Nickel-Catalyzed C(2)-H Arylation of Indoles with Aryl Chlorides under Neat Conditions

Article abstract of DOI:10.1021/acs.joc.9b01375

Nickel-catalyzed regioselective C(2)-H arylation of indoles and pyrroles with aryl chlorides is achieved under neat conditions. This method allows the efficient coupling of diverse aryl chlorides employing a user-friendly and inexpensive Ni(OAc)₂

Full text of DOI:10.1021/acs.joc.9b01375

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Article
Nickel-Catalyzed C(2)–H Arylation of Indoles
with Aryl Chlorides under Neat Condition
Dilip K Pandey, Muniyappa Vijaykumar, and Benudhar Punji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01375 • Publication Date (Web): 19 Jul 2019
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The Journal of Organic Chemistry
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Nickel-Catalyzed C(2)H Arylation of Indoles with Aryl Chlorides un-
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der Neat Condition
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†,‡
†,‡
*,†,‡
Dilip K. Pandey, Muniyappa Vijaykumar, and Benudhar Punji
†
‡
Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, Academy of Scientific and Innovative
Research (AcSIR), CSIR–National Chemical Laboratory (CSIR–NCL), Dr. Homi Bhabha Road, Pune 411 008, Maharashtra,
India
ABSTRACT: Nickel-catalyzed regioselective C(2)H arylation of indoles and pyrroles with aryl chlorides is achieved under neat
condition. This method allows the efficient coupling of diverse aryl chlorides employing a user-friendly and inexpensive
o
Ni(OAc) /dppf catalyst system at 80 C. Numerous functionalities, such as halides, alkyl ether, fluoro-alkyl ether and thioether,
2
substituted amines, including heteroarenes like benzothiazolyl, pyrrolyl, indolyl and carbazolyl are well tolerated under the reaction
conditions. Preliminary mechanistic study highlights a single-electron transfer (SET) pathway for the arylation reaction.
INTRODUCTION
Arylated indole motifs are the important structural features
often found in many bioactive natural products and pharma-
1
ceutical relevant compounds. Thus, there is growing interest
in the synthesis of such moiety via the regioselective C−H
2
bond functionalization of indoles. Particularly, the metal-
catalyzed C−H functionalization strategy has led to the selec-
tive C-3, C-4, C-5, C-6 and C-7 arylation of indoles through
the regiocontrol directing group approach. Considering the
biological significance of C-2 arylated indoles (Figure 1), the
regioselective C-2 arylation has extensively been demonstrat-
3
4
5
6
7
ed using precious metal catalysts, i.e Ru, Rh and Pd. How-
ever, in recent years, there is strong inclination towards the
development of C–H bond functionalization protocol employ-
ing naturally abundant and inexpensive 3d metals to promote
8
the sustainable synthesis. In that direction, the group of Song
has demonstrated the cobalt-catalyzed oxidative arylation of
indoles with arylboronic acids employing an excess of second-
9
ary metal oxidant Mn(OAc) (Scheme 1a). Similarly, Acker-
2
mann has reported the C-2 arylation of indoles with aryl car-
bamates under cobalt-catalysis using the Grignard base,
10
CyMgCl (Scheme 1b). On the other hand, Gaunt has re-
ported a Cu-catalyzed indole arylation employing diaryliodo-
1
1
nium salt [TRIP-I-Ar]OTf (Scheme 1c), wherein the diaryli-
odonium salts are prepared from corresponding aryl iodides.
Recently, we have reported the C-2 arylation of indoles, in-
cluding other arenes, using aryl iodides as the coupling part-
Figure 1. C-2 Arylated indole moieties in bioactive molecules.
1
2
ners, and a well-defined nickel catalyst (Scheme 1d).
Surprisingly, the use of challenging, more demanding and
widely available aryl chlorides in the C(2)–H arylation of in-
doles is extremely rare. For example, Ackermann has shown
only one example on the coupling of indole with 4-methoxy
chlorobenzene using a Co-catalyst, and CyMgCl as a base
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1
3
(
Scheme 1e). Thus, to address the challenges on existing
occur without Ni(OAc) precursor (entry 17). The defined
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indole C-2 arylation methods and to promote sustainable and
complex (dppf)NiCl or Ni(cod) /dppf as catalysts were found
2
2
14
environmentally benign protocols, herein, we report the
nickel-catalyzed C(2)–H arylation of indoles with more de-
manding aryl chlorides (Scheme 1f). The arylation proceeded
smoothly under mild conditions using a simple and inexpen-
to be slightly less effective for the arylation reaction (entries
18, 19). Upon lowering the catalyst loading to 5 mol %, the
reaction provided 75% of 3aa (entry 20).
The effectiveness of different substituents/directing group at
the N-center of indole was screened. Notably, the free-NH
indole and indoles with N-acetyl or N-Boc groups were de-
composed under the reaction conditions, whereas N-Me indole
was unreactive. Similarly, the indoles bearing 2-pyrimidinyl
and 2-pyrazinyl as directing groups were ineffective and de-
composed under the reaction conditions. The 3-pyridinyl and
sive catalyst system, Ni(OAc) /dppf. Notably, the arylation
2
occurs even in the absence of solvent. Preliminary mechanistic
investigation has been performed to understand the working
mode of the nickel-catalyzed arylation.
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Scheme 1. Examples on C-2 Arylation of Indoles using
Base-Metal Catalysis
4
-pyridinyl-substituted indoles were unreactive, suggesting
that the strong sigma-coordination of 2-pyridynyl is essential
for the reaction and the electronic features on the N-substituent
has no influence on the reaction.
a
Table 1. Optimization of Reaction Parameters
o
b
entry
[Ni]
ligand
Xantphos
Binap
DPEphos
dppe
temp. ( C)
yield (%)
43
1
2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
110
110
110
110
110
110
110
110
110
110
110
110
110
80
74
3
77
4
74
5
dppf
94 (89)
65
6
bpy
7
Ni(OAc)2
Ni(OTf)2
phen
57
RESULTS AND DISCUSSION
8
dppf
60
Optimization of Reaction Parameters. We have initiated
the optimization study for the coupling of 1-(pyridin-2-yl)-1H-
indole (1a) with 1-chloro-4-methylbenzene (2a) employing
9
(dme)NiCl2 dppf
55
10
(thf) NiBr
dppf
dppf
dppf
dppf
dppf
dppf
--
75
2
2
c
Ni(OAc) /Xantphos catalyst system, and LiHMDS base in 1,4-
11
Ni(OAc)
2
65
2
d
dioxane (Table 1). The reaction afforded the coupled product
12
Ni(OAc)2
68
1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3aa) in 43% yield at
e
1
3
Ni(OAc)2
96 (90)
96 (91)
--
o
1
10 C (entry 1). Among various bidentate phosphine ligands
e
e,f
e
1
4
Ni(OAc)2
screened (entries 1-5), the dppf ligand along with Ni(OAc)2
1
5
Ni(OAc)2
80
was found to be very efficient and produced 3aa in 89%
isolated yield. The nitrogen-donor ligands like bpy and phen
are slightly less effective for the arylation reaction (entries
1
6
Ni(OAc)2
80
55
e
17
18
--
dppf
80
--
e
6
,7). Other nickel(II) precursors, such as Ni(OTf)2,
(dppf)NiCl2 --
80
65
(
dme)NiCl , (thf) NiBr along with dppf ligand were found to
e
2
2
2
1
9
Ni(cod)2
dppf
dppf
80
62
produce lower yield than the Ni(OAc) /dppf system (entries 8-
2
e,g
2
0
Ni(OAc)2
80
75
1
0). The arylation reaction in toluene or p-xylene was found to
a
be slightly less efficient (entries 11,12). To our surprise, the
arylation reaction proceeded smoothly even in the absence of
solvent and produced product 3aa in 90% yield (entry 13).
Notably, under the neat reaction condition, the reaction af-
Reaction Conditions: Indole 1a (0.039 g, 0.20 mmol), 2a
(0.051 g, 0.40 mmol), [Ni] cat (0.02 mmol, 10 mol %), ligand
(0.02 mmol, 10 mol %), LiHMDS (0.067 g, 0.40 mmol), solvent
b
1
(
1.0 mL). Yield by H NMR using CH Br as internal standard,
2 2
c
d
o
and isolated yield is in parenthesis. Toluene as a solvent. p-
Xylene as a solvent. Without solvent and 16 h. Using LiO Bu,
KHMDS or LDA as base. [Ni] cat. (5.0 mol %). LiHMDS =
forded similar yield even at 80 C (entry 14). The low melting
e
f
t
temperature of base LiHMDS makes the reaction homogene-
ous, which probably helped the reaction to proceed smoothly
in the neat condition. Notably, the arylation reaction did not
g
Lithium bis(trimethylsilyl)amide {LiN(SiMe ) }, dme = 1,2-
3
2
t
dimethoxyethane, dppf = 1,1'-bis(diphenylphosphino)ferrocene,
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,
DPEphos = bis[(2-diphenylphosphino)phenyl] ether.
occur in the presence of LiO Bu, KHMDS or LDA as a base
=
(entry 15). The arylation reaction in the absence of dppf ligand
gave 55% yield of 3aa (entry 16), whereas arylation did not
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Substrate Scope of Arylation. After successfully optimiz-
ing the reaction conditions for the arylation of indole with
arylated (3f’a) products in 26% and 37% yields, respectively
(Scheme 4). Even after the increased concentrations of 2a, we
could not achieve the selective formation of 3f’a. Particularly,
the formations of products, 3da-3fa and 3f’a were unsatisfac-
tory at 80 C, thus, the reactions were performed at 110 C.
Unfortunately, the substrates benzo[h]quinoline and N-
pyridinyl carbazole were failed to undergo arylation under the
optimized conditions. Though the regioselective arylation of
indoles using various coupling partners is well precedented,
we have shown here the use of challenging and widely availa-
ble aryl chlorides in the arylation reaction under mild and sol-
vent-free conditions, which makes this methodology more
unified.
1
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challenging aryl chloride using an inexpensive Ni(OAc) /dppf
2
catalyst system, we have explored the scope and limitations of
the reaction. The arylation was compatible with a variety of
simple and functionalized aryl chlorides as the electrophilic
coupling partners (Scheme 2). Various functional groups, such
as alkyl, ether, trifluoromethyl ether, thioether, substituted-
amine were well tolerated under the reaction conditions and
delivered the desired arylated products, 3aa-3ai in good to
o
o
o
excellent yields. Notably, an elevated temperature of 110 C
0
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was essential for the satisfactory formation of product 3ah.
The aryl chloride having methyl-substituent at the ortho- or
meta-position reacted efficiently (3aj, 3ak), whereas an ortho
MeO-substituted aryl chloride 2l is less reactive. We assume
that the probable coordination of MeO-functionality on 2l to
the nickel-species inhibits the reactivity by forming a more
stable Ni-complex. Notably, the sterically demanding electro-
phile, 2-chloro-1,3-dimethylbenzene (2m) reacted smoothly to
deliver the coupled product 3am in 82% yield. Similarly, the
In order to demonstrate the practical utility of the nickel-
catalyzed method, a gram scale reaction was performed. Thus,
the reaction of 1.0 g of indole 1a with 4-chlorotoluene (2a)
under the standard catalytic conditions afforded 3aa in 1.14 g,
which accounts for the 78% yield.
1
-chloronaphthalene electrophile reacted efficiently with in-
Scheme 2. Scope of Ni-Catalyzed C-2 Arylation with Aryl
dole 1a to produce 3an in 95% yield. The arylation is highly
a
2
Chlorides
chemoselective in terms of C(sp )halide bond activation,
thus, producing arylated product 3ao from the reaction of in-
2
dole 1a with 1-iodo-4-chlorobenzene (2o) via C(sp )I bond
H
Ni(OAc)2 (10.0 mol %)
dppf (10.0 mol %)
LiHMDS (2.0 equiv)
neat condition
H
activation, albeit in moderate yield. Most importantly, the aryl
chloride bearing nitrogen-heterocycles like N-pyrrolyl, N-
indolyl, N-carbazolyl at the para position of aryl-ring were
reacted smoothly and delivered the desired arylated products
R
+
Cl
R
H
N
N
2-py
2-py
0 oC, 16 h
8
(1a)
(2)
(3)
3
ap-3ar in moderate to good yields. Particularly, the coupling
R
CH3
of heterocycle-containing aryl chlorides (2p-2r) required an
N
N
o
N
R
elevated temperature of 110 C; and 1,4-dioxane was needed
2-py
2-py
2
-py
for the formation of 3ar. The heteroarene electrophile, 5-
chloro-1-methyl-1H-indole reacted with indole 1a and pro-
duced bi(indolyl) compound 3as in 60% yield. A challenging
and sensitive electrophile, 2-chlorobenzo[d]thiazole was
coupled successfully with indole affording product 3at in 57%
yield. Notably, aryl chlorides containing electron-withdrawing
R = CH3
(3aa): 91%
(3ab): 92%
(3ac): 90%
(3ad): 87%
(3ae): 61%
(3af): 88%
(3ag): 73%
R = CH3 (3ak): 80%
R = OCH3 (3al): 42%b
(3aj): 87%
R = C H5
2
R = H
R = OCH3
R = OCF3
H3C
R = OPh
R = SPhb
R = N(tolyl)2b,c (3ah): 86%
N
N
2-py
H3C
2-py
functional groups, such as –F, –CF at the para-position of
(3am): 82%
(3an): 95%
3
R = Ph
(3ai): 95%
aryl-ring were unreactive under the reaction conditions, whe-
reas those bearing sensitive functional groups like –CN, –NO2,
N
–
COOMe were decomposed under reaction conditions. Simi-
N
Cl
N
2
-py
N
N
2
-py
larly, aryl chlorides bearing electron-donating substituents at
the meta-position, such as 3-methoxy chlorobenzene and 3,5-
dimethoxy chlorobenzene were unreactive during the arylation
reaction. Additionally, the aryl chlorides having alkyl-
substituted amines, –NMe , –NEt were unreactive in the ary-
2-py
(3ao): 51%
(3ap): 58%c
3aq): 75%c
(
2
2
N
N
N
2-py
N
N
lation reaction, which might be due to their interference on
nickel catalyst by the nitrogen lone-pair coordination.
N
S
2
-py
2-py
CH3
(3ar): 66%b,c,d
(3at): 57%b
(
3as): 60%
Furthermore, the regioselective coupling of aryl chloride
was explored with the substituted indole derivatives (Scheme
3). Thus, the indole having electron-donating substituents,
methyl and methoxy at the C-5 position, reacted smoothly to
give the products 3ba and 3ca in 80% and 79% yields, respec-
tively. However, the fluoro-substituted indole reacted with 4-
chloro toluene with a low efficacy and needed elevated tem-
a
Reaction Conditions: Compound 1a (0.039 g, 0.20 mmol), sub-
b
c
strate 2 (0.40 mmol). Reaction time 24 h. Reaction performed at
110 C. 1,4-Dioxane was used as solvent.
o
d
o
perature (110 C) to produce 3da in 41% yield. Notably, a
sterically hindered 3-methyl-indole upon arylation with 4-
chloro toluene gave product 3ea in 66% yield. In addition to
indoles, the 2-pyridinyl pyrrol was arylated under the reaction
conditions affording a mixture of mono-arylated (3fa) and bis-
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Scheme 3. Scope of the Ni-Catalyzed C-2 Arylation of
Substituted Indoles
To get insight into the C–H bond activation process of in-
dole during the arylation, initial rates of the reaction using
indole 1a and [2-D]-1a were determined (Scheme 6a). The
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
2a
R2
R2
kinetic isotopic effect (KIE) value k /k = 0.80 observed from
H D
Ni(OAc)2 (10.0 mol %)
dppf (10.0 mol %)
LiHMDS (2.0 equiv)
neat condition
the independent rates indicates that the C–H bond activation is
not involved in the rate-determining step. Notably, a substan-
tial H/D exchange was observed between the indole [2-D]-1a
and 5-methoxy-1-(pyridine-2-yl)-1H-indole (1c) at the C(2)H
position, when the arylation was performed in one pot and
quenched at an early reaction time (Scheme 6b). This observa-
tion suggests the reversibility of the CH nickelation step dur-
ing the reaction. Furthermore, the attempted arylation reaction
in the absence of Ni(OAc) /dppf was quenched with D O in
R1
R1
H
N
N
CH3
2
-py
2-py
80 oC, 16 h
(
1)
(3)
H3C
H3CO
N
N
CH3
CH3
(3ca): 79%
0
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3
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0
1
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3
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5
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7
8
9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-py
2-py
(
3ba): 80%
2
2
F
the early stage, and the starting precursor 1a was recovered
CH3
1
(Scheme 6c). The H NMR analysis of the recovered 1a does
N
N
not show deuterium incorporation at the C(2)H or C(3)H
position, which ruled out the simple base-mediated deprotona-
tion pathway for the indole CH nickelation. The initial rates
of the arylation reaction for the substrates 1-(pyridin-2-yl)-1H-
indole (1a), 5-methoxy-1-(pyridin-2-yl)-1H-indole (1c), and 5-
fluoro-1-(pyridin-2-yl)-1H-indole (1d) with 4-chlorotoluene
were determined (Scheme 7), wherein the arylation is slightly
favored for the electron-deficient substrate.
CH3
CH3
2
-py
2-py
3da): 41%b,c
(3ea): 66%c
(
a
Reaction Conditions: Substrate 1 (0.20 mmol), substrate 2a
b
c
(0.051 g, 0.40 mmol). Reaction time 24 h. Reaction performed
o
at 110 C.
Scheme 4. Ni-Catalyzed Arylation of Pyrrole
Scheme 6. Deuterium Labeling Experiments
Mechanistic Aspects. We have performed preliminary me-
chanistic study to understand the progress of nickel-catalyzed
C-2 arylation of indole. Initial experiments were performed to
probe the radical pathway of the reaction. Thus, the standard
arylation reaction was attempted in the presence of radical
scavengers, TEMPO (2.0 equiv) or galvinoxyl (2.0 equiv),
wherein the arylation was completely inhibited (Scheme 5).
Additionally, the standard arylation reaction in the presence of
radical inhibitor such as butylated hydroxytoluene (BHT) was
completely suppressed. These observations suggest the proba-
ble involvement of a radical intermediate during the arylation
process. Unfortunately, the coupling of radical species with
TEMPO or galvinoxyl was not detected.
Scheme 5. External Additive Experiments
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represents a rare example of the coupling of aryl chlorides
Scheme 7. Reaction Rates for Substituted Indoles
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with CH bond of arenes. The reaction is compatible with a
range of simple and functionalized aryl chlorides as well as
electronically distinct indoles. The reaction tolerated various
functional groups, such as halides, ethers, and amines, as well
as pyrrolyl, indolyl and carbazolyl heterocycles. Based on the
preliminary mechanistic experiments, we proposed two proba-
ble mechanistic cycles that follow a single electron transfer
(SET) pathway.
On the basis of our preliminary mechanistic study and litera-
0
1
2
3
4
5
6
7
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9
0
1
2
3
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7
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9
0
1
2
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9
0
1
2
3
4
5
6
7
8
9
0
1
2,15
ture precedents,
we have proposed two tentative mechanis-
EXPERIMENTAL SECTION
tic cycles for the Ni-catalyzed arylation of indoles with aryl
chlorides (Figure 2). Initially, the coordination of indole 1a to
the complex A, followed by reversible CH nickelation in the
presence of LiHMDS would lead to the species (dppf)Ni(II)(2-
py-indolyl) (B). The electron-rich complex B would then trig-
ger the one-electron oxidative addition of aryl chloride leading
to C, which is followed by radical recombination to generate
D. The reductive elimination of product 3 from D would rege-
nerate the catalyst A. Alternatively, the aryl chloride would be
activated in a bimetallic oxidative fashion on B to give (2-py-
General Information. The arylation reactions were performed
in flame-dried reaction vessels with Teflon screw cap under an argon
atmosphere. Solvents were dried over Na/benzophenone and distilled
prior to use. Liquid reagents were flushed with argon prior to use. The
base LiHMDS was purified by sublimation. The aryl chloride electro-
1
8
19
20
21
22
23
24
philes 2f, 2g, 2h, 2p, 2q, 2r and 2s were prepared follow-
ing the literature procedure. High resolution mass spectrometry
(
HRMS) mass spectra were recorded on a Thermo Scientific Q-
1 13
Exactive, Accela 1250 pump. NMR: ( H and C) spectra were rec-
orded at 400 or 500 MHz ( H), 100 or 125 MHz { C, DEPT (distor-
tionless enhancement by polarization transfer)}, 377 MHz ( F), re-
1
13
19
1
6
indolyl)Ni(Ar)(X) (E) and (dppf)Ni(III)Cl (Path II). The
reductive elimination of arylated product 3 from species E
would produce (dppf)NiX, which upon comproportionation
with (dppf)Ni(III)Cl will regenerate the catalyst. Although, we
have proposed Ni(II) as an active catalyst, the possibility of
spectively in CDCl
shifts (δ) are given in ppm. The H and C NMR spectra are refe-
3
solutions, if not otherwise specified; chemical
1 13
renced to residual solvent signals (CDCl
ppm).
3
: δ H = 7.26 ppm, δ C = 77.2
17
Ni(I) as an active catalyst cannot be ruled out at this moment.
Representative Procedure for the Arylation: Synthesis of 1-
(Pyridin-2-yl)-2-(p-tolyl)-H-indole (3aa). To a flame-dried screw-
cap tube (5 mL) equipped with a magnetic stir bar was introduced 1-
pyridin-2-yl-1H-indole (1a, 0.039 g, 0.20 mmol), 1-chloro-4-
Considering the low product yield of arylation using a Ni(0)
complex and non-reactivity of electron-deficient aryl chlorides
during arylation, the probability of a Ni(0) species as an active
catalyst is less likely. Further studies to probe precise reaction
mechanism by detailed kinetics analysis and DFT energy cal-
culation are currently under investigation.
2
methylbenzene (2a, 0.051 g, 0.40 mmol), Ni(OAc) (0.0036 g, 0.02
mmol, 10.0 mol %), dppf (0.011 g, 0.02 mmol, 10.0 mol %) and
LiHMDS (0.067 g, 0.40 mmol) inside the glove box. The resultant
reaction mixture was stirred at 80 °C in a preheated oil bath for 16 h.
At ambient temperature, the reaction mixture was quenched with
distilled H
The crude product was then extracted with EtOAc (20 mL × 3). The
combined organic extract was dried over Na SO , and the volatiles
2
O (10 mL) and then neutralized with 2N HCl (0.5 mL).
2
4
were evaporated in vacuo. The remaining residue was purified by
column chromatography on silica gel (petroleum ether/EtOAc: 20/1)
to yield 3aa.
Gram Scale Synthesis: Representative procedure was followed,
using 1-pyridin-2-yl-1H-indole (1a, 1.0 g, 5.15 mmol), 1-
chlorotoluene (2a, 1.30 g, 10.30 mmol), Ni(OAc) (0.091 g, 0.515
2
mmol, 10.0 mol %), dppf (0.285 g, 0.515 mmol) and LiHMDS (1.72
g, 10.30 mmol), and the reaction was heated for 24 h. Yield: 1.14 g,
7
8%.
Procedure for External Additive Experiments. The representa-
tive procedure of the arylation reaction was followed, using substrate
1a (0.039 g, 0.20 mmol), 4-chlorotoluene (0.051 g, 0.40 mmol),
2
Ni(OAc) (0.0036 g, 0.02 mmol, 10.0 mol %), dppf (0.011 g, 0.02
mmol, 10.0 mol %), LiHMDS (0.067 g, 0.40 mmol), TEMPO (0.062
g, 0.40 mmol) [or galvinoxyl (0.169 g, 0.40 mmol) or dibutylhydrox-
ytoluene (BHT; 0.088 g, 0.40 mmol)] and the reaction mixture was
stirred for 16 h. At ambient temperature, the reaction was quenched
Figure 2. Plausible mechanistic pathways.
CONCLUSION
In summary, we have developed an efficient method for the
regioselective coupling of unactivated aryl chlorides with in-
doles and pyrroles under neat condition. The use of an inex-
pensive and air-stable dppf ligand along with the naturally
abundant nickel as catalyst allowed the arylation of indoles
with widely available and challenging aryl chlorides. This
2
with H O (10 mL) and diluted with EtOAc (10 mL). The GC analysis
of the crude reaction mixture does not show the formation of product
3aa. In addition, the coupled product of TEMPO or galvinoxyl with
aryl was not observed in the GC-MS.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1
2
Procedure for H/D Scrambling Experiment: To a Teflon-screw
capped tube equipped with magnetic stir bar were introduced 1-
2-(4-Methoxyphenyl)-1-(pyridin-2-yl)-1H-indole (3ad): Light
o 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yellow solid (0.052 g, 87%). M.p. = 85-87 C. H-NMR (400 MHz,
(
pyridine-2-yl)-1H-indole-2-d ([2-D]-1a; 0.019 g, 0.10 mmol), 5-
methoxy-1-(pyridine-2-yl)-1H-indole (1c; 0.022 g, 0.10 mmol), 4-
chlorotoluene (2a; 0.051 g, 0.40 mmol), Ni(OAc) (0.0036 g, 0.02
CDCl ):  = 8.65 (d, J = 3.8 Hz, 1H), 7.76-7.55 (m, 3H), 7.30-7.12
3
(m, 5H), 6.89 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.74 (s,
13
1
2
1H), 3.79 (s, 3H, CH3). C{ H}-NMR (100 MHz, CDCl ):  = 159.2
3
mmol, 10.0 mol %), dppf (0.011 g, 0.02 mmol, 10.0 mol %),
LiHMDS (0.067 g, 0.40 mmol) inside the glove-box. The resultant
reaction mixture was stirred at 80 °C in a preheated oil bath for 60
min. At ambient temperature, the reaction mixture was quenched with
distilled H
EtOAc (20 mL x 3). The combined organic extract was dried over
Na SO and the volatiles were evaporated in vacuo. The remaining
residue was subjected to column chromatography on silica gel (petro-
leum ether/EtOAc: 20/1) to recover the starting compounds 1a and 1c.
The H NMR analysis of the compound 1c show 25% incorporation
of deuterium at the C(2)‒H position.
(C ), 152.3 (C ), 149.3 (CH), 140.0 (C ), 138.5 (C ), 137.9 (CH),
q
q
q
q
130.1 (2C, CH), 128.9 (C ), 125.3 (C ), 122.8 (CH), 122.2 (CH),
q
q
121.7 (CH), 121.4 (CH), 120.5 (CH), 114.0 (2C, CH), 111.6 (CH),
+
104.8 (CH), 55.4 (CH ). HRMS (ESI-TOF) m/z: [M + H] Calcd for
3
2
O (10 mL). The crude product was then extracted with
C H N O 301.1335; Found 301.1334.
2
0
17
2
1-(Pyridin-2-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indole
1
2
4
(3ae): Light yellow liquid (0.043 g, 61%). H-NMR (500 MHz,
CDCl ):  = 8.67 (d, J = 3.8 Hz, 1H), 7.79-7.68 (m, 2H), 7.66 (d, J =
.4 Hz, 1H), 7.33-7.23 (m, 5H), 7.15 (d, J = 8.0 Hz, 2H), 6.99 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
8
8
1
1
1
13
1
.0 Hz, 1H), 6.84 (s, 1H). C{ H}-NMR (125 MHz, CDCl
51.9 (C ), 149.6 (CH), 148.7 (C ), 138.7 (q, JC–F = 11.6 Hz, C
38.3 (CH), 131.6 (C ), 130.1 (2C, CH), 128.9 (CH), 128.7 (C
), 123.6 (CH), 122.2 (q, JC–F = 2.3 Hz, 2C, CH), 122.0 (q,
C–F = 247.4 Hz, C ), 121.7 (CH), 121.0 (2C, CH), 111.6 (CH), 106.3
3
):  =
),
),
q
q
q
q
q
Representative Procedure for Kinetics Analysis: To the Teflon-
127.6 (C
q
J
screw capped tube equipped with magnetic stir bar was introduced
catalyst Ni(OAc)
q
1
9
2
(0.0036 g, 0.02 mmol, 0.02 M), dppf (0.011 g, 0.02
(CH). F-NMR (377 MHz, CDCl ):  = –57.8 (s). HRMS (ESI-TOF)
m/z: [M + H] Calcd for C H ON F 355.1053; Found 355.1050.
3
+
mmol, 0.02 M), LiHMDS (0.067 g, 0.40 mmol), substrate 1a (0.039
g, 0.20 mmol, 0.20 M) and 4-chlorotoluene (0.051 g, 0.40 mmol, 0.40
M). n-Hexadecane (0.025 mL, 0.085 mmol, 0.085 M) was added as an
internal standard and 1,4-dioxane (0.87 mL) was added to make the
total volume to 1.0 mL. The reaction mixture was then stirred at 110
2
0
14
2 3
2-(4-Phenoxyphenyl)-1-(pyridin-2-yl)-1H-indole (3af): Light
1
yellow liquid (0.064 g, 88%). H-NMR (400 MHz, CDCl
dd, J = 5.3, 1.5 Hz, 1H), 7.76-7.64 (m, 3H), 7.43-7.34 (m, 2H),
7.30-7.21 (m, 5H), 7.19-7.12 (m, 1H), 7.07 (d, J = 7.6 Hz, 2H), 7.01-
3
):  = 8.68
(
o
1
3
1
C in a pre-heated oil bath. At regular intervals (15, 30, 45, 60, 75, 90,
6
1
1
1
.91 (m, 3H), 6.82 (s, 1H). C{ H}-NMR (100 MHz, CDCl
57.1 (C ), 156.8 (C ), 152.2 (C ), 149.4 (CH), 139.6 (C ), 138.6 (C
38.0 (CH), 130.3 (2C, CH), 130.0 (2C, CH), 128.9 (C ), 127.7 (C
3
):  =
1
05, 120 min) the reaction vessel was cooled to ambient temperature
q
q
q
q
q
),
),
and an aliquot of sample was withdrawn to the GC vial. The sample
was diluted with acetone and subjected to GC analysis. The concen-
tration of the product 3aa obtained in each sample was determined
with respect to the internal standard n-hexadecane. The data of the
concentration of the product vs time (min) plot was drawn and fitted
linear with Origin Pro 8, and the rate was determined by initial rate
method (up to 120 minutes). The slope of the linear fitting represents
the reaction rate.
q
q
23.8 (CH), 123.1 (CH), 122.2 (CH), 121.9 (CH), 121.5 (CH), 120.6
(
CH), 119.5 (2C, CH), 118.5 (2C, CH), 111.6 (CH), 105.3 (CH).
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C25
H
19
N
2
O 363.1492;
Found 363.1492.
2
-(4-(Phenylthio)phenyl)-1-(pyridin-2-yl)-1H-indole
(3ag):
1
Light yellow liquid (0.055 g, 73%). H-NMR (400 MHz, CDCl
.65 (dd, J = 4.6, 1.5 Hz, 1H), 7.74-7.66 (m, 3H), 7.44-7.38 (m, 2H),
7.37-7.29 (m, 3H), 7.25-7.22 (m, 3H), 7.21 (s, 4H), 6.96 (d, J = 8.4
3
):  =
8
12
1
-(Pyridin-2-yl)-2-(p-tolyl)-H-indole (3aa): Light yellow solid
13
1
Hz, 1H), 6.83 (s, 1H). C{ H}-NMR (100 MHz, CDCl
), 149.4 (CH), 139.3 (C ), 138.7 (C ), 138.1 (CH), 135.8 (C
34.8 (C ), 131.9 (2C, CH), 131.2 (C ), 130.1 (2C, CH), 129.4 (2C,
CH), 129.4 (2C, CH), 128.8 (C ), 127.7 (CH), 123.3 (CH), 122.1
CH), 121.9 (CH), 121.6 (CH), 120.8 (CH), 111.6 (CH), 105.9 (CH).
3
):  = 152.0
o
1
(
0.052 g, 91%). M.p. = 65-67 C. H-NMR (500 MHz, CDCl
.68 (dd, J = 5.0, 1.1 Hz, 1H), 7.76-7.67 (m, 2H), 7.65 (td, J = 7.8, 1.9
Hz, 1H), 7.29-7.16 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0
3
):  =
(
C
q
q
q
q
),
8
1
q
q
q
13
1
Hz, 1H), 6.81 (s, 1H), 2.37 (s, 3H). C{ H}-NMR (125 MHz,
CDCl ):  = 152.4 (C ), 149.3 (CH), 140.3 (C ), 138.6 (C ), 137.9
CH), 137.5 (C ), 130.0 (C ), 129.2 (2C, CH), 129.0 (C ), 128.8 (2C,
CH), 123.0 (CH), 122.2 (CH), 121.7 (CH), 121.5 (CH), 120.6 (CH),
11.7 (CH), 105.3 (CH), 21.4 (CH ). HRMS (ESI-TOF) m/z: [M +
285.1386; Found 285.1384.
-(4-Ethylphenyl)-1-(pyridin-2-yl)-1H-indole (3ab): Light yel-
(
+
3
q
q
q
HRMS (ESI-TOF) m/z: [M + H] Calcd for
25 19 2
C H N S 379.1263;
(
q
q
q
Found 379.1261.
4
-Methyl-N-(4-(1-(pyridin-2-yl)-1H-indol-2-yl)phenyl)-N-(p-
1
1
3
tolyl)aniline (3ah): Light yellow liquid (0.080 g, 86%). H-NMR
400 MHz, CDCl ):  = 8.67-8.57 (m, 1H), 7.72-7.57 (m, 3H), 7.25-
7.12 (m, 3H), 7.09-7.02 (m, 6H), 7.01-6.94 (m, 5H), 6.87 (d, J = 8.4
+
17 2
H] Calcd for C20H N
(
3
5
b
2
1
1
3
1
low liquid (0.055 g, 92%). H-NMR (400 MHz, CDCl
3
):  = 8.74-
.64 (m, 1H), 7.77-7.69 (m, 2H), 7.65 (td, J = 7.8, 1.9 Hz, 1H), 7.30-
.21 (m, 5H), 7.19-7.11 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.84 (s,
H), 2.68 (q, J = 7.6 Hz, 2H, CH ), 1.28 (t, J = 7.6 Hz, 3H, CH ).
):  = 152.4 (C ), 149.3 (CH), 143.8
), 137.9 (CH), 130.1 (C ), 129.0 (C ), 128.8
2C, CH), 128.0 (2C, CH), 123.0 (CH), 122.3 (CH), 121.7 (CH),
21.4 (CH), 120.6 (CH), 111.6 (CH), 105.4 (CH), 28.7 (CH ), 15.5
). HRMS (ESI-TOF) m/z: [M + H] Calcd for C21
299.1543; Found 299.1541.
2-Phenyl-1-(pyridin-2-yl)-1H-indole (3ac): Light yellow solid
Hz, 2H), 6.73 (s, 1H), 2.29 (s, 6H, CH
CDCl ):  = 152.4 (C ), 149.3 (CH), 147.7 (C
), 138.6 (C ), 137.9 (CH), 133.1 (2C, C ), 130.1 (4C, CH), 129.5
2C, CH), 129.0 (C ), 125.0 (C ), 125.2 (4C, CH), 122.8 (CH), 122.3
CH), 121.8 (CH), 121.4 (2C, CH), 121.3 (CH), 120.4 (CH), 111.5
3
). C{ H}-NMR (125 MHz,
8
7
1
3
q
q
), 145.0 (2C, C ), 140.3
q
(
(
(
C
q
q
q
2
3
q
q
13
1
C{ H}-NMR (100 MHz, CDCl
), 140.3 (C ), 138.6 (C
3
q
+
(
(
1
C
q
q
q
q
q
(CH), 104.7 (CH), 21.0 (2C, CH
Calcd for C33 466.2278; Found 466.2276.
-([1,1'-Biphenyl]-4-yl)-1-(pyridin-2-yl)-1H-indole (3ai): Light
3
). HRMS (ESI-TOF) m/z: [M + H]
28 3
H N
2
2
+
o
1
(
CH
3
19 2
H N
yellow solid (0.066 g, 95%). M.p. = 135-138 C. H-NMR (500
MHz, CDCl ):  = 8.76-8.61 (m, 1H), 7.78-7.69 (m, 2H), 7.67 (vt, J
7.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.46
(vt, J = 7.2 Hz, 2H), 7.38 (m, 3H), 7.30-7.20 (m, 3H), 7.00 (d, J = 8.0
3
6a
=
o
1
(
=
1
0.049 g, 90%). M.p. = 125-127 C. H-NMR (400 MHz, CDCl
8.64 (d, J = 3.7 Hz, 1H), 7.77-7.64 (m, 2H, Ar‒H), 7.60 (td, J = 7.6,
.8 Hz, 1H, Ar‒H), 7.32-7.25 (m, 5H, Ar‒H), 7.25-7.17 (m, 3H,
3
): 
13
1
Hz, 1H), 6.90 (s, 1H). C{ H}-NMR (125 MHz, CDCl
3
):  = 152.3
), 138.8 (C ), 138.0
), 129.2 (2C, CH), 129.0 (2C, CH), 128.9 (C ), 127.6
CH), 127.1 (2C, CH), 127.0 (2C, CH), 123.3 (CH), 122.3 (CH),
21.9 (CH), 121.6 (CH), 120.8 (CH), 111.7 (CH), 105.9 (CH). HRMS
(
(
(
C
q
), 149.4 (CH), 140.5 (C
q
), 140.2 (C
q
), 139.8 (C
q
q
13
1
Ar‒H), 6.89 (d, J = 7.9 Hz, 1H, Ar‒H), 6.82 (s, 1H, Ar‒H). C{ H}-
NMR (100 MHz, CDCl ):  = 152.2 (C ), 149.3 (CH), 140.1 (C ),
138.7 (C ), 137.9 (CH), 132.8 (C ), 128.9 (C ), 128.9 (2C, CH), 128.5
(
(
[
CH), 131.8 (C
q
q
3
q
q
q
q
q
1
+
2C, CH), 127.6 (CH), 123.2 (CH), 122.2 (CH), 121.8 (CH), 121.5
(ESI-TOF) m/z: [M + H] Calcd for
47.1541.
-(Pyridin-2-yl)-2-(m-tolyl)-1H-indole (3aj): Light yellow solid
25 19 2
C H N 347.1543; Found
CH), 120.7 (CH), 111.7 (CH), 105.8 (CH). HRMS (ESI-TOF) m/z:
3
+
5
b
M + H] Calcd for C19
H
15
N
2
271.1230; Found 271.1229.
1
o
1
(
0.049 g, 87%). M.p. = 90-92 C. H-NMR (400 MHz, CDCl
3
):  =
6
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
8
.65 (d, J = 4.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz,
 = 152.2 (C ), 149.5 (CH), 139.9 (C ), 139.3 (C ), 138.8 (C ), 138.1
q
q
q
q
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1H), 7.28-7.16 (m, 4H), 7.14 (d, J = 7.6 Hz, 1H), 7.11-7.05 (m, 1H),
.01 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 2.30
q q
(CH), 130.1 (C ), 130.0 (2C, CH), 128.9 (C ), 123.3 (CH), 122.2
7
(CH), 122.0 (CH), 121.6 (CH), 120.8 (CH), 120.2 (2C, CH), 119.2
1
3
1
(
(
1
s, CH
CH), 140.3 (C
29.6 (CH), 128.9 (C
(CH), 122.2 (CH), 121.7 (CH), 121.5 (CH), 120.7 (CH), 111.6 (CH),
3
). C{ H}-NMR (100 MHz, CDCl
), 138.6 (C ), 138.2 (C ), 137.9 (CH), 132.7 (C
), 128.4 (CH), 128.3 (CH), 126.0 (CH), 123.1
3
):  = 152.3 (C
q
), 149.3
(2C, CH), 111.6 (CH), 110.9 (2C, CH), 105.8 (CH). HRMS (ESI-
+
q
q
q
q
),
TOF) m/z: [M + H] Calcd for C23
H
18
N
3
336.1495; Found 336.1492.
q
2-(4-(1H-Indol-1-yl)phenyl)-1-(pyridin-2-yl)-1H-indole (3aq):
o 1
Light yellow solid (0.058 g, 75%). M.p. = 140-143 C. H-NMR (400
+
1
C
05.6 (CH), 21.6 (CH
285.1386; Found 285.1385.
-(Pyridin-2-yl)-2-(o-tolyl)-1H-indole (3ak): Light yellow solid
3
). HRMS (ESI-TOF) m/z: [M + H] Calcd for
MHz, CDCl ):  = 8.69 (d, J = 3.8 Hz, 1H), 7.81-7.66 (m, 4H), 7.60
3
20
H
1
17
N
2
(d, J = 7.6 Hz, 1H), 7.50-7.37 (m, 4H), 7.34 (d, J = 3.1 Hz, 1H), 7.32-
7.13 (m, 5H), 7.06 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.71 (d, J = 3.1
12
o
1
13
1
(
8
0.045 g, 80%). M.p. = 124-126 C. H-NMR (400 MHz, CDCl
.66-8.53 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.74-7.65 (m, 1H), 7.50
(td, J = 7.8, 1.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.31-7.21 (m, 3H), 7.21-
3
):  =
Hz, 1H). C{ H}-NMR (100 MHz, CDCl ):  = 152.1 (C ), 149.5
3
q
q q q q
(CH), 139.2 (C ), 139.0 (C ), 138.8 (C ), 138.2 (CH), 135.7 (C ),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
q q q
130.8 (C ), 129.9 (2C, CH), 129.6 (C ), 128.8 (C ), 127.8 (CH), 124.0
7
.10 (m, 3H), 6.72 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 2.08 (s, 3H,
(2C, CH), 123.4 (CH), 122.6 (CH), 122.2 (CH), 122.1 (CH), 121.7
(CH), 121.3 (CH), 120.8 (CH), 120.7 (CH), 111.6 (CH), 110.7 (CH),
106.0 (CH), 104.1 (CH). HRMS (ESI-TOF) m/z: [M + H] Calcd for
1
3
1
CH
1
(
3
). C{ H}-NMR (125 MHz, CDCl
), 137.7 (CH), 137.6 (C ), 137.3 (C
CH), 130.3 (CH), 128.8 (C ), 128.4 (CH), 125.8 (CH), 123.0 (CH),
121.4 (CH), 121.2 (CH) 120.7 (CH), 120.5 (CH), 112.1 (CH), 106.3
3
):  = 152.0 (C
q
), 149.0 (CH),
+
39.1 (C
q
q
q
), 132.9 (C
q
), 131.2
q
C
27
H
20
N
3
386.1652; Found 386.1648.
9-(4-(1-(Pyridin-2-yl)-1H-indol-2-yl)phenyl)-9H-carbazole
+
12
1
(CH), 20.3 (CH
285.1386; Found 285.1385.
-(2-Methoxyphenyl)-1-(pyridin-2-yl)-1H-indole (3al): Light
3
). HRMS (ESI-TOF) m/z: [M + H] Calcd for
(3ar): Light yellow liquid (0.057 g, 66%). H-NMR (500 MHz,
C
20
H
2
17
N
2
CDCl ):  = 8.76-8.65 (m, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.84-7.65
3
6
b
(m, 3H), 7.56-7.47 (m, 4H), 7.46-7.38 (m, 4H), 7.37-7.20 (m, 5H),
o
1
13
1
yellow solid (0.025 g, 42%). M.p. = 80-82 C. H-NMR (400 MHz,
CDCl ):  = 8.58 (dd, J = 4.6, 1.5 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H),
7.67 (d, J = 6.9 Hz, 1H), 7.56 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J =
7.11 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H). C{ H}-NMR (125 MHz,
3
CDCl ):  = 152.1 (C ), 149.6 (CH), 140.8 (2C, C ), 139.3 (C ), 138.9
3
q
q
q
(C ), 138.3 (CH), 137.0 (C ), 131.8 (C ), 130.1 (2C, CH), 128.9 (C ),
q
q
q
q
7
7
3
1
.6, 1.5 Hz, 1H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 7.27-7.11 (m, 3H),
.02 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.78-6.70 (m, 2H),
126.9 (2C, CH), 126.1 (2C, CH), 123.7 (2C, C ), 123.5 (CH), 122.3
q
(CH), 122.2 (CH), 121.7 (CH), 120.9 (CH), 120.5 (2C, CH), 120.3
1
3
1
.32 (s, 3H, CH
52.9 (C ), 148.8 (CH), 137.5 (C
) 123.0 (CH), 122.5 (C
121.0 (CH), 121.0 (CH), 120.6 (CH), 119.8 (CH), 111.8 (CH), 110.9
3
). C{ H}-NMR (100 MHz, CDCl
), 137.4 (CH), 137.3 (C
), 121.1 (CH),
3
):  = 156.5 (C
q
),
(2C, CH), 111.6 (CH), 109.9 (2C, CH), 106.3 (CH). HRMS (ESI-
+
q
q
q
), 131.8
TOF) m/z: [M + H] Calcd for C31
H
22
N
3
436.1808; Found 436.1804.
(
CH), 129.9 (CH), 128.8 (C
q
q
1'-Methyl-1-(pyridin-2-yl)-1H,1'H-2,5'-biindole (3as): Light yel-
o 1
low solid (0.039 g, 60%). M.p. = 175-177 C. H-NMR (400 MHz,
+
(
CH), 106.3 (CH), 54.9 (CH
Calcd for C20 O 301.1335; Found 301.1334.
-(3,5-Dimethylphenyl)-1-(pyridin-2-yl)-1H-indole (3am): Light
3
). HRMS (ESI-TOF) m/z: [M + H]
CDCl ):  = 8.68 (dd, J = 5.3, 1.5 Hz, 1H), 7.80-7.73 (m, 1H), 7.71-
3
H
17
N
2
7.67 (m, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.52 (td, J = 7.8, 1.9 Hz, 1H),
7.25-7.16 (m, 4H), 7.11 (dd, J = 8.4, 1.5 Hz, 1H), 7.06 (d, J = 3.1 Hz,
1H), 6.84 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 6.46 (d, J = 3.1 Hz, 1H),
2
o
1
yellow solid (0.049 g, 82%). M.p. = 90-92 C. H-NMR (400 MHz,
CDCl ):  = 8.56-8.50 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.72-7.67
(m, 1H), 7.49 (td, J = 7.8, 1.9 Hz, 1H), 7.34-7.20 (m, 2H), 7.20-7.13
1
3
1
3
3.77 (s, 3H, CH3). C{ H}-NMR (125 MHz, CDCl ):  = 152.6 (C ),
3
q
149.1 (CH), 141.7 (C ), 138.4 (C ), 137.8 (CH), 136.3 (C ), 129.7
q
q
q
(
(
(
(
m, 1H), 7.10 (dd, J = 6.9, 5.3 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.71
q q q
(CH), 129.1 (C ), 128.5 (C ), 124.1 (C ), 123.1 (CH), 122.6 (CH),
13
1
d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 2.09 (s, 6H, CH
100 MHz, CDCl ):  = 151.8 (C ) 149.0 (CH), 138.6 (2C, C
CH), 137.6 (C ), 136.8 (C ), 132.7 (C ), 129.0 (C ), 128.6 (CH),
3
). C{ H}-NMR
122.3 (CH), 121.6 (CH), 121.5 (CH), 121.3 (CH), 120.3 (CH), 111.7
(CH), 109.2 (CH), 105.0 (CH), 101.5 (CH), 33.0 (CH ). HRMS (ESI-
324.1495; Found 324.1494.
2-(1-(Pyridin-2-yl)-1H-indol-2-yl)benzo[d]thiazole (3at): Light
3
q
q
), 137.7
3
+
q
q
q
q
18 3
TOF) m/z: [M + H] Calcd for C22H N
127.4 (2C, CH), 122.7 (CH), 121.3 (CH), 121.2 (CH), 120.5 (CH),
19.6 (CH), 112.4 (CH), 105.6 (CH), 20.8 (2C, CH ). HRMS (ESI-
299.1543; Found 299.1541.
-(Naphthalen-1-yl)-1-(pyridin-2-yl)-1H-indole (3an): Light yel-
o
1
1
3
yellow solid (0.037 g, 57%). M.p. = 90-92 C. H-NMR (400 MHz,
+
TOF) m/z: [M + H] Calcd for C21
H
19
N
2
CDCl ):  = 8.64 (d, J = 3.8 Hz, 1H), 7.87-7.77 (m, 3H), 7.74 (d, J =
3
2
7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43-7.34 (m, 4H), 7.34-7.27
1
13
1
low liquid (0.061 g, 95%). H-NMR (400 MHz, CDCl
J = 3.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
7.80 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 6.9 Hz, 1H), 7.44-7.22 (m, 7H),
3
):  = 8.50 (d,
(m, 2H), 7.27-7.20 (m, 1H). C{ H}-NMR (100 MHz, CDCl ):  =
3
159.2 (C ), 153.7 (C ), 151.4 (C ), 149.5 (CH), 139.8 (C ), 138.3
q
q
q
q
(CH), 135.2 (C ), 132.7 (C ), 127.9 (C ), 126.3 (CH), 125.2 (CH),
q
q
q
6
.97 (dd, J = 6.9, 5.3 Hz, 1H), 6.85 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H).
125.1 (CH), 123.4 (CH), 123.0 (CH), 122.9 (CH), 121.9 (CH), 121.8
1
3
1
C{ H}-NMR (100 MHz, CDCl
), 137.7 (C ), 137.6 (CH), 133.6 (C
CH), 128.8 (C ), 128.7 (CH), 128.3 (CH), 126.6 (CH), 126.1 (2C,
3
):  = 152.0 (C
q
), 148.9 (CH), 137.8
(CH), 121.4 (CH), 111.5 (CH), 109.9 (CH). HRMS (ESI-TOF) m/z:
+
(
(
C
q
q
q
), 132.3 (C
q
), 130.7 (C ), 129.1
q
[M + H] Calcd for C20
H
14
N
3
S 328.0903; Found 328.0900.
12
q
5-Methyl-1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3ba):
Light
o
1
CH), 125.2 (CH), 123.3 (CH), 121.6 (CH), 121.3 (CH), 120.8 (CH),
120.7 (CH), 112.1 (CH), 107.8 (CH). HRMS (ESI-TOF) m/z: [M +
H] Calcd for C23
yellow solid (0.048 g, 80%). M.p. = 70-72 C. H-NMR (400 MHz,
CDCl ):  = 8.62 (dd, J = 4.6, 1.5 Hz, 1H), 7.65-7.52 (m, 2H), 7.43 (s,
3
+
H
17
N
2
321.1386; Found 321.1385.
1H), 7.22-7.11 (m, 3H), 7.10-6.98 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H),
1
2
13
1
2
-(4-Chlorophenyl)-1-(pyridin-2-yl)-1H-indole (3ao):
Light
):  = 8.68-
.52 (m, 1H), 7.70-7.57 (m, 3H), 7.31-7.13 (m, 7H), 6.92 (d, J = 7.6
3 3
6.69 (s, 1H), 2.45 (s, 3H, CH ), 2.32 (3H, CH ). C{ H}-NMR (100
1
yellow liquid (0.031 g, 51%). H-NMR (400 MHz, CDCl
8
3
MHz, CDCl ):  = 152.5 (C ), 149.2 (CH), 140.2 (C ), 137.8 (CH),
3
q
q
q q q q q
137.3 (C ), 137.0 (C ), 130.7 (C ), 130.1 (C ), 129.5 (C ), 129.1 (2C,
13
1
Hz, 1H), 6.79 (s, 1H). C{ H}-NMR (100 MHz, CDCl
(C ), 149.5 (CH), 138.9 (C ), 138.7 (C ), 138.2 (CH), 133.6 (C
31.3 (C ), 130.0 (2C, CH), 128.7 (2C, CH), 128.4 (C ), 123.5 (CH),
22.1 (CH), 122.0 (CH), 121.7 (CH), 120.8 (CH), 111.6 (CH), 106.1
3
):  = 151.9
CH), 128.7 (2C, CH), 124.5 (CH), 122.1 (CH), 121.5 (CH), 120.3
(CH), 111.4 (CH), 105.1 (CH), 21.6 (CH ), 21.4 (CH ). HRMS (ESI-
299.1543; Found 299.1541.
5-Methoxy-1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3ca): Light
q
q
q
q
),
3
3
+
1
1
q
q
19 2
TOF) m/z: [M + H] Calcd for C21H N
+
o
1
(
CH). HRMS (ESI-TOF) m/z: [M + H] Calcd for C19
H14ClN
2
yellow solid (0.050 g, 79%). M.p. = 125-127 C. H-NMR (500 MHz,
3
05.0840; Found 305.0841.
CDCl ):  = 8.66-8.59 (m, 1H), 7.65-7.55 (m, 2H), 7.20 (dd, J = 7.1,
3
2-(4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-2-yl)-1H-indole
5.1 Hz, 1H), 7.18-7.14 (m, 2H), 7.12 (d, J = 2.7 Hz, 1H), 7.08 (m,
1
2
o
1
(
(
7
1
3ap): Brown solid (0.039 g, 58%). M.p. = 140-142 C. H-NMR
400 MHz, CDCl ):  = 8.78-8.60 (m, 1H), 7.81-7.62 (m, 3H), 7.42-
.31 (m, 4H), 7.31-7.22 (m, 3H), 7.12 (br s, 2H), 7.01 (d, J = 7.9 Hz,
2H), 6.90-6.81 (m, 2H), 6.70 (s, 1H), 3.88 (s, 3H, OCH ), 2.33 (s, 3H,
3
1
3
1
3
CH3). C{ H}-NMR (125 MHz, CDCl ):  = 155.4 (C ), 152.5 (C ),
3
q
q
q q q
149.2 (CH), 140.8 (C ), 137.9 (CH), 137.5 (C ), 133.9 (C ), 130.0
13
1
H), 6.87 (s, 1H), 6.38 (br s, 2H). C{ H}-NMR (100 MHz, CDCl
3
):
q q
(C ), 129.5 (C ), 129.2 (2C, CH), 128.8 (2C, CH), 122.0 (CH), 121.5
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
(
3
CH), 112.8 (CH), 112.6 (CH), 105.3 (CH), 102.5 (CH). 56.0 (OCH ),
+
ACKNOWLEDGMENTS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
21.4 (CH
15.1492; Found 315.1490.
-Fluoro-1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3da): Light yel-
3 19 2
). HRMS (ESI-TOF) m/z: [M + H] Calcd for C21H N O
3
This work was financially supported by SERB, New Delhi, India
EMR/2016/000989). D.K.P. and M.V. thanks UGC - New Delhi
5
o
1
(
low solid (0.025 g, 41%). M.p. = 90-92 C. H-NMR (400 MHz,
and CSIR – New Delhi, respectively, for research fellowships. We
are grateful to Dr (Mrs) Shanthakumari for HRMS and Dr. S.P.
Borikar for GC-MS analysis
CDCl
7
9
3
):  = 8.69-8.61 (m, 1H), 7.66-7.58 (m, 2H), 7.32-7.27 (m, 1H),
.26-7.21 (m, 1H), 7.18-7.13 (m, 2H), 7.13-7.05 (m, 2H), 6.95 (td, J =
.2, 3.1 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 2.34 (s, 3H,
1
3
1
CH
3
). C{ H}-NMR (100 MHz, CDCl
), 149.3 (CH), 141.7 (C ), 138.0 (CH), 136.5 (d, JC–F
), 129.5 (d, JC–F = 19.2 Hz, C ), 129.3 (C
28.8 (CH), 128.7 (d, JC–F = 35.5 Hz, CH), 122.2 (CH), 121.9 (CH),
3
):  = 160.1 (C
q
), 157.7 (C
q
),
=
1
1
2
1
52.1 (C
79.9 Hz, C
q
q
REFERENCES
3
q
q
q
), 129.2 (CH),
(
1) (a) Sharma, V.; Kumar, P.; Pathak, D. Biological Importance of
2
the Indole Nucleus in Recent Years: A Comprehensive Review. J.
Heterocyclic Chem. 2010, 47, 491-502. (b) Kaushik, N. K.; Kaushik,
N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H.
Biomedical Importance of Indoles. Molecules 2013, 18, 6620-6662.
4
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
112.6 (d, JC–F = 9.6 Hz, CH), 111.5 (d, JC–F = 25.9 Hz, CH), 105.3
2
19
(
CH), 105.2 (d, JC–F = 44.1 Hz, CH), 105.1 (CH), 21.4 (CH
3
). F-
NMR (377 MHz, CDCl
3
):  = ‒123.1 (s). HRMS (ESI-TOF) m/z: [M
F 303.1292; Found 303.1288.
+
+
H] Calcd for C20
H
16
N
2
(
2) For selected recent reviews on C–H Functionalization, see: (a)
12
3
-Methyl-1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3ea):
Light
Zhang, F.; Spring, D. R. Arene C–H Functionalisation Using a
Removable/Modifiable or a Traceless Directing Group Strategy.
Chem. Soc. Rev. 2014, 43, 6906-6919. (b) Zhang, M.; Zhang, Y.; Jie,
X.; Zhao, H.; Li, G.; Su, W. Recent Advances in Directed C–H
Functionalizations Using Monodentate Nitrogen-Based Directing
Groups. Org. Chem. Front. 2014, 1, 843-895. (c) Sandtorv, A. H.
Transition Metal-Catalyzed C–H Activation of Indoles. Adv. Synth.
Catal. 2015, 357, 2403-2435. (d) Gensch, T.; Hopkinson, M. N.;
Glorius, F.; Wencel-Delord, J. Mild Metal-Catalyzed C–H Activation:
Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900-2936. (e)
Wedi, P.; van Gemmeren, M. Arene-Limited Nondirected C−H
Activation of Arenes. Angew.Chem. Int. Ed. 2018, 57, 13016-13027.
o
1
yellow solid (0.039 g, 66%). M.p. = 130-132 C. H-NMR (400
MHz, CDCl ):  = 8.62 (d, J = 3.7 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H),
.66 (d, J = 6.7 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 7.39-7.23 (m, 3H),
.20-7.11 (m, 4H), 6.78 (d, J = 7.9 Hz, 1H), 2.42 (s, 3H, CH ), 2.38
):  = 152.5 (C ),
), 135.9 (C ), 130.3
), 129.1 (2C, CH), 123.2 (CH), 121.7
(CH), 121.0 (CH), 121.0 (CH), 118.9 (CH), 112.5 (C ), 111.6 (CH),
1.4 (CH ), 9.7 (CH ). HRMS (ESI-TOF) m/z: [M + H] Calcd for
299.1543; Found 299.1541.
-(2-(p-Tolyl)-1H-pyrrol-1-yl)pyridine (3fa): Light yellow liquid
3
7
7
3
13
1
(
1
s, 3H, CH
3
). C{ H}-NMR (100 MHz, CDCl
49.0 (CH), 137.6 (CH), 137.4 (C ), 137.2 (C
), 129.6 (C
3
q
q
q
q
(2C, CH), 129.9 (C
q
q
q
+
2
3
3
21 19 2
C H N
2
1
(
0.012 g, 26%). H-NMR (400 MHz, CDCl
3
):  = 8.57-8.42 (m, 1H),
(f)
Das, R.; Kapur, M. Transition-Metal-Catalyzed C–H
7.52 (td, J = 7.8, 1.9 Hz, 1H), 7.39-7.31 (m, 1H), 7.19-7.12 (m, 1H),
Functionalization Reactions of π-Deficient Heterocycles. Asian J.
Org. Chem. 2018, 7, 1217-1235.
7
.07 (m, 4H), 6.79 (d, J = 8.4 Hz, 1H), 6.44-6.33 (m, 2H), 2.33 (CH
3
).
C{ H}-NMR (100 MHz, CDCl ), 149.0 (CH), 137.5
q
CH), 136.5 (C ), 133.3 (C ), 130.4 (C ), 129.1 (2C, CH), 128.4 (2C,
1
3
1
3
):  = 152.3 (C
q
(3) For selected examples, see: (a) Modha, S. G.; Greaney, M. F.
Atom-Economical Transformation of Diaryliodonium Salts: Tandem
C–H and N–H Arylation of Indoles. J. Am. Chem. Soc. 2015, 137,
1416-1419. (b) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. Cu-
Catalyzed Direct C6-Arylation of Indoles. J. Am. Chem. Soc. 2016,
138, 8734-8737. (c) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z.
Palladium-Catalyzed C–H Arylation of Indoles at the C7 Position. J.
Am. Chem. Soc. 2016, 138, 495-498. (d) Yang, Y.; Gao, P.; Zhao, Y.;
Shi, Z. Regiocontrolled Direct C–H Arylation of Indoles at the C4 and
C5 Positions. Angew. Chem. Int. Ed. 2017, 56, 3966-3971. (e) Qiu,
(
q
q
CH), 123.3 (CH), 121.3 (CH), 119.4 (CH), 112.2 (CH), 110.0 (CH),
+
2
1.3 (CH
235.1230; Found 235.1228.
-(2,5-Di-p-tolyl-1H-pyrrol-1-yl)pyridine (3f’a): Light yellow
3 15 2
). HRMS (ESI-TOF) m/z: [M + H] Calcd for C16H N
2
o
1
solid (0.024 g, 37%). M.p. = 115-117 C. H-NMR (400 MHz,
CDCl ):  = 8.67-8.57 (m, 1H), 7.76 (td, J = 7.8, 1.9 Hz, 1H), 7.38
dd, J = 6.9, 5.3 Hz, 2H), 7.17 (m, 8H), 6.62 (s, 2H), 2.46 (s, 6H,
3
(
1
3
1
CH
137.8 (CH), 136.1 (2C, C
28.9 (4C, CH), 128.5 (4C, CH), 124.0 (CH), 122.7 (CH), 110.1 (2C,
3
). C{ H}-NMR (100 MHz, CDCl
3
):  = 152.6 (C
q
), 149.1 (CH),
III
q
), 136.0 (2C, C
q
), 130.5 (C
q
), 129.2 (C ),
q
X.; Wang, P.; Wang, D.; Wang, M.; Yuan, Y.; Shi, Z. P -Chelation-
1
Assisted Indole C7-Arylation, Olefination, Methylation, and
Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis.
Angew. Chem. Int. Ed. 2019, 58, 1504-1508. For reviews, see: (f)
Joucla, L.; Djakovitch, L. Transition Metal-Catalysed, Direct and
Site-Selective N1-, C2- or C3-Arylation of the Indole Nucleus: 20
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+
CH), 21.3 (2C, CH
C H N
23 21 2
3
). HRMS (ESI-TOF) m/z: [M + H] Calcd for
325.1699; Found 325.1695.
ASSOCIATED CONTENT
Supporting Information
7
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AUTHOR INFORMATION
Corresponding Author
*E-mail for B.P.: b.punji@ncl.res.in
Notes
The authors declare no competing financial interests.
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