Expeditious and Solvent-Free Nickel-Catalyzed C?H Arylation of Arenes and Indoles

Article abstract of DOI:10.1002/cssc.201700321

An efficient solvent-free nickel-catalyzed method for C?H bond arylation of arenes and indoles has been developed, which proceeds expeditiously through chelation assistance. The reaction is highly selective for mono-arylation and tolerates sensitive and structurally diverse functionalities, such as halides, ethers, amines, indole, pyrrole and carbazole. This reaction represents the first example of a nickel-catalyzed C?H arylation by monochelate assistance and symbolizes a rare precedent in solvent-free C?H arylation. Mechanistic investigations by various controlled reactions, kinetic studies, and deuterium labeling experiments suggest that the arylation follows a single electron transfer (SET) pathway involving the turnover-limiting C?H nickelation process.

Full text of DOI:10.1002/cssc.201700321

Accepted Article
Title: Expeditious and Solvent-Free Nickel-Catalyzed C‒H Arylation of
Arenes and Indoles
Authors: Rahul A Jagtap, Vineeta Soni, and Benudhar Punji
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10.1002/cssc.201700321
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Expeditious and Solvent-Free Nickel-Catalyzed C‒H Arylation of
Arenes and Indoles
Rahul A. Jagtap, Vineeta Soni, and Benudhar Punji*
Abstract: An efficient solvent-free nickel-catalyzed method for the
C‒H bond arylation of arenes and indoles is described that proceeds
expeditiously via chelation-assistance. The reaction is highly
selective for mono-arylation, and tolerates sensitive and structurally
diverse functionalities, such as halides, ethers, amines, indole,
pyrrole and carbazole. This reaction represents the first example of
nickel-catalyzed C‒H arylation by mono-chelate assistance, and
unactivated (hetero)arenes by the monodentate chelation-
assistance has not been precedented.[9]
Most importantly, the majority of C‒H arylation reported till
date often suffer from the use of toxic solvents, long reaction
times and/or moderate selectivities. Undisputedly, modern
chemical research stressed on the processes that reduce or
exclude the use of hazardous materials.[10] In this vein, the
solvents used in the reaction represent the vital component, that
constitute the vast majority of mass wasted in syntheses.[11] One
of the encouraging methods to reduce the waste would be the
solvent-free C‒H arylation, which could make the synthesis
easier due to reduction in size of reaction vessel and simple
workup. Further, the shorter reaction time and solvent-free
condition would save lot of energy, reduce hazards and toxicity.
To our knowledge, only few examples of the solvent-free
direct arylation have known, wherein the precious Pd-catalysts
are employed and the methods have very limited scope.[12] On
the other hand, the solvent-free C‒H arylation of arenes and
heteroarenes by the abundant base-metal catalysts has not
been reported. Herein, as a part of our program,[13] to address
the limitations on existing arylation methods and to promote the
sustainable and environmentally benign protocols, we report the
first nickel-catalyzed solvent-free C‒H arylation of arenes and
indoles that proceeds by simple chelation-assistance. This
reaction is highly selective for mono-arylation, occurs
expeditiously (within 30-120 min), and affords the arylated
products in excellent yields with remarkable tolerance in
functionality.
symbolizes
a rare precedent of solvent-free C‒H arylation.
Mechanistic investigations by various controlled reactions, kinetic
studies and deuterium labelling experiments suggest that the
arylation follows a single electron transfer (SET) pathway involving
the turnover-limiting C‒H nickelation process.
Introduction
Selective functionalization of C‒H bonds is one of the most
attractive ways for synthesizing complex organic molecules.[1]
More specifically, the C‒H arylation with aryl halides is
considered as an environment-friendly method for the synthesis
of diverse biaryl-motifs, because the major byproducts of such
reaction comprise of base-HX (X = halide) rather the metallic
salts that is produced under traditional couplings. Moreover, this
method bypasses the preparation of sensitive organometallic
compound, thus lessening the number of steps, and proven a
versatile approach for step-economical synthesis.
In particular, the C‒H arylation has most extensively been
studied with the precious 4d transition-metal catalysts;[1l,2]
however, currently research effort is being focused on the
development of such transformation using naturally-abundant 3d
metals, like nickel as catalyst.[3] Several distinct arylation
reactions featuring nickel-catalyst have been found, but most of
them demonstrated for the activated heterocycles[4] and
substrates containing activated C‒H bond.[5] Recently, the
nickel-catalyzed C‒H arylation[6] via the bidentate chelation-
assisted strategy has been developed,[7,8] which is limited only to
the amide derivatives, whereby the prerequisition of fancy
bidentate motif on each substrate is a major disadvantage.
Surprisingly, nickel-catalyzed regioselective C‒H arylation of
Results and Discussion
Optimization of reaction conditions
We initiated the optimization studies for the arylation of
benzo[h]quinoline (2a) with 4-iodotoluene (3a) coupling partner
employing nickel catalysts 1a,b,[13b] (Table 1 and Table S1 in the
Supporting Information). Initial experiments were conducted to
screen the suitable bases, and the reactions were performed in
o
toluene at 160 C using catalyst 1a. Various mild bases as well
as LiOtBu, NaOtBu screened were ineffective; however, the
reaction in the presence of LiHMDS {LiN(SiMe3)2} afforded 63%
yield of product 4aa (entries 1-3). An appropriate combination of
LiHMDS and 4-iodotoluene was optimized to minimize the
competitive reaction of LiHMDS with 4-iodotoluene, and found
that the arylation in the presence of 2.0 equiv of LiHMDS and
2.4 equiv of 3a afforded improved yield of 4aa (entries 4-6). To
our surprise, the arylation reaction produced 4aa in 83% yield
even at 120 oC and without the use of solvent (entries 7,8).
Notably, the arylation reaction found to be completed in 1 h
affording the product 4aa in 87% yield (entry 9). Slightly low
loading of catalyst 1a (3 mol %) resulted in lower yield of 4aa
[a]
R. A. Jagtap, V. Soni, Dr. B. Punji
Organometallic Synthesis and Catalysis Group
Chemical Engineering Division, CSIR–National Chemical Laboratory
(CSIR–NCL), Dr. Homi Bhabha Road, Pune, 411 008
Maharashtra (India)
E-mail: b.punji@ncl.res.in
Home page: http://academic.ncl.res.in/b.punji
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/cssc.xxxxxx
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10.1002/cssc.201700321
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(entry 10). The arylation reaction with the catalyst 1b gave 4aa
in 59% yield, whereas, the coupling was not observed in the
absence of Ni-catalyst (entries 11,12). The employment of other
nickel precursors, such as Ni(OAc)2, (DME)NiCl2 and Ni(COD)2
afforded moderate yield (32-55%) of coupled product 4aa (see
the Supporting Information). Since the employment of catalyst
1a consistently delivered higher yields, this catalyst was used
throughout the arylation reactions. Under the optimized reaction
conditions with catalyst 1a, 4-bromotoluene as coupling partner
also efficiently coupled to give 4aa in 62% yield, whereas 4-
chlorotoluene electrophile reacted sluggishly and gave a small
amount of 4aa.
heating and proceeded effectively in the absence of solvent.
Thus, all the arylation reactions were performed without the
addition of solvent and carried out for 30-120 min, unless noted
otherwise.
Scope of Ni-catalyzed C‒H bond arylation
With the optimized reaction conditions in hand, we tested the
reactivity of various aryl electrophiles with benzo[h]quinoline, 2a
(Scheme 1). Thus, the monodentate chelation-assisted C‒H
arylation of 2a proceeded smoothly with the aryl halides bearing
different substituents and afforded moderate to excellent yields
of the desired products (4aa-ak). The reaction tolerated diverse
functional groups, such as halides, ethers and amines. Alkyl
substitution at different positions of the phenyl ring did not stage
problem for the coupling and gave excellent yield of the arylated
products. Interestingly, the functional groups MeO, Cl and NMe2
as well as the methyl substituent at the ortho position of aryl
iodide are well compatible to deliver the products 4am-ap in
moderate to good yields. In contrast, 2,6-disubstituted aryl
halides, such as 2,6-dimethyl iodobenzene or 2,6-dimethoxy
iodobenzene were inactive for the arylation reaction. We were
pleased to observe that the aryl iodides bearing synthetically
important heterocycles, such as indole, pyrrole and carbazole
efficiently coupled to afford very good yields of the products 4as-
au. Unfortunately, the functional groups, like ester, cyano, nitro,
etc. were not tolerated under the optimized reaction conditions.
Table 1. Optimization of reaction conditions for nickel-catalyzed C‒H
arylation.[a]
[Ni]-catalysts
O
I
cat. 1a
(5 mol %)
N
N
Me
N
Ni
X
+
Et2N
N
H
base, solvent
T (oC), time (h)
Me
3a
X = OAc, (1a)
1b
)
2a
4aa
X = Cl,
(
3a
(equiv)
T (oC)/
time (h)
4aa
Entry
Base (equiv)
Solvent
(%)[b]
n.d.
n.d.
63
1
LiOtBu (1.5)
1.5
1.5
1.5
4.0
2.0
2.4
2.4
2.4
2.4
2.4
2.4
2.4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
--
160/16
160/16
160/16
160/16
160/16
160/16
120/16
120/16
120/1
2
NaOtBu (1.5)
LiHMDS (1.5)
LiHMDS (2.0)
LiHMDS (1.7)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
N
N
N
3
cat. 1a (5 mol %)
+
I
R
H
LiHMDS (2.0 equiv)
no solvent
R
4
69
2a
120 oC, 1 h
3
4
5
73
N
R
N
6
77
Me
7
84
R
R = Me (4am): 92%
R = OMe (4an): 72%
R = Me (4aa):
87%
62%[a]
86%
81%
81%
4al: 96%
8
83
4ao
R = Cl (
):
53%
R = H (4ab):
R = Et (4ac):
R = iPr (4ad):
R = tBu (4ae): 98%
R = OMe (4af): 86%
R = NMe2 (4ap): 80%
9
--
87
Me
N
10
11[e]
12[f]
--
120/1
55[c,d]
59[c]
n.d.
N
R = F (4ag):
R = Cl (4ah):
53%
79%
--
120/1
Me
R = CF3 (4ai): 51%
R = NMe2 (4aj): 67%[a]
R = OCF3 (4ak): 79%
--
120/1
4ar: 90%[b]
4aq: 83%
Me
[a] Reaction conditions: 2a (0.036 g, 0.201 mmol), 3a (0.104 g, 0.48 mmol, for
entries 6-12), [Ni]-catalyst (5.0 mol %), LiHMDS (0.067 g, 0.4 mmol, for entries
6-12), toluene (0.5 mL, for entries 1-7). [b] Isolated yield. [c] GC yield using n-
dodecane as internal standard. [d] Employing 3 mol % of 1a. [e] Using cat. 1b.
[f] Without [Ni]-catalyst. n.d. = not detected.
N
N
N
N
N
N
4at: 82%
4au: 76%
4as: 80%
After an exhaustive screening of all the reaction components
and parameters, the arylation found to occur efficiently in the
presence of catalyst 1a using 2.4 equiv of iodide 3a along with
2.0 equiv of LiHMDS at 120 oC. The success of solvent-free
arylation can be partially accredited to the low melting and/or
good miscibility of LiHMDS with other reaction components.
Generally, the reaction forms a homogeneous mixture upon
Scheme 1. Scope of nickel-catalyzed C‒H arylation. Reaction conditions: 2a
(0.201 mmol), aryl halide 3 (0.48 mmol), LiHMDS (0.4 mmol), cat 1a (5.0
mol %). Yield of isolated compounds. [a] Using aryl bromide and reaction time
12 h. [b] Reaction time 12 h, yield by 1H NMR.
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10.1002/cssc.201700321
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distinct aryl iodides to afford the desired products in good yields.
To our delight, 2-phenylpyridine or 4-substituted-2-arylpyridine
as substrate solely affords the mono-arylated product with
diverse aryl iodides; similar selectivity is rarely seen with other
metal-catalysts. We assume that the steric around the Ni-
catalyst is responsible for the selective mono-arylation, which
may not allow the coordination of mono-arylated substrate for
further arylation to yield the di-arylation. In comparison to the
reactivity of benzo[h]quinoline, the substrate 2b reacted at a low
pace with the pyrrolyl and carbazolyl-aryl iodides to give 4bt,bu
in moderate yields. The C‒H arylation of meta-disubstituted
arene 2c proceeded with good site selectivity at the less
sterically demanding position. Notably, during the arylation of 2-
pyridinyl arenes, the competitive side reaction of aryl iodides
with LiHMDS was significant; hence, the iodides 3 and LiHMDS
were added in two phases to achieve good yields of arylation.
Though, there exist several methods for the arylation of
2-Py
2-Py
H
1a
cat.
(5 mol %)
R2
LiHMDS (4.0 equiv)
+
I
R1
R1
no solvent
R2
120 oC, 2 h
3
2
4
R2
Me
2-Py
2-Py
2-Py
Me
Me
R2 = Me (
4ba
): 82%
(60%)[a]
): 79%
4bl
: 75%
4bq
: 46%
R2 = H (
4bb
R2 = OMe (
): 80%
4bf
N
N
2-Py
2-Py
4bu
: 50%
4bt
: 52%
benzo[h]quinoline
and
2-arylpyridine,[14]
herein,
we
Me
Me
2-Py
R1
2-Py
demonstrated a rare solvent-free C‒H arylation protocol, and the
first Ni-catalyzed C‒H arylation by monodentate chelation-
assistance.
R1 = OMe (
): 73%
4da
Me
4ca
: 62%
R1 = CF3 (4ea): 26%[b]
Thereafter, we exploited the Ni-catalyzed protocol for the
C‒H arylation of biologically relevant indole derivatives (Scheme
3). Thus, the N-2-pyridinyl-indole (5a) smoothly reacted with
diverse aryl iodide and/or bromide electrophiles to produce C-2
arylated indoles just in 30 min. Important functional groups, such
as chloro, ether, amine as well as heteroarene functionalities,
like pyrrolyl and carbazolyl were well tolerated and afforded
moderate to good yields of desired product. Sterically
demanding 2-bromotoluene also coupled efficiently to afford
product 6am in moderate yield. Similarly, the sterically more
congested 3-methylindole delivered the arylated product 6da in
59% yield. Notably, quantitative conversions of indoles 5 were
observed in the arylations, even though only moderate to good
yields of products are isolated. This could be attributed to the
partial decomposition of starting compounds 5 or the products 6
during the reaction.
Scheme 2. Nickel-catalyzed C‒H arylation of (2-pyridinyl)arenes. Reaction
conditions: 2 (0.201 mmol), aryl halide 3 (0.96 mmol, added in two phases),
cat 1a (5.0 mol %), LiHMDS (0.8 mmol, added in two phases). Yield of isolated
compounds. [a] Using 4-bromotoluene in single phase and reaction was
conducted for 12 h. [b] Yield by 1H NMR.
R2
R2
cat. 1a (5 mol %)
R1
R1
H
+
X
LiHMDS (2.0 equiv)
no solvent
120 oC, 30 min
R3
N
R3
N
2-Py
2-Py
3
6
5
Me
Me
Me
R3
N
2-Py
N
2-Py
N
2-Py
R3 = Me (6aa): 68% (X = Br or I)
(78%)[a]
6am: 59% (X = Br)
6aq: 58% (X = Br)[a]
R3 = iPr (6ad): 62% (X = I)
R3 = OMe (6af): 60% (X = I)
51% (X = Br)
62% (X = I)
R3 = NMe2 (6aj): 68% (X = Br)
Mechanistic consideration
In view of the excellent catalytic activity of 1a under the solvent-
free conditions, we sought to investigate the mechanistic
pathway for the arylation reaction.[15] The catalytic reaction was
slightly affected by the addition of Hg (600 equiv w.r.t. 1a,
Scheme 4a), which tentatively rules out the heterogeneous
particles as the active catalyst. Kinetic analysis of the reaction
using electronically distinct aryl iodides 3f and 3i highlighted that
the electron-rich electrophile reacts slightly faster than the
electron-poor one (Scheme 4b). Notably, the electron-rich
substrate 2d reacted with 5.4 times faster than the electron-
deficient 2e (Scheme 4b), which indicates the probability of an
electrophilic-type C‒H activation. The H/D scrambling was not
observed between [D5]-2b and 2d, when the reaction was
performed (in the presence or absence of cat 1a) employing
both the substrates in one reaction vessel (Scheme 5a). This
demonstrated that the C‒H bond nickelation is mostly
irreversible and does not occur via simple deprotonative
pathway. A kinetic isotope effect (KIE) value of 3.9 was achieved
N
R3 = Cl (6ah):
N
2-Py
N
N
2-Py
6at: 63% (X = I)
6au: 71% (X = I)
Me
Me
N
2-Py
Me
MeO
OMe
Me
N
6ba: 63% (X = Br)
N
2-Py
2-Py
6cf: 50% (X = Br)
6da: 59% (X = Br)
Scheme 3. Nickel-catalyzed C‒H arylation of indoles. Reaction conditions: 5
(0.201 mmol), aryl halide 3 (0.48 mmol), LiHMDS (0.4 mmol), cat 1a (5.0
mol %). Yield of isolated compounds. [a] Yield by 1H NMR.
We have extended the scope of C‒H arylation to 2-pyridinyl
(2-Py) substituted arenes (Scheme 2). The substrate 2-
phenylpyridine (2b) reacted with the electronically and sterically
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from the initial rates of the arylation of 2b and [D5]-2b (Scheme
5b), suggesting a turnover-limiting C‒H nickelation step for the
arylation reaction.[16]
Probability of Ni(0) as active species is unlikely, as the
reaction of two equiv of benzo[h]quinoline with 1a in the
presence of LiHMDS did not produce benzo[h]quinolinyl
dimer.[4g] In support to this, the arylation by (COD)2Ni(0) with or
without ligand afforded considerably low yield of coupled product.
The analysis of the catalytic reaction mixture (25 mol % of 1a
was used in toluene-d8) by 1H NMR spectroscopy does not show
the nickel species (1a or its derivatives) or the free-ligand; which
indicates the possible involvement of a paramagnetic catalyst
species. Additionally, upon performing the arylation in the
presence of TEMPO or galvinoxyl the catalytic reaction was
completely suppressed (Scheme 4a), which supports the
existence of a radical manifold.
a) External additive experiments:
N
Me
N
cat. 1a (5 mol %)
I
Me
+
LiHMDS (2.0 equiv)
no solvent
120 oC, 1 h
3a
2a
(
)
4aa
( )
(
)
additive (w.r.t 1a)
yield
No additive
86%
76%
14%
--
Hg (600 equiv):
TEMPO (20 equiv):
TEMPO (40 equiv):
On the basis of above experimental observations and
literature reports,[6a,e,17] a plausible mechanism for the arylation
is shown in Scheme 6. Mostlikely, the catalyst 1 transformed into
the active complex A, which reacts with 2a via the turnover-
limiting C–H nickelation to deliver the nickelacycle B.
Alternatively, in parallel, the complex 1 would directly react with
2a in the presence of LiHMDS to generate intermediate B.
Species B would trigger the radical generation via the iodine
atom transfer (IAT) process to form C, followed by the radical
rebound to produce Ni(IV) species D. Reductive elimination will
give the product 4aa and reproduce the catalyst 1. Alternately, B
would activate 4-Me-C6H4‒I by bimolecular oxidative fashion to
deliver NiIII(C6H4-4-Me) (E) and NiIIII (C).[18] Reductive elimination
of 4aa from E would produce Ni(I) species F, which upon
disproportionate with NiIIII (C) will regenerate 1 and B to
complete the cycle.[19] The MALDI-TOF-MS analysis provided
evidence for the probable formation of intermediate species A, C,
D and E.
galvinoxyl (20 equiv): --
b) Kinetic experiments for electronic effect:
I
2a
(0.2 mmol)
N
OMe
N
)
CF3
1a
cat.
LiHMDS (2.0 equiv)
toluene, 120 o
(5 mol %)
C
OMe/CF3
4af
(
)
4ai
k4af : k4ai = 1.51
(
3f
3i
) or (
(
)
Me
or
Me
2-Py
2-Py
2-Py
3a
(0.2 mmol)
1a
cat.
(5 mol %)
LiHMDS (2.0 equiv)
toluene, 120 oC
OMe//CF3
OMe
4da
CF3
2d
(
2e
) or (
4ea
)
(
)
(
)
k4da : k4ea= 5.4
Scheme 4. External additive and kinetic experiments.
a) H/D scrambling experiment:
100% D
100% D
100% D
+
Me
2-Py
2-Py
D
2-Py
4-Me-C6H4
D
D
D
D
O
O
D
D
D
D
D
D
Et2N
Et2N
Me
I
N
III
+
N
I
D
I
N
IV
N
Ni
D
(0.72 mmol)
Ni
N
D
N
C6H4-4-Me
2b
[D5]-
1a
cat
(5 mol%)
4ba (trace)
4-Me-C6H4
83% (recovered)
(0.15 mmol)
+
LiHMDS (0.6 mmol)
120 oC, 10 min
+
+
(C)
4-Me-C 6H4-I
Me
(D)
0% D
0% D
4aa
2-Py
2-Py
2-Py
H
H
O
+
Et2N
2a
LiN(SiMe3)2
O
O
N
OMe
NiII
OMe
OMe
58% (recovered)
N
N
N
N
2d
4da: 17%
Et2N
N
Et2N
N
Ni
X
Ni
(0.15 mmol)
HN(SiMe3)2
LiX
N(SiMe3)2
(X = OAc or
halide)
(1)
(B)
b) KIE experiments:
(A)
(B)
1a
cat.
(5 mol %)
LiHMDS
4-Me-C 6H4-I
N
Me
N
+
[Ni]III
(C)
I
O
N
Me
I
toluene, 120 o
C
O
[Ni]III
(C)
I
Et2N
I
Et2N
N
N
Ni
kH = 5.32 x 10-3 M min-1
III
N
3a
4ba
2b
Ni
N
(F)
C6H4-4-Me
4aa
(E)
1a
cat.
(5 mol %)
LiHMDS
N
Me
N
Me
I
+
toluene, 120 o
C
D
D
D
D
D
D
D
Scheme 6. Plausible mechanistic cycles.
D
D
kD = 1.37 x 10-3 M min-1
3a
2b
[D5]-
4ba
[D4]-
Scheme 5. H/D scrambling and KIE experiments.
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10.1002/cssc.201700321
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make the total volume 1.0 mL. The reaction mixture was then stirred at
120 oC in a preheated oil bath. At regular intervals (2, 4, 6, 10, 15, 20, 25
min) the reaction vessel was cooled to ambient temperature and an
aliquot of sample was withdrawn to GC vial. The sample was diluted with
acetone and subjected to GC analysis. The concentration of the product
4ba or [D4]-4ba 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 25 minutes).
The slope of the linear fitting represents the reaction rate. The reported
data represents the average of two independent experiments.
Conclusions
In summary, we have reported the solvent-free nickel-catalyzed
arylation of benzo[h]quinoline, 2-phenyl pyridine and indole
derivatives. An unprecedented reactivity of various arenes was
presented that occurs expeditiously through monodentate
chelation-assistance.
The
reaction
tolerated
various
functionalities, such as halides, ethers, amines, as well as
heterocycles, like indole, pyrrole and carbazole. This nickel-
catalyzed protocol is highly selective for mono-arylation. To date,
this is the only successful example on solvent-free C‒H arylation
by a base metal-catalyst. Based on the preliminary mechanistic
finding, a single electron transfer (SET) pathway is deliberated
that involves the turnover-limiting C‒H nickelation step.
Acknowledgements
This work was financially supported by SERB, New Delhi, India
(SR/S1/IC-42/2012). We are thankful to the Alexander von
Humboldt Foundation, Germany for an equipment grant. R.A.J.
and V.S. thank UGC-New Delhi and CSIR-New Delhi,
respectively, for research fellowships.
Experimental Section
Representative procedure for arylation
Procedure A (for benzo[h]quinoline and indoles): Synthesis of
10-(p-tolyl)benzo[h]quinoline (4aa). To a flame-dried screw-cap tube
equipped with magnetic stir bar was introduced benzo[h]quinoline, 2a
(0.036 g, 0.201 mmol), 4-iodotoluene (3a; 0.104 g, 0.48 mmol), cat 1a
(0.0037 g, 0.010 mmol, 5.0 mol %) and LiHMDS (0.067 g, 0.4 mmol)
inside the glove box. The resultant reaction mixture in tube was
immersed in a preheated oil bath at 120 °C and stirred for 1 h, during
which the mixture became homogeneous and solidified after some time.
At ambient temperature, the reaction mixture was quenched with distilled
H2O (10 mL) and the crude product was extracted with EtOAc (15 mL ×
3). The combined organic extract was dried over Na2SO4 and the
volatiles were evaporated in vacuo. The remaining residue was purified
by column chromatography on silica gel (petroleum ether/EtOAc: 50/1) to
yield 4aa (0.047 g, 87%) as a light yellow liquid.
Keywords: arylation • C‒H activation • indole • nickel • solvent-
free
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equipped with magnetic stir bar was introduced 2-phenyl pyridine 2b
(0.031 g, 0.2 mmol), 4-iodotoluene (3a; 0.104 g, 0.48 mmol), cat 1a
(0.0037 g, 0.010 mmol, 5.0 mol %) and LiHMDS (0.067 g, 0.4 mmol)
inside the glove box. The resultant reaction mixture was immersed in a
preheated oil bath at 120 °C (approximately 1 h). At ambient temperature,
the reaction tube was introduced into the glove box, and second phase of
4-iodotoluene (3a; 0.104 g, 0.48 mmol), and LiHMDS (0.067 g, 0.4 mmol)
was added. The reaction mixture was further immersed in preheated oil
bath at 120 °C and stirred for 1 h, during which the reaction mixture
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mL) and the crude product was extracted with EtOAc (15 mL × 3). The
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evaporated in vacuo. The remaining residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc: 10/1) to yield 4ba
(0.040 g, 82%) as a light yellow liquid.
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Representative procedure for kinetic experiment (KIE study)
To the teflon-screw capped tube equipped with magnetic stir bar was
introduced catalyst 1a (0.0056 g, 0.015 mmol), LiHMDS (0.1 g, 0.6 mmol),
substrate 2b (0.047 g, 0.3 mmol, 0.3 M) or [D5]-2b (0.048 g, 0.3 mmol,
0.3 M) and 4-iodotoluene (0.157 g, 0.72 mmol), n-hexadecane (0.025 mL,
0.085 mmol, internal standard), and toluene (0.932 mL) was added to
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Entry for the Table of Contents
Layout 2:
FULL PAPER
Rahul A. Jagtap, Vineeta Soni, and
Benudhar Punji*
Page No. – Page No.
Expeditious and Solvent-Free Nickel-
Catalyzed C‒H Arylation of Arenes
and Indoles
A solvent-free method for the C‒H arylation of arenes and indoles is developed that
proceeds by nickel catalysis via the monodentate chelation-assistance. The cost-
effective Ni-catalyst promotes the selective mono-arylation and the reaction
tolerates a wide range of functional groups.
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