Rh(III)-catalyzed decarboxylative ortho -heteroarylation of aromatic carboxylic acids by using the carboxylic acid as a traceless directing group

Article abstract of DOI:10.1021/acs.orglett.5b00532

Highly selective decarboxylative ortho-heteroarylation of aromatic carboxylic acids with various heteroarenes has been developed through Rh(III)-catalyzed two-fold C-H activation, which exhibits a wide substrate scope of both aromatic carboxylic acids and heteroarenes. The use of naturally occurring carboxylic acid as the directing group avoids troublesome extra steps for installation and removal of an external directing group.

Full text of DOI:10.1021/acs.orglett.5b00532

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Decarboxylative ortho-Heteroarylation of Aromatic
Carboxylic Acids by Using the Carboxylic Acid as a Traceless
Directing Group
Xurong Qin,†,‡ Denan Sun,† Qiulin You,† Yangyang Cheng,† Jingbo Lan,*,† and Jingsong You*,†
†Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
‡College of Pharmaceutical Science, Southwest University, 2 Tiansheng Road, Chongqing 400716, China
S
* Supporting Information
ABSTRACT: Highly selective decarboxylative ortho-hetero-
arylation of aromatic carboxylic acids with various heteroarenes
has been developed through Rh(III)-catalyzed two-fold C−H
activation, which exhibits a wide substrate scope of both
aromatic carboxylic acids and heteroarenes. The use of naturally occurring carboxylic acid as the directing group avoids
troublesome extra steps for installation and removal of an external directing group.
ryl−heteroaryl scaffolds are highly important structural
containing directing groups including pyridyl, pyrimidinyl,
pyrazolyl, and amides enable ortho-selective heteroarylation of
arenes via two-fold C−H activation (Scheme 1).
A
motifs frequently found in natural products, pharmaceut-
icals, and functional materials (Figure 1).1 From the step- and
Scheme 1. Direct ortho-Heteroarylation of Aromatic
Carboxylic Acids via Transition-Metal-Catalyzed Oxidative
C−H/C−H Cross-Coupling
Figure 1. Selected molecules containing aryl−heteroaryl scaffolds.
atom-economic perspective, transition-metal-catalyzed oxida-
tive C−H/C−H cross-coupling between a simple arene and a
heteroarene is one of the most attractive approaches to access
these bi(hetero)aryl moieties, which obviates tedious and
wasteful prefunctionalization of coupling partners in C−H/C−
X or C−X/C−M coupling reactions.2 Although the realm has
undergone rapid growth with a number of impressive examples
over the past few years,3 two major barriers make this pathway
greatly challenging and impose severe limitations on synthetic
applications: (1) a troublesome regioselectivity issue with the
substituted arene partner and (2) a required large excess of
arene (usually as solvent or cosolvent) due to the generally low
reactivity of C−H bonds. Recently, methods involving directing
groups for the selective cleavage of the proximal aromatic C−H
bond have been considered as an efficient strategy to overcome
these difficulties.4 The groups of Miura,4a,e Glorius,4d Kambe,4c
and You4b have independently disclosed that several nitrogen-
In principle, the most ideal directing group should be an
intrinsic part of the substrate, which avoids extra and
cumbersome steps for installation and detachment (even
nonremovability) of an external directing group. Aromatic
carboxylic acids are prevalent in natural and synthetic products.
The direct use of the naturally occurring carboxylic acid as the
directing group instead of the mostly used amide and oxazoline
can obviate the extra derivatization step of the carboxylate
group.5 Another substantial advantage is that the carboxylate
Received: February 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00532
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Letter
a b
,
group could be tracelessly removed by protodecarboxylation to
produce decarboxylative ortho-functionalized products. Both
ortho- and para-substituted aromatic carboxylic acids could be
transformed into the “formal” meta-substituted species via a
decarboxylative ortho-functionalization, which is otherwise
more difficult to reach in the presence of the ortho/para-
orientation of substituents.6
Scheme 2. Scope of Heteroarenes
Although a number of successful examples of transition-
metal-catalyzed carboxyl-directed ortho-C−H functionalizations
of anenes have been explored,7 the oxidative ortho-C−H
heteroarylation of aromatic carboxylic acids with heteroarenes
through double C−H activation still remains scarce (Scheme
1).7b To perform the ortho-selective heteroarylation process, a
series of fundamental challenges should be surmounted: (1)
Can less thermodynamically stable cyclometalated intermedi-
ates formed by the weakly coordinating carboxylate group
cleave the C−H bond of heteroarene coupling partner?5a (2)
Can decarboxylative ipso-heteroarylation of aromatic carboxylic
acids be prevented?8 (3) Can protodecarboxylation of the
starting aromatic carboxylic acids be restrained?9 (4) Can
homocoupling10 and decomposition of heteroarenes be sup-
pressed and eliminated? As a part of our program focusing on
oxidative C−H/C−H cross-coupling of two (hetero)arenes, we
describe the solution to these challenges and disclose the
rhodium-catalyzed decarboxylative ortho-heteroarylation of
aromatic carboxylic acids. During the submission of this
paper, Su et al. reported Rh(III)-catalyzed decarboxylative
C−H arylation of thiophenes.7b However, only thiophenes,
benzothiophenes, and benzofuran were employed as the
coupling partners in their work.
a
Reaction conditions: aromatic carboxylic acid (0.25 mmol),
heteroarene (3.0 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol
%), Ag2CO3 (3.0 equiv), K2HPO4 (2.0 equiv), 4 Å MS (100 mg), and
b
NMP (1.0 mL) at 150 °C for 24 h under a N2 atmosphere. Isolated
yields. [Cp*RhCl2]2 (5.0 mol %) and AgSbF6 (20 mol %) at 160 °C
for 48 h.
c
ybenzoic acid to produce the meta-heteroarylated products in
synthetically useful yields (Scheme 2, 3k−o). Moreover,
electron-deficient heteroarenes such as caffeine and thiazoles
could undergo decarboxylative ortho-coupling with benzoic
acids at the C2 site of azoles (Scheme 2, 3p,q). The 2-
substituted thiazole selectively underwent the cross-coupling at
the C5 position to form 5-arylthiazole (Scheme 2, 3r).
The scope of aromatic carboxylic acids was next examined
(Scheme 3). The ortho- or para-substituted benzoic acids
bearing both electron-donating and electron-withdrawing
groups regioselectively afforded the meta-heteroarylated prod-
ucts in moderate to good yields (Scheme 3, 3a, 4a−g). When a
meta-substituted benzoic acid was used, the heteroarylation
Allured by the success of palladium catalysis, we initially
investigated the palladium-catalyzed oxidative C−H/C−H
cross-coupling reaction between 2-methoxybenzoic acid (1a)
with benzothiophene (2a) (eq 1). To our disappointment, the
ab
,
Scheme 3. Scope of Aromatic Carboxylic Acids
reaction was very complicated and no obvious product was
observed (Table S1, entries 1−7). Subsequently, encouraged by
our recent results of Rh(III)-catalyzed oxidative C−H/C−H
cross-couplings of pyridyl- or pyrimidinyl-containing (hetero)-
arenes with heteroarenes,4b,11 we resorted to the rhodium
catalytic systems. The coupling reaction of 1a with 2a led to the
desired product 3a in 35% yield with concomitant proto-
decarboxylation in the presence of [Cp*RhCl2]2 by using
Ag2CO3 as the oxidant (Table S1, entry 8). In view of the
importance of the decarboxylative ortho-heteroarylated prod-
ucts, the reaction conditions were further optimized. After
screening several parameters (Tables S2−S5), the reaction
proceeded well and gave 3a in 83% yield when [Cp*RhCl2]2
(2.5 mol %) was used in combination with AgSbF6 (10 mol %),
K2HPO4 (2.0 equiv), and Ag2CO3 (3.0 equiv) in N-methyl-2-
pyrrolidone (NMP) at 150 °C for 24 h (Table S5, entry 4).
Under the optimized reaction conditions, a broad range of
thiophenes reacted smoothly with 2-methoxybenzoic acid to
afford the meta-heteroarylated products (Scheme 2, 3a−j).
More importantly, this protocol was compatible with the
presence of synthetically important functional groups such as
fluoro, chloro, bromo, aldehyde, ketone, ester, and cyano
(Scheme 2, 3d−j). Other electron-rich heteroarenes such as
furans, indoles, and indolizines also reacted with 2-methox-
a
Reaction conditions: aromatic carboxylic acid (0.25 mmol),
heteroarene (3.0 equiv), [Cp*RhCl2]2 (5.0 mol %), AgSbF6 (20 mol
%), Ag2CO3 (3.0 equiv), K2HPO4 (2.0 equiv), 4 Å MS (100 mg), and
b
NMP (1.0 mL) at 150 °C for 48 h under a N2 atmosphere. Isolated
yields.
B
DOI: 10.1021/acs.orglett.5b00532
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Organic Letters
Letter
occurred at the less hindered site, exclusively providing the
para-heteroarylation isomer (Scheme 3, 4i). The coupling of
2,3- and 3,4-disubstituted benzoic acids with benzothiophene
gave the 3,4-disubstituted aryl benzothiophenes in good yields
(Scheme 3, 4j,k). In addition, α-naphthoic acid was amenable
to the ortho-heteroarylation at the β-position in 62% yield
(Scheme 3, 4l).
To gain insight into the mechanism, a series of deuteration
experiments was conducted. First, the exposure of the
deuterated [D5]-1c to the rhodium catalytic system in the
presence of K2HPO4 for 1 h gave a loss of 55% deuterium (eq
2), whereas the H/D exchange ratio of [D1]-2a was only 6%
Although the detailed mechanism is not clear, a plausible
pathway could involve (1) coordination of the carboxylate
oxygen atom to Cp*Rh(III) to give a rhodium(III) carboxylate
and a subsequent electrophilic ortho-C−H bond activation of
arene; (2) the resulting rhodacycle intermediate IM1 reacting
with a heteroarene partner to give the critical heteroaryl−
rhodacycle intermediate IM2; and (3) reductive elimination
and subsequent protodecarboxylation giving the decarboxyla-
tive ortho-heteroarylated product (Scheme 4).
Scheme 4. Plausible Mechanism for ortho-Heteroarylation of
Aromatic Carboxylic Acids by Using the Carboxylic Acid as a
Traceless Directing Group
(eq 3). These observations suggested that the cross-coupling
reaction might initiate from the cyclometalation of benzoic
acids.4a,b,12 Next, kinetic isotope effects (KIE) for both coupling
partners were studied with regard to the C−H/D bonds. An
intermolecular competition reaction between benzothiophene
2a and its deuterated derivative did not give a significant KIE
value (kH/kD = 1.3) (eq 4), indicating that the C−H bond
cleavage of 2a could not be the rate-determining step. However,
a significant KIE of 3.4 was determined for benzoic acid 1c (eq
5). These results suggested that the C−H bond breaking of 1c
might be the rate-limiting step.13
Subsequently, the competition experiments among electroni-
cally differentiated 4-methoxybenzoic acid, 4-bromobenzoic
acid, and 4-cyanobenzoic acid indicated that the reactivity of
electron-rich benzoic acid is higher than that of electron-
deficient benzoic acid (Table S6). Thus, the cyclometalation
might proceed via an electrophilic C−H bond activation.14
Finally, the influence of [Cp*RhCl2]2 and silver salt on the
decarboxylation step was investigated. In the absence of
[Cp*RhCl2]2, 2-(benzothiophen-2-yl)-6-methoxybenzoic acid
(3a′) could smoothly decarboxylate to afford the desired
product 3a in 82% yield (eq 6). In sharp contrast, a trace
In summary, we have developed a highly regioselective
Rh(III)-catalyzed decarboxylative ortho-heteroarylation of ar-
omatic carboxylic acids with various heteroarenes (e.g.,
thiophenes, furans, indoles, indolizines, azoles, and xanthines)
by using the carboxylic acid as a traceless directing group. This
process offers an efficient alternative synthesis of the formal
meta-substituted adducts from ortho- and para-substituted
aromatic carboxylic acids and the para-heteroarylated adducts
from meta-substituted substrates. The current catalytic system
efficiently restrains homocoupling of heteroarene substrates.
Furthermore, the use of naturally occurring carboxylic acid as
the directing group avoids troublesome extra steps for
installation and removal of an external directing group.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jingbolan@scu.edu.cn.
*E-mail: jsyou@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from 973 Program
(2011CB808601), the National NSF of China (Nos.
21432005, 21372164, 21172155, 21272160, and 21321061),
Sichuan Provincial Foundation (2012JQ0002), and Fundamen-
tal Research Funds for the Central Universities
amount of decarboxylated product 3a was observed without
silver salt (eq 7). These observations suggested that the
decarboxylation step could be mediated by silver salt rather
than [Cp*RhCl2]2.15
C
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