RhCl3·3H2O-Catalyzed C7-Selective C-H Carbonylation of Indolines with CO and Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b02321

An attractive method for the synthesis of indoline-7-carboxylates through RhCl₃-catalyzed C-H carbonylation of indolines with CO and alcohols was developed. The copper-based oxidant and removable pyrimidyl directing group played important roles in achieving high-level yields of the title products. Based on control experiments, a possible catalytic cycle was proposed.

Full text of DOI:10.1021/acs.orglett.9b02321

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
RhCl3·3H2O‑Catalyzed C7-Selective C−H Carbonylation of Indolines
with CO and Alcohols
Rongrong Du,†,‡ Kang Zhao,† Jianhua Liu,*,† Feng Han,§ Chungu Xia,† and Lei Yang*,†,‡,∥
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Lanzhou 730000, China
‡Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University,
Hangzhou 311121, China
§College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018, China
∥Engineering Research Center of High Performance Polymer and Molding Technology, Ministry of Education, College of Chemistry
and Molecular Engineering, Qindao University of Science and Technology, Qingdao 266042, China
S
* Supporting Information
ABSTRACT: An attractive method for the synthesis of indoline-7-carboxylates through RhCl3-catalyzed C−H carbonylation of
indolines with CO and alcohols was developed. The copper-based oxidant and removable pyrimidyl directing group played
important roles in achieving high-level yields of the title products. Based on control experiments, a possible catalytic cycle was
proposed.
ecently, transition-metal-catalyzed chelation-assisted site-
Rselective C−H carbonylation with carbon monoxide (CO)
has appeared as one of the most straightforward tools for the
formation of carbonyl compounds due to its excellent
regioselectivity and reactivity.1 Within this reaction class,
spectacular advances have been achieved mainly using palladium
catalysts. In contrast, although the utilization of rhodium
catalysts could offer unique synthetic methods to achieve
structural diversity and molecular versatility of C−H carbon-
Figure 1. Selected bioactive molecules based on indoline-7-carboxylic
ylation reactions, which are inaccessible under palladium
catalysis,2 rhodium-catalyzed chelation-assisted site-selective
acid and their derivatives.
C−H carbonylation with CO has been less developed.3
carboxylated indolines and their derivatives mainly involve
commonly used organometallic reagents by direct functionaliza-
tion of indoline cores7a or cyclization reactions to form the
indoline cycles.7b−d In recent years, transition-metal-catalyzed
site-selective C−H carbonylation with CO and different
nucleophiles has emerged as an attractive method enabling the
straightforward synthesis of C7-carbonylated indolines or their
derivatives (Scheme 1).8 In 2012, a study on Ru0-catalyzd direct
C7 carbonylation of N-pyridylindolines with CO and olefins
appeared for accessing C7-aliphatic acyl-derived compounds
(Scheme 1a).8a However, high reaction temperature was
required, and the substrate scope was narrow with respect to
Furthermore, to access high catalytic turnover, an olefin-
coordinated RhI or RhIII complex, which is generally prepared
from the coordination reaction of RhCl3·3H2O with an olefin,
was usually required in this type of rhodium-catalyzed chelation-
assisted C−H carbonylation with CO. Thus, development of
efficient synthetic methodologies via simple RhCl3·3H2O-
catalyzed C−H carbonylation with CO is highly appealing.4
C7-substituted indoline scaffolds are ubiquitous structural
motifs found in many natural products and pharmaceutically
important compounds.5 In particular, C7-carboxylated indolines
or their derivatives usually display particular biological activities
(Figure 1).6 For this reason, development of effective methods
for the access of C7-carboxylated indolines and derivatives
thereof has been disclosed, and a host of reactions have been
reported.7,8 Conventional procedures for preparing C7-
Received: July 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Transition-Metal-Catalyzed C7-Selective C−H
Carbonylation of Indolines with CO
Table 1. Reaction Development
temp
yield
b
entry
catalyst
[Cp*RhCl2]2
[Cp*Rh(OAc)2(H2O)]2 Cu(OAc)2
oxidant
(°C)
(%)
1
2
3
4
5
6
7
8
Cu(OAc)2
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
34
49
56
54
trace
54
0
RhCl3·3H2O
RhCl3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
[Rh(OAc)2]2
[Rh(cod)Cl]2
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
AgSbF6
K2S2O8
0
0
0
9
10
11
12
13
14
15
PhI(OAc)2
Cu(EtCO2)2
Cu(i-PrCO2)2
Cu(n-PrCO2)2
Cu(OPiv)2
Cu(1-AdCO2)2
both olefins and indolines. Recently, an expedient synthesis of
pyrroloquinazolinediones was achieved via PdII-catalyzed
intermolecular C7-selective C−H carbonylation of indolines
with CO in AcOH (Scheme 1b).8b Despite these advances,
access to C7-carbonylated indolines of structural diversity via
this strategy is still limited; in particular, there is no catalytic
method for the synthesis of indoline-7-carboxylic esters despite
the synthetic attractiveness of esters. Inspired by the well-
developed transition-metal-catalyzed direct C7 C−H function-
alization of indolines8,9a and as part of our continuing interests in
simple rhodium-catalyzed C−H activation,10b herein, we
successfully demonstrate the first RhCl3·3H2O-catalyzed
chelation-assisted C7-selective C−H carbonylation of indolines
with CO and alcohols.
To test the feasibility of C7-selective carbonylation, we started
our investigations by exploring the use of a rhodium catalyst in
the presence of an oxidant. Initially, the pyrimidine group
directed indoline 1a and n-BuOH 2a were used as model
substrates for the carbonylation. Gratifyingly, a promising yield
of 34% was observed when common [Cp*RhCl2]2 was
employed as the Rh catalyst, and Cu(OAc)2 served as the
oxidant in toluene (Table 1, entry 1). Encouraged by this initial
result, we evaluated the effect of other common rhodium
catalysts (Table 1, entries 2−6). Interestingly, it turned out that
RhCl3·3H2O is the best choice in our case, affording 3aa in 56%
yield (Table 1, entry 3). Comparable yields were also obtained
for RhCl3 and [Rh(cod)Cl]2, whereas [Rh(OAc)2]2 was
completely inert for this transformation. In contrast, a set of
widely used Pd, Ru, and Ir catalysts was also examined.11
However, the reaction did not occur in most cases, or only a
trace amount of product was detected, thus showing the unique
features of rhodium catalysts in the current transformation. In
addition, after an extensive screening of solvents, it was found
that performing the reactions in aromatic solvents led to the
improved yield of 3aa, in which toluene is the best choice.
Notably, among the oxidants tested, only copper-based oxidants
were workable and Cu(EtCO2)2 gave the best result (Table 1,
entries 7−16). Interestingly, alkoxycarbonylation could occur in
the presence of catalytic amounts of Cu(EtCO2)2 under mixed
CO/O2 gas (Table 1, entry 16). Finally, further refinement of
the reaction parameters was conducted using Cu(EtCO2)2,
including reaction temperature, catalyst loading, and reaction
time. These studies allowed an 85% isolated yield of 3aa to be
achieved when using 5 mol % of RhCl3·3H2O in combination
with 2 equiv of Cu(EtCO2)2, in toluene at 110 °C after 24 h
(Table 1, entry 23). The structure of the desired product 3aa
76
57
63
32
0
c
16
Cu(EtCO2)2/
O2
30
17
18
19
20
21
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
Cu(EtCO2)2
Cu(EtCO2)2
Cu(EtCO2)2
Cu(EtCO2)2
Cu(EtCO2)2
Cu(EtCO2)2
Cu(EtCO2)2
130
140
110
100
80
62
30
77
70
62
83
86(85)
d
22
23
110
110
de
,
f
a
Reaction conditions: 1a (0.2 mmol), 2a (1 mmol), catalyst (2 mol
%), oxidant (2 equiv), toluene (2.0 mL), CO (1 atm), 12 h. Yield
determined by H NMR using 1,3,5-trimethoxybenzene as internal
standard. CO/O2 = 1:1 (1 atm). RhCl3·3H2O (5 mol %). 24 h.
Isolated yield.
b
1
c
d
e
f
was confirmed unambiguously by single-crystal X-ray diffraction
analysis.
With the optimized reaction conditions in hand, we then
began scoping studies with respect to the alcohol coupling
partner (Scheme 2). We were pleased to find that the simple
linear alkyl alcohols including low-carbon aliphatic alcohols,
such as methanol and ethanol, were all suitable for this
transformation (3aa−3ag). Notably, the reaction could be
performed on a gram scale. Treatment of 5 mmol of 1a and 25
mmol 2a under standard reaction conditions furnished 1.33 g of
3aa (90% yield). Introduction of functionalities such as alkoxy,
cyclopropyl, aryl, alkenyl, phthalamidyl, and methoxy into the
scaffolds of aliphatic alcohols did not greatly influence the
transformation in most cases (3ah−3an), hence demonstrating
the high compatibility of the catalytic system. Moreover,
benzylic alcohols also proved to be ideal alcohol coupling
partners under the standard reaction conditions (3ao and 3ap).
When secondary alcohols were used, desired products were
smoothly delivered as well in good to excellent yields (3aq−
3at). Unfortunately, only moderate yields of the desired
products (3au and 3av) were obtained when tertiary alcohols
such as tert-pentyl alcohol and tert-amyl alcohol were employed
as the coupling partner, even prolonging the reaction time and
increasing the concentration of the catalyst, probably due to
steric hindrance of the alcohol coupling partner.
B
DOI: 10.1021/acs.orglett.9b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Alcohols
Scheme 3. Scope of Indolines
a
Reaction conditions: 1 (0.2 mmol), 2a (1 mmol), RhCl3·3H2O (5
mol %), Cu(EtCO2)2 (2 equiv), toluene (2.0 mL), CO (1 atm), 110
°C, 24 h. Isolated yields of 3 are given. 1n (0.4 mmol), 2a (2 mmol),
b
RhCl3·3H2O (5 mol %), Cu(EtCO2)2 (2 equiv), toluene (2.0 mL),
CO (1 atm), 110 °C, 36 h. Isolated yield of 3na is given.
to 90%. Indolines bearing an electron-donating group (methyl
or methoxyl group) on the benzene ring showed better reactivity
compared to those bearing an electron-withdrawing group, such
as fluoro, chloro, bromo, and nitro, at the same position (3fa vs
3ga, 3ha and 3ia vs 3ja−3ma). However, the carbonylation of
C6-substituted indolines 1n and 1o was found to be relatively
less efficient, suggesting that this method was sensitive to steric
factors.
The present RhCl3·3H2O-based catalytic system was not
limited to C−H functionalization of indolines. For example, the
C−H carbonylation of carbazole 4 with CO and n-BuOH
catalyzed by RhCl3·3H2O in the presence of Cu(EtCO2)2 gave a
∼3:1 mixture of mono- and double alkoxycarbonylation
products (Scheme 4).
a
Reaction conditions: 1a (0.2 mmol), 2 (1 mmol), RhCl3·3H2O (5
mol %), Cu(EtCO2)2 (2 equiv), toluene (2.0 mL) CO (1 atm), 110
°C, 24 h. 1a (0.2 mmol), 2u or 2v (1 mmol), RhCl3·3H2O (5 mol
%), Cu(EtCO2)2 (2 equiv), toluene (1.0 mL) CO (1 atm), 110 °C, 48
h. Isolated yields of 3 are given.
b
Apart from the gram-scale reaction, the synthetic utility of this
RhCl3·3H2O-catalyzed C−H carbonylation strategy was further
illustrated by facile diversification of 3ac to prepare indole-7-
carboxylic acid derivatives (Scheme 5). For instance, indole-7-
We next applied the developed reaction protocol to naturally
occurring or bioactive alcohols. For instance, citronellol was
successfully acylated to deliver 3aw in 86% yield under the
optimal conditions. In addition, secondary alcohols, such as
dehydroepiandrosterone and L-menthol, could also be used to
afford the corresponding products 3ax and 3ay12 in 66 and 63%
yield, respectively.
Scheme 4. C−H Carbonylation of Carbazole
Subsequently, to further expand the scope of our protocol, we
applied the present catalytic system to a variety of N-substituted
indolines. As shown in Scheme 3, a variety of N-pyrimidylindo-
lines and alcohol 2a were efficiently transformed into the desired
indoline-7-ester derivatives 3 with good yields and excellent
positional control. Notably, other carbonyl or carbamoyl
directing groups were found to be ineffective in the C7
carbonylation of indolines.11 The carbonylation reactions of C2-
or C3-substituted indolines 1b−1e provided the desired C7-
carbonylated products 3ba−3ea in good yields ranging from 69
C
DOI: 10.1021/acs.orglett.9b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Synthetic Derivatization of Indoline-7-
carboxylates
Scheme 7. Plausible Reaction Mechanism
ester 8 could be obtained via an oxidation/removal of the
pyrimidyl group sequence.13 Thus, this methodology would be
of interest for facile synthesis of those bioactive inhibitors from
readily available starting materials.6
To perceive the reaction mechanism, the following reactions
were conducted as described in Scheme 6. First, H/D
Scheme 6. Mechanistic Experiments
rhodacycle I forms a seven-membered species II,15 which
undergoes ligand exchange to generate the rhodacycle III.
Subsequent reductive elimination of rhodacycle III affords
carbonylation product 3aa and Rh(I), which is oxidized to
Rh(III) by Cu(II) to regenerate the catalyst and complete the
catalytic cycle.
In summary, we have developed an efficient rhodium(III)-
catalyzed C7-selective oxidative C−H carbonylation of indo-
lines with alcohols to afford indoline-7-carboxylic acid esters
under 1 atm of CO using simple inorganic salt RhCl3·3H2O as
the catalyst. The protocol features good functional group
tolerance, broad substrate scope, and efficient scale-up. The
present results demonstrate a new route for the synthesis of
indoline- and indole-7-carboxylic acid esters and their
derivatives. Further detailed studies to understand the reaction
mechanism and potential application of this transformation are
ongoing in our lab.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02321.
scrambling experiments using CD3OD as the alcohol coupling
partner in the presence and in the absence of CO were
suggestive of a reversible C−H rhodation. Moreover, an
intermolecular kinetic isotope effect study from two parallel
kinetic experiments on 1a or [7-D]-1a (93% D) with 2a revealed
a low kH/kD value of 1.56.11 These results indicated that the C−
H cleavage is not likely to be the rate-limiting step. In addition, a
catalytic reaction of 1a and 2a using cyclometalated Rh(III)
complex A10b as the catalyst was conducted. As a result, desired
product 3aa was obtained in 72% yield, together with the H/D
scrambling experiments, indicating the plausible intermediacy of
an active six-membered rhodacycle species in this trans-
formation.
Based on our mechanistic studies and literature prece-
dent,3,10b,14 we have proposed a tentative catalytic cycle for
this carbonylation process. As depicted in Scheme 7, the
chelation-assisted reversible C−H cleavage produces a cyclo-
metalated Rh(III) intermediate I. Coordination and insertion of
one molecule of CO to the C−Rh bond of the putative
Experimental details and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1904900 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jhliu@licp.cas.cn.
*E-mail: lyang@hznu.edu.cn or lyang@licp.cas.cn.
ORCID
Feng Han: 0000-0003-0707-8575
D
DOI: 10.1021/acs.orglett.9b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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R.; Payne, J.; Miller, D. D.; Bamborough, P.; Christopher, J. A.;
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Lei Yang: 0000-0001-9172-0879
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Grant Nos. 21372231, 21173241, and
21673260), Youth Innovation Promotion Association CAS
(No. 2013270), and Hangzhou Normal University for financial
support. We thank Mr. Zhiqiang Shen for assistance with NMR
experiments, Ms. Xiaoxue Hu for HRMS analyses, and Ms. Peiju
Yang for X-ray diffraction analyses. We also thank Prof. Wei Sun
and Dr. Qiangsheng Sun for their help with HPLC separation.
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