Dual Benzophenone/Copper‐Photocatalyzed Giese‐Type Alkylation of C(sp³)−H Bonds

Abstract

Photocatalyzed Giese‐type alkylations of C(sp3)−H bonds are very attractive reactions in the context of atom‐economy in C−C bond formation. The main limitation of such reactions is that when using highly polymerizable olefin acceptors, such as unsubstituted acrylates, acrylonitrile, or methyl vinyl ketone, radical polymerization often becomes the dominant or exclusive reaction pathway. Herein, we report that the polymerization of such olefins is strongly limited or suppressed when combining the photocatalytic activity of benzophenone (BP) with a catalytic amount of Cu(OAc)2. Under mild and operationally simple conditions, the Giese adducts resulting from the C(sp3)−H functionalization of amines, alcohols, ethers, and cycloalkanes could be synthesized. Preliminary mechanistic studies have revealed that the reaction does not proceed through a radical chain, but through a dual BP/Cu photocatalytic process, in which both CuII and low‐valent CuI/0 species, generated in situ by reduction by the BP ketyl radical, may react with α‐keto or α‐cyano intermediate radicals, thus preventing polymerization.

Phenylglyoxylic Acid: An Efficient Initiator for the Photochemical Hydrogen Atom Transfer C−H Functionalization of Heterocycles

“…[19] Finally, Vincent and co-workers reported the benzophenone photocatalyzed Giese-type alkylations of CÀ H bonds using unsubstituted acrylates, acrylonitrile, and methyl vinyl ketones as acceptors, in the presence of a catalytic amount of Cu(OAc) 2 . [20] We have recently developed a photochemical protocol that is easy to operate, employing cheap household lamps as the irradiation source and phenylglyoxylic acid, a cheap, organic, and commercially available molecule, as the initiator for the functionalization of aldehydes or alcohols (Scheme 2A). [21] A fast and efficient visible-light metal-free hydroacylation of dialkyl azodicarboxylates, was developed, [21a] and extended in the synthesis of hydroxamic acids [21b] and amides, [21c] finding application in the synthesis of the drugs Vorinostat and Moclobemide.…”

“…Also, Nicewicz and co‐workers presented the alkylation of carbamate‐protected amines, using an organic acridinium photoredox catalyst and 445 nm LEDs as the irradiation source (Scheme 1F) [19] . Finally, Vincent and co‐workers reported the benzophenone photocatalyzed Giese‐type alkylations of C−H bonds using unsubstituted acrylates, acrylonitrile, and methyl vinyl ketones as acceptors, in the presence of a catalytic amount of Cu(OAc) 2 [20] …”

Emergent synthetic methods for the modular advancement of sp3-rich fragments

“…Scheme 10 Benzophenone/Cu-catalysed coupling of alkyl radicals and electron deficient alkenes. 61 † Scheme 11 Cross-dehydrogenative couplings between saturated heterocycles and benzophenone imines. 66 † a 5.0 eq.…”

Carbonyl-Photoredox/Metal Dual Catalysis: Applications in Organic Synthesis

“…Vincent and co-workers have developed a UVA-mediated Giese-type alkylation using photocatalyst benzophenone (P1) with Cu(OAc) 2 under a low-pressure mercury lamp (320-390 nm) (Scheme 34). 27 Cyclic Boc-protected amines reacted well with acrylate derivatives to afford alkylated products in ca. 50% yield.…”

“…The first report of this chemistry was in 1976 by Jones and co-workers who discovered the dehydrogenation of alkanes using benzophenone (P1) in conjunction with Cu(OPiv) 2 . 22 This study was followed by a 40 year hiatus until reports began emerging of dual photocatalytic systems that could mediate the homocoupling of aryl halides, 23 arylation and alkylation of C(sp 3 )-H bonds, 24 carboxylation of allylic, benzylic, and aliphatic bonds with CO 2 , 25 acylation of benzylic C(sp 3 )-H bonds with acid anhydride or chlorides, 26 hydroalkylation of olefins, 27 hydroalkylation of imines, 28 arylation of aromatic aldehydes, 29 aryl esterification, 30 and enantioselective oxidation of -keto esters. 31 These recent discoveries are reviewed herein, categorized by reaction X = Br, Y = Me, 70% X = Cl, Y = Me, 14% X = I, Y = Me, 72% X = Br, Y = OMe, 67% X = Br, Y = tBu, 74% X = Br, Y = CN, 52% X = Br, Y = CO 2 Me, 62% X = Br, Y = CF 3 , 84% a X = Br, Y = Ph, 79% X = Br, Y = Bpin, 67% under these reaction conditions, giving the desired product in 67% yield.…”