Direct trifluoromethylation of imidazoheterocycles in a recyclable medium at room temperature

Abstract

Regioselective C–H trifluoromethylation of imidazoheterocycles with Langlois' reagent in a recyclable mixed medium of 1-butyl-3-methylimidazoliumtetrafluoroborate ([Bmim]BF₄) and water at room temperature has been developed. In the presence of catalytic cupric acetate and 2-methyl-2-(methylperoxy)propane (TBHP), this green strategy tolerates a wide range of functional groups to afford diverse trifluoromethylated imidazoheterocycles in moderate to good yields.

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Introduction

Imidazoheterocycles are privileged scaffolds with diverse bioactivity,¹ which have been used as SIRT1 activator,² RSK2 inhibitors,³ anticancer agents,⁴ and antiviral agents,⁵ and in the treatment of cystic fibrosis.⁶ Several commercially available drugs, such as alpidem, olprinone, necopidem, zolimidine, and saripidem, have been developed by the modification of imidazoheterocyclic skeletons.⁷ Thus significant progress has been made in the functionalization of imidazoheterocycles.^8,9 The C–H bond functionalization strategy is an ideal route to the preparation of diverse imidazoheterocycles as it is a straightforward, atom economical, and synthetic step economical method. C–H sulfenylation,¹⁰ arylation,¹¹ alkenylation,¹² and carbonylation¹³ have been employed for the functionalization of imidazoheterocycles. However, little attention has been paid to the C–H trifluoromethylation of imidazoheterocycles.¹⁴

The presence of a trifluoromethyl group commonly strengthens the bioactivity of drug candidates,¹⁵ which promotes us to focus on the C–H trifluoromethylation of imidazoheterocycles. Among the trifluoromethylating reagents (including Umemoto's reagent,¹⁶ Ruppert's reagent,¹⁷ Togni's reagent,¹⁸ and Langlois' reagent¹⁹), Langlois' reagent is a preferable trifluoromethylating reagent as it is stable, inexpensive, and environmental friendly, which has been extensively used in the preparation of diverse trifluoromethylated compounds.^19,20 Baran group^20b–d,20g has made a great contribution to the field of the trifluoromethylation of heterocycles using Langlois' reagent. Despite great success has been achieved, green strategy for the trifluoromethylation remains scarce. The first example for C–H trifluoromethylation using water as a medium was recently reported by Lipshutz group.^20k Despite the C–H trifluoromethylation of imidazoheterocycles was just carried out in DMSO using silver nitrate as catalyst,^14b the development of C–H trifluoromethylation of imidazoheterocycles in an environmental friendly medium is highly desirable, which meets the guiding principles of green chemistry.²¹ A challenge we are facing is the insolubility of imidazoheterocycles in water at room temperature. We hypothesized that the addition of an ionic liquid to the water may figure out the insolubility problem of imidazoheterocycles; additionally, ionic liquids are commonly stable, non-volatile, and recyclable, which are widely used as green mediums in various reactions.²² As a part of our continuing interest in the C–H functionalization of imidazoheterocycles,^10h we report a method for regioselective C–H trifluoromethylation of imidazoheterocycles in a mixed medium of [Bmim]BF₄ and water at room temperature (Scheme 1).

Scheme 1 The trifluoromethylation of imidazoheterocycles.

Results and discussion

Initially, we used the trifluoromethylation of 6-phenylimidazo[2,1-b]thiazole 1a with sodium trifluoromethanesulfonate as the model reaction (Table 1). Several organic solvents were investigated in the presence of 5 mol% of Cu(OAc)₂ and 3 equivalents of TBHP at 25 °C: DMSO was preferable for the trifluoromethylation to afford the product 2a in 75% (entry 4); whereas other solvents such as CH₃CN, CH₃NO₂, and DMF gave low yields (entries 1–3). The trifluoromethylation of imidazoheterocycles was examined in water as a green solvent.^20k Unfortunately, the insolubility of 1a in water leads to the failure of the trifluoromethylation (entry 5). The commercially available [Bmim]BF₄ ionic liquid is a suitable reaction medium for the trifluoromethylation at room temperature, giving product 2a in 62% yield (entry 6). To our delight, the yield of product 2a was improved to 73% in the mixed medium of [Bmim]BF₄ and H₂O (v/v = 1 : 1) (entry 7). Increasing the proportion of water in the mixed medium decreased the yield of 2a to 46% (entry 8). The reaction of 1a at 40 °C appeared to have no change in the yield of 2a (entry 9); whereas the reaction at 80 °C produced multi-ditrifluoromethylated products, leading to lower yield of 2a (entry 10). Other copper catalysts, including CuCl, CuCl₂·2H₂O, Cu(OTf)₂, and Cu(TFA)₂, were then evaluated in [Bmim]BF₄/H₂O at 25 °C, all of these gave lower yields than that obtained with Cu(OAc)₂ (entries 11–14). The results show that using 2 equivalents of TBHP decreased the yield of 2a to 61% (entry 15), and no product was obtained in the absence of TBHP (entry 16). It was demonstrated that only a small amount of 2a was obtained in the absence of Cu(OAc)₂ (entry 17). These suggest that both TBHP and Cu(OAc)₂ are key to this transformation. The addition of 3 equivalents of 2,2,6,6-tetramethylpiperdin-1-oxyl (TEMPO) led to the failure of this reaction, suggesting that this reaction may undergo a radical pathway (entry 18).

Table 1 Screening of optimal conditions^a

Entry	[Cu]	Solvent	T (°C)	Isolated yield (%)
a Reaction conditions: 1a (0.2 mmol), CF3SO2Na (0.4 mmol, 2 equiv.), [Cu] (5 mol%), TBHP (3 equiv., 5–6 M solution in decane), solvent (2 mL), [Bmim]BF4/H2O (v/v = 1 : 1), at 25 °C, reaction for 24 h.b [Bmim]BF4/H2O (v/v = 1 : 2).c TBHP (2 equiv.).d In the absence of TBHP.e TEMPO (3 equiv.) was added.
1	Cu(OAc)2	CH3CN	25	46
2	Cu(OAc)2	CH3NO2	25	47
3	Cu(OAc)2	DMF	25	43
4	Cu(OAc)2	DMSO	25	75
5	Cu(OAc)2	H2O	25	0
6	Cu(OAc)2	[Bmim]BF4	25	62
7	Cu(OAc)2	[Bmim]BF4/H2O	25	73
8^b	Cu(OAc)2	[Bmim]BF4/H2O	25	46
9	Cu(OAc)2	[Bmim]BF4/H2O	40	73
10	Cu(OAc)2	[Bmim]BF4/H2O	80	56
11	CuCl	[Bmim]BF4/H2O	25	53
12	CuCl2·2H2O	[Bmim]BF4/H2O	25	41
13	Cu(OTf)2	[Bmim]BF4/H2O	25	52
14	Cu(TFA)2	[Bmim]BF4/H2O	25	53
15^c	Cu(OAc)2	[Bmim]BF4/H2O	25	61
16^d	Cu(OAc)2	[Bmim]BF4/H2O	25	Trace
17	—	[Bmim]BF4/H2O	25	<10
18^e	Cu(OAc)2	[Bmim]BF4/H2O	25	Trace

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With this optimized reaction conditions in hand, the scope of imidazothiazoles was investigated (Table 2). 6-Arylimidazo[2,1-b]thiazoles containing a methyl, methoxyl, chloro, bromo, fluoro, or cyano group on the benzene ring were well tolerated under the standard conditions. For example, both methyl and methoxyl substituted substrates underwent the reaction smoothly to give the corresponding products 2b and 2c in 74% and 70% yields, respectively. The halo-substituted substrates have good reactivity in the trifluoromethylation giving products 2d–2f in good yields. These products are synthetically useful for further modification by coupling reaction at the halo groups. Cyano group also favoured the reaction in [Bmim]BF₄ to give product 2g in 72% yield. Difluoro-substituted substrate also underwent the reaction successfully to afford product 2h in 45% yield. Different substituents on the thiazole ring were also investigated (products 2i–2k). It is noteworthy that the substrate bearing an ester group was well tolerated in [Bmim]BF₄ to give product 2j in 65% yield, which enables a further chemical transformation at the ester group. To our delight, benzo[d]imidazo[2,1-b]thiazole exhibits good reactivity under the standard conditions, affording product 2k in 81% yield.

Table 2 The Scope of trifluoromethylation of imidazoheterocycles^a

a Reaction conditions: 1 (0.2 mmol), CF₃SO₂Na (0.4 mmol, 2 equiv.), Cu(OAc)₂ (5 mol%), TBHP (3 equiv.), [Bmim]BF₄/H₂O (v/v = 1 : 1, 2 mL), at 25 °C, reaction for 24 h.b In [Bmim]BF₄ (2 mL).

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To further demonstrate the versatility of this trifluoromethylation strategy, the scope of imidazo[1,2-a]pyridines was investigated (products 2l–2w). 2-Arylimidazo[1,2-a]pyridines with a methyl, methoxyl, chloro, bromo, or phenyl group on the benzene ring were well tolerated under the standard conditions, giving the corresponding product in moderate yield (products 2l–2q). A 51% yield of 2r was also obtained despite the hindrance of the naphthyl group. The results show that substrates with a halo group on the pyridine ring are suitable for this transformation (products 2t–2v). For example, a 75% yield of product 2v was obtained in the reaction of 8-bromo-2-phenylimidazo[1,2-a]pyridine, to which various functional groups can be introduced by the disconnection of C–Br bond. The reaction of 2-ethylimidazo[1,2-a]pyridine was also carried out under the standard conditions, albeit with a low yield of product 2w that cannot be obtained in the previous work.^14b Finally, 2-phenylimidazo[1,2-a]pyrimidine was reacted with sodium trifluoromethanesulfonate to give product 2x in 65% yield.

Next, we focused on the trifluoromethylation of imidazoles to expand the scope of application of this methodology (Table 3). The results showed that the reactions of 1H-imidazole and methyl-substituted 1H-imidazoles did not proceed under the standard conditions. To our delight, a small amount of product 4d was observed in the trifluoromethylation of 1-phenyl-1H-imidazole. Encouraged by this result, other phenyl-substituted imidazoles such as 2-phenyl-1H-imidazole and 4-phenyl-1H-imidazole were reacted with sodium trifluoromethanesulfonate, both reactions proceeded smoothly, giving products 4e and 4f in 42% and 51% yields, respectively. Based on these results, we can conclude that the phenyl substituent is essential to the trifluoromethylation of imidazoles. The presence of a phenyl group as a conjugated group in substrates 3e and 3f can stabilize the imidazole ring, which may facilitate the trifluoromethylation. Whereas the phenyl group on the nitrogen has weaker conjugation effect on the imidazole ring, leading to the bad result. Substrates 3a–c did not work at all under the standard conditions may result from the absence of a conjugated group.

Table 3 The scope of trifluoromethylation of imidazoles^a

a Reaction conditions: 3 (0.2 mmol), CF₃SO₂Na (0.4 mmol, 2 equiv.), Cu(OAc)₂ (5 mol%), TBHP (3 equiv.), [Bmim]BF₄/H₂O (v/v = 1 : 1, 2 mL), at 25 °C, reaction for 24 h.

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To test their potential in large scale synthesis, the reaction of 1a was conducted at 2.0 g (10 mmol) scale, and it performed well under the standard conditions to give 2a in 70% yield (Table 4). In the treatment of the reaction mixture with Et₂O, three-phase (from top to bottom is ether, water, and [Bmim]BF₄) can be observed. Thus product 2a is readily isolated from the reaction medium, and cupric acetate was mainly distributed in [Bmim]BF₄ and water phases for the reaction cycle (Table 4). The results show that the 1^st–3^rd recycles appear to have no obvious change in term of yield of 2a (entries 1–3); whereas the yield was reduced to 53% and 48% in the 4^th and 5^th recycles, respectively (entries 4 and 5). It is noteworthy that Et₂O used for extraction can be easily recovered for next extraction. These results suggest that the newly established strategy for the trifluoromethylation of imidazoheterocycles has potential for industrial applications.

Table 4 Recycling of the reaction medium^a

Entry	Cycle	Yield (%)
a Reaction conditions: 1a (10 mmol), CF3SO2Na (20 mmol, 2 equiv.), [Cu] (5 mol%), TBHP (3 equiv., 5–6 M solution in decane), [Bmim]BF4/H2O (v/v = 1 : 1, 30 mL), at 25 °C, reaction for 24 h.b Extracted with Et2O; [Bmim]BF4/H2O medium was recycled for next reaction.
1	1^b	70
2	2^b	70
3	3^b	65
4	4^b	53
5	5	48

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According to the present results and previous reports,^14b,19,20 a possible mechanism is proposed in Scheme 2. The copper catalysts may facilitate the generation of t-butoxyl radical from TBHP, the t-butoxyl radical reacts with sodium trifluoromethanesulfonate to afford a trifluoromethyl radical in situ. The trifluoromethyl radical then reacts with compound 1 to produce intermediate A. The intermediate A is oxidized to a carbonication B, followed by an oxidative dehydrogenation process to afford target product 2.

Scheme 2 A possible mechanism.

Conclusions

In summary, the mixture of [Bmim]BF₄ and H₂O has been found to be an effective reaction medium for the trifluoromethylation of imidazoheterocycles with Langlois' reagent at room temperature. In the presence of catalytic cupric acetate and TBHP, a wide range of functional groups were well tolerated to afford diverse trifluoromethylated imidazoheterocycles in moderate to good yields. Moreover, several phenyl-substituted 1H-imidazoles are also suitable for the trifluoromethylation under the standard conditions. This strategy has several advantages: (1) using green and recyclable reaction medium, (2) room temperature reactions, and (3) good toleration with various functional groups.

Experimental section

General remarks

¹H and ¹³C NMR spectra were measured on a Bruker Avance-III 500 instrument (500 MHz for ¹H, 125 MHz for ¹³C NMR spectroscopy) using CDCl₃ or DMSO-d₆ as the solvent. Referenced to internal TMS (0.0 ppm) as the standard. Mass spectra were measured on a Shimadzu GC-MS-QP2010 Plus spectrometer (EI). HRMS (ESI) analysis was measured on a Bruker micrOTOF-Q II instrument. IR analysis was measured on Nicolet IS10 spectrometer (ATR).

General procedure for C–H trifluoromethylation of imidazoheterocycles

A 15 mL tube with a Teflon cap, equipped with a magnetic stirring bar, was charged with substrate 1a (0.20 mmol), CF₃SO₂Na (0.40 mmol, 2.0 equiv.), Cu(OAc)₂ (5 mol%), TBHP (0.60 mmol, 3.0 equiv.), and [Bmim]BF₄/H₂O (v/v = 1 : 1, 2 mL) was then added sequentially. The tube was then capped and stirred at 25 °C for 24 h. The product was extracted by Et₂O (3 × 10 mL), the ether phase was collected and dried (Na₂SO₄), filtered through a Celite pad, and washed with Et₂O. The filtrate was concentrated in vacuo (Et₂O was recovered for next extraction), and the resulting residue was purified by column chromatography (hexane–EtOAc) to afford product 2a as a light yellow solid; yield: 39.1 mg (73%).

6-Phenyl-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2a). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.72 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 4.5 Hz, 1H), 7.46–7.39 (m, 3H), 6.98 (d, J = 4.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 149.3, 132.8, 129.0, 128.9, 128.5, 121.8 (q, J_C–F = 265.3 Hz), 119.1 (q, J_C–F = 2.8 Hz), 114.4, 112.0 (q, J_C–F = 41.6 Hz). IR (ATR, cm⁻¹): 1576, 1433, 1335, 1187, 1132, 785. LRMS (EI, 70 eV) m/z (%): 268 (100), 249 (11), 229 (6), 134 (6), 58 (7). HRMS (ESI) for C₁₂H₈F₃N₂S (M + H)⁺: calcd 269.0355, found 269.0350.

6-(p-Tolyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2b). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 4.5 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 4.5 Hz, 1H), 2.40 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 151.4, 149.2, 138.8, 129.8, 129.1, 128.6, 121.7 (q, J_C–F = 265.6 Hz), 119.0 (q, J_C–F = 2.8 Hz), 114.0, 111.5 (q, J_C–F = 40.6 Hz), 21.3. IR (ATR, cm⁻¹): 2921, 1528, 1327, 1169, 1090, 832. LRMS (EI, 70 eV) m/z (%): 282 (100), 207 (14), 133 (8), 116 (7), 115 (8). HRMS (ESI) for C₁₃H₁₀F₃N₂S (M + H)⁺: calcd 283.0511, found 283.0520.

6-(4-Methoxyphenyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2c). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 6.98–6.96 (m, 3H), 3.85 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 160.2, 151.4, 149.0 (d, J_C–F = 2.4 Hz), 130.1, 125.2, 121.8 (q, J_C–F = 265.3 Hz), 119.0 (q, J_C–F = 2.8 Hz), 114.0, 113.9, 111.2 (q, J_C–F = 40.5 Hz), 55.4. IR (ATR, cm⁻¹): 3059, 2966, 1428, 1353, 1275, 1182, 865. LRMS (EI, 70 eV) m/z (%): 298 (100), 283 (3), 281 (7), 73 (8). HRMS (ESI) for C₁₃H₉F₃N₂NaOS (M + Na)⁺: calcd 321.0280, found 321.0301.

6-(4-Chlorophenyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2d). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.66–7.60 (m, 3H), 7.42 (d, J = 6.5 Hz, 2H), 7.05–7.02 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 147.9, 135.0, 131.1, 130.1, 128.7, 121.6 (q, J_C–F = 265.5 Hz), 119.0, 114.6, 111.9 (q, J_C–F = 45.3 Hz). IR (ATR, cm⁻¹): 1538, 1453, 1385, 1126, 1075, 986. LRMS (EI, 70 eV) m/z (%): 302 (100), 283 (9), 267 (6), 207 (11), 58 (8). HRMS (ESI) for C₁₂H₇ClF₃N₂S (M + H)⁺: calcd 302.9965, found 302.9960.

6-(4-Bromophenyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2e). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.59–7.58 (m, 5H), 7.01 (d, J = 4.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 147.9, 131.6, 131.6, 130.4, 123.3, 121.5 (q, J_C–F = 265.3 Hz), 119.0 (q, J_C–F = 2.8 Hz), 114.6, 111.9 (q, J_C–F = 42.3 Hz). IR (ATR, cm⁻¹): 1528, 1437, 1218, 1182, 1120, 973. LRMS (EI, 70 eV) m/z (%): 348 (100), 346 (93), 268 (6), 169 (9). HRMS (ESI) for C₁₂H₇BrF₃N₂S (M + H)⁺: calcd 346.9460, found 346.9456.

6-(4-Fluorophenyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2f). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.69 (dd, J = 8.4, 5.3 Hz, 2H), 7.59 (d, J = 4.5 Hz, 1H), 7.13 (t, J = 8.7 Hz, 2H), 7.00 (d, J = 4.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 163.2 (d, J_C–F = 247.1 Hz), 151.5, 148.1, 130.7 (d, J_C–F = 8.4 Hz), 128.78 (d, J_C–F = 3.3 Hz), 121.6 (q, J_C–F = 265.4 Hz), 119.0 (q, J_C–F = 2.8 Hz), 115.4 (d, J_C–F = 21.6 Hz), 114.4, 111.7 (q, J_C–F = 41.4 Hz). IR (ATR, cm⁻¹): 1487, 1243, 1187, 1169, 819, 765. LRMS (EI, 70 eV) m/z (%): 286 (100), 265 (7), 133 (6), 121 (7), 58 (6). HRMS (ESI) for C₁₂H₇F₄N₂S (M + H)⁺: calcd 287.0261, found 287.0276.

4-(5-(Trifluoromethyl)imidazo[2,1-b]thiazol-6-yl)benzonitrile (2g). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H), 7.68–7.64 (m, 1H), 7.14–7.10 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 152.0, 146.7, 137.0, 132.2, 129.3, 121.4 (q, J_C–F = 265.6 Hz), 119.0 (q, J_C–F = 2.8 Hz), 118.70, 115.4, 112.7 (q, J_C–F = 41.0 Hz), 112.4. IR (ATR, cm⁻¹): 2226, 2098, 1517, 1480, 1175, 1149, 1082, 986, 971. LRMS (EI, 70 eV) m/z (%): 293 (100), 281 (17), 243 (7), 73 (7), 58 (7). HRMS (ESI) for C₁₃H₇F₃N₃S (M + H)⁺: calcd 294.0307, found 294.0309.

6-(3,4-Difluorophenyl)-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2h). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.61–7.46 (m, 3H), 7.26–7.04 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 151.5, 150.8 (dd, J_C–F = 242.4, 11.5 Hz), 150.2 (dd, J_C–F = 244.9, 11.7 Hz), 146.8, 129.5, 125.0, 121.4 (q, J_C–F = 265.5 Hz), 118.9, 117.8 (d, J_C–F = 18.5 Hz), 117.3 (d, J_C–F = 17.4 Hz), 114.7, 112.0 (q, J_C–F = 43.4 Hz). IR (ATR, cm⁻¹): 3037, 1518, 1398, 1178, 1150, 1090, 969. LRMS (EI, 70 eV) m/z (%): 304 (100), 285 (17), 265 (7), 187 (9), 58 (8). HRMS (ESI) for C₁₂H₆F₅N₂S (M + H)⁺: calcd 305.0166, found 305.0186.

2-Methyl-6-phenyl-5-(trifluoromethyl)imidazo[2,1-b]thiazole (2i). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J = 7.4 Hz, 2H), 7.45–7.39 (m, 3H), 7.30 (s, 1H), 2.46 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 150.9, 147.9, 132.8, 128.8, 128.7, 128.4, 128.4, 121.7 (q, J_C–F = 265.5 Hz), 115.5 (q, J_C–F = 2.8 Hz), 111.5 (q, J_C–F = 40.4 Hz), 14.1. IR (ATR, cm⁻¹): 2931, 1435, 1352, 1183, 1150, 837. LRMS (EI, 70 eV) m/z (%): 282 (100), 263 (7), 261 (7), 103 (5), 72 (3). HRMS (ESI) for C₁₃H₁₀F₃N₂S (M + H)⁺: calcd 283.0511, found 283.0508.

Ethyl-6-phenyl-5-(trifluoromethyl)imidazo[2,1-b]thiazole-2-carboxylate (2j). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s, 1H), 7.64 (d, J = 6.5 Hz, 2H), 7.38–7.37 (m, 3H), 4.35 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 159.5, 151.0, 149.2, 130.8, 128.2, 127.7, 127.4, 123.3, 122.7, 120.2 (q, J_C–F = 265.7 Hz), 110.9 (q, J_C–F = 40.4 Hz), 61.4, 13.1. IR (ATR, cm⁻¹): 1735, 1600, 1563, 1387, 1162, 1139, 1089, 975. LRMS (EI, 70 eV) m/z (%): 340 (100), 312 (62), 207 (21), 267 (8), 73 (11). HRMS (ESI) for C₁₅H₁₂F₃N₂O₂S (M + H)⁺: calcd 341.0566, found 341.0559.

2-Phenyl-3-(trifluoromethyl)benzo[d]imidazo[2,1-b]thiazole (2k)^14a. Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 1H), 7.59–7.54 (m, 3H), 7.37–7.31 (m, 4H), 7.25 (t, J = 7.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 149.9, 149.1, 131.9, 131.1, 129.1, 128.6, 127.9, 127.1, 125.8, 124.6, 123.3, 120.5 (q, J_C–F = 265.3 Hz), 113.7 (q, J_C–F = 4.6 Hz), 111.5 (q, J_C–F = 40.5 Hz). IR (ATR, cm⁻¹): 3072, 1551, 1478, 1296, 1178, 1157, 1093, 976, 773. LRMS (EI, 70 eV) m/z (%): 318 (100), 297 (10), 159 (11), 108 (10), 69 (10).

2-Phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2l)^14a. Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J = 3.0 Hz, 1H), 7.61–7.60 (m, 3H), 7.35–7.22 (m, 4H), 6.82 (t, J = 6.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.0, 145.1, 131.9, 128.5, 127.9, 127.1, 125.9, 124.5, 121.9 (q, J_C–F = 265.2 Hz), 117.0, 112.9, 108.5 (q, J_C–F = 38.4 Hz). IR (ATR, cm⁻¹): 3059, 1580, 1510, 1405, 1385, 1198, 1116, 1062, 995, 781. LRMS (EI, 70 eV) m/z (%): 262 (100), 241 (15), 212 (10), 192 (5), 78 (13).

2-(p-Tolyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2m). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J = 7.2 Hz 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J = 7.0 Hz, 2H), 6.94 (d, J = 6.5 Hz, 1H), 2.41 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 148.2, 146.2, 139.0, 130.0, 129.5, 129.0, 126.9, 125.5, 122.1 (q, J_C–F = 265.5 Hz), 118.0, 113.9, 109.4 (q, J_C–F = 40.6 Hz), 21.4. IR (ATR, cm⁻¹): 3045, 2973, 1539, 1462, 1327, 1251, 1152, 1073, 983, 754. LRMS (EI, 70 eV) m/z (%): 276 (100), 255 (5), 205 (7), 103 (5), 78 (11). HRMS (ESI) for C₁₅H₁₂F₃N₂ (M + H)⁺: calcd 277.0947, found 277.0960.

2-(3-Methoxyphenyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2n). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J = 4.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.39–7.36 (m, 2H), 7.28–7.25 (m, 2H), 7.00 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 159.4, 147.9, 146.1, 134.2, 129.3, 127.1, 125.6, 122.1, 121.9 (q, J_C–F = 265.4 Hz), 118.1, 115.1, 114.7, 114.1, 109.7 (q, J_C–F = 36.0 Hz), 55.4. IR (ATR, cm⁻¹): 3021, 2962, 1538, 1458, 1397, 1263, 1082, 767. LRMS (EI, 70 eV) m/z (%): 292 (100), 273 (10), 241 (10), 78 (3). HRMS (ESI) for C₁₅H₁₂F₃N₂O (M + H)⁺: calcd 293.0896, found 293.0898.

2-(4-Chlorophenyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2o). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 6.5 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 6.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 146.7, 146.0, 135.0, 131.3, 130.8, 128.3, 127.1, 125.4 (q, J_C–F = 3.3 Hz), 121.7 (q, J_C–F = 265.6 Hz), 117.9, 114.0, 109.5 (q, J_C–F = 39.0 Hz). IR (ATR, cm⁻¹): 1567, 1436, 1332, 1189, 1109, 1116, 752. LRMS (EI, 70 eV) m/z (%): 296 (100), 277 (9), 241 (6), 138 (7), 51 (14). HRMS (ESI) for C₁₄H₉ClF₃N₂ (M + H)⁺: calcd 297.0401, found 297.0414.

2-(4-Bromophenyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2p). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 7.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.60–7.57 (m, 4H), 7.40 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 6.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 146.9, 146.2, 131.9, 131.5, 131.2, 127.3, 125.6 (q, J_C–F = 3.5 Hz), 123.5, 121.9 (q, J_C–F = 265.3 Hz), 118.1, 114.2, 109.7 (q, J_C–F = 39.4 Hz). IR (ATR, cm⁻¹): 1530, 1398, 1181, 1139, 726, 628. LRMS (EI, 70 eV) m/z (%): 340 (100), 342 (97), 261 (30), 207 (21), 73 (11). HRMS (ESI) for C₁₄H₉BrF₃N₂ (M + H)⁺: calcd 340.9896, found 340.9891.

2-([1,1′-Biphenyl]-4-yl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2q). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 6.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.76–7.64 (m, 5H), 7.46 (t, J = 7.3 Hz, 2H), 7.36 (d, J = 6.5 Hz, 2H), 6.97 (t, J = 7.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.8, 146.2, 141.8, 140.6, 131.8, 130.0, 128.8, 127.6, 127.2, 127.0, 126.9, 125.4 (q, J_C–F = 3.6 Hz), 122.0 (q, J_C–F = 265.5 Hz), 118.0, 114.0, 109.6 (q, J_C–F = 39.3 Hz). IR (ATR, cm⁻¹): 1506, 1421, 1368, 1261, 1017, 729. LRMS (EI, 70 eV) m/z (%): 338 (100), 317 (5), 281 (5), 169 (4), 78 (7). HRMS (ESI) for C₂₀H₁₃F₃N₂Na (M + Na)⁺: calcd 361.0923, found 361.0940.

2-(Naphthalen-2-yl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2r). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 7.0 Hz, 1H), 8.21 (s, 1H), 7.93–7.81 (m, 4H), 7.75 (d, J = 9.0 Hz, 1H), 7.51–7.50 (m, 2H), 7.36–7.33 (m, 1H), 6.94 (t, J = 6.8 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 148.0, 146.2, 133.5, 133.1, 130.3, 129.3, 128.6, 127.8, 127.7, 127.0, 126.7, 126.3, 125.5 (q, J_C–F = 3.5 Hz), 122.0 (q, J_C–F = 265.4 Hz), 118.1, 114.0, 109.8 (q, J_C–F = 39.1 Hz). IR (ATR, cm⁻¹): 3019, 1526, 1366, 1157, 1075, 971. LRMS (EI, 70 eV) m/z (%): 312 (100), 291 (13), 273 (8), 156 (5), 73 (5). HRMS (ESI) for C₁₈H₁₂F₃N₂ (M + H)⁺: calcd 313.0947, found 313.0962.

6-Methyl-2-phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2s). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.08 (s, 1H), 7.69 (d, J = 6.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 7.5 Hz, 3H), 7.22 (d, J = 9.0 Hz, 1H), 2.38 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 147.9, 145.3, 133.2, 130.1, 129.6, 128.9, 128.2, 123.9, 123.2 (q, J_C–F = 3.5 Hz), 122.1 (q, J_C–F = 265.6 Hz), 117.3, 109.2 (q, J_C–F = 32.9 Hz), 18.4. IR (ATR, cm⁻¹): 2931, 1540, 1259, 1165, 1098, 825, 796. LRMS (EI, 70 eV) m/z (%): 276 (100), 237 (4), 226 (8), 128 (4), 92 (10). HRMS (ESI) for C₁₅H₁₂F₃N₂ (M + H)⁺: calcd 277.0947, found 277.0964.

6-Fluoro-2-phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2t). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (s, 1H), 7.78–7.62 (m, 3H), 7.46–7.45 (m, 3H), 7.33–7.29 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 153.8 (d, J_C–F = 238.4 Hz), 149.1, 143.8, 132.6, 129.5, 129.2, 128.3, 121.7 (q, J_C–F = 265.5 Hz), 119.1 (d, J_C–F = 25.2 Hz), 118.6 (d, J_C–F = 8.9 Hz), 112.8 (dq, J_C–F = 42.5, 3.75 Hz), 111.0 (q, J_C–F = 39.4 Hz). IR (ATR, cm⁻¹): 1510, 1483, 1386, 1265, 1173, 916. LRMS (EI, 70 eV) m/z (%): 280 (100), 261 (10), 259 (17), 210 (6), 96 (17). HRMS (ESI) for C₁₄H₉F₄N₂ (M + H)⁺: calcd 281.0696, found 281.0709.

8-Chloro-2-phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2u). Light green solid. ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.42–7.37 (m, 4H), 6.85 (t, J = 7.1 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.5, 142.6, 131.4, 128.7, 128.2, 127.2, 124.9, 123.1 (q, J_C–F = 3.6 Hz), 123.0, 120.5 (q, J_C–F = 265.4 Hz), 112.6, 110.2 (q, J_C–F = 39.6 Hz). IR (ATR, cm⁻¹): 3029, 1550, 1376, 1187, 1117, 1090, 783, 687. LRMS (EI, 70 eV) m/z (%): 296 (100), 298 (33), 275 (12), 138 (8), 76 (10). HRMS (ESI) for C₁₄H₈ClF₃N₂Na (M + Na)⁺: calcd 319.0220, found 319.0227.

8-Bromo-2-phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2v). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J = 7.0 Hz, 1H), 7.66–7.58 (m, 2H), 7.58–7.52 (m, 1H), 7.40–7.32 (m, 3H), 6.77 (t, J = 7.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 147.7, 143.3, 131.6, 128.9, 128.5, 128.3, 127.3, 123.9, 120.7 (q, J_C–F = 265.3 Hz), 113.1, 111.4, 110.5 (q, J_C–F = 39.6 Hz). IR (ATR, cm⁻¹): 1538, 1472, 1335, 1156, 980, 712. LRMS (EI, 70 eV) m/z (%): 340 (100), 342 (98), 321 (12), 170 (9), 158 (10). HRMS (ESI) for C₁₄H₈BrF₃N₂Na (M + Na)⁺: calcd 362.9715, found 362.9738.

2-Ethyl-3-(trifluoromethyl)imidazo[1,2-a]pyridine (2w). Brown oil. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 2.94 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 147.8, 135.9, 129.8, 126.3, 125.2, 120.7 (q, J_C–F = 265.5 Hz), 117.4, 113.4, 31.1, 13.7. IR (ATR, cm⁻¹): 2931, 1512, 1255, 1221, 1186, 1122, 726. LRMS (EI, 70 eV) m/z (%): 214 (51), 213 (100), 195 (7), 145 (6), 78 (22). HRMS (ESI) for C₁₀H₁₀F₃N₂ (M + H)⁺: calcd 215.0791, found 215.0795.

2-Phenyl-3-(trifluoromethyl)imidazo[1,2-a]pyrimidine (2x). Light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.74–8.64 (m, 2H), 7.78 (d, J = 4.0 Hz, 2H), 7.59–7.39 (m, 3H), 7.13–7.10 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 149.5, 148.6, 133.5, 132.1, 129.6, 129.5, 128.3, 121.5 (q, J_C–F = 265.5 Hz), 110.2, 108.1 (q, J_C–F = 39.6 Hz). IR (ATR, cm⁻¹): 1636, 1510, 1483, 1381, 1215, 1172, 1086, 980, 712. LRMS (EI, 70 eV) m/z (%): 263 (100), 242 (19), 79 (2), 73 (11). HRMS (ESI) for C₁₃H₈F₃N₃Na (M + Na)⁺: calcd 286.0563, found 286.0562.

2-Phenyl-4-(trifluoromethyl)-1H-imidazole (4e)²³. White solid. ¹H NMR (500 MHz, acetone) δ 12.19 (brs, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.61 (s, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H). ¹³C NMR (125 MHz, acetone) δ 148.7, 130.7, 130.1, 129.7, 127.0, 126.5, 123.4 (q, J_C–F = 265.3 Hz), 118.9. IR (ATR, cm⁻¹): 2932, 2306, 1578, 1556, 1359, 1172, 1148, 975. LRMS (EI, 70 eV) m/z (%): 212 (100), 192 (18), 165 (49), 116 (36), 77 (23).

5-Phenyl-4-(trifluoromethyl)-1H-imidazole (4f)²³. Light yellow solid. ¹H NMR (500 MHz, DMSO) δ 13.22 (brs, 1H), 7.97 (s, 1H), 7.61–7.41 (m, 5H). ¹³C NMR (125 MHz, DMSO) δ 136.5, 131.4, 128.8, 128.6, 128.4, 122.6 (q, J_C–F = 265.5 Hz). IR (ATR, cm⁻¹): 2928, 1567, 1263, 1178, 1152, 798. LRMS (EI, 70 eV) m/z (%): 212 (100), 192 (18), 165 (23), 109 (21), 89 (29).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C spectra for all compounds. See DOI: 10.1039/c5ra02888d

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