Direct C–H Arylation of Heteroarenes with Aryl Chlorides by Using an Abnormal N-Heterocyclic-Carbene–Palladium Catalyst

Article abstract of DOI:10.1002/ejoc.201601218

Herein, we report a versatile catalytic system for the direct C–H arylation of heteroarenes with activated aryl chloride substrates. The catalyst works successfully for a variety of heteroarenes and aryl chloride coupling partners under very low catalyst-loading conditions. We have successfully performed the direct C–H arylations of 1-methylpyrrole, 1-methylindole, furan, thiophene, furfural, and N-benzyl-1,2,3-triazole with aryl chloride partners in good yields without the use of any additives. Furthermore, we used this catalytic process to develop a one-pot synthetic protocol for the muscle relaxant dantrolene on a gram scale. Additionally, the present catalytic system can be used to perform consecutive arylations in one pot.

Full text of DOI:10.1002/ejoc.201601218

A Journal of
Accepted Article
Title: Direct C-H Arylation of Heteroarenes with Aryl Chlorides using
Abnormal NHC Coordinated Palladium Catalyst
Authors: Swadhin Kumar Mandal, Jasimuddin Ahmed, Samaresh Sau,
Sreejyothi P, Pradip Hota, Pavan Vardhanapu, and Gonela
Vijaykumar
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601218
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601218
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
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Direct C-H Arylation of Heteroarenes with Aryl Chlorides using
Abnormal NHC Coordinated Palladium Catalyst
Jasimuddin Ahmedǂ, Samaresh Chandra Sauǂ, Sreejyothi P, Pradip Kumar Hota, Pavan K. Vardhanapu, Gonela Vijaykumar and
Swadhin K. Mandal*
Abstract: Herein we report a versatile catalytic system for direct C-H
arylation of heteroarenes using activated aryl chloride substrates. The
catalyst successfully works for a variety of heteroarenes and aryl
chloride coupling partners under very low catalyst loading condition.
We have successfully performed direct C-H arylation of 1-
methylpyrrole, 1-methylindole, furan, thiophene, furfural and N-
benzyl-1, 2, 3-triazole with aryl chloride partners in good yield without
using any additive. Furthermore, we used this catalytic process to
develop one-pot synthetic protocol for a muscle relaxant drug,
dantrolene in gram scale. Additionally, the present catalytic system is
successful in performing consecutive arylation in one-pot.
It is to be noted that from industrial perspective, aryl chlorides
are much cheaper than their bromide or
iodide analogs. In 2004, Sadighi and co-workers showed an
effective way for palladium catalyzed arylation of pyrrolylzinc
chloride, generated in situ from pyrrolyl sodium and zinc
chloride with up to 93% yield affording arylated pyrrole as
product using aryl chloride as well as aryl bromide coupling
partner.[14] Daugulis and co-workers established a catalytic
protocol for arylation of heteroarenes with aryl chloride
coupling partners using 5 mol % of Pd(OAc)2, 10 mol % of
BuAd2P at 125 oC, resulting up to 84% yield of coupled
product.[15] These catalysts reported for activation of aryl
chloride partners utilized supporting phosphine ligands and
an additive other than the base. Importantly, most of these
catalysts described above were found to be specifically
active to a particular class of heteroarene’s arylation like C-2
arylation or C-3 arylation or decarboxylative arylation thus
lacking general versatility towards a variety of heteroarene’s
arylation by a single catalytic system. As a result, there is a
continuous urge to develop an effective direct C-H arylation
method, which can be successfully applied for a variety of
heteroarenes using aryl chloride coupling partners under low
catalyst loading condition.
Introduction
Arylation of heteroarenes has received considerable
attention in the last decade as a very important process
owing to its application in medicinal chemistry and material
science.[1] Arylated heteroarenes have been widely used as
important building blocks in designing organic field-effect
transistors (OFETs),[2] organic light emitting diodes
(OLEDs)[3] and organic solar cells (OSC).[4] Traditional ways
to prepare arylated heteroarenes utilize palladium-catalyzed
Suzuki, Stille or Negishi cross-coupling reactions, which
require appropriate functionalization of one or both coupling
partners incurring additional cost to the process. In order to
avoid these inconveniences, in 1990, Ohta and co-workers
developed a palladium catalyzed direct C-H arylation
method of heteroarenes.[5] Gryko,[6] Doucet,[7] Fagnou,[8] Itam
i[9] and other research groups[10] later came up with further
improvement to this particular reaction process. The
literature reports on this direct C-H arylation are based
mainly on palladium[10] rhodium[11] and iridium[12] metal
catalysts. Most of the reports used costly halide coupling
partners like aryl iodide or aryl bromide and till date very few
reports are available on aryl chloride as coupling partner.[13]
Scheme 1. The present work describing use of a variety of heteroarenes
for coupling reaction.
Moreover, most of the previous reports are exclusively on the
arylation at C-2 or C-5 positions as these positions of a five
membered heteroarenes are generally more reactive. Till
now, there are very few reports on the palladium catalyzed
direct arylation of heteroarenes at C-3 or C-4 position.[16]
Herein, we additionally aimed to perform the arylation at C-3
or C-4 position when C-2 and C-5 positions are blocked. In
this study, we explore the potential of a bis{1,3-bis(2,6-
[a] Department of Chemical Sciences, Indian Institute of Science
Education and Research, Kolkata, Mohanpur-741246, India.
Phone: 91-9903676563, Fax: (+)91-33-48092033,
E-mail: swadhin.mandal@iiserkol.ac.in,
ǂ These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
FULL PAPER
that even at 0.1 mol % catalyst loading, the catalyst results in quite
good conversion (nearly 80%, Table 1, entries 21 and 22).
diisopropylphenyl)-2,4-diphenylimidazolium}halobridged
Pd(II) dimer (X = Cl, Catalyst I; X = Br, Catalyst II) as a
catalyst in the arylation of heteroarenes. Till now there is no
report of well-designed abnormal N-heterocyclic carbene
based Pd catalyst in this area of direct arylation of
heteroarenes. In 2004, Lebel and co-workers reported that
abnormal N-heterocyclic carbenes are catalytically more
efficient building block than their normal NHC counterpart.[17]
Later on, Guy Bertrand and co-workers reported the isolation
of the first abnormal N-heterocyclic carbene.[18] Our group
recently established the application of this isolated abnormal
carbene in designing catalysts for a number of homogeneous
organic transformations.[19],[20] Herein, we report direct C-H
arylation of a variety of heteroarenes using activated aryl
chlorides as coupling partners under low catalyst loading (1
mol %) condition (Scheme 1). Also we used the present
catalyst for carrying out multicatalytic process adopting
consecutive arylation process. The present protocol has
considerable functional group tolerance, which has been
successfully applied in one pot synthesis of a muscle
relaxant drug molecule, dantrolene in gram scale.
Table 1. Influence of different reaction conditions on the direct arylation of 1-
methylpyrrole (1a) with 4-chlorobenzonitrile (2a).[a]
Entry
Solvent
Base
Catalyst
T
Temp
(oC)
Conversion
(%)
(h)
1
2
3
DMAc
KOAc
KOAc
KOAc
II
II
II
12
150
150
100
87%[b]
DMF
12
12
10
1,4-
Dioxane
NMP
N.R
4
5
KOAc
KOAc
II
II
II
II
II
II
II
II
II
II
II
I
12
12
12
12
12
12
12
12
12
12
12
12
12
12
10
8
150
150
70
72
20
DMSO
THF
6
KOAc
25
7
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
K2CO3
K3PO4
NaOMe
KOtBu
NaOtBu
Na2CO3
Cs2CO3
LiOtBu
KOAc
150
150
150
150
150
150
150
150
150
100
130
150
150
150
150
N.R
N.R
N.R
N.R
40
8
9
Results and Discussion
10
11
12
13
14
15
16
17
18
19
20
21[c]
Palladium (II) dimers (catalysts I and II) bearing an aNHC
backbone were synthesized by following the synthetic route
reported previously.[20] 1-Methylpyrrole was used as a benchmark
substrate for our optimization study. We studied the coupling
reaction between 1-methylpyrrole (1a) and 4-chlorobenzonitrile
(2a) to optimize the best condition for C-2 arylation reaction (Table
1). This reaction was first optimized with respect to different
solvents, in presence of 1 mol % catalyst loading and 2 equiv. of
KOAc for 12 h. The product formation was monitored by 1H NMR
spectroscopy. In case of N, N-dimethylacetamide (DMAc) as
solvent, the isolated yield was 87% of the product 3a (Table 1,
entry 1). When NMP was the solvent, it led to 72% conversion
(Table 1, entry 4). In DMF, DMSO or THF reaction proceeds with
very low conversion of 10%, 20% and 25% respectively (Table 1,
entries 2, 5 and 6). In case of 1,4-dioxane as solvent, no reaction
was observed (Table 1, entry 3) at 100 oC. To study the effect of
base on this reaction, different bases were tested. In presence of
K2CO3, K3PO4, NaOMe, KOtBu and Cs2CO3 the reaction did not
proceed (Table 1, entries 7-10 and 13). Both NaOtBu and Na2CO3
led nearly 40% conversion (Table 1, entries 11 and 12). The use
of LiOtBu as a base led to 70% conversion (Table 1, entry 14).
When the reaction was performed at 100 oC and 130 oC, it
resulted in 10% and 82% conversion, respectively (Table 1,
entries 16-17). During optimization study, 90% conversion was
observed after 6 h (Table 1, entry 20). We did not find any further
improvement in the yield when this reaction was allowed for 8 h
or 10 h (Table 1, entries 18 and 19). Under the standardized
reaction condition, catalyst I was found to be less efficient,
affording only 70% conversion of product (Table 1, entry 15)
whereas catalyst II led to 87% yield (Table 1, entry 1). Next we
performed the low catalyst loading experiments. It was noticed
40
N.R
70
70
KOAc
II
II
II
II
II
II
10
KOAc
82
KOAc
92
KOAc
92
KOAc
6
90
KOAc
12
85
22[d]
23
24[e]
DMAc
DMAC
DMAC
KOAc
KOAc
KOAc
II
-
12
8
150
150
150
72
N.R
N.R
II
8
[a] Reaction conditions: N-methylpyrrole (2.75 mmol), 4-chlorobenzonitrile (0.69
mmol), KOAc (1.37 mmol), catalyst II (0.0069 mmol) and solvent DMAc (3 mL).
[b] Isolated yield. [c] 0.5 mol% catalyst loading. [d] 0.1 mol% catalyst loading.
[e] 1-tert-Butyl-4-chlorobenzene (0.69 mmol) coupling partner. N.R. stands for
“No Reaction”. “T” Stands for time.
We tested the blank reaction without using the catalyst while
keeping other conditions similar. The reaction without catalyst did
not produce any arylated product indicating the importance of the
catalyst during this reaction (Table 1, entry 23). This protocol was
not successful for arylation of 1-methylpyrrole (1a) when tested
with different unactivated arylchloride coupling partners 1-tert-
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
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butyl-4-chlorobenzene (Table 1, entry 24), chlorobenzene, 4-
chloroanisole and 4-chloro-N, N-dimethylaniline (see SI, Table
S1). After looking at these results, we can conclude that for the C-
H arylation of 1-methylpyrrole (1a) with 4-chlorobenzonitrile (2a)
in DMAc solvent in presence of 2 equiv. of KOAc using 1 mol %
catalyst II can give coupling product (3a) with the most effective
yield within 8 h at 150 oC (Table 1, entry 1).
afforded lower yield (64%) of coupled product 7a. When 2-
chlorobenzonitrile and 1-chloro-2-nitrobenzene were subjected to
this coupling reaction, it yielded 58% and 88% of corresponding
products 7d and 7g, respectively (Scheme 2).
To elaborate the scope of this arylation process, at first 1-
methylpyrrole (1a) was successfully coupled with six different aryl
chlorides in presence of 1 mol % catalyst II and 2 equiv. of KOAc
as base in DMAc at 150 oC. Selective C-2 arylated products (3a-
f) were obtained with 56 - 87% isolated yield (Scheme 2). To
check the effect of sterically hindered as well as heterocyclic
arylchloride coupling partner on the catalytic reaction, we
performed the arylation of 1-methylpyrrole (1a) with sterically
hindered (1-chloronaphthalene and 2,6-dimethylchlorobenzene)
and heterocyclic arylchloride coupling partners (2-chloropyridine
and 2-chlorothiophene), which did not yield the desired product
(see SI, Table S1). Using aryl iodide coupling partners, Gryko and
o
co-workers have earlier performed the same reaction at 100 C
with 5 mol % PdCl2(PPh3)2 catalyst in presence of AgOAc as
additive, affording 50-80% yield of arylated product.[6] This recent
catalytic protocol was effectively applied on arylation of different
heteroarenes, like 1-methylindole, furan, thiophene and 2-
furfuraldehyde with moderate to good yield of arylated products
(Scheme 2).1-Methylindole was coupled with different
activated aryl chloride coupling partners to afford 19% to
92% yield of C-2 arylated products (4a-c, 4e and 4g)
(Scheme 2). Doucet and co-workers have earlier performed
similar coupling reaction at 150 oC with 0.5 mol % of
Pd(OAc)2 as catalyst in presence of 0.5 mol % of sylphos and
1 equivalent of Bu4NBr using 4-chlorobezonitrile as coupling
partner which afforded 4a in 42% yield along with minor C-3
arylated product.[16] Arylation of both furan and thiophene is
very important for synthesis of materials with interesting
electronic properties[2],[3] and biomedical applications.[21] With
our standard catalytic condition, direct C-H arylation at C-2
position of furan and thiophene using aryl chlorides, which
Scheme 2. Direct arylation of heteroarenes with aryl chlorides. Reaction
conditions:
1-methylpyrrole/1-methylindole
(2.75
mmol),
furan/2-
resulted in good yield of the corresponding products 5a
, 5b,
furfuraldehyde/benzofuran/benzothiophene (1.37 mmol), thiophene (3.44
mmol), aryl chlorides (2, 0.69 mmol), KOAc (1.37 mmol), catalyst II (0.0069
mmol) and solvent DMAc (3 mL), 8 h, 150 oC. Isolated yields. [a] At 130 oC. [b]
NMR spectroscopic conversion.
5g 6a 6b and 6g respectively (Scheme 2) with 50-70%
,
,
isolated yields. The lower yield may be attributed to low
boiling point of furan (30-34 oC) and thiophene (84 oC).
Denmark and co-workers have earlier performed the same
reaction with 5 mol % Pd2(dba)2.CHCl3 catalyst in presence of
NaH as additive, which afforded 67% yield of arylated product 6a
using silanolates and aryl iodide coupling partners.[22] This
protocol was extented on the arylation of 2-furfuraldehyde,
on which very few reports are there due to the presence of a
chemically reactive formyl group. McClure and co-workers have
earlier performed arylation reaction of furfural with 5 mol % PdCl2
catalyst in presence of Bu4NBr (1equiv.) and Cy3P (10 mol %) as
additive, affording 88% yield of arylated product 7b using aryl
iodide coupling partners.[23] In the present study, we used only 1
This versatile catalytic protocol was carried out with comparatively
low catalst loading (1 mol %) with out any additives other than
o
base at 150 C. From the yields, it may be noted that ortho
substitution in the aryl chloride coupling partner has to some
extent negative impact on yield (3d, 4g, 5g, 6g, 7g and 7d)
which may be attributed to the steric reason. Another
important thing to notice here that formyl group is well
tolerated in this reaction condition (Scheme 2). Here we
obtained only mono-substituted product at C-2 position of
heteroarene partners (1-methylpyrrole, 1-methylindole, furan, 2-
furfuraldehyde and thiophene), no bi-substitution or C-3
arylation was observed. Our protocol has been successfully
o
mol % catalyst II at 150 C to obtain 92% yield of product 7b by
coupling between furfural and aryl chloride coupling partner, 1-
chloro-4-nitrobenzene. However, 4-chlorobenzonitrile (2a)
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
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of arylated 1, 2, 3-triazoles are copper[28], [19] or ruthenium[29]
catalyzed 1, 3-dipolar [3+2] cycloadditions of azides and
alkynes.[30] These catalytic [3+2] cycloadditions are highly
regio-selective with terminal alkynes, but in the case of
internal alkynes regio-selectivity is less, leading to mixture of
arylated triazoles. To overcome this problem, direct C-H
arylation can be considered as a very good approach. Most
of the known direct arylations of 1, 2, 3-triazoles have been
accomplished under rhodium or palladium catalysis, applying
aryl iodides, bromides, or triflates as electrophiles.[31] We
probed the scope of our catalyst in the direct arylation of N-
benzyle-1, 2, 3-triazoles (1f) with various electron deficient
aryl chlorides 2 (Scheme 4) under the optimized catalytic
condition. N-benzyl-1, 2, 3-triazole was efficiently converted
into corresponding product 12a with 78% yield (Scheme 4)
after coupling with 4-chlorobenzonitrile (2a). Other aryl
chlorides as coupling partners, in this direct Arylation of N-
benzyl-1, 2, 3-triazole delivered moderate to good yields
extended to arylation of benzothiophene and benzofuran
with 4-chlorobenzonitrile (2a), affording 41% and 50% yield
of 8a and 9a, respectively.
As seen in scheme 2, the arylation of 2-furfuraldehyde can
be performed with different aryl chlorides (
catalytic condition delivering good yield of the coupled
products (7a 7b 7d and 7g). Thus, to further demonstrate
2) using this
,
,
the synthetic potential of our catalytic condition, we
undertook one pot synthesis of a commercially available
muscle relaxant drug, dantrolene (11) in the same reaction
pot (Scheme 3). Snyder et al.[24] earlier reported the
Meerwein arylation reaction[25] as a key step in the synthesis
of dantrolene and related compounds by the coupling of
arenediazonium salts, prepared from anilines, with furfuralin
the presence of Cu(II) catalyst, followed by condensation of
5-aryl-2-furaldehydes with 1-aminohydantoin hydrochloride
(10).This method was suffering from reaction step economy
due to the preparation of arenediazonium salt. Suzuki and
co-workers also employed a general synthetic procedure of
dantrolene analogs by palladium-catalyzed cross-coupling
reactions of aryl derivatives and a stannylated or boronated
furfural.[26] This method also suffers from the fact that Suzuki
coupling condition mandates the use of appropriately
functionalized coupling partners, which is not cost-effective.
(Scheme 4) of the corresponding products 12c, 12d and 12e.
Scheme 4. Direct arylation of N-benzyl-1, 2, 3-triazole with aryl chlorides.
Reaction conditions: N-Benzyl-1, 2, 3-triazole (1.035 mmol), aryl chlorides (0.69
mmol), KOAc (1.37 mmol), catalyst II (0.0069 mmol) and solvent DMAc (3 mL),
8 h, 150 oC. [a] NMR spectroscopic conversion.
Scheme 3. One pot synthesis of the muscle relaxant drug dantrolene in
gram scale
When 1-chloro-2-nitrobenzene was used as the coupling
partner, it resulted in very low conversion (12g, Scheme 4).
In 2008, Ackermann and co-workers had reported this direct
arylation of 1, 2, 3-triazoles with aryl chloride coupling
partners using Pd(OAc)2 (4 mol %), and PCy3 (8 mol %) at
In this regard, we successfully applied our coupling protocol
in the one-pot synthesis of dantrolene.[27] We performed the
arylation of furfural (1e) with 1-chloro-4-nitrobenzene (2b
)
using this catalytic condition, followed by condensation of the
resulting coupled product 7b with1-aminohydantoin
hydrochloride (10) within the same reaction pot. It resulted
dantrolene in 52% overall yield. This synthetic protocol was
successfully extended for gram scale synthesis of dantrolene
(Scheme 3).
o
120 C, which resulted in 71% yield of product 12a and the
present study reports 78% yield of 12a using 1 mol % catalyst
II [32]
.
Also we tested this coupling reaction when the arylation
process was forced to take place at C-3 after blocking the C-
2 position chemically. Here we report the C-H arylation of 1-
Furthermore, arylation of 1, 2, 3-triazoles is considered
as a very important reaction due to its relevance in medicinal
chemistry. The conventional way to synthesize different kind
methyl-2-phenylindole
(1g) at C-3 position using our
optimized catalytic condition (Table 1, entry 1). 1-Methyl-2-
phenylindole (1g) was successfully coupled with activated
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
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1
aryl chloride partners (
2
) in the presence of palladium
mixture after initial workup. The H NMR spectrum indicates that
this catalyst can perform heteroarenes arylation efficiently upto
fifth catalytic cycle (for details, see supporting information).
catalyst (II) to yield corresponding products (Scheme 5). In
this catalytic condition, 4-chlorobenzonitrile (2a) as chloride
coupling partner led to the highest yield (85%) of the coupled
product 13a (Scheme 5). When other three aryl chloride partners
were coupled at C-3 position of 1-methyl-2-phenylindole (1g),
they afforded corresponding products 13b, 13d and 13g
respectively with satisfactory yields (62-78%, Scheme 5). C-3
arylation of 1g using 4-chloroacetophenone (2e) was performed
with 2 mol % catalyst loading to obtain 65% yield of product 13e
(Scheme 5). In 2012, Doucet and co-workers reported the C-3
arylation of 1-ethyl-2-phenylindole using different aryl chlorides in
This catalyst longevity experiment encouraged us to
perform consecutive arylation at C-2 followed by C-3 position in
the same reaction pot by adding 2 equivalent of aryl chloride
coupling partners (same or different) consecutively after 8 h
interval.Consecutive arylation has been attempted first with this
catalytic system using 1-methylindole (1b) and coupling partner
1-chloro-4-nitrobenzene (2b) for the coupling in both C-2 and C-
3 positions, leads to formation of 14a with 46% yield (Scheme 6).
This protocol to synthesize bis-arylated product in one reaction
pot was further utilized for the consecutive arylation at C-2 and C-
presence of 0.5 mol
% of Pd(OAc)2 and 0.5 mol %
ferrocenyldiphosphane (sylphos) ligand at 150 oC with 31-88%
yield of corresponding products.[16] The result indicates that our
catalytic condition is equally efficient in arylation at C-3 as well as
C-2 position.
3
positions with two different coupling partners, 4-
chlorobenzonitrile (2a) as the first coupling partners for arylation
at C-2 position. The resulting product was then subjected within
the same reaction pot for second arylation at C-3 position with 1-
chloro-4-nitrobenzene (2b) to yield the final bis-arylated product
(14b) in 38% overall yield (Scheme 6).
Scheme 6. Consecutive bi-arylation of 1-methylindole with different
coupling partner. Reaction conditions: 1-Methylindole (0.69 mmol), 2b/2a
(0.69 mmol), KOAc (1.37 mmol), catalyst II (0.0069 mmol) and solvent
DMAc (3 mL), 1-chloro-4-nitrobenzene (0.69 mmol) at 150 oC. Compound
14a and 14b were isolated.
Scheme 5. Direct arylation of C-2 blocked indole with aryl chlorides. Reaction
conditions: 1-Methyl-2-phenylindole (0.69 mmol), aryl chlorides (0.69 mmol),
KOAc (1.37 mmol), catalyst II (0.0069 mmol) and solvent DMAc (3 mL), 8 h, 150
oC.
Conclusions
As the present catalyst can perform arylation at C-2 position
as well as at C-3 position (when C-2 position is blocked) with
almost equal efficiency, it may be interesting to see whether it can
perform the consecutive arylation process or not. One of the major
problems in such consecutive catalytic reactions is the catalyst’s
stability in multiple catalytic cycles for long time. For this we first
checked the in situ longevity of our catalyst. We performed
consecutively five successive catalytic runs by using 1 mol % of
catalyst II. In this experiments, after every 8 h interval, we added
fresh batch of substrates (1-methylpyrrole, 4-chlorobenzonitrile)
and base without adding any additional catalyst into the reaction
vessel. After each 8 h interval, we checked the substrate
consumption by recording 1H NMR spectrum of the reaction
From the above results, it can be observed that our catalytic
condition is able to conduct the arylation of diverse range of
heteroarene compounds such as 1-methylpyrrole, 1-
methylindole, furan, thiophene, furfural, benzothiohene,
benzofuran and N-benzyl-1, 2, 3-triazole resulting only
mono-substituted product. Thus the catalyst is quite versatile
in terms of its activity towards a number of different types of
heteroarenes. Moreover, the catalyst can work under low
catalyst loading condition (up to 0.5 mol %). All these
reactions have been performed without any additive other
than base and using activated aryl chloride coupling partners
which are cheaper compared to commonly used aryl iodide
and aryl bromide coupling partners. Furthermore, it was
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10.1002/ejoc.201601218
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210 mg (2 mol %) catalyst II, 1.2 mL of furfural (14.4 mmol), 1.27 g
of KOAc (14.4 mmol), 1.138 g of 1-chloro-4-nitrobenzene (7.22
mmol) and 6 mL of DMAc as solvent were taken in a 25 mL pressure
tube. Then the catalytic reactions were performed at 150 oC in a
capped tube using metal clip for 8 h. After that DMAc and excess
furfural were evaporated under high vacuum at 100 oC.
Subsequently, to the reaction pot, 6 mL of DMF, 1.09 g of 1-
aminohydantoin hydrochloride (6.5 mmol) and 7 mL of 35% HCl were
added at 0 oC temperature. This resulting reaction mixture was then
allowed to stir for 8 h at room temperature. After condensation
reaction, the reaction mixture was filtered and residue was washed
with 30 mL of water. The residue was dissolved in ethyl acetate and
filtered, when a reddish-yellow colored filtrate was obtained, which
was dried under reduced pressure. The product was re-dissolved in
DCM and small amount of hexane was added to precipitate pure
dantrolene (1.18 g, Overall yield: 52%).
observed that the present catalytic condition can sustain the
formyl group, which is generally considered as a challenge.
Considering this as advantage of our catalyst, we have
further explored successfully the gram scale one pot
synthesis of a clinically active molecule, dantrolene in a cost
effective route applying this catalytic protocol. It was
established that the catalyst can perform C-3 arylation when
the C-2 position of the heteroarene is blocked with almost
equal efficiency as that of C-2 arylation. We found the
catalyst can stay alive for consecutive catalytic cycles and it
does not loose any efficiency up to three consecutive
catalytic cycles. This prompted us to try the catalyst for multi-
arylation study in the same reaction pot.
General procedure for catalytic C-H arylation N-benzyl-1, 2, 3-
triazole
10 mg (1 mol %) catalyst II, N-benzyl-1, 2, 3-triazole (0.69 mmol),
KOAc (1.37 mmol), aryl chloride (0.69 mmol) and 3 mL of DMAc as
solvent were taken in a 5 mL pressure tube. Then the catalytic
reactions were performed at 150 oC in a capped tube using metal clip
for 8 h. After completion, the reaction mixture was diluted with
dichloromethane and transferred into a separating funnel. The
combined organic layer was completely evaporated under reduced
pressure and the remaining residue was then purified through a short
column chromatography (neutral aluminum oxide) using the
appropriate ratio of hexane and ethyl acetate to provide pure
products.
Experimental Section
Experimental Materials and Instrumentation
Catalyst synthesis was performed under dry and oxygen free
atmosphere (Argon) using standard Schlenk line techniques, oven-
dried glass wares (130 °C) and evacuated while hot prior to use. All
solvents were distilled from Na/benzophenone prior to use. All
chemicals were purchased and used as received. The 1H and 13C
{1H} NMR spectra were recorded on 400 and 500 MHz spectrometers
in CDCl3/DMSO-d6 with residual undeuterated solvent (CDCl3,
7.26/77.0; DMSO-d6, 2.50/39.5) as an internal standard. Chemical
shifts (δ) are given in ppm, and J values are given in Hz. All chemical
shifts were reported in ppm using tetramethylsilane as a reference.
Chemical shifts (δ) downfield from the reference standard were
assigned positive values. The melting points were measured in a
Procedure for catalyst longevity experiment
10 mg (1 mol%) catalyst II, 1-methylpyrrole (2.75 mmol), KOAc (1.37
mmol), 4-chlorobenzonitrile (0.69 mmol) and 3 mL of DMAc as
solvent were taken in a 5 mL pressure tube. Then the catalytic
reactions were performed at 150 oC in a capped tube using metal clip
for 8 h. The reaction mixture was monitored by 1H NMR spectroscopy
by taking aliquots of the reaction mixture at certain interval and the
reaction was stopped when the substrate consumption was
complete. The fresh substrates, 1-methylpyrrole (2.75 mmol), KOAc
(1.37 mmol), and 4-chlorobenzonitrile (0.69 mmol) were added and
the similar process was repeated for a total of five consecutive
catalytic runs without addition of any further catalyst to the reaction
mixture.
sealed glass tube on
a melting point apparatus and were
uncorrected. Open-column chromatography and thin-layer
chromatography (TLC) were performed on silica gel (Merck silica gel
100−200 mesh). Evaporation of solvents was performed at reduced
pressure using a rotary evaporator. Catalysts
synthesized using the experimental procedure reported in
literature.[20]
I and II were
General procedure for catalytic C-H arylation at C-2 position of
heteroarenes
Catalytic reaction for consecutive bi-arylation of 1-methylindole
10 mg (1 mol %) catalyst II, 1-methylindole (0.69 mmol), KOAc (1.37 mmol),
1-chloro-4-nitrobenzene /4-chlorobenzonitrile (Scheme 6) (0.69 mmol) and
3 mL of DMAc as solvent were taken in a 5 mL pressure tube. Then the
catalytic reactions were performed at 150 oC in a capped tube using metal
clip for 8 h. After completion of this reaction, the reaction mixture was
cooled and 1-chloro-4-nitrobenzene (0.69 mmol) was added to the same
pot, and the resulting reaction mixture was allowed to continue for another
10 h at 150 oC. After completion, the reaction mixture was diluted with
dichloromethane and transferred into a separating funnel. The combined
organic layer was completely evaporated under reduced pressure and the
10 mg (1 mol %) catalyst II, 1-methylpyrrole (2.75 mmol) / 1-
methylindole, benzothiophene, benzofuran (1.37 mmol) / furan (3.44
mmol) / thiophene (3.44 mmol) / furfural (1.37 mmol), KOAc (1.37
mmol), aryl chloride (0.69 mmol) and 3 mL of DMAc as solvent were
taken in a 5 mL pressure tube. Then the catalytic reactions were
performed at 150 oC in a capped tube using metal clip for appropriate
time as mentioned in Table 1. After completion, the reaction mixture
was diluted with dichloromethane and then transferred into a
separating funnel. The combined organic layer was completely
evaporated under reduced pressure and the remaining residue was
then purified through a short column chromatography (silica gel 100-
200 mesh) using appropriate ratio of hexane and ethyl acetate to
provide pure products.
remaining residue was then purified through
a
short column
chromatography (silica gel 100-200 mesh) using appropriate ratio of
hexane and ethyl acetate to provide pure products.
X-Ray Crystallographic Details for Compounds 14a and 14b
Gram scale synthetic procedure of dantrolene (11) in one pot
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10.1002/ejoc.201601218
European Journal of Organic Chemistry
FULL PAPER
Suitable single crystal of 14a and 14b were selected and an intensity data
were collected on a SuperNova, Dual, Cu at zero, Eos diffractometer.
Using Olex2,[33] the structure was solved with the Superflip[34] structure
solution program using Charge Flipping and refined with the ShelXL[35]
refinement package using Least Squares minimization. CCDC 1440714
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(14a)
and
the
CCDC
1440715
(14b)
contain
supplementary
crystallographic
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Acknowledgements
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We thank CSIR, India (Grant No. (01(2779)/14/EMR-II) for
financial support. J.A, S.P and P.K.H thank to IISER-Kolkata for
research fellowship. S.C.S, P.K.V and V.K.G are thankful to UGC,
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Keywords: Abnormal Carbene • Palladium (II) • C-H Activation •
Aryl Chlorides • Dantrolene
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FULL PAPER
Catalytic C-H functionalization of
heteroarenes with aryl chlorides
efficientin one-pot synthesis of a
muscle relaxant drug.
Palladium catalyzed direct C-H
arylation, applied in consecutive
arylation.
Jasimuddin Ahmedǂ, Samaresh Chandra
Sauǂ, Sreejyothi P, Pradip Kumar Hota,
Pavan K. Vardhanapu, Gonela
Vijaykumar and Swadhin K. Mandal*
Page No. – Page No.
Direct C-H Arylation of Heteroarenes
with Aryl Chlorides using Abnormal
NHC Coordinated Palladium Catalyst
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