Reductive Radical Conjugate Addition of Alkyl Electrophiles Catalyzed by a Cobalt/Iridium Photoredox System

Article abstract of DOI:10.1021/acs.orglett.1c02114

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 tha

Full text of DOI:10.1021/acs.orglett.1c02114

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Letter
Reductive Radical Conjugate Addition of Alkyl Electrophiles
Catalyzed by a Cobalt/Iridium Photoredox System
Randolph A. Escobar* and Jeffrey W. Johannes*
Cite This: Org. Lett. 2021, 23, 6046−6051
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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
C
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
https://doi.org/10.1021/acs.orglett.1c02114
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6046−6051
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Table 1. Optimization of the Cobalt-Catalyzed Reductive
Radical Conjugate Addition
a
b
cd
,
entry
[Co]
reductant
PC
3a (%)
1
2
3
4
5
6
7
8
Co(Pc)
CoBr2
DBU
DBU
DBU
H. ester
DIPEA
TEA
PC-1
PC-1
PC-1
PC-1
PC-1
PC-1
PC-2
PC-3
n.r.
10
35
n.r.
45
86
Figure 1. Activation of alkyl electrophiles to form alkyl radicals.
CoBr2, 4
CoBr2, 4
CoBr2, 4
CoBr2, 4
CoBr2, 4
CoBr2, 4
(TEA) was used as the organic reductant,16 an optimal yield of
86% was attained (Table 1, entries 5 and 6). Other
photocatalysts were also evaluated, and no reactivity was
observed (Table 1, entries 7 and 8).
TEA
TEA
n.r.
n.r.
a
Conditions: reactions were performed with 1a (0.25 mmol, 1 equiv),
Control experiments showed that the cobalt, ligand, photo-
catalyst, and TEA were all necessary for the formation of 3a
(Table 2). As described above, a precedent was set by Leonori
and co-workers that under photoredox conditions triethylamine
forms an α-aminoalkyl radical, which it can serve as a XAT
mediator to form alkyl radicals from alkyl halides. While this
method was optimized for alkyl iodides, alkyl bromides gave
trace amounts of the product when triethylamine was used.
When cobalt and the ligand (4) were omitted, a minimal
background reaction was observed (Table 2, entry 2). This
background reaction is presumed to occur through direct XAT
by an α-aminoalkyl radical.17 When a CH3CN/H2O solvent
mixture, which was deemed critical in Leonori’s method, was
used in our method, an inferior yield was observed (Table 2,
entry 8). The optimization experiments in Table 1 and control
experiments in Table 2 suggest that cobalt plays a critical role in
the reaction mechanism.
With the optimal conditions in hand, we decided to probe the
mechanism of the reaction. In order to determine the role of
TEA, we performed two mechanistic studies: (1) Stern−Volmer
(SV) quenching studies (Figure 2a) to verify that TEA quenches
Ir(III)* faster than the cobalt/XantPhos complex does and (2) a
deuterium incorporation experiment (Figure 2b) to determine
whether TEA is involved in a product-forming hydrogen atom
transfer, which is proposed to be our termination step. The SV
2a (0.5 mmol, 2 equiv), Co source (10 mol %), ligand (10 mol %),
photocatalyst (2 mol %), and organic reductant (2 equiv) in CH3CN
(0.3 M) in a capped 1 dram vial under blue LED irradiation in a
HepatoChem reactor equipped with a Kessil lamp and a fan with
stirring for 18 h. PC = photocatalyst. Isolated yields. n.r. = no
reaction (no conversion of alkyl halide).
b
c
d
studies revealed that the luminescence of Ir(III)* is quenched
significantly faster by TEA (KSV = 456 M−1) than by the cobalt/
XantPhos complex (KSV = 232 M−1). The labeling experiment
showed 86% deuterium incorporation, signifying that TEA not
only participates in electron transfer with Ir(III)* but also
performs a hydrogen atom transfer (HAT) in order to terminate
the radical process. Additionally, the calculated quantum
efficiency of the reaction is less than 1, suggesting that while
chain reactions are still possible, they are not solely responsible
for product formation (Figure 2c).18 In an attempt to elucidate
the role of cobalt, we performed a stereochemistry retention
experiment and an electrophile screen. The stereochemistry
retention experiment showed that when a chiral starting material
was used, complete ablation of the stereochemistry was
observed, suggesting the presence of a free radical mechanism
(Figure 2d).19 Finally, as shown in the Supporting Information,
screening of different electrophiles showed that electrophiles
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that are unreactive to SET displayed no reactivity. These data
suggest that the cobalt performs outer-sphere electron transfer
or oxidative addition and not two-electron nucleophilic
substitution.12 The presence of the alkyl radical was supported
by the complete shutdown of reactivity in the presence of radical
scavengers such as TEMPO (see the Supporting Information).
On the basis of our control experiments and mechanistic
studies, we propose the mechanism shown in Figure 3. The
Table 2. Control Experiments
a
b
c d
,
entry
conditions
3 (%)
1
2
3
4
5
6
7
8
as shown
no CoBr2, no 4
no 4
no PC
no PC, no light
no PC, no light, at 70 °C
no TEA
10:1 CH3CN/H2O
86
20
10
n.r.
n.r.
n.r.
n.r.
25
a
Conditions: reactions were performed with 1a (0.25 mmol, 1 equiv),
2a (0.5 mmol, 2 equiv), Co source (10 mol %), XantPhos (10 mol
%), photocatalyst (2 mol %), and organic reductant (2 equiv) in
CH3CN (0.3 M) in a capped 1 dram vial under blue LED irradiation
in a HepatoChem reactor equipped with a Kessil lamp and a fan with
b
c
d
stirring for 18 h. PC = photocatalyst Isolated yields. n.r. = no
reaction (no conversion of alkyl halide)
Figure 3. Proposed mechanism.
reaction starts with excitation of the Ir(III) photocatalyst with
blue light, which produces a long-lived (τ = 2.3 μs) excited-state
Ir(III)* complex. As a powerful single-electron oxidant
(Er1e/d2[Ir(III)*/Ir(II)] = +1.21 V vs SCE),14 it reductively
quenches TEA (Er1e/d2 = +0.77 V vs SCE),16 yielding the reduced
Ir(II) complex and the oxidized amino radical cation. Catalyst
turnover occurs through reduction of the Co(II)/XantPhos
complex by Ir(II) to afford the nucleophilic Co(I) complex20
and Ir(III).21 The Co(I) complex then undergoes oxidative
addition and homolytic cleavage to form Co(II) and the free
alkyl radical, which is then captured by the olefin.22 The
resulting radical is then terminated by HAT facilitated by the
amino radical cation to form the product.
With a better understanding of the mechanism, we set out to
explore the scope of the reaction. First, we decided to investigate
the generality of the method with respect to the halides and
other leaving groups (see the Supporting Information). It should
be noted that when alkyl iodide 1c was used, the reaction time
decreased, and when alkyl chloride 1d was used, we observed a
decrease in the yield to 55%. Next, other leaving groups, such as
OMs (in 1e) and OAc (in 1f) were explored, and no reaction
was observed. We then explored the alkyl bromide scope using
phenyl acrylate (2b) as the olefin (Figure 4). The protecting
group on the piperidine was first screened, and N-tosyl,
benzamide, and N-Boc all produced high yields (3b−d).
Similarly, N-Boc azetidine, tetrahydropyran, and oxetane all
gave excellent yields (3e−g). Isopropyl, tert-butyl, and
adamantyl halides were all successfully coupled under the
optimized conditions (3h−j). When benzyl bromide and
chloride were screened, moderate to high yields of product 3l
were observed. Pyridine-containing product 3m was also made
in synthetically useful yields from a heterobenzylic halide. Other
common functionalities were screened, including silane, free
alcohol, and primary alkyl chloride, and all were tolerated,
generating their corresponding products 3k, 3n, and 3o in
moderate to excellent yields. 3o also demonstrates the halide
selectivity of bromides over chlorides.
Figure 2. (a) Stern−Volmer quenching studies. (b) Deuterium
incorporation experiment. (c) Quantum yield determination. (d)
Stereochemistry retention study.
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Figure 5. Olefin scope for the cobalt-catalyzed reductive radical
conjugate addition. Reactions were performed with 1b (1 mmol, 1
equiv), 2 (2 mmol, 2 equiv), CoBr2 (10 mol %), XantPhos (10 mol %),
photocatalyst (2 mol %), and TEA (2 equiv) in CH3CN (0.3 M) in a
capped 1 dram vial under blue LED irradiation in a HepatoChem
reactor equipped with a Kessil lamp and a fan with stirring for 18 h.
Figure 4. Halide scope for the cobalt-catalyzed reductive radical
conjugate addition. Reactions were performed with 1 (1 mmol, 1
equiv), 2b (2 mmol, 2 equiv), CoBr2 (10 mol %), XantPhos (10 mol %),
photocatalyst (2 mol %), and TEA (2 equiv) in CH3CN (0.3 M) in a
capped 1 dram vial under blue LED irradiation in a HepatoChem
reactor equipped with a Kessil lamp and a fan with stirring for 18 h.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02114.
■
The scope of the olefins was then explored using tosyl-
protected bromopiperidine 1b as the alkyl halide (Figure 5).
Acrylates containing ethyl, methyl, benzyl, tert-butyl, and 2,2,2-
trifluoroethyl gave high to excellent yields (3p−t). Acrylamides
3u and 3v were obtained in excellent yields under the standard
conditions. Other olefins that could successfully participate in
the reaction include acrylates containing α-methyl, α-phenyl, α-
trifluoromethyl, and α-acetamide (3w−z), diethyl 2-ethyl-
idenemalonate (3aa), and α-methylene-γ-butyrolactone (3ab).
Other electron-deficient olefins screened include acrylonitrile,
diethyl vinyl phosphonate, phenyl vinyl sulfone, and vinyl 2-
pyridine, all of which gave excellent yields (3ac−af). It should be
noted that when styrene was attempted under the optimized
conditions, no desired product was isolated.
sı
General experimental details, procedures, and character-
ization data for all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Randolph A. Escobar − Medicinal Chemistry, Research and
Early Development, Oncology R&D, AstraZeneca, Waltham,
Massachusetts 02451, United States; orcid.org/0000-
0001-7476-7747; Email: randolph.escobar@
astrazeneca.com
Jeffrey W. Johannes − Medicinal Chemistry, Research and
Early Development, Oncology R&D, AstraZeneca, Waltham,
Massachusetts 02451, United States; orcid.org/0000-
0001-7242-6682; Email: jeffrey.johannes@
astrazeneca.com
Herein we have described a reductive radical conjugate
addition method via cobalt/iridium dual-catalyzed activation of
alkyl halides to form alkyl radicals. This method is a mild and less
toxic mode of activation of alkyl bromides that uses TEA as an
organic reductant along with commercially available cobalt,
XantPhos ligand, and iridium photocatalyst. The control
experiments and preliminary mechanistic studies support a
SET mechanism to generate the electron-rich Co(I) complex,
which is believed to mediate the reduction of the alkyl halide to
the alkyl radical. We believe that this mild alkyl halide activation
could be combined with other metals such as copper and nickel.
We also envision that the presented method can be applied to
various synthetic targets in total synthesis and the pharmaceut-
ical industry.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02114
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Sharon Tentarelli (AstraZeneca) for HRMS
analysis.
■
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