Communication
Copper Catalyzed C(sp3)−H Bond Alkylation via Photoinduced
Ligand-to-Metal Charge Transfer
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ABSTRACT: Utilizing catalytic CuCl2 we report the functionalization of numerous feedstock chemicals via the coupling of
unactivated C(sp3)−H bonds with electron-deficient olefins. The active cuprate catalyst undergoes Ligand-to-Metal Charge Transfer
(LMCT) to enable the generation of a chlorine radical which acts as a powerful hydrogen atom transfer reagent capable of
abstracting strong electron-rich C(sp3)−H bonds. Of note is that the chlorocuprate catalyst is an exceedingly mild oxidant (0.5 V vs
SCE) and that a proposed protodemetalation mechanism offers a broad scope of electron-deficient olefins, offering high
diastereoselectivity in the case of endocyclic alkenes. The coupling of chlorine radical generation with Cu reduction through LMCT
enables the generation of a highly active HAT reagent in an operationally simple and atom economical protocol.
he catalytic functionalization of unactivated C(sp3)−H
the substrate as well as diminishing the coupling partners
available for the generated alkyl radical due to the limited
reduction potentials available to highly oxidizing photocatalysts
(Scheme 1B-2).
T
bonds has been a long-standing goal in synthetic methods
development.1,2 Due to the inert and nonpolarized nature of
C(sp3)−H bonds, manipulation of these positions requires the
formation of high energy intermediates that must differentiate
Photoinduced ligand-to-metal charge transfer (LMCT) has
proven to be an effective means toward the formation of HAT
reagents in organic synthesis.43 Coordination of the reactive
functional group with the metal complex enables chemo-
selective oxidation via direct excitation of the metal−ligand
complex. Through the coupling of the ligand oxidation with
metal reduction, the reactive radical may be generated under
low electrochemical potentials, complementing strategies
enabled by SET. Pioneering work by the Doyle, Wu, and
Zuo laboratories has shown LMCT as an effective strategy to
catalyze the formation of chlorine and alkoxy radicals to
functionalize strong C(sp3)−H bonds43−47 (Scheme 1B-3).
Previous work in our group demonstrated the ability of CoII−
acetylides to undergo LMCT toward CoI catalyzed [2 + 2 + 2]
cycloaddition of alkynes.48 Hypothesizing that other air stable
metal salts could complement these HAT centered protocols
in terms of substrate scope, selectivity, and reactivity, we
explored the competency of various metal halides to undergo
LMCT to enable novel reactivity in HAT catalysis. Stimulated
by early work from Kochi who proved the competence of
cupric chloride in the stoichiometric chlorination of alkanes in
acetonitrile,49−54 we noted Tarnovsky’s follow-up work
characterizing the various photoactive species capable of
LMCT for CuII chlorocomplexes in acetonitrile.55 Recent
reports have utilized this mechanism toward the chlorination
comparable sites of reactivity to enable selectivity,3,4
a
challenge made more profound when one also targets the
desirable outcome of sustainability.5
In recent years, intermolecular hydrogen atom transfer
(HAT) has evolved into a synthetically viable mechanism for
the selective C−H functionalization of alkanes6−10 (Scheme 1
A). The generated alkyl radical provides a reactive intermediate
poised for bond formation with myriad coupling partners
including those activated via transition-metal catalysis.11−15
Selectivity of HAT is governed by the electronic and steric
characteristics of both the C(sp3)−H bonds of the substrate as
well as the HAT reagent.16−21 The recent expansion of
photoredox catalysis in organic synthesis has enabled the
formation of reactive radicals capable of HAT for myriad
functional groups in a catalytic fashion.22−31
Due to the abundance and inexpensive nature of chloride
salts, the formation of a chlorine radical from a chloride anion
for use as a HAT reagent has long been an attractive strategy
toward the functionalization of C(sp3)−H bonds. HAT with
chlorine radical forms a strong polarized bond in HCl (BDE =
103 kcal/mol), enabling the abstraction of strong electron-rich
C(sp3)−H bonds to form the corresponding alkyl radical
(Scheme 1B-1). While there exists a surfeit of HAT reagents
capable of abstracting relatively weak C(sp3)−H bonds, there
are relatively few methods capable of HAT of strong C(sp3)−
H bonds.32−36 Classical methods of chlorine radical generation
require the employment of reactive reagents such as chlorine
gas or N-chlorosuccinimide,37,38 but recent methods have
enabled the generation of chlorine radicals via direct oxidation
of dissolved chloride through photoredox catalysis.39−42 This
direct oxidation requires potentials exceeding +1.21 V vs
SCE,42 limiting synthetic utility due to oxidation sensitivity of
Received: January 19, 2021
Published: February 12, 2021
J. Am. Chem. Soc. 2021, 143, 2729−2735
© 2021 American Chemical Society
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