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Angewandte
Communications
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spread compounds, their oxidative C H/C H cross-coupling
reactions with various heteroarenes would doubtless offer
a new, straightforward pathway to diverse ortho-carboxy-
substituted bi(hetero)aryls through the direct use of the
naturally occurring carboxy group as the directing group to
this coupling reaction could tolerate a wide range of hetero-
arene substrates including thiophenes, furans, and azoles to
deliver ortho-carboxy bi(hetero)aryls in satisfactory yields
(3a–j). Carboxylic acids with both electron-rich and electron-
poor substituents reacted with various heteroarenes in
acceptable yields (3k–t). It is emphasized that 2-(benzo[b]-
thiophen-2-yl)benzoic acid (3k) could be obtained without
problem on a gram scale in 70% yield, thus providing
a bench-scale preparation. 3k could also react further with 1-
(furan-2-yl)ethanone to deliver the biheteroarylated benzoic
acid 3t in 68% yield. More importantly, thiophene-3-carbox-
ylic acids were capable of reacting with thiophenes to yield
the important ortho-carboxy bithiophenes 3u and 3v in
synthetically useful yields. 3v is the key intermediate for the
preparation of CPDT and DTP. Diarylation smoothly oc-
curred to afford 3w in a moderate yield given the two possible
reaction sites on the benzodithiophene. Notably, this type of
oxidative cross-coupling reaction could tolerate a wide vari-
ety of reactive functional groups such as ester, aldehyde,
acetyl, cyano, methoxy, chloride, and even the more challeng-
ing bromide.
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selectively activate the ortho C H bond, thus avoiding
tedious steps for installation and removal of an extra directing
group. Despite a number of successful examples of carboxy-
directed ortho C H functionalizations of arenes,[5,6] the direct
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oxidative ortho C H (hetero)arylation of (hetero)aromatic
carboxylic acids to construct diverse ortho-carboxy-substi-
tuted bi(hetero)aryls through double C H activation still
remain unsolved. To achieve these transformations, several
obstacles need to be faced: 1) (Hetero)aromatic carboxylic
acids have a tendency to undergo protodecarboxylation,
decarboxylative ipso-heteroarylation, and homocouplings;[7]
and 2) heteroarenes are easily subjected to homocoupling and
decomposition.[8]
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To evaluate the feasibility of the double C H activation
strategy, we initiated our investigation by using the cross-
coupling between 2-methoxybenzoic acid (1a) and benzo-
thiophene (2a) as a model reaction. After screening several
parameters (catalyst, oxidant, additive, solvent, etc.), the
cross-coupling proceeded well when 5 mol% of
[{Cp*RhCl2}2] (Cp* = pentamethyl cyclopentadienyl) was
employed in combination with K2HPO4 (2.0 equiv) and
Ag2O (2.0 equiv) in tBuOH at 1308C for 24 hours (see
entry 7 in Table S3 of the Supporting Information).
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To elucidate whether the C H activation of the aromatic
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carboxylic acid foreran the C H activation of heteroarene or
vice versa, deuterium-labeling experiments of benzoic acid
(1b) and benzothiophene (2a) were conducted alone (see
Eqs S1 and S2). The exposure of benzoic acid to the catalytic
conditions in CD3OD for 1 hour at 1308C led to a significant
deuterium incorporation at the ortho-position (44% D),
whereas the H/D exchange ratio of benzothiophene (2a) was
less than 5%. These observations suggested that the cross-
coupling reaction might start from the cyclometalation of
benzoic acid.[9] Next, kinetic isotope effects (KIE) were
With the optimized reaction conditions in hand, we first
evaluated the substrate scope (Scheme 3). It was found that
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studied with regard to the C H/D bonds for both coupling
partners. The parallel reactions were performed by the use of
2,3,4,5,6-pentadeuteriobenzoic acid and 2-deuterio-benzo-
thiophene under the optimized reaction conditions (see
Eqs S3 and S4). The KIE values of 3.9 and 1.1 were observed
for 2,3,4,5,6-pentadeuteriobenzoic acid and 2-deuteriobenzo-
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thiophene, respectively. These results indicated that the C H
bond breaking of benzoic acid might be the rate-limiting
step.[10] Thus, a plausible mechanism could consist of 1) the
coordination of the carboxylate oxygen atom to [Cp*RhIII]
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and subsequent ortho-C H activation of the arene, 2) the
reaction of the resulting rhodacycle intermediate with a het-
eroarene to give the key aryl-RhIII-heteroaryl, and 3) the
reductive elimination to deliver the ortho-heteroarylated
product.[11]
The development of construction strategies for p-conju-
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gated polyheterocycles through C H activation is becoming
a hot topic in the field of organic functional materials.[12]
Traditional synthetic accesses to CPDTO (5b; see Scheme 5)
and DTPO (4b; see Scheme 4), the key intermediates for
CPDT and DTP, respectively, are hampered by multistep
processes and harsh reaction conditions, thus always resulting
in erratic and unfavorably low yields (for example, for DTPO,
nine steps and 7% yield; for CPDTO, eight steps and 23%
yield).[13] The complete build-up strategies developed herein
could greatly streamline accesses to such poly-heterocycles.
With the ortho-carboxy bi(hetero)aryls in hand, we first
Scheme 3. ortho-Heteroarylation of (hetero)aromatic carboxylic acids.
Reaction conditions: (hetero)aromatic carboxylic acid (0.25 mmol),
heteroarene (3.0 equiv), [{Cp*RhCl2}2] (5.0 mol%), Ag2O (2.0 equiv),
and K2HPO4 (2.0 equiv) in tBuOH (2.0 mL) at 1308C for 24 h.
[a] Benzoic acid (10.0 mmol) in tBuOH (10.0 mL) at 1308C for 36 h.
[b] 1208C for 36 h. [c] 1308C for 48 h, then K2CO3, CH3I, and DMF at
RT. DMF=N,N-dimethylformamide.
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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