Switching the site-selectivity of C–H activation in aryl sulfonamides containing strongly coordinating N-heterocycles

Switching the site-selectivity of C–H activation in aryl sulfonamides containing strongly coordinating N-heterocycles was achieved using a RhIII-catalyst.


Results and discussion
Initially, this Rh(III)-catalyzed site-selective C-H carbenoid functionalization was investigated for solvent effects (0.05 M concentration) by using AgOAc as an additive at 60 C, with the results summarized in Table 1 (entries 1 to 5). When 3-methyl-4thiazole-N-acetyl sulfonamide (1a) was used as a model substrate, C-H carbenoid functionalization product 3 0 at the ortho-position of thiazole was only observed and isolated in 79% yield when MeOH (a polar protonic solvent) was used as the reaction solvent (Table 1, entry 1). Other tested polar solvents, such as DMF and MeCN, also favored generation of the C-H activated product at the ortho-position of the thiazole group (Table 1, entries 2 and 3). When non-polar solvents were used, such as DCE and toluene, the thiazole-directed C-H activated product was decreased signicantly (Table 1, entries 4 and 5). It was notable that the amount of sulfonamide directed C-H activated product 3 was close to thiazole directed C-H activated product 3 0 (3/3 0 ratio, 1 : 1.6) when less-polar toluene was used as the reaction solvent (Table 1, entry 5). These results suggested that the polarity of the solvent strongly determined the site-selectivity of this rhodium catalyzed C-H carbenoid functionalization: the less polar the solvent, the more favorable was the sulfonamide-directed C-H activation product. Importantly, this phenomenon was more obvious at low concentrations (Table 1, entries [6][7][8], and when the reaction concentration was reduced to 0.01 M in DCE or toluene, an increasing amount of sulfonamide-directed activation product 3 was observed. It was worth noting that product 3 was isolated as the major product and the 3/3 0 ratio could reach 33 : 1 when the reaction was carried out in toluene at 0.01 M concentration (Table 1, entry 7). The result given by a solvent mixture of DCE and toluene (v/v ¼ 1 : 1) more clearly reected the solvent polarity effect on this Rh(III)-catalyzed site-selective C-H carbenoid functionalization (Table 1, entry 8). Further decreasing the concentration to 0.005 M resulted in an excellent site-selectivity of 3 (3/3 0 ratio, >99 : 1, Table 1, entry 9). Reducing the amount of [RhCp*Cl 2 ] 2 to 2.5 mol% resulted in a decreased 3 : 3 0 ratio of 28 : 1, which showed that 5 mol% of the catalyst loading amount was necessary for this selective sulfonamide directed C-H carbenoid functionalization (entry 10). In contrast, increasing the reaction concentration led to increase of the thiazole-directed product 3 0 , which also well reected the signicant solvent effect of this site-selective C-H carbenoid  . These results showed that increasing the amount of AgOAc favored C-H functionalization at the thiazole ortho-position. It may be possible that changing the AgOAc concentration affected the polarity of the reaction environment, inuencing the site-selectivity. It is also possible that AgOAc plays the role of a Lewis acid which could bind to an N-heterocycle or diazo compound and affect the site-selectivity. 82 When a more economic acetate salt tetrabutylammonium acetate was used as an additive instead of AgOAc, similar yields were obtained. However, the site-selectivities of the C-H carbenoid functionalization were signicantly reduced (entries 17 and 18). Therefore, two optimal conditions to switch site-selectivity at the ortho-position of sulfonamide and N-heterocycle were chosen respectively (entries 9 and 15). These two methods not only gave good yields, but more importantly excellent site-selectivities.
With the two optimal conditions in hand, sulfonamide substrates containing various N-heterocycles in a competitive position were further investigated, including thiazole, pyrazole, imidazole, pyridine, pyrimidine, and pyrazine substrates (Scheme 1). As expected, sulfonamide-group-directed ortho-C-H carbenoid functionalization proceeded in the presence of 5.0 mol% [RhCp*Cl 2 ] 2 catalyst and 20 mol% AgOAc as the additive in less-polar toluene (0.005 M) at 60 C, affording excellent site-selectivity (Scheme 1A, Method A, [4][5][6][7][8][9][10][11][12][13][14]. In addition to phenyl sulfonamides, thienyl sulfonamides also showed excellent site-selectivity (15 and 16), while substrates containing phosphate ester and sulfone ester diazo groups instead of dimethyl 2-diazomalonate also gave satisfactory results (17 and 18). Notably, C-H di-activation at the ortho-positions relative to the sulfonamide group afforded the major product when paraheterocycle-substituted benzenesulfonamide was used (19)(20)(21)(22). As shown in Scheme 1B, when the reaction was conducted in DCE (0.05 M), the N-heterocycle-directed C-H carbenoid functionalization of this difunctional compound performed well in the presence of 2.5 mol% [RhCp*Cl 2 ] 2 catalyst and 60 mol% AgOAc as the additive at 60 C, with good yields and excellent site-selectivity (Method B, [23][24][25][26][27][28][29][30]. A 1,2-disubstituted substrate was also tried, but no desired carbenoid functionalization product was obtained, which may be the result of a bidentate coordination, impeding the free coordination site for cyclometallation. Intermolecular competition experiments were conducted to explore the unique chemoselectivity of difunctional sulfonamides containing N-heterocycle substrates (Scheme 2). Notably, X-type sulfonamides outcompeted strongly coordinating L-type thiazole, pyrazole, and pyridine substrates using method A. In contrast, when the competition reaction was conducted using method B, N-heterocycle-oriented C-H carbenoid functionalization was the major pathway. These intermolecular competition results implied that changing the C-H carbenoid functionalization reaction conditions could affect the competitive reactivity between X-type and L-type directing groups. More importantly, this strategy could prevent interference from L-type N-heterocycles to afford X-type sulfonamide-oriented C-H activation, despite N-heterocycles possessing strongly coordinating properties with metal catalysts.
The mechanism of the site-selective aryl C-H carbenoid functionalization between sulfonamide and N-heterocycles was further investigated by experimental studies and theoretical calculations. The mechanism of directing group oriented aryl C-H carbenoid functionalization has been illustrated in the previous literature, and three major steps including C-H activation, metal-carbene formation and nal C-C bond formation process were proposed to take place. 50 Firstly, as shown in Scheme 3, isotope-labelling experiments of 3-methyl-4-thiazole-N-acetyl sulfonamide (1a) by method A and B in the presence of [D 4 ]-MeOD showed that reversible processes for sulfonamide and thiazole directed C-H activation were involved under method A and B conditions. [83][84][85] Notably, there was a relatively slight H/D exchange (5%) at the ortho position of the thiazole group using [D 4 ]-MeOD as a co-solvent in the method A catalytic system, implying weak reversible properties. As shown in Scheme 4, kinetic isotope effect (KIE) experimental results showed a relatively small value, indicating that C-H bond cleavage was likely not the rate-determining step in the catalytic cycle. 86,87 These results suggested that the selectivity does not appear in the rst C-H activation step, but in the subsequent steps possibly.
In order to delve into our conjecture about the mechanism on selectivity, density functional theory (DFT) calculations were performed. The RhCp*(OAc) 2 complex was commonly considered as the active catalyst under the conditions of [RhCp*Cl 2 ] 2 with an abundant AgOAc additive. 51,54,57 As implied in our experiments, the results of site-selective C-H carbenoid functionalization catalyzed by RhCp*(OAc) 2 were similar to those catalyzed by RhCp*Cl 2 /AgOAc, which proved that RhCp*(OAc) 2 was an active catalyst for the C-H carbenoid functionalization (details in the ESI †). An easier N-H deprotonation of the acetylsubstituted sulfonamide was predicted, and the active catalyst RhCp*(OAc) 2 would rstly dissociate one OAc À ligand to coordinate with the deprotonated sulfonamide substrate to form the reactant complex RC. Similar to previous reports, domino C-H activation, metal-carbene formation, and nally C-C bond formation processes were predicted to take place. [88][89][90] The deprotonated sulfonamide moiety or para-thiazole group would act as a directing group to locate the Rh(III) center adjacent to the ortho-C-H bond of either the sulfonamide or thiazole group, which guaranteed facilitation of the ortho-C-H activation processes in the transition state TS1 or TS1 0 . Both aryl C-H deprotonation to the mono-coordinated OAc À ligand and Rh-C bond formation processes were observed in the concertedmetalation-deprotonation (CMD) 91-93 type C-H activation transition state TS1 or TS1 0 . Subsequently, the Rh(III)-bound neutral HOAc molecule would be easily replaced by the diazo compound 2a, and metal-carbene formation through clear nitrogen extrusion processes was observed in both TS2 and TS2 0 . The active metal-carbene would attack an adjacent aryl carbon center to generate C-C bond formation transition state TS3 or TS3 0 . Finally, transient product PC or PC 0 was obtained through site-selective carbenoid functionalization at the orthoposition of either the sulfonamide or thiazole moiety. Alternatively, the active catalyst RhCp*(OAc) 2 might directly react with diazo compound 2a to form a metal-carbene complex via a similar nitrogen extrusion process in TS carbene .
The proles of the potential energy surface proposed above are shown in Fig. 3. It can be noted that the energies of the direct metal-carbene formation transition state TS carbene (31.2 and 34.2 kcal mol À1 in toluene and DCE, respectively) were higher than the barriers depicted in Fig. 3, which reconrmed the fact that the active Rh(III) catalysts would preferentially react with aryl substrates (details in the ESI †). As depicted in Fig. 3, the free energy barrier in the metal-carbene formation was higher than those of the C-H activation process and C-C formation step. The calculated results demonstrated that the C-H activation step was not rate-determining, which was consistent with experimental KIE results. In addition, stoichiometric C-H rhodation experiments were conducted (Scheme 5). As shown in Scheme 5A, 14% and 0% D, respectively, were incorporated at the ortho-positions of the sulfonamide and thiazole groups at a lower reaction concentration (0.005 M) in toluene, which was supported by the energy barrier of the ortho-sulfonamide C-H activation in toluene (TS1 is 8.6 kcal mol À1 lower than TS1 0 ). Furthermore, the competitive C-H activation results shown in Scheme 5B conrmed the calculated narrow free energy gap between TS1 and TS1 0 (2.1 kcal mol À1 ) in DCE. The concentration factor was considered in Scheme 3, which implied that the increased concentration of reaction complexes and more polarized solvent would favour thiazole-directed C-H activation. The experimental observations were in consistence with calculated C-H activation barriers, especially in the pathway of the more polarized solution (3 ¼ 25.0) wherein a narrower free energy gap between TS1 and TS1 0 was observed (1.2 kcal mol À1 ). More importantly,  a stable thiazole-directed intermediate IM 0 -OAc was generated, which was responsible for more deuteration at the thiazole side in Scheme 3B.
The reaction selectivities were further rationalized. As depicted in Fig. 3, the sulfonamide-directed pathway was more energetically favourable than the thiazole-directed pathway in toluene (red pathway). The calculated results were in good agreement with the experimental observations that orthosulfonamide C-H carbenoid functionalization product 3 was the major product in toluene (Table 1, entries 7, 9 and 10). Furthermore, close relative free energy barriers of C-H activation transition states TS1 (18.8 kcal mol À1 ) and TS1 0 (20.9 kcal mol À1 ), and of metal-carbene formation transition states TS2 (25.1 kcal mol À1 ) and TS2 0 (25.7 kcal mol À1 ) in DCE were observed (black pathway). The calculated competitive reaction pathways in DCE were in good agreement with experimental ndings that both ortho-sulfonamide product 3 and ortho-thiazole product 3 0 were obtained in DCE at a lower AgOAc concentration (Table 1, entry 6). The use of a more polarized solvent and/or high concentration of reaction complexes was also investigated, which together contributed to the increasing polarity of the reaction environment. As described above, the metal-carbene formation process was the rate-determining step, and therefore, the energy alterations of TS2 and TS2 0 under various polarization conditions were investigated. As depicted in Fig. 4A, the thiazole-directed TS2 0 was more polarized than the sulfonamide-directed TS2, which would rationalize the free energy changes in Fig. 4B wherein the thiazoledirected TS2 0 was better stabilized in high polarity surroundings. Therefore, PES proles in a more polarized solution are also provided in Fig. 3 (blue pathway). As demonstrated in Fig. 3, the energies of the thiazole-directed reaction species were decreased and the free energy of the rate-determining TS2 0 was lower than that of TS2. Meanwhile, as mentioned above, the introduction of excess OAc À ligand would result in a more stable thiazole-directed intermediate IM2 0 -OAc. Thereby, the decreased thiazole-directed energy barriers and the important OAc À ligand participation demonstrated in Fig. 3 (blue), as well as the better stabilization of TS2 0 in more polarized surroundings shown in Fig. 4B, would reasonably explain the reaction selectivities under the conditions of more polarized solvent and/or high concentration of reaction complexes demonstrated in Table 1.

Conclusions
In summary, we have developed a Rh(III)-catalyzed arene C-H carbenoid functionalization with good yields and excellent siteselectivity switching for aryl sulfonamides containing strongly coordinating N-heterocycles. The polarity of the reaction environment was an important factor inuencing the siteselectivity. Notably, the combination of a less-polar solvent, such as toluene, and a lower additive concentration favored C-H functionalization at the ortho-position relative to the sulfonamide group with excellent site-selectivity. Furthermore, strongly coordinating N-heterocycles, including pyridine, pyrrole, thiazole, pyrimidine, and pyrazine, were tolerated. This switchable site-selectivity carbenoid functionalization methodology is suitable for the late-stage modication of N-heterocyclederived sulfonamide drugs.

Conflicts of interest
There are no conicts to declare.