.2, 118.1, 117.1, 112.1, 112.0, 111.1, 55.8, 50.0, 36.1; FT-IR (ATR) _Vmax/cm⁻¹ 3319 (N-H), 1608 (C-O); HRMS (ESI): m/z calcd. for C₂₄H₂₂N₃O₄S⁺ 448.1325, found to be 448.1315.

4. Conclusions

This work is a contribution to the synthesis of bis-heterocycles containing the imidazo[2,1-b]thiazole framework bound with chromone via a GBBR with classical conditions under free catalysts. The synthesized products may have interesting applications because they contain heterocyclic frameworks such as chromone, present in numerous compounds exhibiting biological properties.