Rh(iii)-catalyzed C-7 arylation of indolines with arylsilanes via C-H activation

Article abstract of DOI:10.1039/c9ra04142g

Site-selective synthesis of C-7 arylated indolines has been achieved via oxidative arylation of indolines with arylsilanes under Rh(iii)-catalyzed C-H activation of indolines by using CuSO₄ as a co-oxidant. This transformation has been explored for a wide range of substrates under mild conditions.

Full text of DOI:10.1039/c9ra04142g

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Rh(III)-catalyzed C-7 arylation of indolines with
arylsilanes via C–H activation†
Cite this: RSC Adv., 2019, 9, 18191
*
Haiqing Luo,
Qi Xie, Kai Sun, Jianbo Deng, Lin Xu, Kejun Wang
*
and Xuzhong Luo
Received 1st June 2019
Accepted 4th June 2019
Site-selective synthesis of C-7 arylated indolines has been achieved via oxidative arylation of indolines with
arylsilanes under Rh(III)-catalyzed C–H activation of indolines by using CuSO4 as a co-oxidant. This
transformation has been explored for a wide range of substrates under mild conditions.
DOI: 10.1039/c9ra04142g
rsc.li/rsc-advances
The indole and indoline ring systems represent ubiquitous methods for the construction C–C bonds, the Hiyama cross-
structural motifs as natural alkaloids and biologically active coupling reaction has drawn increasing attention.16 As attrac-
compounds as well as in functional materials.1,2 With the tive organometallic coupling partners with many unique
development of C–H bond functionalization,3 a great deal of advantages such as low toxicity, high stability and environ-
effort has been devoted to the formation C-2 and C-3 func- mental benignity, organosilicon reagents were used as coupling
tionalized indoles.4 Nevertheless, only a few methods have been partners for the C–H arylation of indoles and indolines (Scheme
explored for the direct C–H bond functionalization of indoles at 1b).17 Zhang group reported the Pd-catalyzed C-2 arylation of
the C-7 position,5 in which the unique work for the direct Pd- indoles with arylsilanes in acidic medium in 2010. In 2014, Loh
catalyzed C–H arylation of indoles with arylboronic acids at group developed the Rh(III) catalyzed C-2 C–H arylation of
the C-7 position was developed by the Shi group using indoles with arylsilanes in aqueous media.18 Very recently,
a designed di-tert-butylphosphine oxide (TBPO) directing- Szostak group developed the Ru(II) catalyzed arylation of indoles
group.5b In general, the C-7 arylated indolines can be conve- with arylsilanes via C–H activation,19 it is worth noting that the
niently oxidized to transform into C-7 arylated indoles. So far, reaction was carried out in water. However, the methods for the
transition metals such as Pd,6 Rh,7 Ru,8 Ir,9 etc.,10 have been synthesis of C-7 arylated indolines and C-7 arylated indoles are
employed as catalysts for the C-7 C–H bond functionalization of very limited by using arylsilanes as the coupling partners. To the
indolines, among which the C–H arylation in the C-7 position of best of our knowledge, the Rh(III) catalyzed C-7 arylation of
indoline was mainly established by using Pd complexes as indolines with arylsilanes has not been achieved. Due to our
catalysts (Scheme 1a).11 In 2016, we also reported the Pd- continuous interest in the arylsilanes-based coupling reac-
catalyzed C-7 arylation of indolines with arylsilanes via C–H tion,12,20 we herein would like to report a Rh(III)-catalyzed
bond activation.12 Recently, the Punniyamurthy group devel-
oped the site-selective C-7-arylation of indolines with arylbor-
onic acids by using low-cost and earth-abundant cobalt(II)-PCy3
as a catalyst.13 Even so, in view of the importance of indole and
indoline scaffolds, it is still highly desirable to develop more
convenient and efficient approaches for the synthesis of C-7
arylated indolines and C-7 arylated indoles.
Meanwhile, recent years have witnessed tremendous devel-
opments in the area of Rh(III)-catalyzed C–H bond functionali-
zation,14 which has allowed effective construction of various
C–C bonds. The major advantages of Rh(III) catalysis are (i) high
functional-group tolerance, (ii) broad substrate scope, (iii) low
catalyst loading, high activity, and high catalytic efficiency.
Since the Hiyama cross-coupling reaction had been rst re-
ported in 1988,15 as one of the most useful and reliable synthetic
Department of Chemistry
& Chemical Engineering, Gannan Normal University,
Ganzhou 341000, China. E-mail: luohaiq@sina.com; luoxuzhong@hotmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra04142g
Scheme 1 C-2 arylation of indoles with arylsilanes and C-7 arylation of
indolines.
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regioselective C-7 arylation of indolines with arylsilanes via C–H (Table 1, entry 15). Furthermore, in order to gain the milder
activation (Scheme 1c), the reaction provides a facile access to reaction condition, the reaction temperature was tried to
C-7 arylated indolines.
At the outset of the investigation, various N-protecting 60 ꢀC offered a relatively low yield in 87% (Table 1, entry 16).
indolines (Table 1, 1a–1f) were initially used as coupling With the optimized reaction conditions in hand, we then
reduce. The results revealed that the reaction carried out at
partners for the direct C-7 C–H arylation with phenyl- proceeded to explore the scope of the direct C-7 C–H arylation of
triethoxysilane 2a in the presence of 1 mol% of [Cp*RhCl2]2 N-(2-pyrimidyl)-indoline with a series of arylsilanes (Table 2). It
in dioxane at 80 ꢀC, 3.0 equiv. of AgF as the activator for C–Si was found that various phenylsilanes had good compatibility
bond as well as the oxidant, and 2.0 equiv of Cu(OAc)2 as the under these reaction conditions. At rst, phenyltrimethoxy-
co-oxidant. The choice of the N-protecting group was found silane shows good reactivity affording 67% yield. To investi-
to be crucial for this arylation, and only pyrimidyl-protected gate the steric effect, the phenyltriethoxysilanes bearing methyl
indoline (1f) afforded desired arylated product 3fa. Then, group on different positions of the phenyl ring were employed
different uorine sources such as AgF, CsF, KF, and TBAF as the substrates (3–3fd). The results indicate that the phe-
were examined (Table 1, entries 3–6). Only AgF was found to nyltriethoxysilane with ortho-methyl substituent was found to
be effective, thus affording the desired product 3fa. The afford the desired product for the diminished yield in 33%,
reaction can afford the desired product in 72% yield by using which could be due to the steric effect. The direct C–H arylation
no co-oxidant (entry 7). In order to increase the yield, various of N-(2-pyrimidyl)-indoline has shown excellent tolerance to
co-oxidants such as Ag2CO3, Ag2O, Cu(OAc)2 and CuSO4 were both electron-withdrawing and electron-donating groups as
utilized (entries 8–10), CuSO4 proved to be the optimal aromatic substituents, including alkyl (3–3fe), alkyloxyl (3ff–
choice. Subsequently, the effect of solvent was then investi- 3), aryl (3), uoro (3), chloro (3), and triuoromethyl
gated (entries 10–15), and dioxane was found to be suitable groups (3) in good to excellent yields except the ortho-methyl
for the reaction. To our surprise, this reaction could be per- substituent
(3fd).
In
addition,
the
heterocyclic
formed in aqueous media (dioxane/H2O ¼ 1/10) in 47% yield triethoxy(thiophen-2-yl)silane was also used to explore the
Table 1 Optimization of reaction conditions for the Rh(III)-catalyzed C-7 arylation of indolines with arylsilanea
Entry
Substrates
Co-oxidant
F source
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1a–1d
1e
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
—
AgOAc
Cu(OAc)2
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
AgF
AgF
AgF
CsF
KF
TBAF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
0
0
81
0
0
0
72
89
85
98
62
0
81
Messy
47
87
9
10
11
12
13
14
15
16c
DMSO
iPrOH
H2O
Dioxane/H2O ¼ 1/10
Dioxane
a
Unless otherwise noted, the reaction conditions are as follows: 1 (0.3 mmol), 2a (0.9 mmol), [Cp*Rh(III)Cl2]2 (1 mol%), Co-oxidant (0.6 mmol), F
resource (0.9 mmol), solvent (3.0 mL). b Isolated yield aer purication by ash column chromatography on silica gel, n.d.p or trace product was
c
determined by TLC. The reaction temperature was 60 ꢀC.
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Table 2 Rh(III)-catalyzed the direct C-7 arylation of indoline 1f with Table 3 Rh(III)-catalyzed the direct C-7 arylation of various indolines 1
various phenyltriethoxysilane 2a,b
with phenyltriethoxysilane 2aa,b
a
Unless otherwise noted, the reaction conditions are as follows: 1 (0.3
b
a
mmol), 2a (0.9 mmol), dioxane (3.0 mL). All the yields refer to
Unless otherwise noted, the reaction conditions are as follows: 1f (0.3
mmol), 2 (0.9 mmol), dioxane (3.0 mL). b All the yields refer to isolated
isolated yields.
yields. c Phenyltrimethoxysilane was used.
To further demonstrate the synthetic utility of the method,
the transformation of C-7 arylated indoline into C-7 arylated
indole was studied.13,21 As shown in Scheme 3, the trans-
formation was begun with the oxidation of C-7 arylated N-(2-
pyrimidyl)-indoline 3fa by the use of DDQ (2,3-dicyano-5,6-
dichlorobenzoquinone), followed by removing pyrimidyl
group in the present of base. Finally, 83% yield of the C-
7arylated indole product 7a was successfully obtained.
To gain some preliminary mechanistic insights, kinetic
isotope experiments were conducted. The parallel reactions of
1f and deuterio-1f with 2a resulted kH/KD ¼ 0.80 (Scheme 4),
which suggested that the C–H cleavage was not the rate-
possibility of the C–H arylation. To our delight, the reaction also
afforded the corresponding product in moderate yield (3fm).
To further evaluate the substrate scope, various substituted
N-(2-pyrimidyl)-indolines were used to test the reaction with the
phenyltriethoxysilane 2a under the optimized reaction condi-
tions. The results are summarized in Table 3. In general, the (2-
pyrimidyl)-indolines bearing electron-donating groups on the
aromatic ring such as 5-methyl and 5-alkyloxyl group react
smoothly to afford the corresponding arylated products in
excellent yields (4ga–4ha). In addition, the reactions with the (2-
pyrimidyl)-indolines bearing electron-withdrawing group on
the aromatic ring also afford moderate to good yield (4ja–4oa),
except the substrate 1n with 6-bromo group showed low activity
affording 17% yield, which may be attributed to the steric
hindrance of the bromo functionality. Furthermore, the
substrates with C-2 or C-3 methyl substituted group on the
indoline ring also show excellent compatibility with the reac-
tion condition in 86% (4pa) and 90% yield (4qa), respectively.
To explore the utility of this transformation, we tried to
explore direct C-8 C–H arylation with N-(2-pyrimidyl)-
tetrahydroquinoline 5 and phenyltrimethoxy-silane 2a under
the standard condition, to our delight, the desired C-8 C–H
arylated product was obtained in 48% yield (Scheme 2).
determining step in the catalytic cycle. On the basis of
18,22,23
previous literatures,
a plausible mechanism is proposed
as shown Scheme 5. The process is likely to be initiated by the
Scheme 2 Rh(III)-catalyzed the direct C-8 arylation of N-(2-pyr-
imidyl)-tetrahydroquinoline 5 with phenyltriethoxysilane 2a.
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scopes, various functional groups are well tolerated under the
mild reaction conditions. This reaction constitutes a comple-
ment method for the synthesis the desired C-7 arylated indo-
lines up to excellent yields, which can be conveniently
transformed into C-7 arylated indoles.
Scheme 3 Transformation of C-7-arylated indoline 3fa to the corre-
sponding indole 7a.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The project was supported by the National Natural Science
Foundation of China (No. 21762002, 21562003) and Under-
graduate Training Programs for Innovation and Entrepreneur-
ship of Gannan Normal University (CX170049).
Scheme 4 Parallel kinetic isotope experiment.
Notes and references
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nation would provide C-7 arylated indolines 3fa and regenerate
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