Rhodium(III)-catalyzed ortho c-h heteroarylation of (hetero)aromatic carboxylic acids: A rapid and concise access to π-conjugated poly-heterocycles

Article abstract of DOI:10.1002/anie.201501982

Abstract Rh^III-catalyzed oxidative Ci-H/Ci-H cross-coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho-carboxy-substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one-step synthesis of ortho-carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin-type poly-heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H-dithieno[3,2-b:2',3'-d]pyran-5-one), CPDTO (cyclopentadithiophen-4-one), and indenothiophenes. Under construction: The highly regioselective title reaction directly furnishes ortho-carboxy bi(hetero)aryls. The method has the potential to lead to the rapid construction of a library of appealing poly-heterocycles, given the complete regiocontrol, readily available substrates, and functional-group tolerance.

Full text of DOI:10.1002/anie.201501982

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501982
German Edition: DOI: 10.1002/ange.201501982
À
C H Activation
À
Rhodium(III)-Catalyzed ortho C H Heteroarylation of
(Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to
p-Conjugated Poly-heterocycles**
Xurong Qin, Xiaoyu Li, Quan Huang, Hu Liu, Di Wu, Qiang Guo, Jingbo Lan,* Ruilin Wang,
and Jingsong You*
III
À
À
Abstract: Rh -catalyzed oxidative C H/C H cross-coupling
between (hetero)aromatic carboxylic acids and various hetero-
arenes has been accomplished to construct highly functional-
ized ortho-carboxy-substituted bi(hetero)aryls. The use of
a carboxy group as the directing group obviates tedious steps
for installation and removal of extra directing groups, and
enables a facile one-step synthesis of ortho-carboxy bi-
(hetero)aryls. The method provides opportunities for rapid
assembly of a library of important fluorene and coumarin-type
poly-heterocycles through intramolecular electrophilic substi-
tution or oxidative lactonization. As illustrative examples, the
strategy developed herein greatly streamlines accesses to
a variety of appealing polyheterocycles such as DTPO (5H-
dithieno[3,2-b:2’,3’-d]pyran-5-one), CPDTO (cyclopentadi-
thiophen-4-one), and indenothiophenes.
Scheme 1. Selected examples of ortho-carboxy-substituted bi-
(hetero)aryls and their p-conjugated polycyclic derivatives.
of such poly-heterocycles usually necessitate a multistep
process, which hinders the exploration of organic optoelec-
tronic materials. Once a concise and reliable pathway toward
ortho-carboxy bi(hetero)aryls has been established, it would
provide opportunities for rapid construction of a large library
of polycyclic fluorene and coumarin-like frameworks through
intramolecular electrophilic substitution or oxidative lactoni-
zation (Scheme 2).
Ortho-carboxy-substituted bi(hetero)aryls and their poly-
cyclic derivatives are ubiquitous in synthetic building blocks,
natural products, pharmaceuticals, and organic functional
materials (Scheme 1).[1] In particular, p-conjugated fluorene
and coumarin-type frameworks are well known as excellent
structural units for various photoelectronic materials such as
organic photovoltaic (OPV) and organic field-effect transis-
tor (OFET) materials.[1,2] For example, in OPV material
fields, both cyclopentadithiophene (CPDT) and 5H-
dithieno[3,2-b:2’,3’-d]pyran (DTP) are among the most effi-
cient donors. More than 1000 publications and patents
associated with the CPDT structure can be retrieved from
SciFinder. Because of the lack of rapid, general synthetic
routes to ortho-carboxy bi(hetero)aryls, the present syntheses
[*] Dr. X. Qin, X. Li, Q. Huang, H. Liu, Prof. Dr. D. Wu, Q. Guo,
Prof. Dr. J. Lan, Prof. Dr. J. You
Scheme 2. Synthesis of p-conjugated polyheterocycles through oxida-
À
tive ortho C H heteroarylation of (hetero)aromatic carboxylic acids.
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 (PR China)
E-mail: jingbolan@scu.edu.cn
The existing synthesis of ortho-carboxy-substituted bi-
(hetero)aryls mainly relies on traditional substitution reac-
[3]
À
À
tions and transition-metal-catalyzed C X/C M couplings.
Despite the reliability, these methods generally suffer from
disadvantages such as tedious multistep synthesis and purifi-
cation, inaccessible synthetic precursors, and poor substrate
generality, which to a certain extent limits rapid diversifica-
tion of ortho-carboxy bi(hetero)aryls. The development of
straightforward accesses to highly functionalized molecules
jsyou@scu.edu.cn
Prof. Dr. R. Wang
College of Materials Science and Engineering, Sichuan University
29 Wangjiang Road, Chengdu 610064 (PR China)
[**] This work was supported by grants from 863 Program
(2013AA031901), 973 Program (2011CB808601), the National NSF
of China (Nos 21432005, 21372164, 21172155, 21272160, and
21321061), and the Sichuan Provincial Foundation (2012JQ0002).
À
starting from readily available substrates through C H
activation is an appealing, yet challenging task.[4] Given that
(hetero)aromatic carboxylic acids are one of the most wide-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501982.
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Communications
À
À
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.
À
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
À
À
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]
À
À
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).
À
To elucidate whether the C H activation of the aromatic
À
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
À
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-
À
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]
À
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-
À
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.
2
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Chemie
tion of the indenothiophene-based metal-free organic sensi-
tizer 6d was developed (Scheme 6). The existing synthetic
method of the key bromo-substituted 4,4-dimethyl-4H-
indeno[1,2-b]thiophene (6a) involves a seven-step process
Scheme 4. The construction of coumarin-type polycyclic structures.
Reaction conditions: 3 (0.25 mmol), Pd(OAc)2 (10 mol%), Ac-Gly-OH
(20 mol%), PhI(OAc)2 (2.0 equiv), and KOAc (2.0 equiv) in tBuOH
(2 mL) at 1208C for 24 h. Ac-Gly-OH=N-acetylglycine.
investigated the ring fusion to construct coumarin-type
polycyclic structures (4) by direct intramolecular oxidative
À
À
C H/O H lactonization (Scheme 4). Although the lactoniza-
tions of arenes with carboxylic acids have been reported,[14]
the oxidative lactonization of heteroarenes with carboxylic
acids is still unexplored so far. It was found that the
lactonization could be performed to afford the polycyclic 4
in 60–75% yield by using Pd(OAc)2 as a catalyst. It is
noteworthy that the important scaffold DTPO (4b) could be
readily obtained in 60% yield. Moreover, the bromo group on
aromatic rings could be tolerated in the catalytic cycle, and is
very useful for further synthetic transformations in the
construction of organic conjugated materials (4c).
Scheme 6. Synthesis of the sensitizer 6d. Reaction conditions:
a) [{Cp*RhCl2}2], Ag2O, K2HPO4, and tBuOH; b) K2CO3, CH3I and
DMF; c) MeMgBr and THF. d) BF3·Et2O and CH2Cl2; e) 4-chloroaniline,
tBuONa, [Pd2(dba)3], XPhos, and toluene; f) thiophene-2-carbaldehyde,
Pd(OAc)2, PivOH, Cy3P·HBF4, Cs2CO3, and toluene; g) cyanoacetic
acid, piperidine, and CHCl3. See the Supporting Information for more
details. dba=dibenzylideneacetone.
To further illuminate the synthetic utility of our protocol,
a variety of transformations of ortho-carboxy bi(hetero)aryls
into cyclopentadiene derivatives (5) were investigated
(Scheme 5). The compound 3a could be easily transformed
into the corresponding polyheterocycle 5a through the
Friedel–Crafts acylation and simultaneous demethylation.
starting from methyl 5-bromo-2-iodobenzoate and 2-hexyl-
thiophene,[16] and an extra three-step process for preparing
methyl 5-bromo-2-iodobenzoate.[17] Based on the construc-
tion strategy for poly-heterocycles developed herein, it just
needed four steps to access 6a starting from readily available
substrates. Subsequently, the consecutive three-step proce-
À
dure involving Ullmann reaction, direct C H arylation of
thiophene-2-carbaldehyde, and Knoevenagel condensation
afforded the target 6d. The absorption spectra of 6d in EtOH
solution and on TiO2 film show a broad absorption band in
the range of l = 300-650 nm (see Figure S4 and Part IX in the
Supporting Information for detailed photophysical and elec-
trochemical data). Under simulated AM 1.5G irradiation, the
photocurrent-voltage (J-V) plots exhibited a conversion
efficiency (h) of 6.15% for the 6d-based DSSC (Jsc =
12.97 mA/cm2, Voc = 0.697 V and FF = 0.681), and is close to
N719 with an efficiency of 7.14% (Jsc = 16.84 mA/cm2, Voc =
0.693 V and FF = 0.612) under the same fabrication condi-
tions (see Figure S4), thus suggesting that indenothiophene
may be an ideal donor candidate for organic sensitizers.
In conclusion, a highly regioselective rhodium(III)-cata-
Scheme 5. Transformations of ortho-carboxy-substituted bi(hetero)aryls
into various cyclopentadiene derivatives (5). THF=tetrahydrofuran.
The compound 3v was an extremely useful synthetic handle
À
À
À
for CPDTO (5b). The twofold oxidative C H activation
lyzed oxidative C H/C H ortho heteroarylation of (hetero)-
aromatic carboxylic acids with various heteroarenes (e.g.,
thiophenes, furans, and azoles) has been developed, and
enables a variety of ortho-carboxy bi(hetero)aryls with wide
reactive functional-group tolerance. The construction strategy
developed herein greatly streamlines access to a variety of
appealing polyheterocycles such as CPDTO, DTPO, and
indenothiophenes. Starting from readily available substrates,
DTPO, CPDTO, and bromo-substituted indenothiophene are
readily obtained in two or four steps, whereas the previously
reported synthetic pathways require eight, nine, and ten steps,
respectively. This highly efficient route to diverse poly-
strategy in combination with the intramolecular Friedel–
Crafts-type cyclization also provided us a concise approach to
seven-ringed bis(styryl)benzene 5c, which is a new member of
the family of phenylenevinylene-based ladder molecules, and
may be a promising scaffold for organic electronic devices.[15]
Given that the oxidative protocol developed herein can
tolerate the reactive bromide, the direct use of bromo-
substituted carboxylic acids as a starting material could avoid
the late-stage bromination of resulting poly-heterocycles and
would greatly streamline synthetic routes. As an illustrative
example, a more step-economical pathway for the construc-
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[8] a) K. Masui, H. Ikegami, A. Mori, J. Am. Chem. Soc. 2004, 126,
5074; b) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2009, 131,
17052.
heterocycles has highlighted the appeal of C H activation in
the construction of organic optoelectronic materials.
[9] C.-Y. He, Q.-Q. Min, X. Zhang, Organometallics 2012, 31, 1335.
[10] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066; Angew. Chem. 2012, 124, 3120.
À
Keywords: C H activation · conjugation · cross-coupling ·
heterocycles · rhodium
[11] For the detailed catalytic cycle, see Part VIII in the Supporting
Information.
[12] a) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369; b) Y.
Segawa, T. Maekawa, K. Itami, Angew. Chem. Int. Ed. 2015, 54,
66; Angew. Chem. 2015, 127, 68.
[13] a) C.-H. Chen, C.-H. Hsieh, M. Dubosc, Y.-J. Cheng, C.-S. Hsu,
Macromolecules 2010, 43, 697; b) L. Dou, C.-C. Chen, K.
Yoshimura, K. Ohya, W.-H. Chang, J. Gao, Y. Liu, E. Richard,
Y. Yang, Macromolecules 2013, 46, 3384; c) A. C. J. Heinrich, B.
Thiedemann, P. J. Gates, A. Staubitz, Org. Lett. 2013, 15, 4666.
[1] a) H. Park, S.-K. Jung, D. G. Jeong, S. E. Ryu, S. J. Kim, Bioorg.
Med. Chem. Lett. 2008, 18, 2250; b) C. Wang, H. Dong, W. Hu, Y.
Liu, D. Zhu, Chem. Rev. 2012, 112, 2208; c) J. You, L. Dou, K.
Yoshimura, T. Kato, K. Ohya, T. Moriarty, K. Emery, C.-C.
Chen, J. Gao, G. Li, Y. Yang, Nat. Commun. 2013, 4, 1446.
[2] a) C.-P. Chen, S.-H. Chan, T.-C. Chao, C. Ting, B.-T. Ko, J. Am.
Chem. Soc. 2008, 130, 12828; b) Y.-X. Xu, C.-C. Chueh, H.-L.
Yip, F.-Z. Ding, Y.-X. Li, C.-Z. Li, X. Li, W.-C. Chen, A. K.-Y.
Jen, Adv. Mater. 2012, 24, 6356.
[3] X.-F. Wu, P. Anbarasan, H. Neumann, M. Beller, Angew. Chem.
Int. Ed. 2010, 49, 9047; Angew. Chem. 2010, 122, 9231.
[4] a) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 2011,
40, 5068; b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215; c) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111,
1780; d) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius,
Angew. Chem. Int. Ed. 2012, 51, 10236; Angew. Chem. 2012, 124,
10382.
[5] a) T. Satoh, M. Miura, Synthesis 2010, 3395; b) K. M. Engle, T.-S.
Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788.
[6] a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B.
Saunders, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129, 3510; b) H. A.
Chiong, Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007, 129,
9879; c) P. Mamone, G. Danoun, L. J. Gooßen, Angew. Chem.
Int. Ed. 2013, 52, 6704; Angew. Chem. 2013, 125, 6836; d) F.-N.
Ng, Z. Zhou, W.-Y. Yu, Chem. Eur. J. 2014, 20, 4474.
[14] a) J. Gallardo-Donaire, R. Martin, J. Am. Chem. Soc. 2013, 135,
9350; b) Y. Li, Y.-J. Ding, J.-Y. Wang, Y.-M. Su, X.-S. Wang, Org.
Lett. 2013, 15, 2574; c) X. Wang, J. Gallardo-Donaire, R. Martin,
Angew. Chem. Int. Ed. 2014, 53, 11084; Angew. Chem. 2014, 126,
11264; d) J.-J. Dai, W.-T. Xu, Y.-D. Wu, W.-M. Zhang, Y. Gong,
X.-P. He, X.-Q. Zhang, H.-J. Xu, J. Org. Chem. 2015, 80, 911.
[15] A. Fukazawa, S. Yamaguchi, Chem. Asian J. 2009, 4, 1386.
[16] J.-J. Kim, K. Lim, H. Choi, S. Fan, M.-S. Kang, G. Gao, H. S.
Kang, J. Ko, Inorg. Chem. 2010, 49, 8351.
[17] N. Zhou, L. Wang, D. W. Thompson, Y. Zhao, Tetrahedron 2011,
67, 125.
[7] a) J. S. Dickstein, C. A. Mulrooney, E. M. O’Brien, B. J. Morgan,
M. C. Kozlowski, Org. Lett. 2007, 9, 2441; b) J. Cornella, P. Lu, I.
Larrosa, Org. Lett. 2009, 11, 5506; c) P. Hu, M. Zhang, X. Jie, W.
Su, Angew. Chem. Int. Ed. 2012, 51, 227; Angew. Chem. 2012,
124, 231.
Received: March 4, 2015
Published online: && &&, &&&&
4
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These are not the final page numbers!

Angewandte
Chemie
Communications
À
C H Activation
X. Qin, X. Li, Q. Huang, H. Liu, D. Wu,
Q. Guo, J. Lan,* R. Wang,
J. You*
&&&& — &&&&
À
Rhodium(III)-Catalyzed ortho C H
Heteroarylation of (Hetero)aromatic
Carboxylic Acids: A Rapid and Concise
Access to p-Conjugated Poly-heterocycles
Under construction: The highly regiose-
lective title reaction directly furnishes
ortho-carboxy bi(hetero)aryls. The
rapid construction of a library of appeal-
ing poly-heterocycles, given the complete
regiocontrol, readily available substrates,
and functional-group tolerance.
method has the potential to lead to the
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!