Ruthenium-Catalyzed C-H Arylation of Diverse Aryl Carboxylic Acids with Aryl and Heteroaryl Halides

Article abstract of DOI:10.1021/acs.orglett.6b02862

Ruthenium ligated to tricyclohexylphosphine or di-tert-butylbipyridine catalyzes the arylation of carboxylic acids with diverse aryl halides (iodide, bromide, and triflate; aryl and heteroaryl). In addition, arylations with 2-iodophenol formed benzochromenones, carboxylate was shown to be a stronger donor than an amide, and the arylation of a pyridine carboxylate was demonstrated. Stoichiometric studies demonstrated that the added ligand is required for reaction with the electrophile but not the C-H bond.

Full text of DOI:10.1021/acs.orglett.6b02862

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed C−H Arylation of Diverse Aryl Carboxylic Acids
with Aryl and Heteroaryl Halides
Liangbin Huang and Daniel J. Weix*
University of Rochester, Rochester, New York 14627-0216, United States
S
* Supporting Information
ABSTRACT: Ruthenium ligated to tricyclohexylphosphine or di-tert-butylbipyridine catalyzes the arylation of carboxylic acids
with diverse aryl halides (iodide, bromide, and triflate; aryl and heteroaryl). In addition, arylations with 2-iodophenol formed
benzochromenones, carboxylate was shown to be a stronger donor than an amide, and the arylation of a pyridine carboxylate was
demonstrated. Stoichiometric studies demonstrated that the added ligand is required for reaction with the electrophile but not
the C−H bond.
he synthesis of biaryls by directed C−H arylation has
Although Ru-catalyzed C−H arylation has been extensively
studied9 and Ru-catalyzed C−H functionalization can be
directed by the carboxylic acid group,10 no examples of
carboxylic acid directed C−H arylation have been reported.
The notable lack of examples with ruthenium inspired us to
initially examine a multimetallic solution4c,11 of Ru and Ni, but
the data eventually led us to an overlooked, relatively simple
single-metal system (Scheme 1c).
T
become an essential tool in organic synthesis.1 However,
the majority of arylation methods still rely on strongly
coordinating donor groups that can be inconvenient to
introduce and remove (Scheme 1a).1,2 A major advance was
Scheme 1. C−H Arylation with Aryl Electrophiles
We initially examined a combination of Ru and Ni catalysis
to achieve the transformation (Table 1). Although [Ru(p-
cymene)Cl2]2 or (dtbbpy)NiBr2 alone failed to provide any of
the C−H arylation product, the combination of the two
catalysts formed product 3a in 45% yield (entries 1−3). To our
surprise, however, we found that the ligand on the nickel
complex (4,4′-di-tert-butyl-2,2′-bipyridine, dtbbpy) was the key,
and a reaction run with Ru and dtbbpy provided the same yield
as the reaction run with nickel (entry 4). While many reports
on ligand-free C−H arylation with strong directing groups
exist,9a Ackerman has used PCy3 with ruthemium9l for arylation
with a triazole directing group, and palladium-catalyzed
reactions often use added ligands.12 We report here that this
ruthenium catalyst is a general solution for ortho C−H arylation
of benzoic acid derivatives and overcomes some limitations of
the Pd- and Ir-catalyzed methods.
the finding that certain catalysts are capable of C−H arylation
ortho to a carboxylic acid directing group, a weak donor3 that is
a versatile intermediate in organic synthesis.4 C−H arylation
with arylboron reagents,3b,5 arenes,6 and aryl electrophiles3a,7
(Scheme 1b) has been demonstrated with a variety of metal
catalysts. While powerful, significant challenges remain; for
example, nitrogen-containing heteroaryl substrates have not
been demonstrated for carboxylate directing groups.8
We tested a number of other nitrogen and phosphorus
ligands, but only 4,4′-di-tert-butyl-2,2′-bipyridine (48%), 4,4′-
Received: September 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
cases where lower yields were observed, the reactions were
usually incomplete, with unreacted starting materials remaining.
A variety of benzoic acid derivatives were also arylated in
high yield (Scheme 3). Both electron-rich and electron-poor
Table 1. C−H Arylation Catalyst Optimization
b
a
entry
catalyst
3a (%)
Scheme 3. Scope of Aryl Carboxylic Acid.
1
2
3
[Ru(p-cymene)Cl2]2 (4 mol %)
NiBr2·diglme/dtbbpy (4 mol %)
[Ru(p-cymene)Cl2]2 (4 mol %) and NiBr2·diglme/dtbbpy 45
(4 mol %)
nd
nd
4
5
6
[Ru(p-cymene)Cl2]2 (4 mol %) and dtbbpy (4 mol %)
[Ru(p-cymene)Cl2]2 (4 mol %) and PCy3 (8 mol %)
RuCl3·3H2O (8 mol %) and PCy3 (8 mol %)
48
c
91 (94 )
68
a
Reactions run with 2-methylbenzoic acid 1a (0.25 mmol) and 2a (1.5
b
c
equiv). GC yield of methyl ester, uncorrected. Isolated yield of
methyl ester. Dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.
dimethoxy-2,2′-bipyridine (58%), 6,6′-dimethyl-2,2′-bipyridine
(67%), triphenylphosphine (51%), 1,4-bis(diphenylphos-
phino)butane (44%), and tricyclohexylphosphine (94%) gave
a promising yield of product. The presence of a cymene ligand
is not essential, and a simple RuCl3 hydrate performed nearly as
well (entry 6). See the Supporting Information for details on
the other ligands examined and further optimization data.
Under the optimal conditions, ArI and ArBr are both suitable
for these transformations. Various functional groups are
tolerated including Cl, OMe, CO2Me, Ac, CF3, SF5, F, and
OH groups (Scheme 2, 3a−k). In addition, the dihalide arenes
could undergo selective C−H arylation at less sterically
hindered or more activated positions (Scheme 2, 3l−o).
Finally, while chlorobenzene did not couple in high yield (data
not shown), phenyl triflate coupled in a promising yield. In
a
b
c
Reactions run as in Scheme 2. 2a (3 equiv). 5-Bromo-2-
chloropyridine 1.5 equiv.
aromatic acids are equally tolerated (4ba vs 4ia), and halogens
on the benzoic acids were also tolerated. The latter presents a
convenient handle for further elaboration. Impressively,
thiophene and pyridine carboxylic acids also coupled in
promising yields. While less hindered pyridine carboxylic
acids failed to couple,13 this is the first example of a directed
C−H functionalization on a free pyridine carboxylic acid.8,14
A general advantage of this Ru-catalyzed C−H arylation
method over the previously reported Ir- and Pd-catalyzed
methods is the tolerance of heteroaryl substrates, especially
electrophiles (Scheme 4). For these substrates, the dimerization
a
Scheme 2. Substrate Scope of Aryl Electrophile.
a
Scheme 4. C−H Arylation with Heteroaryl Electrophiles
a
b
Reactions run with 1a (0.25 mmol), 2 (1.5 equiv). Esterification
with EtI instead of MeI, isolated yield of ethyl ester.
of the benzoic acid was a major side reaction (up to 20%).
Switching from K2CO3 to Cs2CO3 as the base suppressed this
side reaction (10% or less).6e 4-Iodo-1H-pyrazole and 5-iodo-1-
methyl-1H-indole were also transformed into the correspond-
ing arylheteroaryl biarenes (Scheme 4, 3q−r). Multifunctional
pyridyl bromides were also transformed into the corresponding
a
b
Reactions run with 1a (0.25 mmol) and 2 (1.5 equiv). Five mol %
c
dtbbpy as ligand at 80 °C. Methylation step was not run. Product
isolated as free acid. The depicted product was isolated along with the
product of substitution at the bromide ortho to the methoxy group
(3l′). 2 (3 equiv) at 80 °C.
d
e
B
DOI: 10.1021/acs.orglett.6b02862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
products in moderate to good yields (Scheme 4, 3s−w). The
C−H arylation also selectively occurred at the less sterically
hindered position (Scheme 4, 3w). Finally, in contrast to cross-
dehydrogenative coupling, which can only couple at the 2-
position of thiophene,6a,d this method allows access to 3-
position of thiophene (Scheme 4, 3p).
Scheme 6. Carboxylic Acid vs Amide as a Directing Group
The tolerance of these reaction conditions to unprotected
phenols prompted us to examine the synthesis of 6H-
benzo[c]chromen-6-ones through the C−H arylation of aryl
carboxylic acids with 2-iodophenol (Scheme 5). Chromenones
of this type have extensive biological activity15 and have never
been assembled by this route before.
a
Scheme 5. Construction of 6H-benzo[c]chromen-6-ones
a
b
Reactions run with 2a (0.25 mmol), 1x−z (1.5 equiv). Methylation
step was not run. Product isolated yield as acid.
since the amide group is a powerful directing group in
combination with various metal catalysts.2,9g,k
We anticipate that the ruthenium-catalyzed, carboxylate-
directed C−H arylation of aromatic and heteroaromatic
carboxylic acids with aryl and heteroaryl halides will find
widespread use in organic synthesis. In addition to having a
different substrate and reactivity profile than the better studied
palladium catalysts, ruthenium is also more abundant and of
lower cost. The ability to utilize heteroaromatic carboxylic acids
as substrates could be of particular utility in the synthesis of
active pharmaceutical ingredients.
a
Reactions run with 1 (0.25 mmol) and 5 (1.5 equiv).
Given that no product was observed in reactions without
added ligand, we briefly examined the role of the ligand in
stoichiometric C−H arylation. C−H arylations with ruthenium
directed by strong donors are proposed to proceed by initial
cyclometalation followed by oxidative addition of the electro-
phile.9f,j,16 Therefore, we reacted (p-cymene)Ru(κ2-O,C-nap-
thenoate) (py) (8) with iodobenzene both with and without
ligand (eq 1).10b Product forms only in the presence of PCy3.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02862.
Additional tables of experimental data, mechanistic
experiments, experimental details, and product character-
ization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: daniel.weix@rochester.edu.
Notes
While we do not know why the yield of 4ha from 8 is lower
than expected, 8 is an excellent catalyst for this transformation
and is kinetically competent (see the Supporting Information).
These studies are consistent with PCy3 reaction with 8 to form
a new intermediate that is capable of reacting with iodobenzene
to form product 4ha, but other mechanisms remain possible.16
This “turn-on” of reactivity with carboxylic acids by the
addition of PCy3 prompted us to compare carboxylic acids to a
stronger amide directing group (Scheme 6). While nitrogen
directing groups are generally considered stronger directors in a
variety of transformations,9g,k,17 under these conditions carboxylic
acids override amides (Scheme 6b, products 3x−z). This opens
up opportunities for sequential, orthogonal functionalization
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge funding from the NIH NIGMS
(R01 GM097243). D.J.W. is a Camille Dreyfus Teacher−
Scholar. Additional funding from Novartis, Pfizer, and
Boehringer Ingelheim is also gratefully acknowledged. We
thank Amanda M. Spiewak (University of Rochester) for
assistance with characterization and the mechanistic experi-
ments and Lifeng Xiao (University of Rochester) for assistance
with substrate synthesis. We thank Prof. Dr. Lukas Goossen
C
DOI: 10.1021/acs.orglett.6b02862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7, 3123−3125. (f) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.;
Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161−10170. (g) Chinnagolla,
R. K.; Jeganmohan, M. Org. Lett. 2012, 14, 5246−5249. (h) Aihara, Y.;
Chatani, N. Chem. Sci. 2013, 4, 664−670. (i) Ackermann, L. Org.
Process Res. Dev. 2015, 19, 260−269. (j) Simonetti, M.; Perry, G. J. P.;
(Ruhr-Universitat Bochum) for agreeing to coordinate
publication.
̈
REFERENCES
■
(1) (a) Ackermann, L. Modern Arylation Methods; Wiley-VCH:
Weinheim, 2009; 543 pp. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147−1169. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J.
Chem. Soc. Rev. 2011, 40, 1885−1898. (d) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960−9009. (e) Chen,
D. Y. K.; Youn, S. W. Chem. - Eur. J. 2012, 18, 9452−9474. (f) Wencel-
Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369−375. (g) Farmer, M.
E.; Laforteza, B. N.; Yu, J.-Q. Bioorg. Med. Chem. 2014, 22, 4445−
4452. (h) Hussain, I.; Singh, T. Adv. Synth. Catal. 2014, 356, 1661−
1696. (i) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org.
Chem. Front. 2015, 2, 1107−1295. (j) Cernak, T.; Dykstra, K. D.;
Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546−
576. (k) Davies, H. M. L.; Morton, D. J. Org. Chem. 2016, 81, 343−
350. (l) Seki, M. Org. Process Res. Dev. 2016, 20, 867−877.
(2) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Org. Chem.
Front. 2014, 1, 843−895.
́ ́
Cambeiro, X. C.; Julia-Hernandez, F.; Arokianathar, J. N.; Larrosa, I. J.
Am. Chem. Soc. 2016, 138, 3596−3606. (k) Nareddy, P.; Jordan, F.;
Brenner-Moyer, S. E.; Szostak, M. ACS Catal. 2016, 6, 4755−4759.
(l) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem 2009, 2, 546−
549.
(10) (a) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L.
Adv. Synth. Catal. 2014, 356, 1461−1479. (b) Warratz, S.; Kornhaaß,
C.; Cajaraville, A.; Niepotter, B.; Stalke, D.; Ackermann, L. Angew.
̈
Chem., Int. Ed. 2015, 54, 5513−5517. (c) Huang, L.; Biafora, A.;
Zhang, G.; Bragoni, V.; Gooßen, L. J. Angew. Chem., Int. Ed. 2016, 55,
6933−6937.
(11) (a) Shibasaki, M.; Yamamoto, Y. Multimetallic Catalysts in
Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Perez-Temprano,
́
M. H.; Casares, J. A.; Espinet, P. Chem. - Eur. J. 2012, 18, 1864−1884.
(c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633−658.
(d) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed. 2005, 44, 455−
457. (e) Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem.
Soc. 2009, 131, 18022−18023. (f) Zhao, Y.; Weix, D. J. J. Am. Chem.
Soc. 2014, 136, 48−51. (g) Ackerman, L. K. G.; Lovell, M. M.; Weix,
D. J. Nature 2015, 524, 454−457. (h) Ackerman, L. K. G.; Anka-
Lufford, L. L.; Naodovic, M.; Weix, D. J. Chem. Sci. 2015, 6, 1115−
1119. (i) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237−
3240.
(3) (a) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879−9884. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129,
3510−3511. (c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2012, 45, 788−802.
(4) (a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1997, 36, 155−156. (b) Myers, A. G.; Tanaka, D.; Mannion, M. R. J.
Am. Chem. Soc. 2002, 124, 11250−11251. (c) Gooßen, L. J.; Deng, G.;
Levy, L. M. Science 2006, 313, 662−664. (d) Forgione, P.; Brochu, M.-
C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am.
Chem. Soc. 2006, 128, 11350−11351. (e) Rodriguez, N.; Goossen, L. J.
Chem. Soc. Rev. 2011, 40, 5030−5048. (f) Dzik, W. I.; Lange, P. P.;
Goossen, L. J. Chem. Sci. 2012, 3, 2671−2678. (g) Cornella, J.;
Larrosa, I. Synthesis 2012, 44, 653−676.
(5) (a) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 17676−17677. (b) Thuy-Boun, P. S.; Villa, G.; Dang, D.;
Richardson, P.; Su, S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 17508−
17513.
(6) (a) Qin, X.; Sun, D.; You, Q.; Cheng, Y.; Lan, J.; You, J. Org. Lett.
2015, 17, 1762−1765. (b) 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. (c) Zhang, X.-S.; Zhang, Y.-F.; Li, Z.-W.; Luo, F.-X.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2015, 54, 5478−5482. (d) Zhang, Y.; Zhao,
H.; Zhang, M.; Su, W. Angew. Chem., Int. Ed. 2015, 54, 3817−3821.
(e) Gong, H.; Zeng, H.; Zhou, F.; Li, C.-J. Angew. Chem., Int. Ed. 2015,
54, 5718−5721.
(12) Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927−8955.
(13) Two other less-hindered pyridine carboxylic acids failed to
couple (nicotinic acid and picolinic acid). This result, along with the
results in Scheme 4 and Figures S3 and S4, suggest that unhindered
pyridines act as ligands and inhibit catalysis.
(14) (a) Huckins, J. R.; Bercot, E. A.; Thiel, O. R.; Hwang, T.-L.; Bio,
M. M. J. Am. Chem. Soc. 2013, 135, 14492−14495. (b) Cai, S.; Chen,
C.; Shao, P.; Xi, C. Org. Lett. 2014, 16, 3142−3145.
(15) (a) Winneker, R. C.; Wagner, M. M.; Singh, B. J. Med. Chem.
1990, 33, 129−132. (b) Kudo, K.; Yamamoto, N. Org. Process Res. Dev.
2015, 19, 309−314.
(16) Grounds, H.; Anderson, J. C.; Hayter, B.; Blake, A. J.
Organometallics 2009, 28, 5289−5292.
(17) Ameline, G.; Vaultier, M.; Mortier, J. Tetrahedron Lett. 1996, 37,
8175−8176.
(7) (a) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed. 2011,
50, 9429−9432. (b) Wu, Z.; Chen, S.; Hu, C.; Li, Z.; Xiang, H.; Zhou,
X. ChemCatChem 2013, 5, 2839−2842. (c) Arroniz, C.; Ironmonger,
A.; Rassias, G.; Larrosa, I. Org. Lett. 2013, 15, 910−913. (d) Arroniz,
C.; Denis, J. G.; Ironmonger, A.; Rassias, G.; Larrosa, I. Chem. Sci.
2014, 5, 3509−3514. (e) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem.
Soc. 2014, 136, 4109−4112. (f) Luo, J.; Preciado, S.; Larrosa, I. Chem.
Commun. 2015, 51, 3127−3130. (g) Huang, L.; Hackenberger, D.;
Gooßen, L. J. Angew. Chem., Int. Ed. 2015, 54, 12607−12611. (h) Zhu,
C.; Zhang, Y.; Kan, J.; Zhao, H.; Su, W. Org. Lett. 2015, 17, 3418−
3421.
(8) (a) Stephens, D. E.; Larionov, O. V. Tetrahedron 2015, 71, 8683−
8716. (b) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed.
2010, 49, 1275−1277. (c) Liu, Y.-J.; Xu, H.; Kong, W.-J.; Shang, M.;
Dai, H.-X.; Yu, J.-Q. Nature 2014, 515, 389−393. (d) Shang, Y.; Jie, X.;
Zhao, H.; Hu, P.; Su, W. Org. Lett. 2014, 16, 416−419. (e) Shang, M.;
Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2014, 16, 5666−5669.
(9) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879−5918. (b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.;
Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579−2581. (c) Kakiuchi, F.;
Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125,
1698−1699. (d) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am.
Chem. Soc. 2005, 127, 5936−5945. (e) Ackermann, L. Org. Lett. 2005,
D
DOI: 10.1021/acs.orglett.6b02862
Org. Lett. XXXX, XXX, XXX−XXX