Letter
Reductive Radical Conjugate Addition of Alkyl Electrophiles
Catalyzed by a Cobalt/Iridium Photoredox System
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ABSTRACT: Alkyl and aryl halides have been studied extensively as radical
precursors; however, mild and less toxic conditions for the activation of alkyl
bromides toward alkyl radicals are still desirable. Reported here is a reductive
radical conjugate addition that allows for the formation of alkyl radicals via
activation of alkyl bromides through cobalt/iridium catalysis. The developed
conditions are emphasized in the broad substrate scope presented, including
benzylic halides and halides containing free alcohols, silanes, and chlorides.
arbon−carbon bond formation reactions via radical
addition to olefins are widely used in synthetic chemistry.1
electron nucleophilic substitution by Co(Pc) followed by
homolysis to afford alkyl radicals.13
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A common approach to achieve these reactions involves the
reductive radical conjugate addition of alkyl and aryl halides to
an electron-deficient alkene, also known as the Giese reaction.2
Besides halides, other functional groups such as alcohols,
amines, and carboxylic acid derivatives have been used as radical
precursors.3−5 Alkyl and aryl halides have played key roles in the
development of radical-based chemistry; however, the gen-
eration of these nucleophilic radicals from alkyl bromides has
been traditionally and reliably achieved via a halogen-atom
transfer (XAT) with tin or silicon reagents or trialkylborane−
O2.6 Because of the toxic and hazardous nature of these reagents,
alternative ways of forming these carbon radicals have been of
great interest.7 Although other methods have recently been
developed using transition metals with green, mild conditions,8
the activation of alkyl bromides to form alkyl radicals remains a
topic of high interest in the synthetic community.
With the advent of visible-light photoredox catalysis, highly
robust methods have been developed wherein a single electron
transfer (SET) to redox-active precursors is performed to allow
access to open-shell intermediates for a variety of different
transformations.9 However, this method is seldom used to
activate organic halides because of their low reduction
potentials. One example includes the use of silicon reagents in
photoredox catalysis to achieve difficult carbon−halide oxidative
additions via XAT or to perform cross-electrophile couplings.10
Notably, Leonori and co-workers recently published an elegant
C(sp3)−C(sp3) bond formation reaction via conjugate addition
to Michael acceptors (Figure 1a).11 This method involves the
formation of an α-aminoalkyl radical under photoredox
conditions, which mediates XAT of halides to form nucleophilic
alkyl radicals. In 2015, Weix and co-workers reported that
cobalt(II) phthalocyanine (Co(Pc)) could be used as a thermal
radical generator that enables the synthesis of diarylmethanes
from two electrophiles (Figure 1b).12 Unique to this system is
that radical generation is proposed to proceed through two-
With this in mind, we hypothesized that we could leverage Co
as a catalytic activating agent of electrophiles and an Ir-based
photoredox manifold to form an even more mild set of
conditions for this transformation. Herein we describe a
reductive conjugate addition using a cobalt/iridum dual-
catalytic system to convert alkyl bromides to alkyl radicals,
which can readily be trapped by olefins (Figure 1c).
We initiated our investigation with alkyl halide 1a (1.0 equiv)
and ethyl acrylate (2a) (2.0 equiv) as our model substrates and
the Co species identified by Weix and co-workers (10 mol %
Co(Pc)).12 These were combined with 2 mol % [Ir(dF(CF3)-
ppy)3(dtbpy)]PF6 (E1re/d2[Ir(III)*/Ir(II)] = +1.21 V vs SCE)14 as
the photocatalyst and 2.0 equiv of 1,8-diazabicyclo(5.4.0)undec-
7-ene (DBU) as the stoichiometric reductant in acetonitrile (0.3
M) under air. Irradiation with blue light for 18 h at room
temperature yielded no desired coupled product 3a (Table 1,
entry 1). To achieve reactivity, cobalt catalysts were screened.
When nonligated CoBr2 was used under the reaction conditions,
a 10% yield of the desired product 3a was observed (Table 1,
entry 2). When 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (XantPhos)15 was used as a ligand, there was a significant
increase in the yield to 35% (Table 1, entry 3). With these results
in hand, we decided to screen different organic reductants to
further optimize our reaction. Use of a Hantzsch ester led to
complete loss of reactivity (Table 1, entry 4). The organic base
diisopropylethylamine (DIPEA) showed a minimal increase in
reactivity, resulting in a 45% yield; however, when triethylamine
Received: June 23, 2021
Published: July 16, 2021
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6046−6051
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