RhCl3·3H2O-Catalyzed Regioselective C(sp2)-H Alkoxycarbonylation: Efficient Synthesis of Indole- and Pyrrole-2-carboxylic Acid Esters

Article abstract of DOI:10.1021/acscatal.9b01193

The C2-selective C-H alkoxycarbonylation of indoles with alcohols and CO catalyzed by RhCl₃·3H₂O is disclosed that offers convenient access to diverse indole-2-carboxylic esters. The rhodium-based catalysts outperformed all other precious-metal catalysts investigated. In addition, this protocal was found applicable to the synthesis of pyrrole-2-carboxylic esters, and allowed the C-H alkoxycarbonylation in an intramolecular fashion. Preliminary mechanistic studies indicate that C-H cleavage is not likely involved in the rate-determining step, and a five-membered rhodacycle might be an intermediate involved in the reaction.

Full text of DOI:10.1021/acscatal.9b01193

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Letter
RhCl3•3H2O-Catalyzed Regioselective C(sp2)-H Alkoxycarbonylation:
Efficient Synthesis of Indole- and Pyrrole-2-carboxylic Acid Esters
Kang Zhao, Rongrong Du, Bingyang Wang, Jianhua Liu, Chun-gu Xia, and Lei Yang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01193 • Publication Date (Web): 13 May 2019
Downloaded from http://pubs.acs.org on May 13, 2019
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RhCl ·3H O-Catalyzed Regioselective C(sp )−H Alkoxycarbonylation:
3
2
Efficient Synthesis of Indole- and Pyrrole-2-carboxylic Acid Esters
Kang Zhao,†,§ Rongrong Du,†,§ Bingyang Wang, Jianhua Liu, Chungu Xia, and Lei Yang*
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†
†
†
,†,‡
†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, P. R. China
‡Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University, Hangzhou 311121, P. R. China
3 2
ABSTRACT: The C2-selective C–H alkoxycarbonylation of indoles with alcohols and CO catalyzed by RhCl ·3H O is
disclosed that offers convenient access to diverse indole-2-carboxylic esters. The rhodium-based catalysts outperformed
all other precious-metal catalysts investigated. In addition, this protocal was found applicable to the synthesis of pyrrole-
-carboxylic esters, and allowed the C–H alkoxycarbonylation in an intramolecular fashion. Preliminary mechanistic
studies indicate that C–H cleavage is not likely involved in the rate-determining step, and a five-membered rhodacycle
might be an intermediate involved in the reaction.
2
KEYWORDS: indole-2-carboxylic esters, pyrrole-2-carboxylic esters, C–H activation, alkoxycarbonylation, rhodium
The indole skeleton has been recognized as a privileged
structural motif in natural products, pharmaceuticals,
agrochemicals, and other functional molecules. In
(a) Selected examples of indole-2-carboxylic acid derivatives with biological
or pharmaceutical activities
N
1
Cl
MeO
OMe
OMe
i-PrHN
N
particular, indole-2-carboxylic esters and derivatives
thereof are ubiquitous structural features in many
biologically active natural alkaloids and pharmaceutical
MeO
MeO
OH
N
N
3
O
O
O
S
2
agents (Scheme 1a). Consequently, considerable efforts
NH
have been directed toward the synthesis of indole-2-
Me
N
H
3
carboxylic esters and their derivatives. Traditionally,
Me
O
Cl
Mcl-1 inhibitor
MsHN
these indole scaffolds are constructed by the well-known
cyclization reactions, such as Hemetsberger indole
tubulin polymerization
inhibitor
delavirdine
4
5
synthesis,
Cadogan-Sundberg
indole
synthesis,
(
b) Previous work on transition-metal-catalyzed intermolecular C2-
selective C–H carbonylation reactions of indoles with CO
6
7
intramolecular Ullmann or Heck coupling reactions .
Though elegant, these cyclization reactions usually
demand the preparation of specific substrates through
multi-step reactions, which dramatically limit its
application. Therefore, the development of a more
efficient and straightforward route to achieve indole-2-
carboxylic esters is still highly desired.
Ar
O2N
I
Ar
R
Ar
Ar
HN
O
O
R
[Pd], [Mo(CO)6]
(Driver 2017)
[Ru], CO
(Beller 2014)
N
N
DG
N
DG
R = H, Me
DG
Recently,
transition-metal-catalyzed
direct
C–H
(
c) This work: RhCl3•3H2O-catalyzed C–H alkoxycarbonylation for the
synthesis of indole- and pyrrole-2-carboxylates
carbonylation of indole framework itself has emerged as a
new avenue to access carbonyl-functionalized indole
derivatives on account of its atom economy and
R2
R2
[
Rh]
CO
1 atm of CO/broad scope
OR
8
R1
R1
simplified procedure. In this context, because of its low
H
+
ROH
N
N
O
price and ready availability, the use of carbon monoxide
DG
DG
(
CO) in transition-metal-catalyzed intermolecular C–H
external acid- and base-free conditions
RhCl3•3H2O instead of [Cp*Rh] complex
carbonylation reactions of indoles with different
9,10
nucleophiles is of great interest. Compared to the well-
established C3 selective C–H carbonylation of indoles
with CO, direct regioselective C2 carbonylation is less
explored. To the best of our knowledge, only two
examples towards the synthesis of ketones or amides have
Scheme
1.
State-of-the-art
on
C2-Selective
Carbonylation of Indoles with CO
1
0
been reported so far (Scheme 1b). In 2014, Beller and co-
workers first reported the ruthenium-catalyzed C2-
selective carbonylative arylation of iodoarene with CO
11
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30 bar) and indoles containing pyridyl or pyrimidyl Table 1. Optimization of the C2-Selective C–H
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(
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5
6
o
a
directing group (DG) in the presence of base at 120 C.
Alkoxycarbonylation
Notably, using pivalic acid as the additive and [Mo(CO)
as the origin of CO and the reductant, the Driver group
6
]
1
2
cat. (1-5 mol%)
On-Bu
CO (1 atm)
H
+
n-BuOH
developed an elegant three-component palladium-
catalyzed aminocarbonylation of 2-aryl- or 2-heteroaryl-
pyridines and nitroarenes. In this case, two 2-pyridyl
indoles were reported to deliver the desired amides. In
view of the potential easy transformation of esters, and
the fact that the C2-selective alkoxycarbonylation of
oxidant (2 equiv)
DMF, temp., time
N
N
3
DG
O
1
DG
2a
Entry Cat. (mol%)
Oxidant
Yield (%)b
1
[Cp*RhCl
[Rh(OAc)
[Rh(cod)Cl]
2
]
2
(2.5)
(2.5)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
2
>99
93
3
indoles with CO still remains a formidable challenge, it
0
1
2
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1
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3
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0
1
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9
0
1
2
3
4
5
6
7
8
9
0
2
3
4
5
6
7
2 2
]
would be particularly attractive to realize the synthesis of
indole-2-carboxylic esters via alkoxycarbonylation of
2
(2.5)
95
1
3
indoles with CO. Herein, we report for the first time the
C2-selective alkoxycarbonylation of indoles with CO
RhCl
RhCl
3
·3H
(5)
2
O (5)
>99
>99
0
1
4
3
catalyzed by RhCl
3 2
·3H O (Scheme 1c), which is seldom
used as the catalyst in C–H activation reactions compared
Pd(OAc)
RuCl ·3H
IrCl ·3H
2
(5)
1
5
to the typically used expensive [Cp*RhCl
We recently reported an efficient Rh/O
for selective oxidative C2-alkenylation of indoles. During
this work, we identified that five-membered
2
]
2
catalyst.
3
2
O (5)
0
2
catalytic system
8
9c
O (5)
0
3
2
1
6
98(94)e
RhCl
RhCl
3
·3H
·3H
2
O (5)
O (5)
a
1
0
3
2
>99
0
cyclometalated Rh(III) complex, which could undergo
migrative insertion of an alkene and then followed by
reductive elimination to produce the final product, was a
key intermediate involved in the catalytic cycle. We were
curious whether this class of five-membered
cyclometalated Rh(III) complex could enable the
migrative insertion of CO and then accept the
nucleophilic attack of an appropriate nucleophile, thus
giving rise to access molecules with increased complexity.
To this end, we initially synthesized cyclometalated Rh(III)
complex A by treatment of 1-(pyrimidin-2-yl)-1H-indole
11
RhCl ·3H O (5)
3
3
3
3
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
2
2
Cu(TFA)2
12
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
·3H
·3H
·3H
·3H
·3H
·3H
·3H
·3H
·3H
·3H
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
O (2)
O (1)
O (2)
Cu(OTf)
Cu(EtCO
Cu(i-PrCO
Cu(OPiv)
2
trace
97
1
3
2 2
)
14
2
)
2
94
1
5
2
50
16
Cu(1-AdCO
2
)
2
0
1
1
1
7
8d
9d
AgOAc
trace
>99
>99(95)e
78
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
1
7
(
1a) with [RhCp*Cl
complex A with 1 atm of CO and n-BuOH (2a, 5 equiv) in
the presence of Cu(OAc) was then conducted (eq 1). To
2
]
2
.
The stoichiometric reaction of
20d
21d,f
2
our delight, the expected ester 3aa could be formed, albeit
in relatively low yield (19%), supporting that the
alkoxycarbonylation of 1a with CO would be indeed
possible. This promising result led us to focus on
developing this C–H alkoxycarbonylation reaction into a
catalytic process.
75
aReaction conditions: 1a (0.2 mmol, 1 equiv), 2a (11 equiv), cat.
1-5 mol%), oxidant (2 equiv), and DMF (2 mL) under 1 atm
(
o
o
of CO in sealed tube at 110 C for 14 h (entries 1-9) or at 90 C
b
1
for 10 h (entries 10-20). Yield determined by H NMR using
c
1
,3,5-trimethoxybenzene as internal standard. 1-(pyridin-2-yl)-
On-Bu
d
e
Cp*
1H-indole was used as the substrate. 2a (5 equiv). Isolated
yield. Performed at 85 C for 10 h.
CO (1 atm)
Rh
n-BuOH
(1)
f
o
N
Cl
+
N
O
Cu(OAc)2 (2 equiv)
o
N
2a
DMF, 90 C, 10 h
N
N
N
RhCl , was introduced to the reaction (entries 4 and 5).
Other simple and readily available palladium, rhuthenium
3
19%
A
3aa
Guided by the preliminary investigation above, we
initially focused on the catalytic C–H alkoxycarbonylation
of 1a with 2a (5-11 equiv) employing readily available
rhodium catalysts. As shown in Table 1, we were
surprised to find that the desired product 3aa was formed
and iridium catalysts were also screened. These efforts,
however, did not produce the desired product (entries 6-
18
8
). Various directing groups were then tested. In
1
8
addition to 2-pyimidinyl group, 2-pyridyl group was also
an effective directing group for this reaction (entry 9).
Investigation on solvents showed that toluene or NMP
2 2
in quantitative yield under the conditions of [Cp*RhCl ]
o
(
1
[
2.5 mol%), Cu(OAc)
4 h (entry 1). Interestingly, switching of the catalyst from
Cp*RhCl to [Rh(OAc) or [Rh(cod)Cl] led to
2
(2 equiv), CO (1 atm), DMF, 110 C,
18
also gave a good yield of 3aa. The reaction temperature
o
could be lowered to 90 C without loss of any reactivity
entry 10). Among the oxidants tested, only copper-based
oxidants were workable and Cu(OAc) gave the best
2
]
2
2
]
2
2
(
excellent NMR yield of 3aa (entries 2 and 3), too. Notably,
we were delighted to find that full conversion of 1a to 3aa
was observed when simple inorgnic salt, RhCl ·3H O or
3 2
2
results (entries 10-17). Moreover, we observed that the
anion size of the copper carboxylate salts affected the
efficiency of the alkoxycarbonylation reaction (entries 10,
1
3-16). Of note, the same yield was maintained while
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R2
R2
R1
R1
RhCl3•3H2O (2 mol% )
R3
1
2
3
4
5
6
7
8
9
R3
R4
OR
CO (1 atm)
H
+
ROH
N
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 10-14 h
R4
N
O
R5
2
R5
N
N
N
N
1
3
A. Variation of alcohols
primary alcohols
OR
3ai: R' = cyclopropyl, 89%
3
3
3
3
aa: R = n-Bu, 95%
ab: R = Me, 95%
ac: R = Et, 97%
ad: R = n-Pr, 89%
NPhth
OCH2R'
O
3
3
aj: R' = CH OMe, 67%
3
2
ak: R' = (CH ) OTBS, 62%
2 2
N
O
N
O
N
O
3al: R' = (CH ) OH, 83%
2 2
N
N
3am: R' = Ph, 67%
3an: R' = 2-furanyl, 68%
3ao: R' = 2-thiophenyl, 66%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
3ae: R = n-pentyl, 93%
af: R = n-octyl, 73%
ag: R = n-dodecyl, 67%
N
N
N
3
3
X-ray
of 3ai
3
aq 75%
3
ap: R' = (CH ) NMe , 0%
3ah: R = (CH ) Ph, 81%
2 2 2
2
4
secondary alcohols
OR
O(CH2)3CH=CH2
O
O
N
O
N
O
N
O
N
N
O
N
N
N
N
3
as 56%
N
3az 61%
from
(±)-Menthol
N
N
from
3
3
3
3
3
at: R = i-Pr, 93%
X-ray of 3ax
3ar 65%
(±)-Citronellol
au: R = cyclobutyl, 86%
av: R = cyclopentyl, 81%
aw: R = cyclohexyl, 62%
B. Variation of indoles
tertiary alcohols
O
ax: R = cyclopent-3-enyl, 89%
H
3ay: R = benzhydryl, 74%
R1
OTBS
On-Bu
O
NPhth
On-Bu
O
OR
O
H
On-Bu
H
N
O
H
H
N
O
N
N
N
O
N
N
N
N
N
N
N
N
O
3
aa' 50%
from
N
N
3ba: R1 = Me 94%
ca: R1 = Cl 0%
3ab': R = t-Bu 81%
Diosgenin
3ac': R = t-pentyl 80%
3da 79%
3ea 98%
3
R2
NPhth
R3
MeO2C
On-Bu
On-Bu
On-Bu
On-Bu
On-Bu
N
O
On-Bu
R4
N
O
N
O
N
O
N
O
N
N
R5
N
N
N
N
N
N
N
O
N
N
N
ja: R3 = Me 91%
3
3
3
N
ka: R3 = OMe 95%
3ga: R2 = Me 94%
ha: R2 = F 58%
ia: R2 = Cl 48%
4
la: R3 = Cl 59%
3ma: R3 = Br 58%
3oa: R = Me 92%
3pa: R4 = F 61%
3qa: R4 = Cl 58%
5
3fa 91%
3ra
: R = F 93%
3ta 80%
3
3
3sa: R5 = Me 77%
3na: R3 = CO Me 62%
b
2
a1 (0.2-1 mmol, 1 equiv), 2a (5 equiv), RhCl
o
3
·3H
2
O (2 mol%), Cu(OAc)
2
(2 equiv), DMF (2 mL/0.2 mmol 1), CO (1 atm), 90 C, 10-14
(2 equiv), DMF (2 mL), CO (1 atm), 110 C, 14 h. Phth=phthaloyl,
b
o
h. 1n (0.2 mmol), 2a (11 equiv), RhCl
3
·3H
2
O (5 mol%), Cu(OAc)
2
TBS=tert-butyldimethylsilyl.
Scheme 2. Scope and Limitations of Alkoxycarbonylation of Indoles and Alcoholsa
lowering both the catalyt loading (to 2 mol%, entry 19)
and the amount of 2a (to 5 equiv, entry 18). Further
lowering the catalyst loading and reaction temperature
resulted in decreased yield of 3aa (entries 20 and 21).
Control experiments indicated that no reaction was
primary alcohols bearing various functional groups were
reacted. Simple aliphatic alcohols with different chain
lengths were all suitable nucleophiles and these reactions
gave the desired products (3aa-3ag) in high yields.
Different functional groups such as aryl (3ah),
1
8
19
detected in the absence of CO or rhodium catalyst.
cyclopropyl (3ai, with crystal structure) , methoxy (3aj),
and tert-butyldimethylsilyl ether (3ak) were well-
tolerated. Interestingly, the direct conversion of 1,3-
propanediol (2l) into its corresponding monoester with a
free hydroxy group (3al) was observed.
or heterobenzylic (3an and 3ao) alcohols also proved to
be efficient coupling partners. Not surprisingly, although
-(dimethylamino)propan-1-ol (2p) was completely
unreactive, N-protected amino alcohol 2q was
Having etablished optimal reaction conditions, we next
investigate the scope and limitations of the reaction.
Initially, we checked the generality of the alcohol
coupling partner. As shown in Scheme 2, the
carbonylative functionalization occurred smoothly at the
C-2 position of N-pyrimidine indole 1a with a variety of
alcohols, giving rise to the corresponding indole-2-
carboxylates in good to excellent yields. Numerous
1
8,20
Benzylic (3am)
3
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successfully converted to 3aq in 75% yield. In addition, we
Scheme 3. Intramolecular C–H Alkoxycarbonylation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found that alkenyl functional group (3ar and 3as) was
also tolerated and in particular, citronellol (2s) was
successfully acylated to furnish 3as in decent yield. To
explore the applicability of alcohols, various secondary
alcohols were then examined. Reactions of simple both
linear and cyclic alcohols, such as isopropanol,
cyclobutanol, cyclopentanol, and cyclohexanol, proceeded
well to afford the corresponding esters in excellent yields
(3at-3aw). Again, we were pleased to find that the cyclic
alcohol 2x bearing one alkenyl double bond could
undergo direct carbonylation to give 3ax (with crystal
We next sought to apply this protocal to intramolecular
C–H carbonylation (Scheme 3). To our delight, the
reaction of 4 with CO gave the desired product 5 (with
1
9
crystal structure ) in 72% yield under standard conditions.
A high isolated yield (85%) of 5 was obtained just by
o
o
increasing the temperature from 90 C to 110 C.
Interestingly, when we exposed 6 and 7 to the standard
conditions, we didn’t observe any carbonylative product,
thereby highlighting the directing role of pyrimidyl group
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
in 4. The present method offers a new complementary
23
1
9
route to synthesize indole δ-lactone motif.
structure ). Gratifyingly, diphenylmethanol 2y was found
to be compatible. Importantly, some structurally complex
secondary alcohols such as diosgenin and (±)-menthol
reacted smoothly with 1a to provide 3aa’ and a racemic
Of note, the C7-selective C–H carbonylation of 3aa
proceeded smoothly in the presence of RhCl /Cu(OAc) in
3
2
n-BuOH, giving rise to 8 in 60% yield, which marks the
1
8
product 3az , respectively, hence indicating a proof of
concept of our methodology for further late-stage
functionalization. It is especially noteworthy that tertiary
alcohols, such as tert-pentyl alcohol and tert-amyl alcohol,
could be used as the nucleophile in this reaction (3ab’ and
first example of rhodium-catalyzed C–H carbonylation of
24
indole with CO at the C7-position (eq 2). The structure
1
9
of 8 was confirmed by single-crystal X-ray diffraction.
RhCl3•3H2O (2 mol% )
CO2n-Bu
CO2n-Bu
CO (1 atm)
N
N
(2)
Cu(OAc)2 (2 equiv)
3
ac’), thus indicating the unique feature of this RhCl
3
-
H
N
o
N
n-BuOH, 90 C, 10 h
N
n-BuO
ON
based system in C–H carbonylation in contrast with
60%
3aa
8
21
previously reported results.
Moreover, this methodology could be used to prepare
ester-functionalized pyrrole derivatives. As shown in
Scheme 4, not unexpectedly, double alkoxycarbonylation
product 10aa was produced in 90% yield when 2-(1H-
pyrrol-1-yl)pyrimidine 9a was used as the substrate. In
contrast, under the optimal reaction conditions, C2-
substituted pyrrole derivatives 9b and 9c afforded the
corresponding pyrrole-2-carboxylate products 10ba and
10ca in 65% and 83% yield, respectively.
Afterward, we explored the scope of the reaction with
respect to different indole derivatives. A series of indole
derivatives with various substituents were subjected to
the alkoxycarbonylation of n-BuOH and CO (Scheme 2).
Generally, the use of electron-rich indoles possessing
methyl (1b, 1g, 1j, 1o and 1s) and methoxy (1k)
substituents at various positions delivered corresponding
products (3ba, 3ga, 3ja, 3oa, 3sa and 3ka) in good to
excellent yields, while indoles with electron-withdrawing
groups, such as fluoro, chloro, and bromo, provided the
corresponding products in moderate to good yields (3ha,
R
RhCl3•3H2O (2 or 5 mol%)
R
On-Bu
CO (1 atm)
N
+
N
n-BuOH
Cu(OAc)2 (2-4 equiv)
O
2a
N
N
DMF, 90 o
N
N
3
ia, 3la, 3ma, 3pa, 3qa, and 3ra). For 3-substituted
C
indoles, the reaction was sensitive to the electronic nature
of the substituents (3ba vs 3ca). It is worth noting that
substituents at the 7-position caused an interesting
electronic/steric synergistic effect (3ra vs 3sa).
Interestingly, electron deficient indole 1n with an ester
group reacted well to give 3na in good yield. More
importantly, pharmaceutically useful compounds, such as
tryptophol, tryptamine and tryptophan derivatives, also
reacted smoothly to provide 3da, 3ea and 3fa in 79-98%
yields. In addition, the C–H carbonylation proceeded
9
10
O
n-BuO
On-Bu
On-Bu
On-Bu
N
Me
N
O
O
O
N
O
N
N
N
N
N
N
1
0aa 90%a
10ba 65%b
1
0ca 83%b
a9a (0.2 mmol, 1 equiv), 2a (20 equiv), RhCl
Cu(OAc)
equiv), 2a (5 equiv), RhCl
·3H
O (5 mol%),
3
2
b
2
(4 equiv), DMF (2 mL), 90 °C, 24 h. 9 (0.2 mmol, 1
3
·3H
2
O (2 mol%), Cu(OAc)
2
(2
o
1
8
equiv), DMF (2 mL), CO (1 atm), 90 C, 10 h.
without racemization of the stereogenic center in 2f.
Finally, reacting 1-(pyrimidin-2-yl)-1H-benzo[g] indole 1t
and 2a under standard conditions led to 3ta in 80% yield.
Scheme 4. Alkoxycarbonylation of Pyrroles with CO
(
a)
CO2Et
OH
O
RhCl3•3H2O (2 mol% )
RhCl3•3H2O (2 mol% )
CO (1 atm)
87%
N
H
CO (1 atm)
H
1a
+
2a
3aa
6%
(1.28g)
11a
N
O
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 24 h
N
Cu(OAc)2 (2 equiv)
8
DMF, 110 o
(b)
C
N
N
CO2H
N
5
84%
4
N
85%
N
H
11b
OH
Reaction conditions: (a) LiOEt (3 equiv, 1 M in EtOH), DMSO,
o
o
90 C, 3 h. (b) NaOEt (3 equiv, 8% in EtOH), DMSO, 100 C,
11 h.
N
R
R = H (6) or Me (7)
unreacted substrates
Scheme 5. Gram-scale Synthesis and Synthetic Utility
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kinetic isotope effect (KIE) study from two parallel kinetic
experiments on 1a or [2-D]-1a (94% D) with n-BuOH
revealed a low k /k value of 1.51 (average of two runs),
H D
1
2
3
4
5
6
7
8
9
18
Considering the synthetic potential of this C–H
alkoxycarbonylation method, the gram-scale experiment
was then performed by utilizing 1a and 2a (10 equiv) on a
25-fold (5 mmol) scale (Scheme 5). Still, very high
efficiency was observed, with an excellent yield of 3aa
obtained. Furthermore, we have tried the removal of
pyrimidyl group from 3aa, as the free N–H estered indole
could bring more synthetic values. The choice of the base
is crucial for the success of this reaction. After several
trials, we were happy to find that the pyrimidinyl group
could be removed efficiently under different conditions to
afford the unprotected transesterification indole 11a or
indole-2-carboxylic acid 11b in 87% and 84% yield,
respectively.
which indicated that the C–H cleavage is not likely to be
the rate-limiting step (Scheme 6b). In addition, when
complex A was used as the catalyst, a high yield of 3aa
(90%) was obtained (Scheme 6c, left). In contrast to the
stoichiometric reaction in the absence of acidic additive
(eq. 1), the reaction of A and 2a in the presence of HOAc
gave 3aa in 60% yield (Scheme 6c, right). These results
support that a rhodacycle species might be most likely as
a reaction intermediate involved in this reaction and the
proton released from the C–H metalation was essential
for catalytic turnover. Moreover, intermolecular
competition experiments between differently substituted
indoles with 2a indicated that while a more electron-rich
indole (1o) reacts to a greater extent than an electron-
deficient one (1q), the difference is not substantial, which
is consistent with the proposal of indole C–H activation
not being turnover-limiting. Reactions of 1a with 2a and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
(a) H/D scrambling experiments
+
CD3OD
H/D
10% D
RhCl3•3H2O (2 mol%)
1a
N
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 10 h
N
N
2
b’ were suggestive of less sterically hindered alcohols are
more reactive in this transformation (Scheme 6d).
[
D]n-1a 95%
+ CD3OD
OCD3
3aa
1a
RhCl3•3H2O (2 mol%)
RhIIILn
1a
H/D
+
CO (1 atm)
N
N
O
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 2 h
H+
2
0% D
Cu0
N
N
N
N
C-H
activation
CuII
[
D]n-1a 60%
b) kinetic isotope effect (parallel experiments)
2a
36%
(
O
+
Ln-3
On-Bu
N
RhIII
N
RhIIILn-2
D
RhCl3•3H2O (2 mol%)
I
III
On-Bu
N
1a
or
N
CO
N
N
CO (1 atm)
N
O
N
N
N
N
IIILn-4
Cu(OAc)2 (2 equiv)
N
Rh
N
IV
N
DMF, 90 o
C
N
On-Bu
kH/kD = 1.51
[
2-D]-1a
3aa
migratory
insertion
ligand
exchange
(
c) stoichiometric and catalytic reactions of rhodacycle A
HOAc
L = OAc
CO
A (2 mol%)
CO (1 atm)
HOAc (30 mol%)
O
1a + 2a
3aa
A
+ 2a
CO (1 atm)
RhIIlLn-2
N
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 10 h
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 10 h
2a
II
N
N
90%
60%
(d) intermolecular competition experiments
Scheme 7. Possible Catalytic Cycle for RhCl
Catalyzed Alkoxycarbonylation
3
-
On-Bu
RhCl3•3H2O (2 mol%)
N
+ 2a
Cl/Me
N
O
R
CO (1 atm)
N
Given the results obtained above and previous
N
N
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 6 h
N
1
3,21a,25
reports,
a
plausible mechanistic pathway is
1o/1q/2a (0.1 mmol, each)
3oa: R = Me, 9% (by NMR)
qa: R = Cl, 6% (by NMR)
postulated (Scheme 7). Initially, coordination of the
nitrogen directing group in 1a to Rh(III) catalyst precedes
the C–H activation event, which gives five-membered
rhodacycle species I. Next, one molecule of CO binds to
the putative rhodacycle, followed by 1,1-migratory
insertion of CO into the Rh–C bond to generate
3
2a
and
RhCl3•3H2O (2 mol%)
1a
+
3aa
8%
CO (1 atm)
2b'
5
Cu(OAc)2 (2 equiv)
DMF, 90 oC, 5 h
(by NMR)
1
a/2a/2b' (0.2 mmol, each)
sole product
26
Scheme 6. Preliminary Mechanistic Studies
intermediate II . Subsequently, alcohol 2a coordinates to
II via ligand exchange with a loss of one molecule of
HOAc, leading to intermediate III. At this point,
reductive elimination can occur to afford the desired
product 3aa and a rhodium(I) species, which requires an
oxidation to re-enter the catalytic cycle. However, a
mechanism involving coordination of CO and 2a to
rhodium via ligand exchange to form intermediate IV and
sequential migratory insertion of CO to afford III could
not be ruled out at this stage.
Several experiments were next conducted in order to gain
some insights into the mechanism of this process
(Scheme 6). First, deuterium labeling experiments were
conducted with 1a. H/D scrambling experiments in the
absence and in the presence of CO were suggestive of a
reversible C–H rhodation and highlighted an
organometallic C–H activation mechanism, albeit this
process is low (Scheme 6a). Second, an intermolecular
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In summary, we have developed a RhCl
3
·3H
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Curr. Opin. Chem. Biol. 2010, 14, 347−361. (g) Bartoli, G.;
Dalpozzo, R.; Nardi, M. Applications of Bartoli Indole Synthesis.
Chem. Soc. Rev. 2014, 43, 4728−4750.
C–H carbonylation of indoles with alcohols and CO. The
reaction generates a diverse range of indole-2-carboxylic
esters. It is noteworthy that the same rhodium-based
catalytic system could be applied to synthesize pyrrole-2-
carboxylic esters and indole δ-lactone moity, and the
(
2) (a) Saxton, J. E. Recent Progress in the Chemistry of Indole
Alkaloids and Mould Metabolites. Nat. Prod. Rep. 1990, 7,
91−243. (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Simple
Indole Alkaloids and Those with Non-rearranged
1
latter
was
produced
via
intramolecular
C–H
a
alkoxycarbonylation. This process represents the first
example of transition-metal-catalyzed C2-selective C–H
alkoxycarbonylation of indoles with CO and the first
Monoterpenoid Unit. Nat. Prod. Rep. 2013, 30, 694−752. (c)
Romero, D. L.; Busso, M.; Tan, C.-K.; Reusser, F.; Palmer, J. R.;
Poppe, S. M.; Aristoff, P. A.; Downey, K. M.; So, A. G.; Resnick,
L.; Tarpley, W. G. Nonnucleoside Reverse Transcriptase
Inhibitors that Potently and Specifically Block Human
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USA. 1991, 88, 8806−8810. (d) Martino, G. D.; Regina, G. L.;
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Hamel, E.; Artico, M.; Silvestri, R. Arylthioindoles, Potent
Inhibitors of Tubulin Polymerization. J. Med. Chem. 2004, 47,
successful example of RhCl
carbonylation of aromatic C–H bonds with CO. We
believe that this RhCl ·3H O-based system might show
3 2
·3H O-catalyzed direct
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27
3
2
broad applicability to different types of including but not
limited to C–H carbonylation reactions. Efforts towards
this direction are currently underway in our laboratory.
6
120−6123. (e) Okano, K.; Tokuyama, H.; Fukuyama, T. Total
Synthesis of (+)-Yatakemycin. J. Am. Chem. Soc. 2006, 128,
136−7317. (f) Friberg, A.; Vigil, D.; Zhao, B.; Daniels, R. N.; Burke,
AUTHOR INFORMATION
Corresponding Author
7
J. P.; Garcia-Barrantes, P. M.; Camper, D.; Chauder, B. A.; Lee, T.;
Olejniczak, E. T.; Fesik, S. W. Discovery of Potent Myeloid Cell
Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
and Structure-Based Design. J. Med. Chem. 2013, 56, 15−30.
(3) Gribble, G. W. Indole ring synthesis: From natural products to
drug discovery; John Wiley & Sons: West Sussex, U.K., 2016.
*
E-mail: lyang@licp.cas.cn
Author Contributions
§(
K.Z., R.D.) These authors contributed equally to this work.
Notes
(
4) For recent examples, see: (a) Stokes, B. J.; Dong, H.; Leslie, B.
E.; Pumphrey, A. L.; Driver, T. G. Intramolecular C−H Amination
Reactions: Exploitation of the Rh (II)-Catalyzed Decomposition
The authors declare no competing financial interest.
2
ASSOCIATED CONTENT
of Azidoacrylates. J. Am. Chem. Soc. 2007, 129, 7500−7501. (b)
Bonnamour, J.; Bolm, C. Iron(II) Triflate as a Catalyst for the
Synthesis of Indoles by Intramolecular C−H Amination. Org. Lett.
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
http://pubs.acs.org.
Experiment details, spectra data, copies of H and C NMR
spectra for all new compounds (PDF)
X-ray data for 3ai (CCDC 1879313) (CIF)
X-ray data for 3ax (CCDC 1879312) (CIF)
X-ray data for 5 (CCDC 1879311) (CIF)
2
011, 13, 2012−2014. (c) Farney, E. P.; Yoon, T. P. Visible-Light
1
13
Sensitization of Vinyl Azides by Transition-Metal Photocatalysis.
Angew. Chem., Int. Ed. 2014, 53, 793−797.
(5) For selected examples, see: (a) Sundberg, R. J.; Yamazaki, T.
Rearrangements and Ring Expansions during the Deoxygenation
of β, β-Disubstituted o-Nitrostyrenes. J. Org. Chem. 1967, 32,
290−294. (b) Cadogan, J. I. G. A New Series of Nitrene-Induced
X-ray data for 8 (CCDC 1879310) (CIF)
Aromatic Rearrangements. Acc. Chem. Res. 1972, 5, 303−310. (c)
Creencia, E. C.; Kosaka, M.; Muramatsu, T. Kobayashi, M.; Iizuka,
T.; Horaguchi, T. Microwave-Assisted Cadogan Reaction for the
Synthesis of 2-Aryl-2H-indazoles, 2-Aryl-1H-benzimidazoles, 2-
Carbonylindoles, Carbazole, and Phenazine. J. Heterocycl. Chem.
2009, 46, 1309−1317.
(6) For recent reports, see: (a) Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei,
D.; Ding, K. Assembly of Indole-2-carboxylic Acid Esters through
a Ligand-free Copper-catalysed Cascade Process. Chem. Commun.
2009, 7581−7583. (b) Koenig, S. G.; Dankwardt, J. W.; Liu, Y.;
Zhao, H.; Singh, S. P. Copper-Catalyzed Synthesis of Indoles and
Related Heterocycles in Renewable Solvents. ACS Sustainable
Chem. Eng. 2014, 2, 1359−1363.
ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (Grant Nos. 21372231, 21173241
and 21673260). L.Y. acknowledges the financial support from
the Hangzhou Normal University. We thank Mr. Zhiqiang
Shen, Mr. Xudong Gao and Ms. Xiaoning Wei 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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(
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(14) For examples on RhCl
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imides with Rhodium(III)–Copper(II) Catalytic System.
3 2
·3H O-catalyzed C–H activation, see:
[
a
Synthesis 2005, 1959−1966. (b) Wang, P.; Rao, H.; Hua, R.; Li, C.-J.
Rhodium-Catalyzed Xanthone Formation from 2-Aryloxybenz-
aldehydes via Cross-Dehydrogenative Coupling (CDC). Org. Lett.
2
3
012, 14, 902−905. (c) Ran, Y.; Yang, Y.; You, H.; You, J. RhCl ‑
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796−1801. (d) Shi, Y.; Zhang, L.; Lan, J.; Zhang, M.; Zhou, F.; Wei,
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between N-Acylanilines and Benzamides Enabled by a Cp*-Free
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108−9012. (e) She, Z.; Wang, Y.; Wang, D.; Zhao, Y.; Wang, T.;
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Hetero)arylimidazolium Salts and (Hetero)arenes. J. Am. Chem.
Soc. 2018, 140, 12566−12573.
3
/TFA Catalytic System. Angew. Chem., Int. Ed. 2018, 57,
9
3
2
(
(
15) For selected reviews on Rh(III)-catalyzed C−H activation, see:
(
a) Satoh, T.; Miura, M. Oxidative Coupling of Aromatic
Substrates with Alkynes and Alkenes under Rhodium Catalysis.
Chem. Eur. J. 2010, 16, 11212−11222. (b) Song, G.; Wang, F.; Li, X.
C–C, C–O and C–N Bond Formation via Rhodium(III)-Catalyzed
Oxidative C–H Activation. Chem. Soc. Rev. 2012, 41, 3651−3678. (c)
Activated Olefins through
a
Long-Range Deconjugative
Isomerization. J. Am. Chem. Soc. 2018, 140, 6062−6066.
Kuhl, N.; Schröder, N.; Glorius, F. Formal S
Rhodium(III)-Catalyzed C−H Bond Activation. Adv. Synth. Catal.
014, 356, 1443−1460. (d) Hummel, J. R.; Boerth, J. A.; Ellman, J. A.
N
-Type Reactions in
(25) (a) Du, Y.; Hyster, T. K.; Rovis, T. Rhodium(III)-Catalyzed
Oxidative Carbonylation of Benzamides with Carbon Monoxide.
Chem. Commun. 2011, 47, 12074−12076. (b) Lang, R.; Wu, J.; Shi,
L.; Xia, C.; Li, F. Regioselective Rh-Catalyzed Direct
Carbonylation of Indoles to Synthesize Indole-3-carboxylates.
2
Transition-Metal-Catalyzed C−H Bond Addition to Carbonyls,
Imines, and Related Polarized π Bonds. Chem. Rev. 2017, 117,
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Chem. Commun. 2011, 47, 12553−12555. (c) Iturmendi, A.; Sanz
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A. Dimethylphosphinate Bridged Binuclear Rh(I) Catalysts for
the Alkoxycarbonylation of Aromatic C–H Bonds. Dalton Trans.
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016, 45, 16955−16965.
26) Although we could not isolate the proposed rhodacycle
species (II) at current stage, ESI-MS studies showed that
rhodacycle (II) might be involved in the catalytic cycle. For
more details, see the Supporting Information.
3
(27) For an elegant work on RhCl -catalyzed carbonylation of
methane to acetic acid, see: Lin, M.; Sen, A. Direct Catalytic
Conversion of Methane to Acetic Acid in an Aqueous Medium
Nature 1994, 368, 613−615.
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[Rh]
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R1
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R1
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N
N
OR
>
50 examples
DG
1 atm of CO
external acid- and base-free conditions
DG


up to 98% yield
 RhCl instead of [Cp*Rh] complex
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