Selective Bromination of sp³ CH Bonds by Organophotoredox Catalysis

Abstract

We report that bromination of aliphatic and benzylic sp3 CH bonds can be achieved with visible light photoredox catalysis by using a low loading of Eosin Y disodium salt, an inexpensive organic dye, as a photoredox catalyst. The light source is a low‐power household lamp and the reaction can be performed without the need of an inert atmosphere and anhydrous solvent. Easy‐to‐handle CBr4 is the source of bromine and morpholine is necessary for the reaction. Preliminary experimental and computational studies on the mechanism strongly suggest that an N‐morpholino radical is responsible for the CH activation step. This led us to propose that this is a radical relay reaction, in which a longer‐lived morpholine radical is generated from a CBr3 radical, which is relatively more transient, by a thermodynamically favorable reaction. Additional evidence for the existence of such an N‐radical was obtained from radical trapping experiments. The strong preference of this reaction for electron‐rich hydrogen atoms, and the high sensitivity to the steric environment around the CH bond enables bromination to occur on the relatively stronger CH bond (as quantified by bond dissociation enthalpy) on the same molecule. The potential for utilizing this reaction to achieve mild and regioselective bromination of sp3 CH bonds in complex molecules is exemplified by the bromination of (+)‐sclareolide and acetate‐protected estrone.

Dual Catalysis Strategies in Photochemical Synthesis

“…238 The Tan group carried out benzylic bromination using a similar strategy with morpholine as the HAT catalyst. 239 Li reported the oxidation of primary alcohols using tandem photoredox/TEMPO catalysis. 240 The authors proposed a mechanism in which photoexcited Ru(bpy) 3 (PF 6 ) 2 oxidizes TEMPO to the corresponding oxammonium, a known reagent for alcohol oxidation.…”

Synthetic applications of eosin Y in photoredox catalysis

“…Recently, Tan and coworkers reported a selective method for the bromination of aliphatic and benzylic C-H bonds via visible light photoredox catalysis using eosin Y (Scheme 12). 53 The reaction was performed under mild conditions using CBr 4 as the bromine source and morpholine as the reducing agent. The amount of water is essential for the reaction: a higher ratio of water to dichloromethane is important for the formation of the brominated product 23.…”

Benzylic C(sp3)–H Functionalization for C–N and C–O Bond Formation via Visible Light Photoredox Catalysis

“…During the past decade, considerable success has been made in this area to functionalize the α-C­(sp 3 )–H bond in t -amines, alcohols, and ethers and used as main streamline reactions in synthetic chemistry . Although reports on simple C­(sp 3 )–H functionalization are infrequent in literature, we had reported earlier a protocol for C–O bond formation using 1,4-dicyanonaphthalene (DCN) as a light harvesting photocatalyst (Scheme ). However, when the same protocol was extended for C–N bond formation, this reaction did not succeed possibly because of competetive electron transfer.…”