Ruthenium-catalyzed heteroatom-directed regioselective C-H arylation of indoles using a removable tether

Article abstract of DOI:10.1021/acs.orglett.5b00535

A new approach to C-2 arylated indoles has been developed by utilizing a ruthenium-catalyzed, heteroatom-directed regioselective C-H arylation. The reaction is highly site-selective and results in very good yields. The highlight of the work is the use of a removable directing group and compatibility of the catalytic system with halogen functional groups in the substrates.

Full text of DOI:10.1021/acs.orglett.5b00535

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Heteroatom-Directed Regioselective C−H
Arylation of Indoles Using a Removable Tether
Virendra Kumar Tiwari, Neha Kamal, and Manmohan Kapur*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Indore Bypass Road, Bhauri, Bhopal 462066,
India
S
* Supporting Information
ABSTRACT: A new approach to C-2 arylated indoles has been developed by utilizing a ruthenium-catalyzed, heteroatom-
directed regioselective C−H arylation. The reaction is highly site-selective and results in very good yields. The highlight of the
work is the use of a removable directing group and compatibility of the catalytic system with halogen functional groups in the
substrates.
ver the past decade and a half, transition-metal-catalyzed
OC−H bond functionalization reactions have revolution-
ized transformations that were considered rather difficult without
prefunctionalization.1 Strategies adopted in C−H functionaliza-
tion are usually atom- and step-economical and have therefore
added a new dimension in organic transformations. These
methods have been widely employed in the synthesis of
biologically important and structurally complex natural prod-
ucts2 and continue to undergo metamorphosis to evolve better
catalyst systems for enhanced control on site-selectivities. Of the
strategies adopted for the control of selectivity (chemo- and
regio-), electronic factors and the use of Lewis-basic directing
groups are the most widely employed methods.3 The direct
arylation reaction,4 using transition-metal catalysis, forms a very
important constituent of C−H functionalization, often proceed-
ing via five- or six-membered cyclometalation. This also forms
the basis of an efficient directing group system design where
tighter transition states and compact metallacycles lead to high
selectivities.5
The indole system has been one of the most studied
heterocycles in terms of skeletal modification.6 This is simply
due to the high biological relevance of indoles being ubiquitous
in nature and by virtue of it being part of several important
natural products or pharmaceuticals including alkaloids. 2-
Arylindoles are the constituent of several natural products and
pharmaceutically important chemical entities (Figure 1).7 The
transition-metal-catalyzed C−H arylation of indoles has been
quite well studied, with several research groups developing
efficient catalyst systems to guide the regioselectivity to either C2
or C3 position of indoles. One of the strategies involving C−H
arylation at the C2-position has utilized a postulated electrophilic
metalation at C3, followed by a 1,2-shift of the metal, to achieve
the desired transformation.8 In other cases, directing groups on
the indole nitrogen guide the site-selectivity.9 In some of the
pioneering works, arylations with high selectivities have been
achieved even with NH-indoles.10 Following an early report by
Figure 1. 2-Arylindole core in biologically active molecules.
Itahara,9a several other directing groups such as amides,
carboxamides, carbamates, N-pyrimidyl, and N-pyridyl have
been used for driving the arylation with C2 selectivity for indoles.
Of these, the synthetic utility of the method is greatly
enhanced when removable directing groups are employed.
Ackermann and co-workers showed the utility of N-pyrimidyl as
well as N-pyridyl groups in the regioselective arylation of indoles
when using a Ru(II)−Ru(IV) catalytic system with aryl
halides.9k,l Recently, Loh and co-workers used N-pyrimidyl as a
directing group and arylsilanes as the coupling partner in a
Rh(III)−Rh(I) catalytic system.9q We report herein the use of a
removable N-pyridyl directing group in regioselective C2 direct
arylation of indoles with arylboronic acids using a Ru(II)−Ru(0)
catalytic system. The reaction works extremely well with a very
broad substrate scope and very good yields. The highlight of the
work is the use of bromo-substituted arylboronic acids as well as
substituted bromoindoles for the coupling, which cannot be used
with most of the methods used in the literature, thereby
providing a handle for further functionalization.
Received: February 20, 2015
Published: March 12, 2015
© 2015 American Chemical Society
1766
DOI: 10.1021/acs.orglett.5b00535
Org. Lett. 2015, 17, 1766−1769

Organic Letters
Letter
Our group has been interested in C−H functionalization of
heterocycles,11 especially the direct arylation reactions of
heteroarenes and their application in natural product synthesis.
In one of the natural product syntheses, we were required to
introduce on a substituted indole, an aryl group, which carried
two bromide substituents for further functionalization. In this
regard, we decided to develop a new catalytic system with a
removable directing group for the direct C2 arylation of indoles.
Our initial efforts started with scanning of several catalyst systems
along-with an appropriate directing group for the indole system.
For this, the acetyl, arylsulfonyl, pyrimidyl, pyridyl groups were
among the ones scanned. The best results were obtained with N-
2-pyridyl as the directing group and [RuCl2(p-cym)]2/Ag2O/
Cu(OTf)2/dioxane with arylboronic acids as the coupling
partner (Table 1).
Table 1. Optimization Studies
entry
1
reaction conditions
yield (%)
trace
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/CHCl3/ 70
°C/12 h
2
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/
ClCH2CH2Cl/70 °C/12 h
trace
a
3
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/DMF/100
°C/12 h
55
4
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/DMSO/100
°C/12 h
trace
a
5
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/THF/50
°C/12 h
47
b
6
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/xylene/100
°C/12 h
5
Under these conditions, use of N-phenyl, N-Ts, or N-
phenylsulfonyl groups resulted only in the homocoupling of
arylboronic acids, and the starting material mostly remained
unreacted. The use of N-Me resulted only into decomposition of
the starting material. With free −NH indole, the reaction was
very sluggish, and it probably deactivated the catalyst. Although
K3PO4 worked well as a base, better results were obtained with
Ag2O. DMA as a solvent also yielded good results; however,
dioxane was the solvent of choice since better yields for the
desired conversions were obtained in it. Reactions in acidic
conditions did not work. Use of palladium catalysts resulted in
sluggish reactions, and selectivity between C2 and C3 was often
compromised. Both the ruthenium catalyst and Cu(OTf)2 were
necessary for the transformation. Without either of them, the
reaction did not work. Use of catalytic quantities of Cu(OTf)2
resulted in low conversions. Therefore, the use of oxidant was
necessary in this transformation. Depicted in Scheme 1 is the
substrate scope for the standardized reaction conditions. The
reaction worked very well for almost all of the arylboronic acids
tried, and the site-selectivity was exclusive. Electronic effects on
the indole were also well tolerated. The reaction worked with
electron-donating as well as electron-withdrawing substituents at
the C5 position of the indole. Better yields were obtained with
electron-withdrawing substituents at C5. This could be
attributed to enhanced acidity of C2 C−H and low nucleophilic
character at C3 of the indole when substituents such as −NO2
were present at C5. The reaction worked beautifully well even
with a methyl substitutent at C3. Electronic effects were well
tolerated on the arylboronic acid, too. Good results were
obtained even with a free hydroxyl substituent (Scheme 1, entry
2ah). In the case of the 2-nitrophenylboronic acid, only the
protodeboronation product was observed. Sterically encumbered
arylboronic acids also worked out quite well (Scheme 1, entry
2an−ao). As desired, the reaction worked extremely well with
bromide substituents on both the coupling partners. With 4-
bromo-N-pyridylindole, small amounts of the cross-coupling
product of the bromide with the boronic acid were observed,
resulting in a C2,C4-diaryl product (∼5%) along with the C2-
monoaryl product (2cc).
7
[RuCl2(p-cym)]2/Cu(OAc)2/Ag2O/dioxane/100 trace
°C/12 h
8
[RuCl2(p-cym)]2/BQ/Ag2O/dioxane/100 °C/
12 h
NR
9
[RuCl2(p-cym)]2/DDQ/Ag2O/dioxane/100 °C/ NR
12 h
10
11
12
13
[RuCl2(p-cym)]2/K2CO3 (2 equiv)/dioxane/100 trace
°C/12 h
[RuCl2(p-cym)]2/Ag2O (2 equiv)/dioxane/100
°C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2 (2 equiv)/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/DMA/100
°C/12 h
trace
a
30
a
86
a
14 [RuCl2(p-cym)]2/Cu(OTf)2/Ag2O/dioxane/
90
100 oC/12 h
a
15
16
17
18
19
20
21
22
23
24
[RuCl2(p-cym)]2/Cu(OTf)2/K3PO4/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/CsOPiv/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/Cs2CO3/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/CF3CO2Na/
dioxane/100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/Ag2CO3/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/CsOAc/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2/AcONa/dioxane/
100 °C/12 h
81
a
51
a
65
a
10
a
58
a
59
a
60
[RuCl2(p-cym)]2/Ag2O (2 equiv)/dioxane/100
°C/12 h
0
[RuCl2(p-cym)]2/Ag2O (2 equiv)/TFA/70 °C/
12 h
0
[RuCl2(p-cym)]2/(1-Ad)CO2H/K2CO3/xylene/
120 °C/30 h
Cu(OTf)2/Ag2O/dioxane/100 °C/16 h
Pd(OAc)2/Cu(OTf)2/Ag2O/dioxane/
100 °C/12 h
Pd(OAc)2/Cu(OTf)2/Ag2O/TFA/70 °C/12 h
Pd(TFA)2/Cu(OTf)2/Ag2O/dioxane/
100 °C/12 h
Pd(TFA)2/Cu(OTf)2/Ag2O/TFA/70 °C/12 h
Pd(OPiv)2/Cu(OTf)2/Ag2O/dioxane/
100 °C/12 h
[RuCl2(p-cym)]2/Cu(OTf)2 (30 mol %), Ag2O
(2 equiv)/dioxane/O2 balloon/100 °C/12 h
trace
0
25
26
b
12
b
c
27
28
25 , 1:3 C2:C3
b
c
9 , 1:7.5 C2:C3
b
29
30
25
b
5
A plausible mechanism is depicted in Scheme 2. The first step
is probably the coordination of the ruthenium catalyst to the N-
pyridyl group. This is followed by C−H activation at C2 to result
in the ruthenacycle. Transmetalation with the arylboronic acid,
followed by reductive elimination, results in the C2-aryl indole.
The Ru(0) is then oxidized to Ru(II) by Cu(II). Silver oxide not
only acts as a base, it facilitates the transmetalation and also
assists the reoxidation step. Since, with this catalyst system, the
reaction did not work with N-phenyl or N-Me groups on the
a
31
25
32
Pd(OAc)2, PPh3, Na2S2O8, AcOH, rt, 5 h
NR
a
b
c
Isolated yields. GC yields. Determined by NMR; NR = no reaction.
indole, the role of the directing group seems to be necessary.
Therefore, it seems rather unlikely that the reaction would be
proceeding by an electrophilic metalation mechanism. An
1767
DOI: 10.1021/acs.orglett.5b00535
Org. Lett. 2015, 17, 1766−1769

Organic Letters
Letter
a
Scheme 1. Substrate Scope
Scheme 3. Kinetic Isotope Effect and Relative Rate Studies
Scheme 4. Removal of the Directing Group
In summary, we have developed a new ruthenium(II)-
catalyzed method for the regioselective C−H arylation of indoles
incorporating a removable directing group. The method provides
access to 2-arylindoles bearing halogen substituents with scope
for further functionalization, thereby opening new avenues for
natural product synthesis. The method is simple, high yielding,
and very selective with very good substrate scope and is expected
to have good synthetic utility.
ASSOCIATED CONTENT
* Supporting Information
a
■
All yields are isolated yields
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2. Plausible Mechanism for the Direct Arylation
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mk@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from DST-India (SB/S1/OC-10/2014) is gratefully
acknowledged. V.K.T. thanks CSIR-India for a Research
Fellowship. N.K. thanks IISERB for a BS−MS Fellowship. We
thank CIF IISERB for the spectral data and Ms. Anusha
Upadhyay, IISERB, for the X-ray data. We also thank the
Director of IISERB for funding and infrastructural facilities.
attempt to study deuteration with this system expectedly resulted
in a mixture of C3 and C2 deuterated products (77:38, C3:C2).
It is, however, difficult to draw conclusions with this observation.
A study of the kinetic isotope effect at C2 gave a value of 2.12 for
initial rates (Scheme 3). This moderate value probably indicated
that the C−H activation via a concerted metalation deprotona-
tion13 may not be the rate-limiting step or may be a reversible
process.14
An attempt to compare rates of reaction for N-pyridylindole
with 3-methyl-N-pyridylindole resulted in a value of 3.62 for
relative rates. This probably could be attributed to steric reasons
arising out of the C3 substituent.
Finally, we successfully removed the directing group from the
arylated product in very high yields by simply treating it with
MeOTf and subsequent base treatment to result in the free NH-
indole (Scheme 4).15 The use of MeI, unfortunately, did not
provide the desired product.
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