Nickel-Catalyzed Straightforward and Regioselective C-H Alkenylation of Indoles with Alkenyl Bromides: Scope and Mechanistic Aspect

Article abstract of DOI:10.1021/acscatal.8b04267

Nickel-catalyzed regioselective C-H bond alkenylation of indoles and related heteroarenes with alkenyl bromides is accomplished under relatively mild conditions. This method allows the straightforward synthesis of C-2 alkenylated indoles employing an air-stable and well-defined nickel catalyst, (bpy)NiBr₂, providing a solution to the limitations associated with hydroindolation and oxidative alkenylation. The reaction conceded the coupling of indole derivatives with various alkenyl bromides, such as aromatic and heteroaromatics, α- and β-substituted as well as exo- and endo-cyclic alkenyl compounds. An extensive mechanistic investigation, including controlled study, reactivity experiments, kinetics and labeling studies, and EPR and XPS analyses, highlights that the alkenylation proceeds through a single-electron transfer process comprising an odd-electron oxidative addition of alkenyl bromide. Furthermore, the alkenylation operates via a probable Ni(I)/Ni(III) pathway involving the rate-limiting C-H nickelation of indole.

Full text of DOI:10.1021/acscatal.8b04267

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Article
Nickel-Catalyzed Straightforward and Regioselective C-H Alkenylation
of Indoles with Alkenyl Bromides: Scope and Mechanistic Aspect
Rahul A. Jagtap, Chathakudath Prabhakaran Vinod, and Benudhar Punji
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ACS Catalysis
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Nickel-Catalyzed Straightforward and Regioselective CH Alkenyla-
tion of Indoles with Alkenyl Bromides: Scope and Mechanistic As-
pect
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Rahul A. Jagtap,†,‡ C. P. Vinod,§ and Benudhar Punji*,†,‡
‡
†Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, Academy of Scientific and Innovative
Research (AcSIR) and §Catalysis Division, CSIR–National Chemical Laboratory (CSIR–NCL), Dr. Homi Bhabha Road,
Pune 411 008, Maharashtra, India
ABSTRACT: Nickel-catalyzed regioselective CH bond alkenylation of indoles and related heteroarenes with alkenyl bromides is
accomplished under relatively mild conditions. This method allows the straightforward synthesis of C-2 alkenylated indoles em-
ploying an air-stable and well-defined nickel catalyst, (bpy)NiBr2, providing a solution to the limitations associated with
hydroindolation and oxidative alkenylation. The reaction conceded the coupling of indole derivatives with various alkenyl bro-
mides, such as aromatic and heteroaromatics, - and -substituted as well as exo- and endo-cyclic alkenyl compounds. An exten-
sive mechanistic investigation, including controlled study, reactivity experiments, kinetics and labeling studies, EPR and XPS ana-
lyses, highlights that the alkenylation proceeds through a single-electron transfer (SET) process comprising an odd-electron oxida-
tive addition of alkenyl bromide. Further, the alkenylation operates via a probable Ni(I)/Ni(III) pathway involving the rate-limiting
CH nickelation of indole.
KEYWORDS: alkenylation, CH activation, indoles, mechanism, nickel, single-electron transfer
a highly sensitive Ni(cod)2/PCyp3 system, thus limiting the
scope and generality of the methodology. Notably, most of the
INTRODUCTION
Indole represents a privileged heterocyclic motif that occurs in
many biologically active natural products, medicinal
compounds, and functional materials.1 Thus, regioselective
direct CH bond functionalization of the indole ring is very
crucial considering the development of diverse structural
entities bearing this unique heterocyclic frame-work.2 Apart
from nitrogen atom, the C-3 position of indole is the most
reactive site for various electrophilic substitution reactions,3
however, recent development of the transition-metal-catalyzed
CH bond functionalization has unraveled numerous methods
for selective C(2)H functionalization.4 Amongst diverse C-2
functionalizations, such as arylation, alkylation, and benzyla-
tion of indoles;4 the alkenylation of indoles is of special inter-
est owing to the involvement of alkenyl-functionality in a
number of processes including pericyclic reactions and macro-
cyclizations,5 in addition to the existence of alkenylated in-
doles in medicinal and natural products.6 Thus far, most of the
C-2 alkenylation of indoles has been realized with relatively
expensive noble-metal catalysts,7 such as rhodium,8 ruthe-
nium,7b,9 and palladium.10 Yet, in recent years, considerable
progress has been made employing naturally abundant first-
row transition-metal catalysts,11 including nickel.12 For exam-
ple, alkenylation of indoles by Mn,13 Fe14 and Co15 catalysis
has been independently reported by the groups of Matsunaga
and Kanai, Yoshikai, Ackermann, Li, and others. Similarly, a
nickel-catalyzed method for the alkenylation of indoles via
hydroindolation is being demonstrated by Nakao and
Hiyama,16 however, this method needs an electron-
withdrawing substituent at the C-3 position of indole and uses
C-2 alkenylations have been accomplished through redox-
neutral hydroindolation of alkynes (Scheme 1a) or oxidative
coupling of indoles with alkenes, i.e., Fujiwara-Moritani (FM)
type reaction (Scheme 1b). Despite significant advances, these
approaches continue to face considerable limitations, includ-
ing the difficulty in controlling regioselectivity, usage of the
stoichiometric amount of secondary metal or peroxide oxi-
dants and are restricted to alkenes bearing an electron-
deficient group.
A straightforward method to synthesize alkenylated indoles
can be envisaged by the direct C(2)H bond alkenylation of
indoles with alkenyl (pseudo)halides. In this direction, Ack-
ermann has demonstrated a method for the coupling of indoles
with alkenyl-enols via CH/CO activation employing cobalt
catalysis (Scheme 1c).17 However, employment of an excess
amount of the Grignard base, CyMgCl is essential for this
method that limits the process. Unfortunately, there are no
precedents on the direct alkenylation of indoles with alkenyl
halides,18 not even using the noble metal catalysis. Therefore,
the development of a straightforward method for the synthesis
of C-2 alkenylated indoles employing a well-defined, inexpen-
sive catalyst system based on naturally abundant first-row
transition-metals, such as nickel, is highly desirable for the
sustainability in modern organic synthesis. Herein, we report
an efficient, straightforward approach for the regioselective
alkenylation of indoles with various alkenyl bromides by the
nickel catalysis (Scheme 1d). Noteworthy features of our
strategy are an excellent predictable regiocontrol, oxidant-free
functionalization, challenging CH alkenylation with unacti-
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vated alkenyl bromides using a defined, air-stable nickel cata- kenylation in solvents such as ortho-xylene, mesitylene, 1,4-
1
2
3
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5
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8
lyst, (bpy)NiBr2, under relatively mild reaction conditions.
Additionally, a comprehensive substrates scope with regards
to alkenyl bromides has been demonstrated, and an extensive
mechanistic study, including control experiment, kinetic anal-
ysis, labeling study, and EPR and XPS analysis, has been per-
formed to understand the reaction pathway.
dioxane was less efficient than the reaction in toluene, which
might be due to the disparity in solubility of the LiOtBu and/or
Ni-precursor (entry 14, Table 1; and Table S1 in the Support-
ing Information). Surprisingly, the isolated nickel complex
(bpy)NiBr2 (1) as catalyst under the optimized conditions in
toluene afforded 50% yield of 6aa (synthesis and characteriza-
tion of the catalyst are described vide infra). However, the
alkenylation reaction using catalyst 1 was highly efficient
when 1,4-dioxane was used as a solvent, and the reaction
yielded 85% of 6aa at 150 oC (entry 16). Notably, the reaction
afforded quantitative yield (84%) even at 120 oC though it
needs 24 h for the completion (entry 17). Other bpy derived
complexes [(bpy)3Ni]NiBr4 (2) and (bpy)2NiBr2 (3) were found
to be as effective and afforded a good yield of the alkenylation
product 6aa (entries 18, 19). Lowering the catalyst loading led
to a decrease in the yield of product 6aa (entry 20). A nickel
catalyst is essential for the reaction, without which no coupl-
ing product was observed (entry 21). Under the optimized
reaction conditions, only traces (< 5%) of homo-coupled
products of indole 4a and alkenyl bromide 5a were observed,
even with the increasing loading of catalyst 1. Considering the
well-defined nature of 1, the scope and mechanistic studies
were performed employing complex 1 in 1,4-dioxane at 120
oC.
Scheme 1. Strategies for CH Alkenylation of Indoles
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RESULTS AND DISCUSSION
Optimization of Reaction Conditions. We initially ex-
amined the alkenylation of 1-(pyridin-2-yl)-1H-indole (4a)
with (2-bromovinyl)benzene (5a, E:Z = 98:2) employing nick-
el catalyst precursors with or without added phosphine ligands
in the presence of LiOtBu in toluene (Table 1, entries 1-4; for
detailed optimization, see Table S1 in the Supporting Informa-
tion). The use of sole nickel precursors (diglyme)NiBr2 or
(thf)2NiBr2 as catalyst did not produce alkenylated product
(E)-1-(pyridin-2-yl)-2-styryl-1H-indole (6aa), however, em-
ployment of the phosphine ligands, such as dppm, dppf along
with (thf)2NiBr2 afforded trace amount of 6aa. Notably, the
alkenylation reaction using nitrogen-donor ligand 1,10-
phenanthroline (phen) with (thf)2NiBr2 afforded 6aa in 47%
yield (entry 5). The nitrogen-containing ligand might essential
in stabilizing the organometallic intermediates during the cata-
lytic process. Surprisingly, the alkenylation reaction produced
a good yield of 6aa (71%) upon employing 2,2’-bipyridine
(bpy) with (thf)2NiBr2 (entry 8). As the bpy/(thf)2NiBr2 cata-
lyst system delivered satisfactory yield for the alkenylation,
we screened several other nickel precursors, such as (dig-
lyme)NiBr2, (CH3CN)2NiBr2 and Ni(cod)2 along with added
bpy ligand, wherein a similar or slightly lower activity was
observed (entries 9-11). Interestingly, better efficiency of the
Ni(II) precursors than a Ni(0) system seems more advanta-
geous due to the stability issues associated with the later. Al-
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Table 1. Optimization of the Reaction Conditionsa
1
2
3
4
5
ACS Catalysis
Effect of the N-Substituents of Indoles on Alkenylation.
We have investigated the effect of the nitrogen substituents of
indole on the C-2 alkenylation reaction employing various N-
protected indoles with alkenyl bromide 5a (Scheme 2). All the
reactions were performed using catalyst 1 (5 mol %) in the
o
presence of LiOtBu in 1,4-dioxane at 120 C. As optimized
before, the reaction of N-(2-pyridyl)-indole (4a) with 5a ex-
clusively afforded the C-2 olefinated product 6aa in 84%
yield. Similarly, the 2-pyrimidinyl as a nitrogen substituent in
the substrate N-(2-pyrimidinyl)-indole reacted efficiently to
produce desired product 6ga in 81% yield. To understand the
directing (coordinating) ability versus the electronic impact of
the N-substitution of indole, the N-(4-pyridyl)-indole was
subjected to the alkenylation reaction, wherein coupling was
not observed suggesting the role of N-substitution as a direct-
ing (coordinating) group rather than the electronic influence of
the same. Additionally, the indole bearing thiophenyl or sul-
phonyl as N-substituent directing group did not afford the al-
kenylation product highlighting that strong -donor nitrogen
coordination is essential for the nickel catalyzed alkenylation
of indole. Notably, the indole containing a –COtBu group as
N-substituent undergone base-assisted N-deprotection and
subsequent nickel-catalyzed N-alkenylation to deliver (E)-1-
styryl-1H-indole in 92% yield (Scheme 2). As expected, the
N-methyl indole did not produce the alkenylation, and a C-2
substituted N-pyridinyl indole unable to deliver the C-3 or C-7
alkenylated product. All these observations indicate that a
nitrogen donor substituent at the N-atom of indole is essential,
and under the optimized conditions a C-2 selective alkenyla-
tion is highly feasible.
6
7
8
9
entry
[Ni]
ligand
base
solvent
6aa
(%)b
--
1
2
3
4
5
6
(diglyme)NiBr2
(thf)2NiBr2
(thf)2NiBr2
(thf)2NiBr2
(thf)2NiBr2
(thf)2NiBr2
--
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
toluene
toluene
toluene
toluene
toluene
toluene
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--
--
dppm
dppf
phen
trace
trace
47
batho
cuproine
neo
cuproine
bpy
26
7
(thf)2NiBr2
LiOtBu
toluene
trace
8
(thf)2NiBr2
LiOtBu toluene
71c
69
9
(diglyme)NiBr2
bpy
LiOtBu
LiOtBu
LiOtBu
toluene
toluene
toluene
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21
(CH3CN)2NiBr2 bpy
65
Ni(cod)2
(thf)2NiBr2
(thf)2NiBr2
(thf)2NiBr2
cat. 1
bpy
bpy
bpy
bpy
--
60
Na2CO3 toluene
--
K3PO4
LiOtBu
LiOtBu
LiOtBu
toluene
--
1,4-dioxane
toluene
69
50
cat. 1
--
1,4-dioxane
85c
84 c,d
82 c,d
79 c,d
64d,e
--
cat. 1
--
LiOtBu 1,4-dioxane
Scheme 2. Effect of Directing Group on Alkenylation
cat. 2
--
LiOtBu
LiOtBu
LiOtBu
LiOtBu
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
cat. 3
--
cat. 1
--
--
--
aReaction Conditions: 4a (0.058 g, 0.3 mmol), 5a (0.110 g, 0.6
mmol), [Ni] precursor (0.015 mmol, 5 mol %), ligand (0.015
mmol, 5 mol %), LiOtBu (0.048 g, 0.6 mmol), solvent (1.0 mL).
Catalyst 1 (0.0056 g, 0.015 mmol), catalyst 2 (0.0068 g, 0.015
b
mmol), catalyst 3 (0.0079 g, 0.015 mmol). GC yield using n-
decane as an internal standard. Isolated yield. dReaction per-
c
Synthesis and Characterization of Nickel Catalysts. As
the nickel precursor (thf)2NiBr2 with added bpy ligand effi-
ciently catalyzes the alkenylation of 1-(pyridin-2-yl)-1H-
indole (4a) with (2-bromovinyl) benzene (5a), we were cu-
rious to identify the type of nickel complex formed during this
process. Besides, we also wanted to know the activity of iso-
lated nickel complex during the catalytic process. In that vein,
we have performed the reaction of (thf)2NiBr2 with 1.0 equiv
of bpy in THF at room temperature, which afforded complex
(bpy)NiBr2 (1)19 as a light green solid (see Figure S1 in the
Supporting Information). However, the treatment of
o
e
formed at 120 C for 24 h. Employing 3.0 mol % of catalyst.
dppm 1,1-bis(diphenylphosphino)methane, dppf 1,1'-
bis(diphenylphosphino)ferrocene, phen = 1,10-phenanthroline,
bpy = 2,2’-bipyridine.
=
=
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(thf)2NiBr2 with 2.0 equiv of bpy produced [(bpy)3Ni].NiBr4
Scheme 3. Substrate Scope for Alkenylation of Indole De-
(2) in quantitative yield.20 Both the complexes 1 and 2 are
NMR silent, and hence, were characterized by elemental anal-
ysis. Compound 2 could exist as a mixture of (bpy)2NiBr2 and
(bpy)NiBr2. We have recently demonstrated the synthesis and
characterization of similar complexes of 1,10-phenanthroline
ligand.21 The composition of all the nickel complexes was
rivativesa
1
2
3
4
5
6
7
8
analyzed by elemental analysis. The complex
3 was
synthesized following the literature procedure.22
9
Substrate Scope for the Alkenylation of Indoles. After an
extensive screening of all the reaction parameters including
various nickel precursors and nickel complexes 1-3 for the
alkenylation of indole, we started substrate scope for the alke-
nylation reaction with diversely substituted indoles and other
azoles (Scheme 3). Indoles bearing alkyl (Me) and alkoxy
(OMe) moieties at C-5 position reacted smoothly with (E)-
(2-bromovinyl) benzene (5a) to yield the desired C-2 alkeny-
lated products 6ba and 6ca in 82% and 86%, respectively.
Indole containing C-5 fluoro group is less reactive and re-
quires 10 mol % loading of catalyst to achieve a good yield of
6da. The 5-Cl and 5-Br indoles reacted with low pace to de-
liver the products 6ea and 6fa in 57% and 32% yields, respec-
tively; which is crucial for potential post-functionalization. As
discussed before, the indoles bearing easily removable 2-
pyrimidinyl group reacted smoothly to deliver the desired
products (6ga-ia) in good yields. Sterically hindered C-3 subs-
tituted indole 4j and 4k were alkenylated in moderate activity
to give 6ja and 6ka, respectively. Unfortunately, the indoles
bearing electron-withdrawing groups, such as −CN, −CHO,
−NO2 at the C-3 or C-5 positions did not undergo alkenylation
reaction under the optimized reaction conditions. The benzy-
loxy substituted indole 4l and azaindole 4m reacted in mod-
erate activity to produce the alkenylation products 6la and
6ma in 57% and 59% yields, respectively. Additionally, a
pyrazole derivative 4n could be easily alkenylated to afford
the C5 alkenylation product 6na in 65% yield. In general, the
present alkenylation protocol is highly selective to the C(2)−H
functionalization, and the C(3)−H and C(7)−H bonds remained
untouched, and provided access to the diversely substituted
indole derivatives.
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aConditions: Substrate 4 (0.30 mmol), 5a (0.110 g, 0.60 mmol),
LiOtBu (0.048 g, 0.60 mmol), cat. 1 (0.0056 g, 0.015 mmol, 5.0
mol %), 1,4-dioxane (1.0 mL). Yield of isolated compound. 10
b
mol % of catalyst 1 was employed.
Further, the feasibility of the alkenylation reaction of 2-py or
2-pym substituted indoles with diversely substituted β-bromo
alkenes was investigated (Scheme 4). Thus, the β-bromo ole-
fins bearing a variety of substituents on the aromatic rings
were subjected for alkenylation, which afforded C-2 olefinated
indoles 6ab-6ag in good to excellent yields with exclusive E-
stereochemistry. The 2-pym substituted indole 4g reacted with
good activity; whereas the C-3 substituted indoles, 4j and 4k
afforded moderate yields of 6jc and 6kc. It is important to note
that a heteroarene such as thiophenyl moiety tolerated under
the optimal reaction condition to provide 43% of product 6ah.
We next turned our attention to the sterically hindered α-
substituted bromo olefins. It was found that α-bromo styrene
reacts smoothly with indole 4a and delivers the product 6ai in
69% yield. In addition to the aromatically substituted bromo
olefins, electronically-rich α-substituted bromo alkene such as
2-bromopropene reacted to produce 50% of desired product
6aj. Interestingly, a SiMe3 group at the α-position is tolerated
under the optimized reaction condition, which could be high
synthetic importance. Further, the scope of the alkenylation is
extended to endocyclic and exocyclic alkenes, which deliver
the products 6al and 6am in low to moderate yields. Notably,
the alkenylation proceeded in a regio specific manner afford-
ing E-stereomers exclusively in good yields. Generally, the
similar regioselectively substituted products 6 are less com-
mon through hydroindolation of alkynes or oxidative alkenyla-
tions.
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Scheme 4. Scope with Various Alkenyl Bromidesa
ACS Catalysis
after 24 h. As the product formation was less using
1
2
3
4
5
6
7
8
Ni(COD)2/bpy system, the kinetic experiment for the same
was not conducted. All these observations highlight that a
nickel(0)-species as an active catalyst is unlikely.
H
H
R2
1
cat. (5 mol %)
Br
LiOtBu (2 equiv)
1,4-dioxane
R2
+
H
N
R1
N
R1
120 oC, 24 h
The rate order of alkenylation reaction was determined to
understand the effect of various reaction components on the
alkenylation by the initial rate method. First, the rate order of
the alkenylation reaction on indole 4a was determined by
measuring the initial rate of reaction at different initial concen-
trations of 4a (0.15, 0.30, 0.60 and 1.20 M) employing 0.045
M of catalyst 1 (see Table S3 in the Supporting Information
for details). As depicted in Figure S3, the rate of the alkenyla-
tion increases upon increased initial concentrations of 4a, and
a slope of 1.09 was acquired from the plot of log(rate) versus
log(conc. 4a) (Figure 1A). This observation highlights a cru-
cial and divergent role of indole 4a in the alkenylation reac-
tion. The reaction rates were almost comparable when differ-
ent initial concentrations of alkenyl bromide 5a were used;
demonstrating zeroeth order behavior with regards to the con-
centration of 5a (see Table S4 and Figure S4 in the Supporting
Information). However, the rate of alkenylation was found to
be inconsistent with different equivalents of LiOtBu. Notably,
the rate of alkenylation reaction increases upon increased load-
ings of catalyst 1; (see Table S5 and Figure S5 in the Support-
ing Information) and a slope of 0.77 was obtained from the
plot of log(rate) versus log(conc. 1) (Figure 1B). This finding
highlights that the reaction is fractional order concerning the
nickel catalyst 1. In light of the participation of catalyst in
multiple steps during the alkenylation reaction, the observed
rate order seems to be reasonable. Considering the positive
fractional rate order with indole 4a and catalyst 1, the catalytic
step involving the activation of indole 4a with cat 1 appears to
be crucial.
4
5
6
R2
OMe
Me
N
N
OMe
2-py
2-pym
R2 = Me, (
):
6ab
N
71%
76%
67%
62%
9
6gc: 64%
R2 = OMe, (
R1
6ac
):
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R2 = F, (
R2 = Cl, (
6ad
):
R
R
1 = 2-py, (6jc): 44%
1 = 2-pym, (6kc): 45%
6ae
):
R2 = Ph, ( ): 70%
6af
S
N
Ph
O
N
2-py
Ph
N
2-py
6ai
: 69%
6ah: 43%
2-py
6ag
: 58%
R3
N
N
N
2-py
2-py
2-py
R3 = Me ( ):
50% b
6aj
6al
: 53%
R3 = SiMe3
b
6am
: 17%
6ak
( ): 50%
aConditions: Substrate 4 (0.30 mmol), alkenyl bromide 5 (0.60
mmol), LiOtBu (0.048 g, 0.60 mmol), cat. 1 (0.0056 g, 0.015
b
mmol), 1,4-dioxane (1.0 mL). Yield of isolated compound. Yield
determined by 1H NMR.
MECHANISTIC CONSIDERATIONS
Kinetics Analysis of Alkenylation. Considering the excel-
lent activity of nickel catalyst (bpy)NiBr2 (1) for the alkenyla-
tion of indoles with alkenyl bromides, we have performed
detailed mechanistic studies to know the working mode of the
catalyst and to gain information about the catalytic process.
Initially, we performed kinetic analysis of the nickel-catalyzed
alkenylation reaction. In the standard rate measurement, a
Teflon screw cap vessel was introduced with catalyst 1
(0.0056 g, 0.015 mmol, 0.015 M), LiOtBu (0.048 g, 0.60
mmol), alkenyl bromide 5a (0.110 g, 0.60 mmol, 0.60 M),
indole 4a (0.058 g, 0.30 mmol, 0.30 M) and n-decane (0.030
mL, 0.154 mmol; internal standard). 1,4-Dioxane (0.9 mL)
was added to the reaction vessel to make the total solution to
1.0 mL. The tube containing the reaction mixture was heated
at 120 oC in a preheated oil bath, and the reaction progress was
monitored by gas chromatography at regular intervals (see,
Table S2 and Figure S2(A) in the Supporting Information).
Notably, the kinetic profile of the alkenylation shows a signif-
icant induction period, 1% of product 6aa detected only after
75 min and 0.015 M (TON = 1) of product formed at 150 min
(Table S2), which highlights that the complex (bpy)NiBr2 is
most likely a precatalyst and the active catalyst generation
occurs during the initial period. Upon performing the reaction
employing 15 mol % (0.045 M) of catalyst, the product forma-
tion was found to be consistent (1% and 2% product formed at
20 and 30 min, respectively; Figure S2B). Assuming the Ni(0)
species might be the active catalyst, a standard alkenylation
reaction was performed using Ni(COD)2/bpy under the opti-
mized conditions at 120 oC, wherein 19% of 6aa was obtained
Further, the rate of the alkenylation reaction was measured
using electronically distinct indoles and alkenyl bromides to
illustrate the electronics effect of substrates on the reaction. As
shown in Scheme 5a, the rate of alkenylation reaction is al-
most similar for both the electron-rich indole 4c (7.34 x 10-4 M
min-1) and electron-deficient indole 4d (8.54 x 10-4 M min-1)
(see Figure S6 in the Supporting Information for details). This
finding rules out the probability of an electrophilic-type CH
activation of indole.23 Notably, the rate of alkenylation using
alkenyl bromide 5d (16.31 x 10-4 M min-1) is almost three-time
faster than that employing an electron-rich alkenyl bromide 5c
(5.19 x 10-4 M min-1) highlighting a reasonable reaction of
alkenyl bromide towards a low-valent nickel-species (Scheme
5b, and Figure S7 in the Supporting Information). Considering
the unlikeliness of Ni(0)-species being an active catalyst (dis-
cussed via supra), the probable reaction of alkenyl bromide
towards a Ni(I)-species can be presumed.
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-2.4
-2.6
-2.8
-3.0
-3.2
-3.4
-3.6
ture of new Ni-species that might have formed.19a,22 A stoichi-
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3
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5
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ometric reaction of indole 4a with (bpy)NiBr2 in the presence
of LiOtBu at 120 oC resulted in the exclusive formation of 1,1'-
di(pyridin-2-yl)-1H,1'H-2,2'-biindole (self-coupling of 4a),
which disrupt the isolation of a possible intermediate
(bpy)Ni(2-indolyl-2-pyridine). However, this Ni-species was
detected by the MALDI-TOF analysis of the reaction mixture.
The oxidative self-coupling of indole could occur via the
Ni(II)-mediated process in the presence of LiOtBu. Notably,
self-coupling of indole was negligible in the presence of elec-
trophile 5a during the standard alkenylation conditions. The
treatment of 5a with (bpy)NiBr2 in the presence of LiOtBu at
(A)
y = 1.0927 x -2.6549
R2 = 0.96668
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-0.8
-0.6
-0.4
-0.2
0.0
0.2
o
120 C did not lead to any product, and alkenyl bromide 5a
log (conc. 4a)
was recovered. This indicates that the nickel-species react with
the indole 4a prior to the electrophile 5a.
-3.20
-3.25
-3.30
-3.35
-3.40
-3.45
-3.50
-3.55
-3.60
(B)
Next, we probed the reactivity pattern of alkenyl bromide
with the nickel-species under catalytic conditions. The alkenyl
bromide would react with nickel species in three different
ways: coordinative insertion, one-electron oxidation (halide-
atom transfer) or two-electron oxidative addition pathway.
Notably, the independent catalytic alkenylation reaction of
indole 4a with (E)-(2-chlorovinyl)benzene or with styrene did
not afford the alkenylation product 6aa. This finding suggests
that the alkenylation reaction via a coordinative insertion/-
halide elimination approach of (E)-(2-halovinyl)benzene is
unlikely because the (E)-(2-chlorovinyl)benzene could have
delivered the desired product if the reaction proceeds through
a coordinative pathway.21 Additionally, the electrophile (Z)-(2-
bromovinyl)benzene affords only a trace of the alkenylated
product upon treatment with 4a, supporting the observations
that the coordinative insertion reaction of alkenyl bromide
with Ni-species is extremely remote. Surprisingly, the reaction
of indole 4a with (E)-(2-iodovinyl)benzene under the catalytic
conditions unable to afford the product 6aa, ruling out a two-
y = 0.77355x -2.1567
R2 = 0.9380
-1.9
-1.8
-1.7
-1.6
-1.5
-1.4
-1.3
log (conc. 1)
Figure 1. (A) Plot of log(rate) vs log(conc. 4a) and (B) plot of
log(rate) vs log(conc. 1).
Scheme 5. Kinetic Analysis of Alkenylation with Electroni-
cally Distinct Substrates
electron
oxidative
addition
approach
of
(E)-(2-
halovinyl)benzene towards nickel enter. Considering our ina-
bility to detect a diamagnetic nickel species during NMR
analysis, we presumed the occurrence of a single-electron
reaction pathway of alkenyl bromide with the nickel catalyst.
Probing Radical Pathway. The standard alkenylation reac-
tion of 4a in the presence of radical inhibitor TEMPO was
suppressed entirely, whereas in the presence of galvinoxyl the
reaction afforded 17% of coupled product 6aa (Scheme 6).
These observations highlight a single-electron pathway for the
reaction. Notably, we could not detect any coupled product
arising from the reaction of TEMPO or galvinoxyl with al-
kenyl bromide 5a. Although the TEMPO or galvinoxyl are
known to react with organic radicals, it has also been
demonstrated that the TEMPO can interact with Ni(I) species
leading to a TEMPO-bound Ni(II) species,24 thus suppressing
a reaction catalyzed by an odd-electron active nickel catalyst.
Controlled Reactivity Studies. The alkenylation reaction was
monitored by H NMR employing 25% of catalyst 1 in tolu-
ene-d8 to detect any observable nickel-intermediates. Unfortu-
nately, neither the nickel-species nor the free-ligand was
encountered in the NMR-tube reaction. Inability to observe
any diamagnetic nickel containing species is likely due to the
tetrahedral geometry of (bpy)NiBr2 and/or paramagnetic na-
1
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Scheme 6. External Additive Experiments
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that the CH nickelation is very crucial and most likely the
turnover-limiting step during the alkenylation.29 This observa-
tion is complemented by the observed rate order with indole
4a and catalyst 1, wherein a significant influence of substrate
4a was observed during the reaction. Further, the H/D scram-
bling was not observed upon performing a reaction of [2-D]-
4a and 4c (in the absence or presence of alkenyl bromide) in
the same reaction vessel for early reaction time (Scheme 7b).
This discloses that the CH activation is an irreversible
process and does not occur via a simple deprotonation-
metalation pathway.
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Electron Paramagnetic Resonance Studies. The EPR
experiments have been carried out on a frozen aliquot of the
incomplete reaction between indole 4a, alkenyl bromide 5a,
(bpy)NiBr2 (1) and LiOtBu, which confirmed the presence of a
nickel-bound organic radical. The g-factor of the cross-over
point of the peak was found to be 2.057 (Figure 2). The spec-
trum was simulated with the Easyspin25 software. Unfortunate-
ly, the hyperfine splitting was not observed. The g-value found
(2.057) is close to a nickel-bound organic free-radical,26 as the
g-values for free-radical nature of an unpaired electron and
Ni(III) are typically found in the range of 2.002-2.00427 and
2.15-2.2028 respectively. Thus, the intermediacy of a carbon-
centered radical of the alkenyl-nickel bound species can be
presumed. EPR experiments on other controlled experiments,
such as i) indole 4a + cat 1 + LiOtBu, ii) alkenyl bromide 5a +
cat 1 + LiOtBu and iii) cat 1 + LiOtBu in 1,4-dioxane led to the
signals that are too broad to make any meaningful judgment
on the nature of radical species. The EPR analysis indicates
that the presence of all the reaction components is essential for
the intermediacy of a radical species.
Scheme 7. Deuterium Labeling Experiments
exp
sim
X-ray Photoelectron Spectroscopy Studies. The XPS
analysis of the incomplete reaction mixture (between indole
4a, alkenyl bromide 5a, (bpy)NiBr2 (1) and LiOtBu) as well as
other controlled reaction mixture has been carried out to de-
termine the oxidation state of involved Ni-species. As shown
in Figure 3(A), the Ni 2p3/2 XPS spectrum of starting complex
(bpy)NiBr2 (1) displays a sharp peak centered around 855.7
eV, which can be assigned to Ni(II) complex. The correspond-
ing 2p1/2 is also indexed at 873.6 eV (matching with a 17 eV
separation between spin-orbit split) along with the satellite
feature at 861 eV. The XPS spectrum of the incomplete reac-
tion mixture between 4a, 5a, (bpy)NiBr2 (1) and LiOtBu also
shows a peak centered around 855.7 eV thus suggesting a
Ni(II)-species (see Figure S9(B) in the Supporting Informa-
tion). Notably, in the case of the controlled reaction mixture
between (bpy)NiBr2 (1), 4a and LiOtBu (in the absence of 5a),
the XPS spectrum is much broader with a larger FWHM indi-
cating multiple oxidation states (Figure 3(B)). Accordingly,
two peaks could be fitted in the main 2p3/2 photoelectron peak
at 853.4 eV and 855.7 eV. The later peak can be easily
assigned to starting Ni(II)-species whereas the former (853.4
eV) has binding energy value higher than the Ni(0) (852.6
eV).30 Since the binding energy 853.4 eV is lower than the
same observed for Ni(II), we can convincingly assign this as a
Ni(I) intermediate formed during the process. XPS analyses of
other controlled experiments, such as i) cat 1 + 5a + LiOtBu
3000 3100 3200 3300 3400 3500 3600 3700 3800
Magnetic Field (G)
Figure 2. EPR spectrum of an incomplete alkenylation reaction
mixture.
Deuterium Labeling Studies. The initial rates of alkenyla-
tion reactions employing indole 4a and indole [2-D]-4a were
calculated independently, wherein the kinetic isotope effect
(KIE) value was found to be 4.7 (Scheme 7a, and Figure S8 in
the Supporting Information). The high KIE value indicates
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and ii) cat 1 + LiOtBu exhibit sharp peak around 855.7 eV
Page 8 of 13
tron-rich Ni(I) center in B rather than with the species A in the
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4
5
6
7
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indicating a Ni(II) complex (Figure S9(A) and S9(C) in the
Supporting Information). All these experiments highlight that
the reaction components (bpy)NiBr2 (1), 4a and LiOtBu are
essential to generate an odd-electron Ni-species. Considering
the trace formation of self-coupling of indole during the cata-
lytic reaction, the initial formation of a Ni(0) species from the
reaction of (bpy)NiBr2 (1) with 4a in the presence of LiOtBu
can be assumed, which in turn can comproportionate with
(bpy)Ni(II)Br2 (1) to produce a Ni(I) complex. This assump-
tion is consistent with the observed induction period employ-
ing Ni(II) catalyst, and low reaction with a Ni(0) complex.
first step, which is also consistent with the high reaction rate
of electron-deficient alkenyl bromide. Intermediate C would
undergo homolytic CBr cleavage and a one-electron oxida-
tive addition to afford Ni(III) complex D. Reductive elimina-
tion of product 6aa from D will regenerate the active catalyst
A. Intermediates B and D were identified by the MALDI-TOF
analysis of an incomplete stoichiometric reaction. Our experi-
mental studies strongly support all the elementary steps dis-
cussed here. Though, many reports suggest the mechanistic
proposal on the Ni-catalyzed CH functionalization,34 the
demonstration of a comprehensive mechanistic study is rare.
Herein, we have explicitly established a unified mechanism
for the Ni-catalyzed CH alkenylation that proceeds via the
Ni(I)/Ni(III) pathway involving a single-electron transfer
(SET) process.
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(A): Cat 1 (experimental)
(A): Cat 1 (peak fitting)
(B): Cat 1 +4a +LiOtBu (experimental)
(B): Cat 1 +4a +LiOtBu [(peak fitting, assigned to Ni(I)]
(B): Cat 1 +4a +LiOtBu [(peak fitting, assigned to Ni(II)]
LiOtBu
(bpy)NiBr2
(bpy)Ni(0)
+
Ni 2p3/2
4a
+ (bpy)NiBr2
Ni 2p1/2
N
+ LiOtBu
Ni Br
Satellite
Satellite
4a
6aa
N
LiBr + tBuOH
(A)
A
(
)
Ph
Ni
(I)
N
N
N
N
N
Ni
N
(B)
N
N
Br
B
(
)
D
)
(
Ph
Ph
Br
850
860
870
880
890
Br
N
N
5a
)
(
Binding Energy (eV)
Ni
N
N
Figure 3. X-ray photoelectron spectra: (A) (bpy)NiBr2 (1) and (B)
reaction mixture containing 1, 4a and LiOtBu.
(C)
Figure 4. Plausible mechanistic pathway for alkenylation cata-
lyzed by (bpy)NiBr2 (1).
Probable Catalytic Cycle. Considering our mechanistic
findings and related literature reports,31 we have proposed a
plausible mechanism for the Ni-catalyzed alkenylation of in-
dole with alkenyl bromide (Figure 4). A portion of catalyst
(bpy)NiBr2 (1) in the presence of LiOtBu and 4a undergo re-
duction to Ni(0), followed by comproportionation with
(bpy)NiBr2 (1) to form an active catalyst (bpy)Ni(I)Br (A).32
Observation of trace self-coupling of indole 4a supports the
probable formation of (bpy)Ni(0) that would comproportionate
with (bpy)NiBr2 to form A, later of which is confirmed by
XPS analysis. The indole 4a reacts with the active catalyst A
in the rate-limiting CH nickelation step to deliver interme-
diate B. The species B would trigger the radical formation on
alkenyl bromide 5a and undergo a one-electron oxidation to
produce intermediate C. Experiments and EPR analysis
strongly support the single-electron transfer (SET) pathway
and involvement of a metal-bound carbon-centered radical.
Notably, the use of -bromoalkene would lead to a relatively
less stable primary radical corresponding to intermediate C.
Nevertheless, the intermediacy of similar primary radicals has
extensively been demonstrated in the alkylation mechanism;
hence, intermediate C is evident enough to propose.31c,d,33 We
assume that alkenyl bromide 5a would react with a more elec-
Gram Scale Synthesis and Synthetic Utility. Given the
significant importance of the C-2 alkenylated indole, we have
scaled up the synthesis of compound 6ga (Scheme 8). Thus,
the compound 4g (1.0 g) was treated with alkenyl bromide 5a
(1.86 g) under the optimized conditions to afford product 6ga
in 76% isolated yield. The scaling up of the compound 6ga
was performed as this compound bears a trace and easily re-
movable directing group. Further, we have demonstrated the
removal of 2-py and 2-pym directing groups from the alkeny-
lated indoles,35 as the free NH alkenylated indole could bring
more synthetic values (Scheme 9). Hence, the treatment of 6aa
with MeOTf and NaOH in dichloromethane and MeOH in
succession afforded the free NH alkenylated indole 7aa. In a
similar vein, the 2-pym group on 6ga was smoothly depro-
tected using NaOEt in DMSO to produce 7aa in good yield.
This free N-H C-2 alkenylated indole can be readily
functionalized at C(3)H and N-H to synthesize biologically
active intermediates.
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Scheme 8. Gram Scale Synthesis of Alkenylated Indole
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AUTHOR INFORMATION
Corresponding Author
*E-mail for B.P.: b.punji@ncl.res.in.
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENTS
Scheme 9. Removal of Directing Groups
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This work was financially supported by SERB, New Delhi, India
(EMR/2016/000989). R.A.J. thanks UGC-New Delhi for a re-
search fellowship. We are thankful to Prof. Debabrata Maiti (IIT,
Bombay) for his help on EPR analysis. We are grateful to Dr
(Mrs) Shanthakumari for HRMS and Dr. S.P. Borikar for GC-MS
analysis.
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CONCLUSION
In summary, we have reported an efficient, straightforward
method for the regioselective C-2 alkenylation of indoles cata-
lyzed by an air-stable, inexpensive and well-defined nickel
complex (bpy)NiBr2. In this approach broad indole substrates,
azaindole and pyrazole were regioselectively alkenylated with
diverse alkenyl bromides under relatively mild reaction condi-
tions. Many alkenyl bromides, such as aromatic and heteroa-
romatics,  and -substituted as well as exo- and endo-cyclic
alkenyl functionality were tolerated. Detailed mechanistic
investigation of the alkenylation reaction by kinetics analysis,
controlled reactivity and deuterium labeling studies, EPR and
XPS analyses highlights that the reaction follows a single-
electron transfer (SET) pathway involving an odd-electron
oxidative addition of alkenyl bromide. Mechanistic findings
strongly support a Ni(I)/Ni(III) process for the reaction com-
prising the rate-limiting CH nickelation of indole. Synthetic
utility of this nickel-catalyzed method is established by the
demonstration of a gram-scale synthesis and by the facile re-
moval of directing groups. We believe the Ni-catalyzed
straightforward alkenylation, and the comprehensive mecha-
nistic investigation demonstrated herein will provide a new
avenue for the design and development of novel catalyst sys-
tem for many other crucial CH functionalization.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publication website at DOI: 10.1021.acscatal.xxxxxx
1
Full experimental and characterization data, including H and
13C NMR of all compounds
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ACS Catalysis
Table of Contents Graphic
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Nickel-Catalyzed Straightforward and Regioselective CH Alkenyla-
tion of Indoles with Alkenyl Bromides: Scope and Mechanistic As-
pect
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Rahul A. Jagtap, C. P. Vinod, and Benudhar Punji*
R2
Br
R3
N
N
N
Br
Br
Ni
Ni
N
N
N
[Ni]
base
Br
H
R2
H
R2
R3
[Ni]
R1
+
H
R1
R3
N
base
N
2-py
2-py
straightforward alkenylation
phosphine-free, inxepensive, defined catalyst
Ni(I)/Ni(III) pathway with SET process
high regioselectivity and excellent scope
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