Site-selective bromination of sp3 C-H bonds

Abstract

A method for converting sp³ C-H to C-Br bonds using an N-methyl sulfamate directing group is described. The reaction employs Rh₂(oct)₄ and a mixture of NaBr and NaOCl and is performed in aqueous solution open to air. For all sulfamates examined, oxidation occurs with high selectivity at the γ-carbon, affording a uniquely predictable method for C-H bond halogenation. Results from a series of mechanistic experiments suggest that substrate oxidation likely proceeds by a radical chain process. Initial formation of an N-halogenated sulfamate followed by Rh-mediated homolysis generates an N-centered radical, which serves as the active oxidant.

Scheme 1. Representative sulfamate displacement reactions.

Scheme 2. N-Bromo sulfamate 5 is a chemically competent intermediate.

Fig. 1. (a) Continuous UV/vis spectrophotometric monitoring of the reaction of 5 shows an absorption spectrum characteristic of the conversion of a dinuclear Rh²⁺/Rh²⁺ complex (λ_max = 418 nm and 655 nm) to a Rh²⁺/Rh³⁺ complex (λ_max = 595 nm and 985 nm). High-resolution ESI-MS detected ion signals of (b) Rh²⁺/Rh³⁺ complex in positive ion mode, and (c) Br^– in negative ion mode; see ESI for experimental details.

Scheme 3. A proposed radical-chain transfer process for C–H bromination.

Fig. 2. High-resolution ESI-MS analysis shows that cross-halogenated products form in a competition experiment between bromosulfamate 5 and chlorosulfamate 10. Experimental m/z values (in the spectrum) agree well with the theoretical m/z values (underneath the chemical structures).

Scheme 4. KIE study suggests reversibility of N-centered radical formation.

Scheme 5. CuBr₂/phenanthroline as an alternate metal complex for reaction initiation.