Site-selective bromination of sp3 C–H bonds

A method for converting sp3 C–H to C–Br bonds using an N-methyl sulfamate directing group is described. For all sulfamates examined, bromination occurs with high selectivity at the γ-carbon, affording a predictable method for C–H bond halogenation.


Results and discussion
Initial optimization of conditions for alkylbromide formation was performed with isopentyl methylsulfamate 1, a simple, unfunctionalized substrate with a single tertiary C-H bond. A variety of transition metal salts were tested in conjunction with 3 equivalents each of NaBr and NaOCl, a reagent combination known to generate hypobromite in situ and used previously for the oxidative cyclization of sulfamate esters. 56 While little to no reaction ensued in the presence of catalytic Mn 3+ , Co 2+ , Cu 2+ ,  8,9), likely owing to the greater solubility of these complexes in dichloromethane. In the complete absence of transition metal, conversion to product still occurred (Table 1, entry 10) in a process that appears to be promoted by ambient light (Table 1, entry 11). A 1 : 1 biphasic mixture of CH 2 Cl 2 /saturated aqueous Na 2 HPO 4 was found to be the optimal solvent combination ( Table 1, entry 5). In neat CH 2 Cl 2 , conversion to product was signicantly reduced, and in unbuffered water with CH 2 Cl 2 a mixture of both brominated and chlorinated products was obtained ( Table 1, entries 12 and 13). Using organic co-solvents other than CH 2 Cl 2 was similarly deleterious to reaction performance (Table 1, entries 14 and 15).
A range of structurally diverse N-methyl sulfamates has been prepared by condensation of the corresponding 1 and 2 alcohols with ClSO 2 NHMe and subjected to the optimized halogenation protocol ( Table 2). Oxidation of both tertiary and benzylic C-H bonds is possible in moderate to good yields, even with Rh 2 (oct) 4 loadings as low as 0.1 mol% (entry 2). Different functional groups, including alkyl and benzyl esters, epoxides, trichloroethylsulfamate-protected aziridines, and silylated alcohols, are compatible with these conditions ( Table  2, entries 3-6). For all substrates examined, C-H bond oxidation occurs nearly exclusively at the g-carbon. This nding compares favorably with other directed C-H halogenation methods, which afford mixtures of constitutional isomers. 15,20 The directed nature of this process is further highlighted in entries 8, 9, and 10. Each of these substrates furnishes the product of g-C-H bond bromination despite possessing an activated benzylic C-H center. Positional selectivity is also noted in entries 11 and 12. Experiments with the latter substrate show that oxidation of an optically active 3 C-H bond gives racemic alkylbromide, a result consistent with the formation of a carbon-centered radical intermediate (vide infra). In addition, we have found that the absence of NaBr leads to generation of the corresponding chlorinated product (entry 12), albeit in reduced yield. All told, this new protocol offers an efficient, predictable, operationally simple method for C-H bond functionalization.
Displacement of the N-methyl alkoxysulfonyl auxiliary can be achieved in a single-ask, two-step protocol that involves initial N-carbamoylation with Boc 2 O followed by an S N 2 reaction (Scheme 1). The N-acylated sulfamate undergoes smooth reaction with nucleophiles such as N 3 À and I À to give the corresponding alkylazide and alkyliodide products, respectively. This method for excising the sulfamate directing group should add to the overall utility of the C-H halogenation process. Previous work exploring the use of NaBr/NaOCl for the synthesis of [1,2,3]-oxathiazinane-2,2-dioxide heterocycles 56 suggested the formation of an N-halogenated species as a rst step in the reaction pathway. In accord with this hypothesis, we Table 2 Oxidative halogenation of N-methyl sulfamate derivatives a Isolated product yield unless otherwise indicated. b Reaction performed with 0.1 mol% Rh 2 (oct) 4 . c Yield estimated by 1 H NMR integration using an internal standard. d Product isolated as a 1 : 1 mixture of diastereomers. e Product isolated as a mixture of diastereomers, ratio undetermined. f Product yield estimated by 1 H NMR integration using an internal standard. Chromatography on SiO 2 facilitates bromide elimination, see Fig. S1 for details. g Product isolated as a racemic mixture, see Fig. S2 for details. h Yield of corresponding chloride product obtained from a reaction performed without NaBr. have demonstrated that the N,N-dimethyl sulfamate 3 is not a competent substrate for oxidation. Additionally, we have prepared an N-brominated sulfamate 5 and have shown that this compound will react with 5 mol% Rh 2 (oct) 4 to form alkylbromide 6 in 40% yield (Scheme 2 and Fig. S3 †). Although the efficiency of this process is reduced from that of the catalytic protocol (entry 1, Table 2), these ndings establish the Nbrominated species as a chemically competent intermediate on the reaction pathway.
The ability to access N-brominated sulfamate 5 has enabled a series of experiments to determine the role of Rh 2 (oct) 4 in the oxidation reaction. UV/Visible spectroscopic monitoring of the reaction of 5 with Rh 2 (oct) 4 in CH 2 Cl 2 reveals a distinct change in the absorption spectrum, evidenced by the disappearance of the feature at l max ¼ 418 nm, shiing of the l max at 655 to 595 nm, and the appearance of a new l max at 985 nm (Fig. 1a). The nal absorption spectrum is indicative of a mixed-valent Rh 2+ /Rh 3+ tetracarboxylate dimer, 57,58 consistent with a mechanism involving one-electron reduction of the N-Br bond to generate an N-centered radical. Support for this conclusion has been obtained through electrospray ionization mass spectrometric (ESI-MS) analysis, which conrms the presence of both the Rh 2+ /Rh 3+ complex and free Br À (Fig. 1b-c) resulting from this reaction.
In a reaction mixture containing 5 and Rh 2 (oct) 4 , the red color ascribed to the mixed-valent dirhodium species persists for several hours. Under standard catalytic reaction conditions, however, the deep green color of intact Rh 2 (oct) 4 bleaches to pale yellow within 30 min following NaOCl addition. A UV/vis spectrum of the reaction mixture at this time point shows a featureless spectrum, consistent with decomposition of the rhodium dimer (Fig. S4a †). Interestingly, at 30 min, product conversion is only $30%, with starting material accounting for the remainder of the mass balance (Fig. S4b †). Aer the full reaction time (15 h), the isolated product yield is 61%. Thus, the reaction appears to proceed beyond the lifetime of Rh 2 (oct) 4 , suggesting its role as an initiator rather than as a catalyst for oxidative halogenation (Scheme 3). Accordingly, these data have led us to favor a mechanism for C-H bromination through a chain transfer process involving N-and C-centered radical intermediates, as depicted in Scheme 3. We cannot, however, discount the possibility that the intermediate carbon radical could also react with [Rh 2 (oct) 4 Br] to give the brominated product.
To test for a radical chain mechanism, a 1 : 1 mixture of brominated sulfamate 5 and chlorinated sulfamate 10 was stirred with catalytic Rh 2 (oct) 4 . ESI-MS analysis of the reaction mixture at 2 h revealed brominated products 2 and 6 and chlorinated products 11 and 12 ( Fig. 2 and S5 †). Such a product distribution lends strong support to our mechanistic scheme, as only an intermolecular collision between intermediates derived from 5 and 10 could lead to cross-halogenated products 2 and 12.
As  deutero-sulfamate substrates, 13 and 14. This result suggests that N-centered radical formation is not a committed, irreversible step. Reactions of 15 with a second N-halogenated sulfamate (or HOBr) to form 16 or with solvent to regenerate 13 are possible pathways that apparently compete with intramolecular g-C-H abstraction, thus giving rise to a non-unitary KIE value in the competition experiment. 59 Given a radical chain mechanism for C-H halogenation, it is possible that metal complexes other than Rh 2 (oct) 4 could serve as initiators. We have found that treatment of 5 with a combination of 15 mol% CuBr 2 and 1,10-phenanthroline forms the tertiary bromide product 6 in 31% yield (Scheme 5 and Fig. S7 †). 60 While the efficiency of this reaction is lower than that with Rh 2 (oct) 4 (Scheme 2), formation of 6 suggests that, at least in principle, new reaction manifolds utilizing rst-row transition metals can be optimized for the oxidative halogenation of sp 3 C-H bonds.

Conclusions
A method for site-selective bromination of sp 3 C-H bonds using N-methyl sulfamate substrates is presented. Following halogenation, the sulfamate directing group can be displaced with nucleophiles to generate value-added alkylbromide products. The scope and predictability of this oxidation reaction distinguish these ndings. UV/visible spectroscopy, ESI-MS analysis, and substrate probe experiments implicate a radical chain mechanism for C-H halogenation, initiated by Rh 2 (oct) 4 . Further exploration of sulfamate directing groups in C-H functionalization catalysis is warranted and should lead to high-precision methods for modifying sp 3 carbon centers.

Conflicts of interest
There are no conicts to declare. Scheme 3 A proposed radical-chain transfer process for C-H bromination.  Scheme 4 KIE study suggests reversibility of N-centered radical formation.