Iridium-Catalyzed, Weakly Coordination-Assisted Ortho-Alkynylation of (Hetero)aromatic Carboxylic Acids without Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b00581

It is reported a weakly coordination-assisted alkynylation of aryl and heteroaryl carboxylic acids with iridium catalysis. The reaction is catalyzed by [{Cpz.ast;IrCl₂}₂] complex without cyclization, forming ortho-alkynylated aryl and heteroaryl carboxylic acids, and features high functional group tolerance and broad substrate scope under an air atmosphere. 2-(Hetero)aryl-substituted acetic acids were amenable to the alkynylation by forming an unusual six-membered ring cycloiridiated intermediate.

Full text of DOI:10.1021/acs.orglett.7b00581

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed, Weakly Coordination-Assisted Ortho-Alkynylation
of (Hetero)aromatic Carboxylic Acids without Cyclization
Changpeng Chen,† Pei Liu,† Jinghua Tang,† Gongda Deng,† and Xiaoming Zeng*,†,‡
†Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710054, China
‡Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: It is reported a weakly coordination-assisted alkynylation of
aryl and heteroaryl carboxylic acids with iridium catalysis. The reaction is
catalyzed by [{Cp*IrCl2}2] complex without cyclization, forming ortho-
alkynylated aryl and heteroaryl carboxylic acids, and features high functional
group tolerance and broad substrate scope under an air atmosphere. 2-
(Hetero)aryl-substituted acetic acids were amenable to the alkynylation by
forming an unusual six-membered ring cycloiridiated intermediate.
Scheme 1. Carboxyl-Directed Functionalization of Aromatic
Carboxylic Acids
romatic alkynes are versatile building blocks in synthetic
chemistry and have been widely used in the preparation of
A
common chemicals and pharmaceutical and material molecules.1
The development of efficient methods to the buildup of these
fundamentally important motifs has attracted broad synthetic
interest. Common approaches that were used to form aromatic
alkynes traditionally involve the Sonogashira cross-coupling
using reactive aromatic halides.2 Recently, introducing directing
groups as auxiliaries for transition-metal catalysis has led to many
breakthroughs in synthetic chemistry,3 remarkably revolutioniz-
ing the manner in the creation of appealing molecules by the
functionalization of unreactive chemical bonds.4 Carboxyls are
synthetically valuable functional groups that are readily amenable
to transform to the relative C−C, C−O, and C−N bonds by the
corresponding decarboxylative cross-coupling reactions.5 How-
ever, the weakly σ-coordination ability of carboxyl groups causes
them difficulty in the direction of transition metals to approach
and break one regiospecific chemical bond. On the other hand,
the reactivity of the resulting cyclometalated intermediates
toward further transformation may be lowered. Methods for the
arylation,6 alkylation,7 alkenylation,8,9 amination,10 acylation,11
annulation,8,12 and deuteration13 have been developed using
carboxyl directing groups (Scheme 1, eq 1). However, to our
knowledge, there is no report of an alkynylation reaction that was
directed by a weak coordination carboxyl functionality, although
approaches mediated by a strong coordination directing group
have been described.14−21 The obstacle may arise from the easy
addition of the carboxyl across the alkyne via a cyclization, which
causes the ortho-alkynylation of aromatic carboxylic acid suffering
from a selectivity issue.8
and heteroaryl carboxylic acids under an air atmosphere (Scheme
1, eq 2). The competitive cyclization by the addition of the
carboxyl across the alkyne did not occur under catalytic
conditions. While unusual six-membered ring cycloiridiated
intermediates can be accessed in the realization of the ortho-
alkynylation of 2-(hetero)aryl-substituted acetic acids.
Herein, we report the first weak coordination-assisted ortho-
alkynylation of aryl and heteroaryl carboxylic acids with iridium
catalysis.22 Carboxyl groups in both aromatic and heteroaromatic
carboxylic acids were able to direct iridium in the cleavage of
aromatic C−H bonds and the formation of ortho-alkynylated aryl
Received: February 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We commenced our studies by choosing the reaction of 2-
methylbenzoic acid (1a) with (bromoethynyl)triisopropylsilane
(2) as a model for optimizing catalytic conditions (Table 1).
Scheme 2. Iridium-Catalyzed Ortho-Alkynylation of Aromatic
a
and (Hetero)aromatic Carboxylic Acids*,
Table 1. Exploring the Effect of Base and Solvent on the
a
Alkynylation of Benzoic Acid
entry
base
solvent
DMF
yield of 3a (%)
b
1
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
none
nd
b
2
DCE
nd
3
DCM
82
85
71
78
4
toluene
5
1,4-dioxane
CH3CN
6
c
7
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
t-amyl-OH
92 (83)
b
8
nd
9
K2CO3
Na2CO3
K3PO4
trace
b
10
11
12
13
14
nd
trace
83
K2HPO4
KOAc
81
CsOAc
KHCO3
77
d
b
15
nd
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), base (0.2
mmol), [{Cp*IrCl2}2] (0.001 mmol), solvent (0.5 mL), 30 °C, 24 h,
b
under air. Yield was determined by HPLC analysis using
c
acetophenone as internal standard. Isolated yield in parentheses.
d
Without [{Cp*IrCl2}2] complex.
Using a commercially available iridium complex of
[{Cp*IrCl2}2] (with 1 mol % loading) under an air atmosphere,
the alkynylation of the ortho-C−H bond did not proceed in the
solvents N,N-dimethylformamide (DMF) and dichloroethane
(DCE) (entries 1 and 2). To our delight, formation of the ortho-
alkynylated benzoic acid 3a was observed in dichloromethane
(DCM) (entry 3). tert-Amyl alcohol (tert-amyl-OH) allowed the
reaction to proceed effectively, leading to 3a in 92% yield (entry
7). Notably, base plays an important role in the alkynylation. The
best result was obtained in the presence of KHCO3. However,
other bases such as Na2CO3, K2CO3, and K3PO4 shut down the
reaction or decreased the reaction rate (entries 9−11). Further
experiments suggested that, without iridium catalyst, the
alkynylation did not take place (entry 15).
*
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), KHCO3 (0.4
mmol), [{Cp*IrCl2}2] (0.002 mmol), t-amyl-OH (1 mL), 30 °C, 24 h,
a
b
c
under air. Isolated yields. 50 °C. [{Cp*IrCl2}2] (0.004 mmol). 2
(0.4 mmol) was used. The ratio of regioisomer was determined by 1H
NMR analysis.
Having establishing the optimal conditions, the substrate
scope in the carboxyl-directed alkynylation was next examined.
As shown in Scheme 2, the o-C−H bonds on electron-rich
aromatics were alkynylated effectively, the related products of
3a−d were isolated in 76−93% yield. In contrast, introducing
electron-deficient groups such as phenyl, chloride, and
trifluoromethyl into the scaffolds of benzoic acids resulted in
relatively low conversions (3e−h,n). Notably, steric hindrance
around the o-C−H bonds has no effect on the alkynylation. It has
been successfully applied in the synthesis of multisubstituted
aromatic alkyne derivatives 3i−l. As expected, the reaction with
meta-substituted benzoic acids preferred to occur at a less
hindered ortho-position (3m,n), whereas the regioselectively was
forfeited using electron-rich 3-methoxybenzoic acid, leading to a
mixed regioisomer (3o,o′). A broad range of functional groups,
including fluoride, chloride, bromide, alkyoxyl, amino, and
hydroxyl, were well tolerated by the catalytic system.
Encouragingly, heteroaromatic carboxylic acids containing
indolyl and thienyl scaffolds were amenable to the alkynylation
(3t−v). However, no expected alkynylated compounds were
detected when aromatic ester, amide, and ketone (3w−y) were
used. These results exclude the feasibility of the direction of
iridium by the relative carbonyl groups.
Because of the relative instability of six-membered ring
cyclometalated intermediates compared to five-membered ring
ones, the functionalization of C−H bond aromatic carboxylic
acids via a six-membered ring cyclometalated species has rarely
been achieved.6f,12,13,23 The success in developing the ortho-
alkynylation of benzoic acids stimulated us to explore the
reaction with 2-phenylacetic acids. Gratifyingly, an increase of
the amount of [{Cp*IrCl2}2] to 2.5 mol % allowed the reaction
B
DOI: 10.1021/acs.orglett.7b00581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to occur smoothly at elevated temperature, forming the
compound 5a in moderate yield (Scheme 3). Both electron-
to the preparation of biologically interesting benzofuranone
motif.
To obtain mechanistic insight, we probed the role of base in
the carboxyl-directed reaction. Starting from potassium
benzoate, the alkynylation of C−H bond proceeded smoothly
without KHCO3 (Scheme 5, eq 3). Furthermore, the deuteration
Scheme 3. Iridium-Catalyzed Ortho-Alkynylation of Aromatic
a
and (Hetero)aromatic Acetic Acids*,
Scheme 5. Mechanistic Studies
*
The reaction was performed on a 0.2 mmol scale at 70 °C for 24 h
a
b
under air. Isolated yields were given. 90 °C. [{Cp*IrCl2}2] (5 mol
%).
rich and electron-deficient aromatics on the scaffolds of acetic
acids can be alkynylated smoothly (5b−g). In addition, 2-
phenylpropanoic acid was also suitable for the transformation
(5h). Interestingly, carboxyl was able to direct iridium to activate
the o-C−H bonds in heterocycles of indole, thiophene, pyrrole,
and benzo[b]thiophene, leading to the formation of the
alkynylated heteroaryl acetic aids 5i−n in moderate to excellent
yields.
The scalability of this reaction was then studied. Using 0.5 mol
% of iridium complex, the alkynylation of benzoic acids on a 1 g
scale proceeded effectively to form 3a in 71% yield (Scheme 4).
The resulting 2-alkynylbenzoic acid can be facilely functionalized
by a late-stage 5-exo cyclization, providing an alternative strategy
of potassium benzoate was accomplished in the absence of base
(Scheme 5, eqs 4 and 5). These results suggest that KHCO3 is
responsible for the deprotonation of benzoic acid rather than for
the assistance of cleavage of the C−H bond. Interestingly, the o-
C−H bond in benzoic acid cannot be cleaved without base. A
high kinetic isotope effect (KIE) value of 3.76 or 4.88 was
obtained in either intramolecular or intermolecular reactions,
indicating that the catalytic cleavage of o-C−H bond of benzoic
acid is likely to be the rate-limiting step in the alkynylation
(Scheme 5, eqs 6 and 7).
Scheme 4. Gram-Scale Reaction and Cyclization
In conclusion, we have developed a weakly coordination-
assisted alkynylation of aromatic and heteroaromatic carboxylic
acids with iridium catalysis. The reaction was directed by a
synthetically useful carboxyl functionality in featuring high
functional group tolerance and broad substrate scope. The
relative cyclization by the addition of a carboxyl group across the
alkyne did not occur under our catalytic conditions. This reaction
provides an efficient methodology for the preparation of ortho-
alkynylated aryl and heteroaryl carboxylic acids under an air
atmosphere.
C
DOI: 10.1021/acs.orglett.7b00581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2007, 129, 3510−3511. (o) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem.
2007, 72, 5362−5367.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00581.
(7) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097−6100. (b) Cheng, G.; Li, T.-J.; Yu, J.-Q. J. Am. Chem. Soc.
2015, 137, 10950−10953. (c) Gandeepan, P.; Rajamalli, P.; Cheng, C.-
H. Chem. - Eur. J. 2015, 21, 9198−9203.
Experimental procedures and characterization data for all
products, including 1H, 13C, and 19F NMR spectra (PDF)
(8) The C−H bond reactions of aromatic carboxylic acids with alkynes
generally formed the lactonized products by cyclization. See:
(a) Warratz, S.; Kornhaaß, C.; Cajaraville, A.; Niepotter, B.; Stalke,
̈
D.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 5513−5517.
(b) Huang, L.; Biafora, A.; Zhang, G.; Bragoni, V.; Gooßen, L. J. Angew.
Chem., Int. Ed. 2016, 55, 6933−6937. (c) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407−1409. (d) Frasco, D. A.; Lilly, C. P.; Boyle, P.
D.; Ison, E. A. ACS Catal. 2013, 3, 2421−2429. (e) Liu, Y.; Yang, Y.; Shi,
Y.; Wang, X.; Zhang, L.; Cheng, Y.; You, J. Organometallics 2016, 35,
1350−1353.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
ORCID
Xiaoming Zeng: 0000-0003-0509-1848
Notes
(9) Kumar, N. Y. P.; Bechtoldt, A.; Raghuvanshi, K.; Ackermann, L.
Angew. Chem., Int. Ed. 2016, 55, 6929−6932.
(10) (a) Ng, F.-N.; Zhou, Z.; Yu, W.-Y. Chem. - Eur. J. 2014, 20, 4474−
4480. (b) Lee, D.; Chang, S. Chem. - Eur. J. 2015, 21, 5364−5368.
(11) (a) Mamone, P.; Danoun, G.; Gooßen, L. J. Angew. Chem., Int. Ed.
2013, 52, 6704−6708. (b) Danoun, G.; Mamone, P.; Gooßen, L. J.
Chem. - Eur. J. 2013, 19, 17287−17290. (c) Jiang, Q.-D.; Zhu, C.-L.;
Zhao, H.-Q.; Su, W.-P. Chem. - Asian J. 2016, 11, 356−359.
(12) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora,
H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236−1239.
(13) Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2014, 53, 734−737.
(14) Selected examples of Pd-catalyzed alkynylation of C−H bonds:
(a) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742−7743. (b) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009,
11, 3250−3252. (c) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed.
2010, 49, 2096−2098. (d) Guan, M.-Y.; Chen, C.-P.; Zhang, J.-Y.; Zeng,
R.-S.; Zhao, Y.-S. Chem. Commun. 2015, 51, 12103−12106.
(15) Selected examples of Rh-catalyzed alkynylation of C−H bonds:
(a) Yang, X.-F.; Hu, X.-H.; Feng, C.; Loh, T.-P. Chem. Commun. 2015,
51, 2532−2535. (b) Xie, F.; Qi, Z.; Yu, S.; Li, X. J. Am. Chem. Soc. 2014,
136, 4780−4787. (c) Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2014,
53, 2722−2726.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
[Nos. 21202128, 21572175), XJTU, and Beijing National
Laboratory for Molecular Sciences for financial support.
REFERENCES
■
(1) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079−3160. (b) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev.
2011, 111, 2937−2980. (c) Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012,
41, 4165−4179. (d) Zeng, X. Chem. Rev. 2013, 113, 6864−6900.
́
(e) Chinchilla, R.; Najera, C. Chem. Rev. 2014, 114, 1783−1826.
(2) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467−4470. (b) Sonogashira, K. J. Organomet. Chem. 2002,
653, 46−49. (c) Negishi, E.-i.; Anastasia, L. Chem. Rev. 2003, 103,
1979−2017.
(3) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726−
11743.
(4) (a) Ackermann, L.; Li, J. Nat. Chem. 2015, 7, 686−687. (b) He, J.;
Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2016,
DOI: 10.1021/acs.chemrev.6b00622. (c) Yang, Y.; Lan, J.; You, J. Chem.
Rev. 2017, x. (d) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017,
DOI: 10.1021/acs.chemrev.6b00644. (e) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074−1086. (f) Sun, C.-L.; Li,
B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−1314. (g) Gensch, T.;
Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016,
45, 2900−2936. (h) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902−4911.
(5) (a) Ackermann, L. Chem. Rev. 2011, 111, 1315−1345. (b) Engle, K.
M.; Mei, T. S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788−802.
(c) Pichette Drapeau, M.; Gooßen, L. J. Chem. - Eur. J. 2016, 22, 18654−
18677. (d) Shi, G.; Zhang, Y. Adv. Synth. Catal. 2014, 356, 1419−1442.
(6) (a) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879−9884. (b) Cornella, J.; Righi, M.; Larrosa, I. Angew.
Chem., Int. Ed. 2011, 50, 9429−9432. (c) Zhu, C.; Zhang, Y.; Kan, J.;
Zhao, H.; Su, W. Org. Lett. 2015, 17, 3418−3421. (d) Luo, J.; Preciado,
S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109−4112. (e) Wu, Z.;
Chen, S.; Hu, C.; Li, Z.; Xiang, H.; Zhou, X. ChemCatChem 2013, 5,
2839−2842. (f) Dastbaravardeh, N.; Toba, T.; Farmer, M. E.; Yu, J.-Q. J.
Am. Chem. Soc. 2015, 137, 9877−9884. (g) Huang, L.; Hackenberger,
D.; Gooßen, L. J. Angew. Chem., Int. Ed. 2015, 54, 12607−12611.
(h) Qin, X.; Li, X.; Huang, Q.; Liu, H.; Wu, D.; Guo, Q.; Lan, J.; Wang,
R.; You, J. Angew. Chem., Int. Ed. 2015, 54, 7167−7170. (i) Zhang, Y.;
Zhao, H.; Zhang, M.; Su, W. Angew. Chem., Int. Ed. 2015, 54, 3817−
3821. (j) Zhang, X.-S.; Zhang, Y.-F.; Li, Z.-W.; Luo, F.-X.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2015, 54, 5478−5482. (k) Biafora, A.; Krause, T.;
Hackenberger, D.; Belitz, F.; Gooßen, L. J. Angew. Chem., Int. Ed. 2016,
55, 14752−14755. (l) Mei, R.-H.; Zhu, C.-J.; Ackermann, L. Chem.
Commun. 2016, 52, 13171−13174. (m) Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 14082−14083. (n) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc.
(16) Selected examples of Ni-catalyzed alkynylation of C−H bonds:
(a) Liu, Y.; Liu, Y.-H.; Yan, S.-Y.; Shi, B.-F. Chem. Commun. 2015, 51,
6388−6391. (b) Yi, J.; Yang, L.; Xia, C.; Li, F. J. Org. Chem. 2015, 80,
6213−6221.
(17) Selected examples of Cu-catalyzed alkynylation of C−H bonds:
(a) Shang, M.; Wang, H.-L.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem.
Soc. 2014, 136, 11590−11593. (b) Liu, Y.-J.; Liu, Y.-H.; Yin, X.-S.; Gu,
W.-J.; Shi, B.-F. Chem. - Eur. J. 2015, 21, 205−209.
(18) Selected examples of Ru-catalyzed alkynylation of C−H bonds,
see: (a) Ano, Y.; Tobisu, M.; Chatani, N. Synlett 2012, 23, 2763−2767.
(b) Kang, D.; Hong, S. Org. Lett. 2015, 17, 1938−1941.
(19) Selected example of Co-catalyzed alkynylation of C−H bonds:
Sauermann, N.; Gonzalez, M. J.; Ackermann, L. Org. Lett. 2015, 17,
5316−5319.
(20) Selected example of Ir-catalyzed alkynylation of C−H bonds:
Zhou, J.; Shi, J.; Qi, Z.; Li, X.; Xu, H.-E.; Yi, W. ACS Catal. 2015, 5,
6999−7003.
(21) For a recent example of meta-selective alkynylation of arenes, see:
Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-X.; Yu, J.-Q. J.
Am. Chem. Soc. 2016, 138, 14092−14099.
(22) Iridium catalysis mediated by carbonyl as directing group has been
reported by Chang’s group. See: Kim, J.; Chang, S. Angew. Chem., Int. Ed.
2014, 53, 2203−2207.
(23) (a) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2010, 49, 6169−6173. (b) Engle, K. M.; Thuy-Boun, P. S.; Dang, M.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 18183−18193. (c) Thuy-Boun, P. S.;
Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 17508−17513. (d) Xiao, K.-J.; Chu, L.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2016, 55, 2856−2860.
D
DOI: 10.1021/acs.orglett.7b00581
Org. Lett. XXXX, XXX, XXX−XXX