Silver-catalyzed intramolecular oxidative decarboxylative C-H arylation reactions for synthesis of biaryl sultams

A mild, versatile and efficient method to form biaryl sultams through silver-catalyzed intramolecular oxidative decarboxylative C-H arylation reactions has been developed. The present protocol features a broad substrate scope and very good tolerance to different substituent groups with satisfactory yields, giving access to a wide range of biaryl sultam derivatives


Introduction
2][3][4][5] Among them, sultams (cyclic sulfonamides) are important structural scaffolds.Thus the pharmaceutically relevant molecules A, B and C (Figure 1) have been found to exhibit broad inhibitory properties against a variety of enzymes as COX-2 , 6 HIV integrase, 7 lipoxygenase, 8 Calpain I, 9 and MMP-2. 10Furthermore, biaryls embedded in cyclic sulfonamide (biaryl sultams) have emerged as privileged structures in drug discovery.For example, carbapenem derived biaryl sultam D provides for potent binding to the target penicillin binding proteins (PBPs). 11The related quinolinederived biaryl sultam E plays an active role in the NF-κB pathway, which has provided a favorable target for pharmacological intervention for chronic inflammation, neurodegenerative diseases, and certain types of cancer. 63][14][15][16][17] However, it was less reported for the synthesis of biaryl based sultams.Recently, some methodologies have also been developed including intramolecular C-H arylation of the 2-halobenzenesulfonamides catalyzed by palladium or with the assistance of a single-electron-transfer pathway [18][19][20][21] and intramolecular oxidative C-H amination of 2phenylarylsulfonamides under metal-free conditions. 22In addtion, palladium catalyzed intramolecular oxidative coupling (IOC) of two C(sp2 )-H bonds was also developed for the synthesis of biaryl sultams. 23Very recently, an alterative approach has been reported for the preparation of biaryl sultams using visible-lightpromoted denitrogenative cyclization of 1,2,3,4-benzothiatriazine-1,1-dioxides. 24Because of its significance in pharmaceutical development, the exploration of a novel and simple synthetic method for the construction of biaryl sultams would be highly desirable.Transition-metal-catalyzed decarboxylative transformations of arenecarboxylic acids through extrusion of the traceless CO 2 have drawn considerable attention in the past decade. 257][28] Crabtree developed an elegant method for the synthesis of biaryl compounds via transition-metal-catalyzed decarboxylative C-H arylation reaction. 29ubsequently, Larrosa, 30 Su, 31 Greaney, 32 and others [33][34][35][36] reported palladium-catalyzed intramolecular and intermolecular decarboxylative arylation of activated heteroarenes for the synthsis of biaryl motifs.][39] Inspired by recently elegant works on the intramolecular or intermolecular decarboxylative C-H arylation of (hetero)arenes with aromatic carboxylic acids. 40In the course of our ongoing investigation on transitionmeta-catalyzed C-H activation reactions to access sulfonamide derivatives. 41We report herein the first example of silver-catalyzed intramolecular oxidative decarboxylative C-H arylation for synthesis of biaryl sultams.

Results and Discussion
Initially, we selected the intramolecular oxidative decarboxylative C-H arylation of 2-phenylsulfamoyl-benzoic acid 1a as a model reaction for optimization studies (Table 1).To our delight, a 72% yield of the desired product 2a was obtained when the reaction was conducted in CH 3 CN at 100 o C for 12h in the presence of AgOAc (20 mol%) with K 2 S 2 O 8 (2 equiv) as an oxidant (Table 1, entry 1).And then, various oxidants were investigated, we found the yield of 2a dropped to 37% (Table 1, entry 2) and 26% (Table 1, entry 3) when (NH 4 ) 2 S 2 O 8 and Cu(OAc) 2 was used, respectively.Surprisingly, No desired product could be detected using PhI(OAc) 2 as the oxidant (Table 1, entry 4).Subsequently, Investigation of different silver catalysts for the reaction revealed that Ag 2 SO 4 was superior, giving 89% yield (Table 1, entries 5-8).It is interesting to find that reducing the amount of catalyst loading from 20 to 10 mol % did not effect on the activity and gave the comparable yield (87%) (Table 1, entry 9).Whereas further reducing the amount of catalyst loading to 5% mol % only affords 64% yield (Table 1, entry 10).Temperature has a great impact on this reaction; the product 2a was obtained in 76% yield at 80 °C (Table 1, entry 11).Control experiments revealed that no such coupling reaction occurred in the absence of the silver catalyst (Table 1, entry 12).Finally, the optimized reaction conditions were identified as follows: Ag 2 SO 4 (10 mol %), and K 2 S 2 O 8 (2 equiv) in CH 3 CN at 100 °C for 12 h under air.With the optimized reaction conditions in hand, we then evaluated the influence of the aniline moiety bearing various substituents on the reactivity and regioselectivity (Table 2).The electronic nature of the substituents seemed to have a little effect on the product yields, for example, substrate 1 with a electrondonating para-methyl or chrolo group on the N-aryl ring afforded the biaryl sultams 2b-c in 83% or 82% yield, respectively (Table 2, entries 2,3), while the slightly higher yield (87%) was obtained for 2d containing an electron-withdrawing para-CF 3 group (Table 2, entry 4).As for substrates 1e-g bearing a meta-group, such as chrolo, floro or methoxyl, Cyclisation only occurs regioselectively on the less hindered position and the desired biaryl sultams 2e-g were obtained in good yields (Table 2, entries 5-7).It should be noted that ortho-chloro or ortho-methoxyl substituted substrates 1g, 1h, and 1i worked well to generate the corresponding desired products 2g-i in excellent yields without the cleavage of the C-Cl bond even though aryl halides are wellknown to participate in Pd-catalyzed decarboxylative coupling reactions (Table 2, entries 8-10).Thus, these halogens can provide the opportunity for further transition metal catalyzed syntheses, thereby broadening the diversity of the products.Furtheromre, methyl protected amino group substrates 1k and 1l also provided the desired products 2k and 2l in very high yield (Table 2, entries 11,12).Notably, heteroaromatic thiophene on the acid moiety 1m was also successfully employed to provide the corresponding biaryl sultam 2m in good yield (Table 2, entry 13).

Conclusions
In summary, we have developed a novel and efficient protocol for the synthesis of biaryl sultams via silvercatalyzed intramolecular oxidative decarboxylative C-H arylation.The reaction proceeds under mild conditions without the use of expensive transition metals or ligands.Many functional groups are tolerated, giving access to a wide range of biaryl sultam derivatives.The cyclization was proposed to proceed via a radical mechanism.Further investigations to the reaction mechanism and utilization of this catalyzed system in other biaryl based heterocyclic compounds are currently in progress.

Experimental Section
General.All reactions were carried out under air atmosphere in oven-dried glassware with magnetic stirring.Unless otherwise specified, all other reagents and solvents were purchased from Energy Chemical, Alfa Aesar or J&K Chemical Company and used without any further purification.TLC information was recorded on GF-254 (Qingdao Haiyang Chemical Co., Ltd.P. R. China) plates.Purification of reaction products was carried out by flash chromatography using Silica gel (200-300 mesh, Qingdao Haiyang Chemical Co. Ltd.P. R. China).All products were recorded using Bruker Avance-400 instruments, calibrated to TMS as the internal reference (0.00 ppm for 1H NMR spectra and 100.00 ppm for 13 C NMR spectra).High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI (electrospray ionization).Melting points were measured uncorrected.

Table 1 .
Optimization of reaction conditions

Table 1 .
Continued b Isolated yields.c at 80 o C.