Ruthenium(II)-Catalyzed Direct C-H Arylation of Indoles with Arylsilanes in Water

Article abstract of DOI:10.1021/acs.orglett.7b03567

The ruthenium(II)-catalyzed, heteroatom-directed C-H arylation of indoles with arylsilanes in water has been developed. The method represents the first example of a ruthenium(II)-catalyzed oxidative C-H arylation in water/aqueous media as a sustainable solvent for C-H functionalization. The reaction enables the synthesis of a wide range of indoles with exquisite selectivity for arylation at the C-2 position. Preliminary mechanistic studies indicate reversibility of the C-H ruthenation step under the developed reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b03567

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium(II)-Catalyzed Direct C−H Arylation of Indoles with
Arylsilanes in Water
Pradeep Nareddy, Frank Jordan, and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: The ruthenium(II)-catalyzed, heteroatom-directed
C−H arylation of indoles with arylsilanes in water has been
developed. The method represents the first example of a ruthenium-
(II)-catalyzed oxidative C−H arylation in water/aqueous media as a
sustainable solvent for C−H functionalization. The reaction enables
the synthesis of a wide range of indoles with exquisite selectivity for arylation at the C-2 position. Preliminary mechanistic studies
indicate reversibility of the C−H ruthenation step under the developed reaction conditions.
n the last 15 years, tremendous advances have been made in
the development of C−H functionalization methods as an
I
enabling tool for organic synthesis.1,2 While the majority of
studies have centered on palladium, ruthenium(II)-catalyzed
direct C−H arylation has received growing interest,3,4
undoubtedly fueled by (1) the low price of ruthenium,5 (2)
broad functional group tolerance,6 (3) operational simplicity,
and (4) orthogonal selectivity.4 Principally, two reaction
pathways for ruthenium(II)-catalyzed direct C−H arylation of
Csp2 bonds have been developed: (1) Ru(II)/Ru(IV) catalytic
cycle with haloarenes as cross-coupling partners7 and (2)
Ru(II)/Ru(0) catalytic cycle with organometallics as attractive
alternative transmetalating reagents under mild, functional group
tolerant, oxidative conditions.8 The inherent advantages of such
Ru(II)-catalyzed C−H functionalizations show a profound
impact on chemical synthesis.3,4
Figure 2. Ru- and Rh-catalyzed C−H arylation of indoles: (a) previous
studies; (b) this work. Pym = 2-pyrimidyl.
Ru(II)/Ru(IV) catalytic cycle.11 More recently, Pilarski et al.12
and Kapur et al.13 independently developed direct C-2 C−H
arylations of N-pyrimidyl indoles with aryl boronic acids via a
Ru(II)/Ru(0) catalytic cycle. In a related development, Loh et
al.14 demonstrated direct C-2 C−H arylation of N-pyrimidyl
indoles with arylsilanes via a Rh(III)/Rh(I) catalytic manifold in
aqueous media.15,16
In this context, direct C−H arylation of indoles at the C-2
position is important because of the prevalence of 2-arylindoles
in a variety of biologically active compounds, complex natural
products, and synthetic materials (Figure 1).9,10 While
As a part of our program in ruthenium catalysis17 and C−H
functionalization,18 herein we advance the concept of Ru(II)-
catalyzed direct Hiyama arylations19 and describe the successful
development of the Ru(II)-catalyzed, heteroatom-directed C−H
arylation of indoles with arylsilanes in water (Figure 2B). The
following features of our findings are notable: (1) cost-effective,
functional group tolerant Ru(II) catalysis; (2) arylsilanes as
attractive, benign organometallic coupling partners;20 (3) the
first Ru(II)-catalyzed oxidative C−H arylation in water/aqueous
media as a sustainable solvent for C−H functionalization.15,16
The method provides a general approach to 2-arylindoles under
sustainable conditions. The combined features of our protocol
could enable the development of a wide range of Ru(II)/(0)-
catalyzed direct C−H arylations in aqueous media.
Figure 1. Selected examples of biologically active 2-arylindoles.
remarkable progress has been made in Pd-catalyzed direct C−
H arylation, including regioselective C2/C3/C7 arylations,
heteroatom-directed arylations, and arylations of unprotected
NH indoles,10 Ru-catalyzed C−H arylation of indoles has been
scarcely studied (Figure 2A). The pioneering work by
Ackermann et al. established the facility of a direct C-2 C−H
arylation of indoles using N-pyrimidyl directing group via a
Received: November 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Recently, our laboratory introduced a new method for the
activator and Ag2O as a Ru(0) reoxidant furnished the desired
product in promising 40% yield (entry 4). The reaction efficiency
could be improved by using i-PrOH as a solvent (entry 5). Of
note, the use of i-PrOH as an inexpensive and environmentally
friendly solvent is desirable in C−H activation protocols.21 While
evaluation of other silane activators together with Ag2O was
unproductive (entries 6−8), a combination of CuF2 and Ag2O
efficiently promoted the coupling (entry 9). Interestingly, the
yield could be further improved by removing Ag2O from the
reaction system (entry 10), presumably due to incompatibility of
the Ru(0) oxidation with silane activation step. At this point, the
influence of solvent on the reaction was examined (entries 11−
20). Importantly, various solvents were compatible with this C−
H arylation, including THF, DCE, dioxane, DMF and toluene
(entries 11−17). In an effort to render the process more
environmentally friendly, we examined the reaction in a 1:1
mixture of i-PrOH/water (entry 18). Pleasingly, the reaction
cleanly delivered the C−H arylation product. Moreover, we were
surprised to find that water can be used as a sole reaction medium
without decrease in the reaction efficiency (entry 19). Seventy
percent conversion is observed at the boiling point of water.
AgSbF6 is required for efficient arylation; in its absence
approximately 50% conversion is observed. Finally, we
determined that stoichiometry of both the silane and CuF2
could be decreased to 1.2 and 1.5 equiv, respectively (entry 20).
To our knowledge, the process represents the first example of
both (1) direct Ru(II)-catalyzed oxidative C−H arylation in
water3,4 and (2) direct Hiyama cross-coupling in water as a sole
reaction medium.14,19,20 Moreover, the employed stoichiometry
of silane/CuF2 (1.2:1.5 equiv) compares very favorably with the
previous examples of Ru(II)-catalyzed direct Hiyama cross-
coupling.17b,c
With the optimized conditions in hand, the scope of indoles
and arylsilanes that could participate in this reaction was
examined (Scheme 1 and Table 2). Typically, water was used as a
sole reaction medium, while i-PrOH/water (1:1 v/vol) was used
for insoluble substrates. As shown in Scheme 1, a wide range of
indoles underwent C−H arylation under the developed
conditions. In all cases examined, exclusive C2 C−H arylation
site-selectivity was observed. Notably, electron-donating and
electron-withdrawing substituents at the C5 position were
readily accommodated (3b−d). Steric substitution at both C3
and C7 was also well-tolerated (3e−f). Importantly, indoles
bearing a wide range of electrophilic functional handles at
different positions around the indole ring, such as bromides (3g−
i), esters (3j,k), and a nitro group (3l), were also competent
electrophiles in this C−H arylation. At present, free indole is not
compatible with the reaction conditions. Of note, aryl bromide
functional handles are not readily accessible by a Ru(II)/(IV)
catalytic cycle,3,4 showing a subtle advantage of the oxidative
coupling manifold.
direct Ru(II)-catalyzed C−H arylation with arylsilanes.17b,c
A
critical feature is the in situ generation of a cationic Ru(II)
catalyst3a to enable C−H arylation by both weakly and strongly
coordinating directing groups.1,2 We hypothesized that indoles
could serve as suitable and general precursors for the direct C−H
arylation under Ru(II)-catalyzed Hiyama conditions. Despite
unique advantages of organosilicon coupling partners in organic
synthesis, including low toxicity, high stability, safe handling,
accessibility, and functional group compatibility,20 the use of
organosilanes as viable cross-coupling partners in C−H arylation
represents a major challenge due to (1) low nucleophilicity of
organosilanes and (2) incompatibility of silane activation and
metal re-oxidation steps.
To test the reaction feasibility, we examined the direct C−H
arylation of N-pyrimidylindole with trimethoxyphenylsilane
under a variety of conditions. Selected optimization results are
summarized in Table 1. The central challenge was to identify a
a
Table 1. Optimization of Reaction Conditions
b
entry
fluoride
oxidant
solvent
DCE
yield (%)
1
AgF (2.0 equiv)
CuF2 (2.0 equiv)
CsF (2.0 equiv)
AgF (2.0 equiv)
AgF (2.0 equiv)
AgF (2.0 equiv)
KF (2.0 equiv)
CsF (2.0 equiv)
CuF2 (2.0 equiv)
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Ag2O
<2
<2
<2
40
2
DCE
3
DCE
4
DCE
5
Ag2O
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
THF
51
6
Cu(OTf)2
Ag2O
<2
<2
<2
60
7
8
Ag2O
9
Ag2O
10
11
12
13
14
15
16
17
18
19
CuF2 (3.0 equiv)
>98
88
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2(3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (2.0 equiv)
CuF2 (2.0 equiv)
CuF2 (1.5 equiv)
DCE
75
dioxane
DMF
76
79
CHCl3
CH3CN
toluene
i-PrOH/H2O
H2O
<2
<2
90
c
>98
>98
>98
d
20
H2O
a
Conditions: 1a (0.2 mmol, 1.0 equiv), [RuCl2(p-cymene)]2 (5 mol
%), AgSbF6 (20 mol %), PhSi(OMe)3 (3.0 equiv), fluoride (1.5−3.0
equiv), oxidant (2.0 equiv), solvent (0.20 M), 140 °C, 20 h.
b
c
d
Determined by 1H NMR and/or GC. 1:1 v/vol. PhSi(OMe)3
(1.2 equiv).
We next turned our attention to the scope of the arylsilane
coupling partner (Table 2). Triethoxyphenylsilane showed
similar efficiency to trimethoxyphenylsilane without modifica-
tion of the reaction conditions (entries 1 and 2).19c Arylsilanes
bearing various substituents, including electron-donating (en-
tries 3 and 4) and electron-withdrawing (entries 5 and 6),
performed well in the reaction. A noteworthy aspect is high
tolerance for halides on the arylsilane component (entries 7 and
8). To our knowledge, the results provide the first example of a
bromo substituent on arylsilane in the Hiyama C−H arylation of
indoles.14,19 Meta-substitution was well accommodated (entry
9). Finally, it is noteworthy that a sterically demanding ortho-
Ru(II)-catalytic system/silane activator that would be compat-
ible with Ru(0) reoxidation. Additionally, the catalyst system
would have to tolerate the C−H functionalization step by a
cationic Ru(II) at the electron-rich C-2 position of the indole
ring.9,10
Initial screenings using established silane activators in
conjunction with Cu(OTf)2 were unsuccessful (entries 1−3).19
This includes copper(II) salts that proved critical in the Ru(II)-
catalyzed C−H arylation of indoles with boronic acids,12,13
highlighting the difficulty in the use of less reactive organosilanes.
Next, we determined that a combination of AgF as a silane
B
DOI: 10.1021/acs.orglett.7b03567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Ruthenium(II)-Catalyzed Direct C−H Arylation of
Table 2. Ruthenium(II)-Catalyzed Direct C−H Arylation of
a,
b
a,b
Indoles with Phenyltrimethoxysilane
1a with Various Organosilanes
a
Conditions: 1a (1.0 equiv), [RuCl2(p-cymene)]2 (5 mol %), AgSbF6
(20 mol %), PhSi(OMe)3 (1.2 equiv), CuF2 (1.5 equiv), H2O (3a−f)
b
or H2O/i-PrOH (1:1) (3g−l), 140 °C (0.20 M), 20 h. Isolated yields.
substituted arylsilane (entry 10) as well as a heterocyclic silane
(entry 11) are suitable coupling partners for the reaction. The
results provide the first examples of sterically demanding and
heterocyclic silanes tolerated in the Ru(II)-catalyzed Hiyama
cross-coupling.17b,c Overall, the reaction exhibits a broad scope
with respect to both the indole and arylsilane components and is
performed in aqueous media.15,21
We further demonstrated the utility of this protocol in the
direct C−H arylation of other N-heterocycles in water (Scheme
2). Moreover, while at this stage of reaction development
pyrroles are not suitable reaction partners under aqueous
conditions, we found that arylation of 1o in THF proceeds
with exclusive diarylation selectivity (di:mono >95:5, 67%). This
provides a synthetically useful alterative to the Ru(II)-catalyzed
arylation with boronic acids, which favors monoselectivity
(mono:di = 62:38, 42%)12 and highlights the useful reactivity
of the Ru(II)/CuF2 catalytic system.
a,b
See Scheme 1. See the Supporting Information for full details.
Scheme 2. Direct C−H Arylation of Other Heterocycles
Studies were conducted to gain insight into the reaction
mechanism (Scheme 3). (1) Electron-deficient arylsilanes are
inherently more reactive (4-CF3/4-MeO = 5.0:1.0), consistent
with Lewis base coordination to Si during the transmetalation
step (Scheme 3A).20a (2) In contrast, electron-rich indoles react
preferentially (5-MeO/5-Cl = 1.7:1.0), consistent with the
heteroatom-directed C−H activation via an electrophilic
substitution mechanism (Scheme 3B).22 (3) Experiments
establish the following order of reactivity of directing groups:
indole >2-phenylpyridine ≫ amide (Scheme 3C). (4)
Deuterium incorporation reveals reversibility of the cyclo-
ruthenation step (Scheme 3D). Deuterium incorporation at
the C-7 position was not observed.23 We propose that the
reaction proceeds via a Ru(II)/Ru(0) cycle, in which CuF2 acts as
a silane activator and Ru(0) reoxidant. Further mechanistic
studies are ongoing.
arylsilanes. The key feature of this reaction involves the use of
water as a cheap, safe, and sustainable solvent for C−H
functionalization.15,21 The reaction proceeds with exclusive C-2
arylation selectivity to deliver functionalized 2-arylindoles and
features a broad substrate scope with respect to both the indole
and arylsilane component. The protocol is distinguished by the
functional group tolerance to aryl halides amenable for further
manipulation. Collectively, the study is an important addition to
the arsenal of Ru(II)-catalyzed direct C−H arylation reactions in
green solvents. Further studies on Ru catalysis are underway, and
these results will be forthcoming.
In summary, we have developed the first general procedure for
ruthenium(II)-catalyzed direct C−H arylation of indoles using
C
DOI: 10.1021/acs.orglett.7b03567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) In October 2017, the average prices of Rh, Ir, Pd, and Ru were
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03567.
■
S
(15) For a review on C−H activation in water, see: Li, B.; Dixneuf, P.
H. Chem. Soc. Rev. 2013, 42, 5744.
(16) For select examples of C−H arylation in water, see: (a) Arockiam,
P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed.
2010, 49, 6629. (b) Ackermann, L.; Pospech, J.; Potukuchi, H. Org. Lett.
2012, 14, 2146. (c) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.;
Dixneuf, P. H. Green Chem. 2013, 15, 67.
(17) Ru(II): (a) Nareddy, P.; Jordan, F.; Brenner-Moyer, S. E.;
Szostak, M. ACS Catal. 2016, 6, 4755. (b) Nareddy, P.; Jordan, F.;
Szostak, M. Chem. Sci. 2017, 8, 3204. (c) Nareddy, P.; Jordan, F.;
Szostak, M. Org. Biomol. Chem. 2017, 15, 4783. Ru(0): (d) Hu, F.;
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Commun. 2016, 52, 9715.
Procedures and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Frank Jordan: 0000-0003-1354-718X
Michal Szostak: 0000-0002-9650-9690
Notes
(18) (a) Meng, G.; Szostak, M. Org. Lett. 2016, 18, 796. (b) Meng, G.;
Szostak. ACS Catal. 2017, 7, 7251. (c) Hu, F.; Nareddy, P.; Lalancette,
R.; Jordan, F.; Szostak, M. Org. Lett. 2017, 19, 2386.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. We
acknowledge a SEED Grant (Rutgers University) to the Center
for Sustainable Synthesis for partial support.
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DOI: 10.1021/acs.orglett.7b03567
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