Cu-catalyzed sulfenylation of imidazol[1,2-a]pyridine via C–H functionalization using a combination of Na₂S₂O₃ and halides

Abstract

A novel copper-catalysed sulfenylation method by using the inorganic salt Na₂S₂O₃ and alkyl halides (Cl, Br, I) or iodobenzene homologues is described. The reactions proceeded smoothly, giving regioselective 2-phenylimidazo[1,2-a]pyridine thioether derivatives in good yields via a C–H functionalization process. More importantly, this method has extended the existing methods by offering a better method which can make both alkyl and aryl thioether derivatives under one set of reaction conditions.

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Sulfides are widely present in nature, many natural products and drugs possess a sulfide function.¹ By the oxidation of sulfide functions, sulfoxides, sulfones and sulfoximines can be easily made.² On the other hand, imidazol[1,2-a]pyridine is also an privileged structure in drug discovery,³ several drugs possessing this moiety have important biological activities, such as anticancer,⁴ sedative-hypnotics,⁵ gout⁶ and Alzheimer's disease,⁷ therefore, much time and effort has been addressed to the synthesis of its derivatives. Among these derivatives, thioether derivatives are very important one. Until now, several methods related to the synthesis of imidazol[1,2-a]pyridine thioether derivatives have been reported.⁸ These thioether derivatives were mainly made by using these sulfur agents, such as ArSSAr,⁹ ArSH,¹⁰ ArSO₂NHNH₂,¹¹ ArSO₂Na,¹² ArSO₂Cl and DMSO¹³ with or without using transition metal catalysts. Here, we reported a new sulfenylation method of imidazol[1,2-a]pyridine by using inorganic Na₂S₂O₃ and different halides.

Actually, Na₂S₂O₃ and alkyl halide were starting materials for making Bunte salt which was first invented by Hans Bunte in 1874.¹⁴ Traditionally, this salt was used to react with nucleophiles such as thiols, Na₂S and cyanide to generate disulfides, trisulfides and thiocyanates,¹⁵ few people used this salt for sulfenylation reaction of other molecules via C–H functionalization process, let alone use aromatic halide and Bunte salt for sulfenylation reaction under the action of transition metal copper catalyst. In this paper, instead of using Bunte salt as reactants, Na₂S₂O₃ (ref. 16) and halides were directly used as starting materials for sulfenylation reaction (Scheme 1).

Scheme 1 Different routes for the synthesis of 2-phenylimidazo[1,2-a]pyridine thioether derivatives.

To find a suitable reaction condition for this sulfenylation, 2-phenylimidazo[1,2-a]pyridine (1a), n-butyl chloride and sodium thiosulfate (Na₂S₂O₃) were chosen as model substrates. Initially, when CuI was used as a catalyst in EtOAc at 120 °C, only 20% yield of 2a was obtained after 12 h (Table 1, entry 1). No product was formed and isolated, when toluene was used as a solvent under the same reaction condition (entry 2). Using DMSO as a solvent increased the yield to 30% (entry 3). Switching solvent from DMSO to CH₃CN generated the expected product 2a in a 45% yield (entry 4). To our delight, when DMF was employed as a solvent, the reaction gave a 75% yield in the presence of CuI catalyst (entry 5). Changing CuI into CuBr decreased the reaction yield to 59% (entry 6). But when CuCl was used as a catalyst, only 10% yield of expected product 2a was produced (entry 7). The reaction catalysed by CuCl₂ didn't afford the desired product (entry 8). Using Cu(OAc)₂ and CuNO₃ gave reaction yields of 25% and 23% respectively (entries 9, 10). When CuO was used as a catalyst, only 15% yield was obtained (entry 11), the usage of FeCl₃ didn't give any product (entry 12). In summary, the suitable condition for the sulfenylation of 2-phenylimidazo[1,2-a]pyridine: 2-phenylimidazo[1,2-a]pyridine (1.0 equiv.), Na₂S₂O₃ (1.25 equiv.), butyl chloride (2 equiv.), and CuI (20 mol%), DMF was used as a solvent and the reaction temperature is 120 °C.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 2-phenylimidazo[1,2-a]pyridine (1.0 mmol, 1.0 equiv.), butyl chloride (2.0 equiv.), Na2S2O3 (1.25 equiv.), CuI (20 mol%.), solvent (0.5 mL).b Isolated yields are based on 2-phenylimidazo[1,2-a]pyridine, the reaction was run for 12 h.
1	CuI	EtOAc	20
2	CuI	Toluene	0
3	CuI	DMSO	30
4	CuI	CH3CN	45
5	CuI	DMF	75
6	CuBr	DMF	59
7	CuCl	DMF	10
8	CuCl2	DMF	Trace
9	Cu(OAc)2	DMF	25
10	Cu(NO3)2	DMF	23
11	CuO	DMF	15
12	FeCl3	DMF	0

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With a suitable reaction condition in hand, we started to determine the limitations and generality of this new sulfenylation method. In addition to 2-phenylimidazo[1,2-a]pyridine (1a) and n-butyl chloride, several other alkyl halides and 2-phenylimidazo[1,2-a]pyridine homologues were used and evaluated. It was found that all tested primary alkyl halides (Bu–Cl, CH₂=C(CH₃)CH₂Cl, EtBr, BnBr, MeI) were suitable for the sulfenylation of 2-phenylimidazo[1,2-a]pyridine (1a), whether they contained Cl, Br or I element in their structures, they all afforded regioselective desired products in good yields. To check if secondary alkyl halides were suitable for the sulfenylation reaction, secondary i-PrBr was tested as a representative halide under the same reaction condition, it was found that the reaction gave a 70% yield. To further explore if tertiary alkyl halide was feasible for this sulfenyaltion process, t-BuCl was also tried, but it was found that only a small amount of the expected product was produced.

To check if aryl halides could be used as reactants for this sulfenylation method, so we selected different aromatic iodobenzene as a model reactant and carried out the sulfenyaltion reaction under the same condition, it was found that this sulfenylation reaction still proceeded well, giving the desired product in a 69% yield. Without further considering for optimized reaction condition, different iodobenzene homologues including electron-donating and electron-withdrawing substituents were used to react with different 2-phenylimidazo[1,2-a]pyridines in the presence of Na₂S₂O₃, all carried-out reactions generated the expected products in good yields via C–H functionalization process, the experimental results are shown in Table 2. But when bromobenzene and chlorobenzene were also tried under the same condition, both reactions failed to provide any the corresponding thioether derivatives. This fact also explained the reason why bromide function on the structures of 2q and 2r didn't have any impact on the sulfenylation reactions (Table 3).

Table 2 Generation of alkyl-S-substituted 2-phenylimidazo[1,2-a]pyridine derivatives via C–H functionalization using alkyl halides and Na₂S₂O₃ as reactants^a

a Reaction conditions: 2-phenylimidazo[1,2-a]pyridine (1.0 mmol, 1.0 equiv.), alkyl chloride (2.0 equiv.), Na₂S₂O₃ (1.25 equiv.), CuI (20 mol%), solvent (0.5 mL). Isolated yields are based on 2-phenylimidazo[1,2-a]pyridine, the reaction was run for 12 h.

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Table 3 Generation of aryl-S-substituted 2-phenylimidazo[1,2-a]pyridine derivatives via C–H functionalization using aryl halides and Na₂S₂O₃ as reactants^a

a Reaction conditions: 2-phenylimidazo[1,2-a]pyridine (1.0 mmol, 1.0 equiv.), aryl chloride (2.0 equiv.), Na₂S₂O₃ (1.25 equiv.), CuI (20 mol%), solvent (0.5 mL). Isolated yields are based on 2-phenylimidazo[1,2-a]pyridine, the reaction was run for 12 h.

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In summary, we have demonstrated a copper-catalysed sulfenylation of 2-phenylimidazo[1,2-a]pyridine by using inorganic salt Na₂S₂O₃ and alkyl halides (Cl, Br, I) or iodobenzene homologues via C–H functionalization process. All reactions proceeded well, giving regioselective 2-phenylimidazo[1,2-a]pyridine thioether derivatives in good yields via C–H functionalization process. More important, this method has extended the existing methods by offering a general method which can make both alkyl and aryl thioether derivatives under one mild reaction condition. Based on what we've found, this method might be even extended for the thioether preparation of other nucleophilic molecules, this work is currently under way in our lab.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra18136h

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