Carboxylic acids as traceless directing groups for the rhodium(iii)-catalyzed decarboxylative C-H arylation of thiophenes

Article abstract of DOI:10.1002/anie.201411701

A rhodium(III)-catalyzed carboxylic acid directed decarboxylative C-H/C-H cross-coupling of carboxylic acids with thiophenes has been developed. With a slight adjustment of the reaction conditions based on the nature of the substrates, aryl carboxylic acids with a variety of substituents could serve as suitable coupling partners, and a broad variety of functional groups were tolerated. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which have conventionally been synthesized through lengthy synthetic sequences. An illustrative example is the one-step gram-scale synthesis of a biologically active 3,5-substituted 2-arylthiophene by way of the current method. Who was in control? A rhodium(III)-catalyzed carboxylic acid directed decarboxylative C-H/C-H cross-coupling of benzoic acids with thiophenes has been developed. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which previously required lengthy synthetic sequences.

Full text of DOI:10.1002/anie.201411701

Angewandte
Chemie
DOI: 10.1002/anie.201411701
Traceless Directing Groups
Carboxylic Acids as Traceless Directing Groups for the Rhodium(III)-
À
Catalyzed Decarboxylative C H Arylation of Thiophenes**
Yuanfei Zhang, Huaiqing Zhao, Min Zhang, and Weiping Su*
Abstract: A rhodium(III)-catalyzed carboxylic acid directed
Serving as versatile arylating reagents through metal-
mediated decarboxylation to generate aryl–metal intermedi-
ates,[4] aryl carboxylic acids can undergo cross-coupling
reactions with aryl halides,[5] olefins,[6] (hetero)arenes,[7] and
even other aryl carboxylic acids;[8] in these processes, the
reaction takes place at the original aryl position of the
À
À
decarboxylative C H/C H cross-coupling of carboxylic acids
with thiophenes has been developed. With a slight adjustment
of the reaction conditions based on the nature of the substrates,
aryl carboxylic acids with a variety of substituents could serve
as suitable coupling partners, and a broad variety of functional
groups were tolerated. This method provides straightforward
access to biaryl scaffolds with diverse substitution patterns,
many of which have conventionally been synthesized through
lengthy synthetic sequences. An illustrative example is the one-
step gram-scale synthesis of a biologically active 3,5-substituted
2-arylthiophene by way of the current method.
carboxylic acid group. The reaction that occurs by a tandem
[9]
À
carboxyl-directed C H functionalization /protodecarboxy-
lation[10] sequence, however, would lead to the ortho-selective
formation of the decarboxylated cross-coupling products and
thus be complementary to the previously established ipso-
selective decarboxylative cross-coupling reactions. Such reac-
tions were pioneered by the groups of Satoh, Miura, Larrosa,
and Gooßen.[11] An interesting example reported by Larrosa
and co-workers[11d] entails the use of an in situ installed
carboxylic acid as a traceless directing group for the facile
synthesis of meta-arylated phenols, a class of compounds that
are generally synthesized from the parent phenols through
lengthy synthetic sequences. This example clearly illustrates
that strategies using carboxylic acids as traceless directing
groups have great potential to streamline the syntheses of
diversely substituted arenes. However, to date, examples of
the use of carboxylic acids as traceless directing groups for
decarboxylative cross-couplings have been scarce.[11] Herein,
we report the first example of the application of a carboxylic
À
T
ransition-metal-catalyzed functional-group-directed C H
functionalization reactions have emerged as a powerful
À
À
method to construct C C and C X (X = heteroatom) bonds
and represent state-of-the-art methods for the modification of
organic molecules in terms of atom and step economy and
regioselectivity.[1] In these reactions, the directing groups are
essential for reaction acceleration and regioselectivity con-
trol.[1,2] Nevertheless, the strategies using directing groups
suffer from limitations when the directing groups or substi-
tution patterns are not present in the target molecules. To
overcome these restrictions, the concept of removable
directing groups (also termed traceless directing groups) has
À
À
À
been put forward and developed for direct C H functional-
acid in a traceless directing group strategy for a C H/C H
cross-coupling reaction. With [(Cp*RhCl2)2]/Ag2CO3 as the
catalyst system, we have achieved the decarboxylative ortho-
arylation of aryl carboxylic acids with thiophenes (Sche-
me 1b). This method is compatible with diverse substitution
patterns on the aryl ring of the benzoic acid and a broad range
of functional groups. Its practical applicability was illustrated
by the gram-scale synthesis of a biologically active compound
that is hard to access through conventional synthetic routes.
The decarboxylative ortho arylation of aryl carboxylic
acids was designed based on the proposed mechanism
ization.[2] In this context, the traceless directing group strategy
À
has been applied to the C H silylation, acyloxylation,
halogenation, and borylation of arenes using Ru,[3a] Pd,[3b–c]
and Ir[3d] catalysts. Although pioneering studies have demon-
strated that the installation of removable directing groups
endowed parent substrates with new reactivity and selectivity,
most of these methods required additional steps to remove
the undesired directing groups from the products. It is highly
desirable to exploit traceless directing group methods with
À
which C H functionalization and removal of the directing
group can be achieved in a one-pot fashion.
[*] Y. Zhang, H. Zhao, M. Zhang, Prof. W. Su
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Yangqiao West Road 155, Fuzhou, Fujian 350002 (China)
E-mail: wpsu@fjirsm.ac.cn
[**] Financial support from the NSCF (21431008, 21332001, 21302184,
and 21202164), and the 973 Program (2011CB932404,
2011CBA00501) is greatly appreciated.
Scheme 1. Two kinds of decarboxylative arylation reactions of aryl
carboxylic acids with heterocycles. Cp*=pentamethyl cyclopentadienyl,
Cy =cyclohexyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411701.
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pleased to find that the reaction
conducted in DMF afforded the
desired product in 63% yield
(entry 5). As we observed that the
reaction of potassium 2,4-dimethoxy-
benzoate with 2-n-butylthiophene
gave only 14% yield in the absence
of K2HPO4 under otherwise identical
conditions, we speculate that
K2HPO4 may act as a base to accept
À
protons generated during the C H/
À
C H cross-coupling process. The
yield increased to 70% when
1.5 equivalents of 2-n-butylthiophene
were used (entry 6). Despite the fact
that AgSbF6 helps to release a more
active cationic rhodium catalyst for
À
Scheme 2. Working hypothesis for the ortho-selective decarboxylative C H arylation of aryl
carboxylic acids with thiophenes.
[13k,l]
À
C H bond activation,
AgSbF6
(Scheme 2), which consists of two catalytic cycles: 1) metal-
Table 1: Optimization of the reaction conditions.[a]
catalyzed carboxylic acid directed ortho arylation, and
2) silver-catalyzed protodecarboxylation. To achieve such
a decarboxylative ortho arylation, the reaction conditions
must ensure that the carboxylic acid directed ortho arylation
occurs prior to the Ag-catalyzed decarboxylation. Computa-
tional studies revealed that ortho-disubstituted aryl carbox-
ylic acids were more reactive towards the Ag-promoted
decarboxylation than ortho-monosubstituted ones.[12] As
a result, the introduction of an aryl group at the ortho
position of aryl carboxylic acids would lead to an increase in
reactivity towards decarboxylation compared with the orig-
inal aryl carboxylic acids, suggesting that the decarboxylative
ortho arylation of aryl carboxylic acids is viable. In spite of
this, the competition between ipso-selective and ortho-
selective decarboxylative arylation reactions should remain
as the ortho-monosubstituted aryl carboxylic acids are
capable of participating in protodecarboxylation.[10] Further-
more, several other unwanted side reactions, such as thio-
phene homocoupling and the protodecarboxylation of the
unreacted aryl carboxylic acids, potentially impede the
realization of the decarboxylative ortho arylation of aryl
carboxylic acids.
The reaction of 2,4-dimethoxybenzoic acid (1a) with 2-n-
butylthiophene (2a) was chosen as a model system for the
optimization of the reaction conditions. Taking into account
the previous studies on PdII/AgI systems,[6–9,11c,d] we assumed
that a Pd catalyst in combination with silver salts may work
for the ortho-selective decarboxylative arylation of aryl
carboxylic acids. However, such catalyst systems failed to
deliver the target product; instead, they gave rise to the
dimerization of 2-n-butylthiophene (see the Supporting
Information, Table S1). Therefore, we turned our attention
towards rhodium catalysts, considering that RhIII catalysts
Entry
1a/2a
Base
Solvent
Yield [%][b]
1
2
3
4
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
–
–
–
–
dioxane
DMF
DMSO
DCE
0
0
0
0
5
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Na2CO3
NaOAc
CsOPiv
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
63
70
67
76
76
65
82 (76)
56
64
56
29
6
7[c]
8[d]
9[e]
10[d,f]
11[d,g]
12[d,h]
13[d,g]
14[d,g]
15[d,g]
[a] Reaction conditions: [(Cp*RhCl2)2] (2.5 mol%), Ag2CO3 (2 equiv),
base (1.5 equiv), solvent (2 mL), 1008C, 24 h. [b] Yield determined by GC
analysis using dodecane as an internal standard; yields of isolated
products given in parentheses. [c] With AgSbF6 (10 mol%). [d] With
TEMPO (20 mol%). [e] With TEMPO (50 mol%). [f] [(Cp*RhCl2)2]
(5 mol%). [g] [(Cp*RhCl2)2] (2 mol%). [h] [(Cp*RhCl2)2] (1 mol%).
Piv=pivaloyl, TEMPO=2,2,6,6-tetramethyl-l-piperidinoxyl.
did not display any beneficial effects on this reaction
(entry 7). Gratifyingly, TEMPO was observed to exert
a positive effect on the reaction outcome presumably as it
accelerates the oxidation of RhI to RhIII as an electron
transfer intermediate (entries 8 and 9).[14] Interestingly,
increasing the catalyst loading decreased the yield whereas
lowering the catalyst loading to 2 mol% gave the best yield
(entries 10–12). In fact, GC-MS analysis revealed that
5 mol% of [(Cp*RhCl2)2] led to homocoupling of 2-n-
butylthiophene, which decreased the efficiency of the target
À
have been shown to be effective in many C H bond
functionalization reactions.[1d,e,13] Initially, we found that the
reaction did not afford any product in various solvents in the
absence of additional base using [(Cp*RhCl2)2] as the catalyst
and Ag2CO3 as the oxidant (Table 1, entries 1–4). Once
K2HPO4 had been introduced as an additional base, we were
2
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Subsequently, we investigated the substrate
scope with regard to the benzoic acids (Scheme 4).
Unlike for the thiophene component, the reaction
conditions had to be varied depending on whether
electron-rich or electron-deficient carboxylic acids
were used, presumably because of differences in
acidity and reactivity. Hence, the base was crucial to
accomplish the reactions. Under the optimized
conditions, 4a was formed in only 15% yield.
Gratifyingly, when the reaction mixture was addi-
tionally heated to 1408C for six hours in NMP, the
yield increased to 73%. This result further con-
firmed our previous hypothesis and indicated that
the temperature was an important factor influencing
the overall yield. With this hypothesis in mind,
satisfying yields were obtained when methyl, chloro,
trifluoromethyl, or nitro substituents were present in
the carboxylic acid scaffold (4b–f). K2HPO4 was an
ineffective base for 2,4-dichlorobenzoic acid. Luck-
ily, the corresponding products were formed when
Li2CO3 was used as an additional base (4g–j). This
approach is especially attractive for the synthesis of
4h, 4i, and 4j because very few methods to access
this important class of compounds were previously
available. The absence of ortho substituents resulted
in the formation of the diarylated products in good
yields (4l and 4m). Heterocyclic carboxylic acids
were also suitable substrates (4n and 4o). Further-
more, benzofuran, a different heterocycle, also
served as an arylating reagent and participated in
this transformation (4p).
Scheme 3. Variation of the thiophene. Reaction conditions: 1a (0.2 mmol), 2
(1.5 equiv), [(Cp*RhCl2)2] (2 mol%), TEMPO (20 mol%), Ag2CO3 (2 equiv),
K2HPO4 (1.5 equiv), DMF (2 mL), 1008C, 24 h. Yields of isolated products are
given. [a] 1a (1.5 equiv), 2 (0.2 mmol), [(Cp*RhCl)2] (2.5 mol%), Ag2CO3 (2 equiv),
Na2CO3 (1.5 equiv). [b] 5 mmol scale, yield of isolated product: 1.11 g. [c] 1a
(3 equiv), 2 (0.2 mmol), [(Cp*RhCl2)2] (5 mol%), Ag2CO3 (4 equiv), K2HPO4
(3 equiv).
The presence of the 2-arylthiophene structural
motif in natural products[16a–c] and biologically active
molecules[16d–h] inspired us to explore the feasibility
of its preparation by utilizing the established
method. To our delight, this decarboxylative cross-
coupling method was applicable to the one-step and
gram-scale synthesis of an intermediate for a 17b-
hydroxysteroid dehydrogenase type 1 inhibitor from
reaction. Other bases and silver salts were inferior to K2HPO4
and Ag2CO3, respectively (entries 13–15; see also Table S2).
With the optimized reaction conditions in hand, we
evaluated the substrate scope of the reaction with respect to
the thiophene component. As depicted in Scheme 3, methyl-
and phenyl-substituted thiophenes gave satisfying yields of
81% and 84%, respectively (3b and 3c). Thiophenes bearing
keto, formyl, ester, alkenyl, chloro, or bromo substituents
could be smoothly transformed into the corresponding
products in good to excellent yields (3d–e, 3j–k). Surprisingly,
this reaction was also compatible with a nitrile group in spite
of its coordinating abilities as 3i was formed in 72% yield.
Benzothiophenes were suitable substrate as well (3l and 3m).
Diarylation occurred swimmingly with moderate to excellent
yields (3o–3q) when two possible reaction positions are
available on the thiophene. These reactions formed extended
p-conjugated systems bearing thiophene subunits (3o–3q), an
important family of optical materials in material science,[15]
and thus provide a complement to our previously reported
method.[7f]
inexpensive and commercially available materials,[17a] which
furnished the isolated product in up to 80% yield (Scheme 5).
Previously, this compound was synthesized in low overall
yields by way of a Suzuki reaction of two coupling partners,
that is, 5-(4-methoxyphenyl)thiophen-2-ylboronic acid and 1-
bromo-3-methoxy-5-methylbenzene, which both require
lengthy synthetic sequences for their preparation (Sche-
me 5).[17b,c] Aside from step economy, our approach effectively
avoided the use of unwelcome bromine and strong bases or
acids and therefore provides rapid and convenient access to
such biologically active 3,5-substituted 2-arylthiophenes.
In conclusion, we have developed a versatile catalyst
À
system for the decarboxylative ortho C H arylation of aryl
carboxylic acids with thiophenes by a tandem RhIII-catalyzed
À
C H arylation/Ag-catalyzed decarboxylative protonation
sequence. The success in the use of a carboxylic acid moiety
as a traceless directing group is, to large extent, ascribed to the
À
À
fact that the ortho-disubstituted products of the C H/C H
cross-coupling process undergo protodecarboxylation more
easily than the ortho-monosubstituted precursor carboxylic
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(20 mol%), Ag2CO3 (3 equiv), K2HPO4 (1.5 equiv), NMP (2 mL),
1008C, 24 h, then stirring for a further 6 hours at 1408C. Yields of
isolated products are given. [a] Stirring for a further 6 hours at 1608C.
[b] [(Cp*RhCl2)2] (2 mol%), Li2CO3 (1.5 equiv), DMF. [c] [(Cp*RhCl2)2]
(4 mol%), Li2CO3 (1.0 equiv), DMF. [d] 2 (4 equiv), [(Cp*RhCl2)2]
(2 mol%), Ag2CO3 (6 equiv), DMF.
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Received: December 4, 2014
Published online: && &&, &&&&
À
Keywords: arylation · C H activation · decarboxylation ·
heterocycles · rhodium catalysis
À
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.
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4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Traceless Directing Groups
Y. Zhang, H. Zhao, M. Zhang,
W. Su*
&&& — &&&
Carboxylic Acids as Traceless Directing
Groups for the Rhodium(III)-Catalyzed
Who was in control? A rhodium(III)-
catalyzed carboxylic acid directed decar-
straightforward access to biaryl scaffolds
with diverse substitution patterns, many
of which previously required lengthy
synthetic sequences.
À
À
À
Decarboxylative C H Arylation of
boxylative C H/C H cross-coupling of
benzoic acids with thiophenes has been
developed. This method provides
Thiophenes
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!