Benzylic C(sp3)-C(sp2) cross-coupling of indoles enabled by oxidative radical generation and nickel catalysis

Article abstract of DOI:10.1039/d0sc06666d

A mechanistically unique functionalization strategy for a benzylic C(sp³)-H bond has been developed based on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical generation at the benzylic position of the substrate, with subsequent transition metal catalysis to complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp²)-based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer (HAT) processes, which are frequently encountered in conventional methods, are not involved in the product formation process of the developed strategy.

Full text of DOI:10.1039/d0sc06666d

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Benzylic C(sp3)–C(sp2) cross-coupling of indoles
enabled by oxidative radical generation and nickel
catalysis†
Cite this: Chem. Sci., 2021, 12, 4119
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Weonjeong Kim,‡ Jangwoo Koo‡ and Hong Geun Lee
A mechanistically unique functionalization strategy for a benzylic C(sp3)–H bond has been developed based
on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical
generation at the benzylic position of the substrate, with subsequent transition metal catalysis to
complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered
from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method
utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp2)-
based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer
(HAT) processes, which are frequently encountered in conventional methods, are not involved in the
product formation process of the developed strategy.
Received 5th December 2020
Accepted 1st February 2021
DOI: 10.1039/d0sc06666d
rsc.li/chemical-science
generally requires the use of a large excess of substrate due to its
insufficient reactivity. More importantly, selectivity problems
Introduction
can arise in complicated systems, as the discrimination of C–H
bonds with comparable bond strength is difficult.8 A potential
alternative to HAT towards selective functionalization of
a benzylic C–H bond is the employment of the sequential
electron transfer–proton transfer (ET/PT) activity of arenes.9
This process involves chemoselective one-electron oxidation
followed by deprotonation, and can preferentially generate
a benzylic radical on the periphery of the arene ring. Although
the ET/PT-based radical formation strategy has found a multi-
tude of applications for organic synthesis,10,11 a synergistical
merger with transition metal catalysis which can dramatically
broaden the scope of benzylic C–H bond functionalization is
underdeveloped.12,13
The development of synthetic strategies that allow direct func-
tionalization of C–H bonds has received considerable attention
from organic chemists because such methods are cost-effective
and environmentally benign.1 Among the various modes of
hydrocarbon modication, the activation of benzylic C(sp3)–H
bonds is of increasing interest because of the abundance and
popularity of arene-based building blocks in organic synthesis.2
Recently, the scope of this transformation has been dramati-
cally expanded by the advent of transition metal catalysis
(Scheme 1a).3 Despite signicant advances in this area, major
challenges associated with reactivity and/or selectivity are
encountered regularly and remain an active target of
investigation.4
Herein, we present the successful interfacing of the ET/PT-
driven indole-derived benzylic radical formation strategy with
a Ni-catalyzed cross-coupling reaction for the construction of
C(sp3)–C(sp2) bonds (Scheme 2a). This method exploits the
Recently emerging radical-based technologies for benzylic
C–H bond activation have contributed signicantly to solving
many of these problems (Scheme 1b). The expeditious intro-
duction of benzylic radical intermediates to a metal center
allows for the efficient generation of metal alkyl species, form-
ing the foundation for subsequent functionalization.5 Conven-
tionally, radical formation events at the benzylic position have
been realized by hydrogen atom transfer (HAT),6 with recent
advances in photoredox catalysis (PC) having greatly broadened
the applicability of this method.7 However, the HAT process
Department of Chemistry, College of Natural Science, Seoul National University, 1
Gwanak-ro, Seoul 08826, South Korea. E-mail: hgleee@snu.ac.kr
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, and spectroscopic data for all new compounds. See DOI:
10.1039/d0sc06666d
‡ These authors contributed equally to this work.
Scheme 1 Strategies for benzylic C(sp3)–H functionalization.
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Results and discussion
The reactivity of the combined catalytic systems was evaluated
using 1,3-dimethyl-1H-indole (1a) and p-bromoacetophenone
(2a) as substrates (Table 1).15 In the presence of an Ir-based
photocatalyst, visible-light irradiation, and a NiCl2$glyme pre-
catalyst with a 1,10-phenanthroline ligand, the desired benzylic
arylation product (3aa) was formed in 83% yield (entry 1). The
reaction was set up with the aid of a glovebox for the optimal
results. However, it is noteworthy that the reactivity could be
preserved even when the reaction was set up outside of a glo-
vebox by using a standard Schlenk technique, or when the
reaction was run under air (76% and 73%, respectively). These
results demonstrate the robustness of the developed method. In
contrast to the HAT-based dual catalytic systems, the use of
excess radical precursor was not required, demonstrating the
efficiency of the transformation. Control experiments indicated
that the presence of both the photoredox system and the Ni
catalyst was crucial for successful reaction (entries 2–4). In
addition, the use of a non-nucleophilic organic base, viz. 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), and the incorporation of
LiCl additive were also important for optimum performance
(entries 5 and 6).16,17 In agreement with the mechanistic
postulate involving radical generation, no arylation product was
detected when a radical scavenger was present (entry 7).18
Finally, the reactivity could be extended to arylation with other
types of aryl (pseudo)halides, among which aryl bromides and
chlorides are the best substrates (entries 8–10).
Scheme 2 Benzylic C(sp3)–H functionalization of indoles by dual
catalysis.
facile oxidation of indoles by photoredox catalysis,14 and has
thus been applied to selective radical generation at the benzylic
position of the indole ring without the involvement of any HAT.
Eventually, a convenient preparation of indole derivatives con-
taining an aryl or an acyl group at the C-3 alkyl group, common
structural motifs with important bioactivity, could be realized
(Scheme 2b).
The generality of the reaction was examined under opti-
mized conditions (Table 2A). Initially, the effect of varying the
N1-substituent was assessed. Although an unmasked 3-methyl
indole furnished the desired product in slightly reduced yield
(3ba), indole derivatives with a variety of N1-alkyl substituents
underwent the desired arylation smoothly (3aa, 3ca–3ea).
Importantly, the placement of Si-based substituents, groups
that can be conveniently removed aer the targeted reaction,
did not affect reactivity (3fa and 3ga). However, the presence of
an electron-withdrawing group at N1 reduced reactivity, indi-
cating the importance of the indole oxidation event (3ha and
3ia). Next, the substituent effects at other positions on the
indole skeleton were explored. Various electron-donating (3ja–
3na) and electron-withdrawing functional groups (3oa–3ra) at
the C4–C8 positions of indole were found to be compatible with
the optimized conditions. Moreover, halogen substituents,
which can be utilized as handles for further functionalization
via cross-coupling reactions, were tolerated (3pa–3ra). The
sterically encumbered 2-(hetero)aryl indole derivatives could
also be arylated at the 3-methyl group in synthetically useful
yields (3sa–3ua). Finally, the protocol was applicable to the
arylation of a 2-methyl indole derivative (3va). It should be
noted that numerous functional groups that are highly
susceptible to HAT-based activation remained intact, indicating
the orthogonality of the discovered reactivity (3ca, 3ea, 3ka,
3ma, 3ta, and 3xp). Substrates based on other types of hetero-
cycles, such as benzofuran, thiophene or pyrrole, were not
Table 1 Optimization of reaction conditionsa
Entry
Conditions
Yield (%)
1
As shown
83 (76b/73c)
N.D.
N.D.
N.D.
10
54
N.D.
76
2
3
No photocatalyst
No light
4
5
No NiCl2$glyme
No DBU
6
No LiCl
7
8
With TEMPO (3.0 equiv.)
ArCl instead of ArBr
ArI instead of ArBr
ArOTf instead of ArBr
9
16
36
10d
a
Reaction conditions: 1a (0.15 mmol), 2a (0.10 mmol), [Ir] (1.0 mol%),
NiCl2$glyme (5.0 mol%), L (7.5 mol%), DBU (0.10 mmol), LiCl (0.15
mmol), and DMA (0.050 M) irradiated with 34 W blue LEDs. Yields
were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane
b
as an internal standard. The reaction was set up using standard
c
Schlenk technique on the benchtop. The reaction was carried out
d
under
ambient
conditions.
Without
LiCl.
[Ir]
¼
Ir(dFCF3ppy)2(dtbbpy)PF6. dtbbpy ¼ 4,40-di-tert-butyl-2,20-bipyridine. L
¼ 1,10-phenanthroline. DMA ¼ N,N-dimethylacetamide. TEMPO ¼
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl. N.D. ¼ not detected.
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Table 2 Benzylic C(sp3)–H arylation of indoles by photoredox/nickel dual catalysisa
a
Reaction conditions: 1 (0.30 mmol), 2 (0.20 mmol), [Ir] (1.0 mol%), NiCl2$glyme (5.0 mol%), L (7.5 mol%), DBU (0.20 mmol), LiCl (0.30 mmol), and
DMA (0.050 M) irradiated with 34 W blue LEDs. All yields are isolated yields. b 18% of the desilylated product was obtained during the course of the
c
d
reaction. The reaction was performed with 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) instead of [Ir] for 23 h. 4,40-dimethoxy-
e
f
g
2,20-bipyridine instead of L. The reaction was conducted at 53 ꢀC. The corresponding vinyl triate was used as substrate. NiCl2$glyme
h
(10.0 mol%), 4,40-dimethoxy-2,20-bipyridine (15.0 mol%), DMA (0.033 M), and ArCl instead of ArBr. NiCl2$glyme (10.0 mol%), L (15.0 mol%),
and DMA (0.033 M). [Ir] ¼ Ir(dFCF3ppy)2(dtbbpy)PF6. dtbbpy ¼ 4,40-di-tert-butyl-2,20-bipyridine. L ¼ 1,10-phenanthroline. DMA ¼ N,N-
dimethylacetamide. N.D. ¼ not detected.
suitable substrates for the transformation due to the inefficient
oxidation process.14
We then examined the mechanistic aspects of the trans-
formation to investigate the potential involvement of HAT
Subsequently, the extent of the aryl (pseudo)halide coupling processes based on the generation of halogen radicals. First, the
partners was investigated (Table 2B). Although highly electron- contribution of metal halide additive (i.e., LiCl) was examined
rich or sterically congested aryl halides underwent the targeted by a Giese addition experiment (Scheme 3A).20 When the radical
transformation with somewhat reduced productivity, a wide generation was attempted in the presence of a radical acceptor,
range of electron-neutral and electron-decient arenes could be the efficiency of the addition process was not affected by the
successfully used with minor modications to the reaction presence of LiCl. Also, a uorescence quenching study of the
conditions (3ab–3ai). In addition, coupling counterparts reaction system showed that LiCl is not the major electron
derived from an extended p-system (3aj), an alkenyl group (3ak), transfer partner of the photocatalyst.21 Thus, it was concluded
or heterocycles (3al–3ao) were also viable substrates.
that LiCl was not involved in radical formation. Second, the
The strength of the developed strategy was further illustrated possibility of the Ni-halide complex initiating radical formation
by applying this method to the preparation of derivatives of was analyzed (Scheme 3B).7b,c,22 Upon exposure to the indole
bioactive molecules (Table 2C). Commercial drug molecules, substrate and the photoredox system, an independently
containing a C–halogen bond, could be successfully employed prepared Ni(II) aryl halide complex ([Ni]-1) failed to deliver the
as an aryl donor, demonstrating the robustness of the protocol expected arylation product (3ad). This result indicated that
(3ap–3as, 3xp). In addition, a novel synthetic pathway could be potential radical generation via HAT from the Ni complex did
devised for the preparation of the complex drug molecule not lead to the desired pathway of product formation.
zarlukast, which enabled late-stage unication of two parts of
Further insight could be gained from the dependence of the
comparable complexity (3wt).19 Indeed, this strategy could be reaction outcome on the electronic nature of the substrates
extended further to the facile preparation of zarlukast deriva- (Scheme 3C). Under the standard conditions, an electron-
tives using readily available aryl halides (3wm–3wn).
decient indole substrate (1h), in stark contrast to the case of
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Scheme 3 Mechanistic studies.
an electron-rich substrate (1a), showed virtually no reactivity the Ni-based catalytic cycle were considered.24 In the path A,
towards arylation. In case
HAT process is operating, radical II can be intercepted by the ligand-bound Ni0 species
a
a comparable product yield should be observed, since the cross- (III) to generate an alkyl-Ni intermediate (IV), which in turn can
coupling step is not signicantly sensitive to the electronic afford a NiIII complex (V) via oxidative addition with an aryl
properties of the arene substrate.23 Therefore, it is concluded halide. In the alternative route (path B), the radical addition is
that a HAT-driven radical generation is not predominantly taking place to a NiII intermediate (VII), which is formed by
involved in the overall transformation. This hypothesis was direct oxidative addition of ligand-bound Ni0 species (III). Our
corroborated by
a
Stern–Volmer analysis of the indole mechanistic experiment suggests that a NiII complex, such as
substrates. The strong correlation between product yield and VII, is unlikely to be involved in the catalytic cycle: an inde-
degree of uorescence quenching suggested the involvement of pendently prepared NiII oxidative addition complex ([Ni]-1,
the ET/PT-based process.
Scheme 3B) does not provide any of the desired cross-coupling
Based on the assembled information, a plausible catalytic product under the radical-generating conditions.25 Further-
cycle was proposed (Fig. 1). Initially, visible-light irradiation of more, it has been shown that the Ni0/NiI/NiIII pathway (path A)
the [IrIII] photocatalyst generates a potent excited-state oxidant is energetically more favored over the Ni0/NiII/NiIII pathway
[IrIII]* (Er*ed ¼ þ1:25 V vs. Ag/AgCl in MeCN), which can oxidize (path B) in related systems.26 Therefore, path B was excluded
the indole 1a (Eox ¼ +1.00 V vs. Ag/AgCl in MeCN). The resulting from further considerations. Finally, subsequent reductive
radical cation (I) can be rapidly deprotonated to form the key elimination from the NiIII complex (V) should furnish the
benzylic radical intermediate (II). At this point, two possible desired product and a NiI–Br species (VI, Ered ¼ ꢁ1.10 V vs. Ag/
downstream sequences of the radical intermediate to engage AgCl in DMF)27 which aer single electron transfer by [IrII] (Ered
¼ ꢁ1.32 V vs. Ag/AgCl in MeCN) will resume the dual catalytic
cycle.
The developed reactivity could be further extended to the Ni-
catalyzed acylation reaction using a symmetric acid anhydride
as the acyl source (Table 3).28 Under slightly modied condi-
tions involving the photocatalytic system, a Ni source, a biden-
tate ligand, and an inorganic base, N-alkyl indole derivatives
underwent facile acylation reactions at the benzylic position.29
The strictly halide-free conditions further supported the
involvement of the ET/PT process instead of HAT during radical
generation. Acyl groups based on a variety of alkyl (5ca–5cd),
aryl (5ce and 5cf), and alkenyl (5cg) groups were successfully
installed. Analogously to the arylation reaction, synthetically
useful yields could be obtained without the use of a glovebox
when the standard Schlenk technique was applied or even when
the reaction was carried out under ambient conditions (93%
and 76% yield for 5cb, respectively). Moreover, the addition of
an aryl substituent at the C2 position, which can pose signi-
cant steric congestion at the reaction center, did not affect
reaction efficiency (5sb). Interestingly, a 3-ethyl indole deriva-
tive also underwent a facile acylation, furnishing a methine
moiety at C3 (5yb). Furthermore, substrates containing
Fig. 1 Proposed reaction mechanism.
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Table 3 Benzylic C(sp3)–H acylation of indoles by photoredox/nickel
applicability should be expanded to other settings with the
development of more efficient and selective arene oxidation
protocols.
dual catalysisa
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Financial support was made by the National Research Foun-
dation of Korea (NRF) funded by the Korean Government (MSIT,
2018R1C1B6008115). W. K. and J. K. were supported by
Fellowship for Fundamental Academic Fields and NRF Grant
funded by the Korean Government (NRF-2018-Global Ph.D.
Fellowship Program, 2018H1A2A1060914), respectively.
Notes and references
1 For selected reviews, see: (a) H. M. L. Davies, J. Du Bois and
J.-Q. Yu, Chem. Soc. Rev., 2011, 40, 1855–1856; (b)
a
Reaction conditions: 1 (0.20 mmol), 4 (0.24 mmol), [Ir] (1.0 mol%),
Ni(cod)2 (5.0 mol%), dtbbpy (7.0 mol%), K2CO3 (0.30 mmol), and
DMF (0.050 M) irradiated with 34 W blue LEDs. All yields are isolated
¨
P. Gandeepan, T. Muller, D. Zell, G. Cera, S. Warratz and
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A. E. Shilov and G. B. Shul'pin, Chem. Rev., 1997, 97, 2879–
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b
yields. The reaction was conducted in the absence of K2CO3. [Ir] ¼
Ir(dFCF3ppy)2(dtbbpy)PF6. dtbbpy ¼ 4,40-di-tert-butyl-2,20-bipyridine.
DMF ¼ N,N-dimethylformamide.
2 For reviews, see: (a) R. Vanjari and K. N. Singh, Chem. Soc.
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3 For a recent review, see: R. Yazaki and T. Ohshima,
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a heteroatom-based substituent (5zb) or an allyl group (5zab)
exhibited excellent reactivities towards the acylation reaction,
demonstrating the pronounced robustness and chemo-
selectivity of the developed method, respectively.30 The protocol
was also applied to the acylation of a 2-methyl indole derivative
(5zbb). Finally, when multiple positions were available for
acylation, a mixture of regioisomeric products was obtained
(5zcb).31
4 For representative approaches, see: (a) M. Rosillo,
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Conclusions
In conclusion, a novel benzylic C(sp3)–H functionalization
method for indoles, introducing C(sp2)-based functional
groups, has been developed. This process is an outcome of the
unprecedented combination of Ni catalysis and ET/PT-driven
radical generation under photoredox conditions. The reaction
exhibited extremely high efficiency under mild conditions, and
was therefore applicable to the preparation of a wide range of
indole products including complex drug molecule derivatives.
Based on mechanistic investigations, it is evident that
a conventionally employed HAT process was not involved in
product formation. Rather, only the ET/PT process functioned
as the major pathway. This distinct mechanistic pathway
provides remarkable selectivity towards the activation of indole-
derived benzylic C–H bonds over others. It is believed that the
underdeveloped orchestration of ET/PT-controlled radical
generation and other types of transition metal catalysis should
provide a mild, robust, and efficient activation strategy for inert
benzylic C(sp3)–H bonds. Moreover, the scope of the
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¨
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28 For related examples of radical formation-based acylation
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29 Other readily available and air-stable Ni(II) salts showed
synthetically useful level of reactivity (5 cases, 79% on
average). However, optimal performance of the system was
© 2021 The Author(s). Published by the Royal Society of Chemistry
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