Visible-light mediated regioselective (phenylsulfonyl)difluoromethylation of fused imidazoles with iododifluoromethyl phenyl sulfone

Introduction

The difluoromethyl moiety is one of the key structural units found in pharmaceuticals, agrochemicals and functional materials mainly due to its excellent binding affinity, enhancement of membrane permeability, and high bioavailability [1]. Consequently, extensive efforts have been devoted to the development of methods for selective introduction of difluoromethyl group onto a particular position [2], [3]. Among the various sources of difluorinated moieties, a (phenylsulfonyl)difluoromethyl group (PhSO₂CF₂) is appealing because of its versatile functionality that can be further modified into other functionalized fluoroalkyl groups [4], [5]. Miscellaneous methods for the incorporation of PhSO₂CF₂ motifs have been extensively investigated over the years. The traditional methods for the synthesis of PhSO₂CF₂-containing molecules typically involve nucleophilic addition, coupling of boronic acids and radical addition [6], [7], [8], [9]. Alternatively, the direct (phenylsulfonyl)difluoromethylation of C-H bonds appears to be more economical and practical synthetic approach towards PhSO₂CF₂-containing heteroarenes. In 2014, Wang and co-workers reported a visible-light photoredox-catalyzed (phenylsulfonyl)difluoromethylation of electron-rich N-, O-, and S-containing heteroarenes with PhSO₂CF₂I [10]. However, these examples are mainly concentrated on pyrroles and indoles. As far as we know, there has been no report on the introduction of a PhSO₂CF₂ group at the imidazo[1,2-a]pyridine system.

Imidazo[1,2-a]pyridines are an important class of heterocycles with unique chemical and biological properties. This fused heterocycle is found in many bioactive natural products, pharmaceuticals and agrochemicals, and many of them exhibit potent biological activities, such as antiviral, antimicrobial, antitumor and anti-inflammatory properties [11], [12], [13]. Attention has been paid to the development of efficient methods for the synthesis of imidazopyridine derivatives [14], [15]. In this regard, the functionalization of imidazo[1,2-a]pyridine derivatives through transition-metal-catalyzed coupling or the electrophile and radical addition reactions at the 3-position have made significant progress [16]. Various functionalized atoms (C, S, N and Se) have been successfully introduced into the 3-position of imidazo[1,2-a]pyridines [17], [18], [19], [20], [21], [22], [23], [24]. Recently, we also developed a visible-light-induced radical pathway to introduce a trifluoroethyl group into the imidazo[1,2-a]pyridine core at the 3-position [25]. As a continuation of our interest in methodology for the synthesis of fluorinated heterocycles [26], [27], [28], we wished to introduce other versatile building blocks into the imidazo[1,2-a]pyridine structure with the aim of synthesizing various 3-functionalized imidazo[1,2-a]pyridines in a radical fashion. We focused our attention on 3-PhSO₂CF₂-containing imidazo[1,2-a]pyridine architectures by visible-light photoredox catalysis.

Results and discussion

Our initial investigation focused on the reaction of 2-phenylimidazo[1,2-a]pyridine (1a) and PhSO₂CF₂I (1.5 equiv) under the catalysis of fac-Ir(ppy)₃ (2 mol%) in DMSO (Scheme 1). The C-3 regioselective (phenylsulfonyl)difluoromethylation reaction proceed smoothly to give the desired product 2a in 68% yield. When Ru(bpy)₃(PF₆)₂ was used instead of fac-Ir(ppy)₃, the yield of this reaction was only 40%, and eosin Y was totally inactive. After screening a series of bases, such as Na₂CO₃, K₂CO₃ and KOAc using fac-Ir(ppy)₃ as the photocatalyst, K₂CO₃ was found to be the best choice and gave 86% yield. Other solvents such as DMF, DCM and acetonitrile were also tested for the (phenylsulfonyl)difluoromethylation reaction of 1a at room temperature, but they all were less efficient compared with DMSO. Moreover, the reaction was completely inhibited in the absence of the photocatalyst or in the dark. Thus, fac-Ir(ppy)₃ (2 mol%), PhSO₂CF₂I (1.5 equiv), and K₂CO₃ (1.5 equiv) in DMSO under 5 W blue LED irradiation have been defined as the optimized reaction conditions.

Scheme 1

Synthesis of PhSO₂CF₂-containing imidazo[1,2-a]pyridines.

With the optimum conditions in hand, we investigated the scope of this visible-light mediated (phenylsulfonyl)difluoromethylation with diverse imidazopyridines and the results are summarized in Scheme 1. It was found that a variety of imidazo[1,2-a]pyridines can be successfully (phenylsulfonyl)difluoromethylated at the C3-position with high selectivity to the desired products in moderate to good yields. We first examined the substituent effect at the 2-arylimidazo[1,2-a]pyridines. In general, the reactions of substrates containing electron-donating groups tend to give the desired products in slightly higher yields (85%–91%) than compound 1m substituted with an electron-withdrawing 5-fluoro atom. Aryl and alkyl substituted substrates are well tolerated in this transformation.

Benzo[d]-imidazo[2,1-b]thiazole derivatives were also successfully applied in the reaction, and the desired products 4a,b were prepared in excellent yield (Scheme 2).

Scheme 2

Regioselective (phenylsulfonyl)difluoromethylation of benzo[d]-imidazo[2,1-b]thiazoles.

As already mentioned, the CF₂SO₂Ph group is an important motif which can be converted into CF₂H group. The product 2a in DMF/HOAc/NaOAc, in the presence of Mg, was converted into difluoromethylated imidazo[1,2-a]pyridine 5 in 77% yield (Scheme 3).

Scheme 3

Desulfonylation of 2a.

Conclusions

We described an efficient and general method for the synthesis of PhSO₂CF₂-containing imidazo[1,2-a]pyridines and benzo[d]-imidazo[2,1-b]thiazoles using a visible-light-mediated reaction of PhSO₂CF₂I with imidazoheterocycles. The reaction of imidazopyridines is regioselective.

Experimental

All reactions were performed in a 20-mL tube equipped with a rubber septum at room temperature. Photo-irradiation was carried out with a 5 W blue LED. Solvents were purified or dried in a standard manner. ¹H NMR (500 MHz), ¹³C NMR (125 MHz) and ¹⁹F NMR (470 MHz) spectra were measured in CDCl₃. HR-MS analyses were recorded using ESI technique.