Sulfamate Esters Guide Selective Radical‐Mediated Chlorination of Aliphatic C−H Bonds

Abstract

Masked alcohols are particularly appealing as directing groups because of the ubiquity of hydroxy groups in organic small molecules. Herein, we disclose a general strategy for aliphatic γ-C(sp )-H functionalization guided by a masked alcohol. Specifically, we determine that sulfamate ester derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide γ-C(sp )-H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.

Sulfamides direct radical-mediated chlorination of aliphatic C–H bonds

“…These C-H bonds have bond dissociation energies (BDEs) that cover a broad range (BDE z 96-101 kcal mol À1 ), 26 demonstrating the generality of the transformation. In particular, this chlorine-transfer reaction provides access to primary alkyl chlorides (4a) in excellent yield, outperforming related sulfamate ester- [11][12][13] and sulfamide-guided 10 methods in transforming strong primary C-H bonds. This sulfamide-guided process oxidizes C-H bonds at acyclic or cyclic centers (entries 4-6), and is compatible with pendant ester (entry 7) and masked amine (entry 8) functionalities.…”

“…Surprisingly, sulfamide substrates undergo competitive gand d-chlorination when they incorporate g-C(sp 3 )-H bonds in proximity to weaker d-C(sp 3 )-H bonds, a phenomenon not generally observed in related sulfamate ester-guided reactions. [11][12][13] For example, N-pentyl sulfamide 1i yields a crude 8.8 : 1 mixture of gand d-chlorinated 4i and 7i from which gchlorinated 4i can be isolated in 75% yield (Scheme 3A). In principle, d-chlorinated minor product 7i could form via either a substrate-guided 1,7-HAT process that relies on an eightmembered transition state, or an intermolecular C-H abstraction process.…”

Benzylation of Arenes with Benzyl Halides under Promoter‐Free and Additive‐Free Conditions

“…In any case, it was observed that methyl group of mesitylene underwent the chlorination, to give 3,5‐dimethyl‐benzyl chloride by‐product (Scheme ). Obviously, this by‐product should be formed via one of the two kinds of pathways based on previous literatures:, One involved the chlorine radical (Scheme a), and the other required the presence of strong oxidants (Scheme b) . Actually, the latter mechanistic pathway should be excluded because there was no any strong oxidant in our reaction system.…”

Pushing the boundaries of C–H bond functionalization chemistry using flow technology

“…The first 1,5-HAT reaction, the classic Hoffmann-Löffler-Freytag reaction, originated in 1883 and involves photolysis of a protonated N-chloroamine after which the resulting aminium radical abstracts a hydrogen from a carbon five atoms away, resulting in δ-chlorination. The 1,5-radical translocation is thermodynamically favourable because the abstraction of the hydridic hydrogen atom is exergonic and occurs through a sixmembered transition state, although 1,6-and 1,7-translocations involving sulfamates and sulfamides have also been reported by the group of Roizen [218,219]. Following the translocation of the halide, an intramolecular nucleophilic substitution reaction then furnishes pyrrolidine products.…”