Rh(III)-catalyzed selective coupling of N-methoxy-1H-indole-1-carboxamides and aryl boronic acids

Article abstract of DOI:10.1021/ol5014312

A Rh(III)-catalyzed selective coupling of N-methoxy-1H-indole-1-carboxamide and aryl boronic acids is reported. The coupling is mild and efficient toward diverse product formation, with selective C-C and C-C/C-N bond formation. Kinetic isotope effects studies were conducted to reveal a mechanism of C-H activation and electrophilic addition.

Full text of DOI:10.1021/ol5014312

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Selective Coupling of N‑Methoxy‑1H‑indole-1-
carboxamides and Aryl Boronic Acids
Jing Zheng, Yan Zhang, and Sunliang Cui*
Institute of Materia Medica and College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058,
P. R. China
S
* Supporting Information
ABSTRACT: A Rh(III)-catalyzed selective coupling of N-
methoxy-1H-indole-1-carboxamide and aryl boronic acids is
reported. The coupling is mild and efficient toward diverse
product formation, with selective C−C and C−C/C−N bond
formation. Kinetic isotope effects studies were conducted to
reveal a mechanism of C−H activation and electrophilic
addition.
Scheme 1. Rh(III)-Catalyzed Arylboronic Acids Involved
Coupling
he indole framework is a structural motif commonly
1
Tfound in pharmaceutical drugs and natural products.
Consequently, great efforts have been devoted to the synthesis
and chemical modification of indoles, especially involving
transition-metal catalysis.2 In the past few years, transition-
metal-catalyzed directing-group assisted C−H functionalization
has emerged as a distinct and powerful method for the
construction of C−C, C−N, C−O, and C−X bonds.3
Recently, Rh(III)-catalyzed C−H functionalization has
advanced significantly for the rapid assembly of various
complex molecular structures, particularly in the fields of
medicinal chemistry.4 Alkynes,5 alkenes,6 allenes,7 organic
azides,8 and diazo copounds9 are frequently used as coupling
partners in Rh(III)-catalyzed C−H functionalization. However,
very few examples of Rh(III)-catalyzed C−H functionalization
and late-stage coupling using organoboron reagents have been
reported. Recently, Miura developed a Rh(III)-catalyzed
oxidative coupling of aryl boronic acids and alkynes for the
synthesis of naphthalenes and anthracenes.10 More recently,
Cheng reported an excellent Rh(III)-catalyzed dual oxidative
coupling of N-methoxybenzamides and aryl boronic acids for
facile access to phenanthridinones (Scheme 1).11
To the best of our knowledge, the Rh(III)-catalyzed coupling
of indoles and aryl boronic acids giving divergent outcomes
remains unreported.12,13 Continuing our interest in Rh(III)-
catalyzed C−H functionalization for biologically interesting
small molecule synthesis,14 herein, we wish to report a Rh(III)-
catalyzed selective coupling of N-methoxy-1H-indole-1-carbox-
amides and aryl boronic acids, for arylation, [4 + 2] cyclization,
and [4 + 1] cyclization respectively (Scheme 1).
showed that [Cp*RhCl2]2 was essential in this reaction (entry
1), and the equivalent addition of Cu(OAc)2 gave a phenylation
product 3a in 94% yield (entry 2). This encouraged us to
further optimize the reaction conditions. When K2S2O8 was
used as an oxidant, no product was observed (entry 3). The use
of AgOAc led to a mixture of 3a and the [4 + 2] cyclization
product 4a (entry 4, 3a, 56%; 4a, 13%). This unpredicted result
prompted us to further examine various silver salts, and we
found that Ag2CO3 was inferior giving 4a as the sole product
only in 11% yield (entry 5). When Ag2O was used as the
We commenced our study by investigating the coupling of
N-methoxy-1H-indole-1-carboxamide 1a and phenyl boronic
with [Cp*RhCl2]2 as the catalyst (Table 1). Control reactions
Received: May 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5014312 | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Model Reaction Optimization
Table 2. Rh(III)-Catalyzed Coupling of Indoles with Various
Aryl Boronic Acids for Arylation
a
b
entry
oxidant
none
solvent
temp (°C)
product/yield (%)
1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
tBuOH
MeOH
MeOH
60
60
60
60
60
60
60
60
60
60
30
80
−
3a/94
2
Cu(OAc)2
c
3
K2S2O8
−
4
AgOAc
3a/56, 4a/13
4a/11
3a/93
4a/76
4a/73
4a/58
−
5
Ag2CO3
d
6
Ag2O
7
Ag2O
ce
,
8
Ag2O/O2
Ag2O
9
10
11
12
Ag2O
Ag2O
−
4a/75
Ag2O
a
The reaction was carried out with 1 (0.2 mmol), 2a (0.4 mmol), and
oxidant (4 equiv) in solvent (2 mL) at indicated temperature for 12 h
b
c
unless otherwise noted. Yields of isolated product. 2 equiv of oxidant
were used. Reaction for 1 h. Balloon of O2 gas was used.
d
e
a
The reaction was carried out with 1 (0.2 mmol), 2 (0.4 mmol), and
Cu(OAc)2 (0.8 mmol) in MeOH (2 mL) at 60 °C for 3 h to be
oxidant, the reaction furnished 3a in 93% yield within 1 h
(entry 6) and 4a in 76% yield with a prolonged reaction time of
12 h (entry 7). This proved that 4a was generated from 3a.
Next, a combination of Ag2O (2 equiv) and oxygen (balloon
gas) was tested to furnish 4a in a slightly lower yield (entry 8,
73%). A survey of the solvent showed that tBuOH and CH3CN
were not optimal (entries 9−10). This indicated that further
optimization revealed that decreasing the reaction temperature
to 30 °C led to starting material recovery (entry 11), while
increasing the temperature to 80 °C gave 4a in 75% yield
(entry 12).
completed.
Table 3. Rh(III)-Catalyzed Coupling of Indoles with Various
a
Aryl Boronic Acids for [4 + 2] Cyclization
Next we proceeded to study the scope of Rh(III)-catalyzed
coupling of indoles with various aryl boronic acids using
Cu(OAc)2 as the oxidant. As depicted in Table 2, various aryl
boronic acids regardless of electron-donating or -withdrawing
groups on the aromatic ring reacted smoothly in this coupling
to furnish the 2-arylated indole products in good yields (Table
2, 3b−3i, 48%−86%), with valuable functional group tolerance.
Thus, the presence of a methyl, phenyl, methoxy, hydroxy,
chloro, bromo, and cyano group offered ample opportunity for
further derivatization. The electron-withdrawing group sub-
stituted aryl boronic acids (3e and 3f) showed less efficiency
than that of electron-donating group substituted aryl boronic
acids in this coupling, probably due to their weaker
nucleophilicity. Variation of indoles showed that differentially
substituted indoles were also applicable in this transformation
to produce the corresponding 2-phenylated products in
moderate to excellent yields (Table 2, 3j−3n, 57%−92%).
Notably, this Rh(III)-catalyzed C−C coupling of indoles with
aryl boronic acids for arylation is simple and proceeds under
mild reaction conditions with a broad substrate scope.15
The scope of this Rh(III)-catalyzed coupling using Ag2O as
the oxidant was also investigated. As shown in Table 3, a broad
range of indoles and aryl boronic acids were amenable to the
reaction. Functionalized boronic acids with methyl, phenyl,
methoxy, chloro, bromo substitution and polysubstituted
boronic acids were compatible with the oxidative coupling
system to deliver the cyclized 5-methoxyindolo[1,2-c]-
quinazolin-6(5H)-ones in moderate to good yields (Table 3,
a
The reaction was carried out with 1 (0.2 mmol), 2 (0.4 mmol), and
Ag2O (0.8 mmol) in MeOH (2 mL) at 60 °C for 12 h to be
completed.
4b−4i, 40%−84%). The slightly lower yield of 4d and 4e is
likely due to the electron-withdrawing nature and steric
hindrance of the starting boronic acids. The generality of
indoles was also demonstrated. Structurally and electronically
varied indoles were explored and found applicable in this
coupling furnishing the corresponding cyclized heterocycles in
moderate to good yield (Table 3, 4j−4n, 40%−70%).
Compared to classical syntheses of indolo[1,2-c]quinazolin-
6(5H)-ones,16 this transformation represents a simple and
direct approach toward this biologically interesting type of
B
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Letter
heterocycle from readily available starting materials under mild
reaction conditions.17
Scheme 2. Proposed Mechanism
Interestingly, when 4-hydroxyphenylboronic acid 2e was
subjected to this reaction with 1a, by elevating the reaction
temperature to 90 °C, unexpected spiro-cyclohexadienone 5a
was exclusively obtained as the [4 + 1] cyclization form (eq 1),
and the slightly low yield was due to the decomposition of
starting materials. This unpredicted result of dearomtization of
the phenol ring indicated that this C−C/C−N coupling
probably occurred via an electrophilic addition process.18,19
Furthermore, the structure of 5a was unambiguously confirmed
by X-ray analysis.
To gain insight into the reaction mechanism, a kinetic effect
study was conducted to probe the mechanism.20 When
Cu(OAc)2 was used as the oxidant, a KIE value of 1.34 was
obtained for the coupling reaction (eq 2). This revealed a small,
with 2a would lead to B, and reductive elimination furnished
the C−C coupling product 3a and a Rh(I) species. Reoxidation
of Rh(I) to Cp*Rh(OAc)2 by Cu(OAc)2 would enable the
catalytic cycle to proceed. With respect to the C−C/C−N
coupling, the initial [Cp*RhCl2]2 could undergo chloride ligand
removal by Ag+ to form Cp*Rh(III). A similar N-metalation/
C−H activation would generate rhodacycle A. Transmetalation
would furnish 3a and a Rh(I) species which could be reoxidized
to Cp*Rh(III) by Ag2O. At this stage, another N-metalation
can occur on 3a in the presence of Cp*Rh(III) to form
intermediate C, and an intramolecular electrophilic addition of
C would lead to the seven-membered rhodacycle D. Reductive
elimination would afford the [4 + 2] cyclization product 4a and
the Rh(I) species. Reoxidation of Rh(I) to Cp*Rh(III) by
Ag2O would enable the catalytic cycle. Regarding the [4 + 1]
cyclization, the mechanism is similar to that of the [4 + 2]
cyclization, except that the intramolecular electrophilic addition
takes place on the para-position of the phenol ring (F to G) to
furnish the dearomatized spirocyclohexadienone product.
In conclusion, we have demonstrated a Rh(III)-catalyzed
selective coupling of N-methoxy-1H-indole-1-carboxamides and
aryl boronic acids, for divergent product formation. Kinetic
isotope effect studies were conducted to reveal a mechanism of
C−H activation and electrophilic addition. Further applications
of this method in pharmaceuticals is in progress.
perhaps secondary isotope effect, suggesting that C−H bond
cleavage occurs as part of the reaction, but cannot be part of the
rate-determining step. When Ag2O was used as the oxidant for
3a synthesis, a KIE value of 1.83 was obtained (eq 3),
suggesting a C−H bond cleavage was occurring during the rate-
determining step. Notably, when [D]-3a was synthesized and
subjected to the [Cp*RhCl2]2/Ag2O oxidative system to obtain
4a, a KIE value of 1.0 was observed which excluded C−H bond
cleavage as the rate-determing step for the C−N bond
formation from 3a to 4a (eq 4), suggesting an intramolecular
electrophilic addition was occurring, which is evidenced by the
dearomatization of 2e. Therefore, this selective coupling is
mechanically unique in comparison to the Rh(III)-catalyzed
traditional coupling of arylboronic acids.11
Based on these experiments, a plausible set of mechanisms
are proposed in Scheme 2 to explain these selective couplings.
When Cu(OAc)2 is used as the oxidant, the dimeric
[Cp*RhCl2]2 changes to Cp*Rh(OAc)2. Cp*Rh(OAc)2 is
then captured by 1a to form the rhodacycle A via N-metalation
and a turnover limiting C−H activation. Transmetalation of A
C
dx.doi.org/10.1021/ol5014312 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization for products, copies
of H and C NMR spectra, and cif file for compound 5a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slcui@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21202143) and Zhejiang University.
■
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