Ruthenium(II)-catalyzed regio- and stereoselective hydroarylation of alkynes via directed C-H functionalization

Article abstract of DOI:10.1021/ol300579m

The ruthenium-catalyzed hydroarylation of alkynes with benzamides proceeds regio- and stereoselectively through a directed C-H bond cleavage. Preliminary mechanistic investigations indicate that the reaction involves amide-directed ortho-metalation, carbo

Full text of DOI:10.1021/ol300579m

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2058–2061
Ruthenium(II)-Catalyzed Regio- and
Stereoselective Hydroarylation of Alkynes
via Directed CꢀH Functionalization
Yuto Hashimoto,† Koji Hirano,† Tetsuya Satoh,*,† Fumitoshi Kakiuchi,‡ and Masahiro Miura*,†
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan, andDepartment of Chemistry, Faculty of Science andTechnology,
Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
satoh@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received March 6, 2012
ABSTRACT
The ruthenium-catalyzed hydroarylation of alkynes with benzamides proceeds regio- and stereoselectively through a directed CꢀH bond
cleavage. Preliminary mechanistic investigations indicate that the reaction involves amide-directed ortho-metalation, carbometalation of alkyne,
and protonolysis. Similarly, phenylazoles also add to alkynes regioselectively.
Catalytic arylꢀvinyl and arylꢀaryl coupling reactions
have been recognized to be one of the most important tools
for constructing π-conjugated molecules. Compared to
conventional cross-coupling reactions of halogenated or
metalated aromatic reagents, the direct couplings of un-
activated aromaticsubstrates throughCꢀH bond cleavage
have attracted significant attention as atom- and step-
economical synthetic methods.1 To activate the ubiqui-
tously available CꢀH bond regioselectively and efficiently,
a directing group is usually utilized. As pioneering work on
such catalytic reactions, Murai and co-workers reported
carbonyl-directed alkylation of aromatic ketones under
ruthenium catalysis, involving ortho CꢀH bond activa-
tion and subsequent insertion of alkenes.2 Related reac-
tions with internal alkynes in place of alkenes have also
been developed as synthetic tools for ortho-olefination,3
although products are usually obtained as regio- and
† Osaka University.
‡ Keio University.
(1) Selected recent reviews for CꢀH functionalization: (a) Colby,
D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. ASAP,
DOI: 10.1021/ar200190g. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu,
J.-Q. Acc. Chem. Res. ASAP, DOI: 10.1021/ar200185g. (c) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d)
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740. (e) Kuninobu, Y.; Takai, K. Chem. Rev. 2011, 111, 1938. (f)
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (g)
Ackermann, L. Chem. Rev. 2011, 111, 1315. (h) Lapointe, D.; Fagnou,
K. Chem. Lett. 2010, 39, 1118. (i) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (j) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (k) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Commun. 2010, 46, 677. (l) Satoh, T.; Miura, M. Chem.;Eur. J. 2010,
16, 11212. (m) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (n) Daugulis, O.; Do, H.-Q.; Shabashov,
D. Acc. Chem. Res. 2009, 42, 1074. (o) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874. (p) McGlacken, G. P.; Bateman, L. M.
Chem. Soc. Rev. 2009, 38, 2447. (q) Li, C.-J. Acc. Chem. Res. 2009, 42,
335. (r) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (s) Ferreira, E. M.;
Zhang, H.; Stoltz, B. M. Tetrahedron 2008, 64, 5987. (t) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (u) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107,
5318. (v) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (w) Godula, K.; Sames, D. Science 2006, 312, 67. (x) Kakiuchi, F.;
Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (y) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698.
(2) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
(3) (a) Kakiuchi, F.; Uetsuhara, T.; Tanaka, Y.; Chatani, N.; Murai,
S. J. Mol. Catal. A: Chem. 2002, 182ꢀ183, 511. (b) Kakiuchi, F.; Sato,
T.; Tsujimoto, T.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett.
1998, 1053. (c) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S.
Chem. Lett. 1995, 681. (d) Trost, B. M.; Imi, K.; Davies, I. W. J. Am.
Chem. Soc. 1995, 117, 5371. (e) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y.
Org. Lett. 2008, 10, 5309. The hydroarylation product was also formed
as a byproduct in the Ru-catalyzed oxidative coupling of N-methylben-
zamide with diphenylacetylene: (f) Ackermann, L.; Lygin, A. V.;
Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379.
r
10.1021/ol300579m
Published on Web 04/05/2012
2012 American Chemical Society

stereoisomeric mixtures. Recently, similar hydroarylation
reactions of alkynes using rhodium,4,5 iridium,6 palla-
dium,7 rhenium,8 nickel,9 and cobalt10 catalysts have
also been reported,11 but the substrate scope remains
limited. Consequently, development of new catalyst sys-
tems with high selectivity and wide applicability is strongly
desired. In the context of our study of ruthenium-catalyzed
CꢀH olefination,3aꢀc,12 we have succeeded in finding that
the regio- and stereoselective hydroarylation of various
alkynes with benzamides involving amide-directed CꢀH
bond cleavage can be realized by using a ruthenium/silver
catalyst system.13 The catalyst was also found to be
effective for the hydroarylation with phenylazoles. These
new findings are described herein.
In an initial attempt, the reaction of N,N-dimethylben-
zamide (1a) (0.25 mmol) with diphenylacetylene (2a)
(0.5 mmol) was conducted in the presence of [Ru(p-
cymene)Cl2]2 (0.0125 mmol, 5 mol %) and AgSbF6 (0.05
mmol) in dioxane at 100 °C for 5 h under N2. As a result,
the hydroarylation product 3a was obtained in 43% yield
(entry 1 in Table 1). The product yield was remarkably
improved to 96% by addition of AcOH (1 mmol) (entry 2).
Decreasing the amount of AcOH to 0.1 mmol reduced the
yield (entry 3). Under conditions using H2O or KOAc in
place of AcOH, 3a could not be obtained at all (entries 4
and 5). Even with a slight excess (0.3 mmol) of 2a, 3a was
formed in 82% yield (entry 6).
(4) For early examples for catalytic hydroarylation, see: (a) Hong, P.;
Cho, B. R.; Yamazaki, H. Chem. Lett. 1979, 339. (b) Hong, P.; Cho,
B. R.; Yamazaki, H. Chem. Lett. 1980, 507. (c) Hong, P.; Yamazaki, H.
J. Mol. Catal. 1983, 21, 133.
(5) (a) Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem.
Soc. 2010, 132, 6910. (b) Shibata, Y.; Otake, Y.; Hirano, M.; Tanaka, K.
Org. Lett. 2009, 11, 689. (c) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano,
K.; Miura, M. Chem. Lett. 2009, 38, 118. (d) Parthasarathy, K.;
Jeganmohan, M.; Cheng, C. H. Org. Lett. 2008, 10, 325. (e) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645.
(f) Lim, S. G.; Lee, J. H.; Moon, C. W.; Hong, J. B.; Jun, C. H. Org. Lett.
2003, 5, 2759. (g) Lim, Y. G.; Lee, K. H.; Koo, B. T.; Kang, J. B.
Table 1. Reaction of N,N-Dimethylbenzamide (1a) with Di-
phenylacetylene (2a)a
€
Tetrahedron Lett. 2001, 42, 7609. (h) Durr, U.; Kisch, H. Synlett 1997,
1335. (i) Aulwurm, U. R.; Melchinger, J. U.; Kisch, H. Organometallics
1995, 14, 3385.
(6) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y. K.; Endo, K.;
Shibata, T. J. Organomet. Chem. 2008, 693, 3939. (b) Satoh, T.;
Nishinaka, Y.; Miura, M.; Nomura, M. Chem. Lett. 1999, 615.
(7) (a) Tsukada, N.; Murata, K.; Inoue, Y. Tetrahedron Lett. 2005,
46, 7515. (b) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.; Inoue, Y.
J. Am. Chem. Soc. 2003, 125, 12102.
(8) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K.
J. Am. Chem. Soc. 2006, 128, 202. (b) Kuninobu, Y.; Kawata, A.; Takai,
K. J. Am. Chem. Soc. 2005, 127, 13498.
(9) (a) Kanyiva, K. S.; Kashihara, N.; Nakao, Y.; Hiyama, T.;
Ohashi, M.; Ogoshi, S. Dalton Trans. 2010, 39, 10483. (b) Nakao, Y.;
Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996.
(c) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
6410. (d) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170. (e) Nakao, Y.; Kanyiva, K. S.; Hiyama, T.
J. Am. Chem. Soc. 2008, 130, 2448. (f) Nakao, Y.; Kanyiva, K. S.; Oda,
S.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 8146. See also a review: (g)
Nakao, Y. Chem. Rec. 2010, 11, 242.
additive
(mmol)
yield of
entry
3a (%)b
1
2
3
4
5
6c
ꢀ
43
AcOH (1)
AcOH (0.1)
H2O (1)
96 (81)
55
0
KOAc (1)
AcOH (1)
0
82
a Reaction conditions: [1a]/[2a]/[{Ru(p-cymene)Cl2}2]/[AgSbF6] =
0.25:0.5:0.0125:0.05 (in mmol), in dioxane (3 mL) at 100 °C for 5 h under
N2. b GC yield based on the amount of 1a used. Value in parentheses
indicates yield after purification. c [2a] = 0.3 mmol.
(10) (a) Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 17283. (b) Ding, Z.; Yoshikai, N. Synthesis 2011, 2561. (c) Yoshikai,
N. Synlett 2011, 1047. (d) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N.
J. Am. Chem. Soc. 2010, 132, 12249.
(11) Reviews: (a) Kitamura, T. Eur. J. Org. Chem. 2009, 1111. (b)
Vasil’ev, A. V. Russ. J. Org. Chem. 2009, 45, 1. (c) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
Next, the hydroarylation of various alkynes with amides
was examined under similar reaction conditions in the
presence of AcOH. Unsymmetrical alkylphenylacetylenes,
1-phenylpropyne (2b) and -hexyne (2c), reacted with 1a to
smoothly produce 3band 3c, respectively (entries 1 and 2 in
Table 2). It should be noted that no regio- and stereo-
isomers could be detected at all. Bis(4-chlorophenyl)-
acetylene (2d) coupled with 1a to form 3d (entry 3). The
reaction of 1-phenyl-2-(trimethylsilyl)acetylene (2e) pro-
ceeded efficiently through hydroarylation and subsequent
desilylation to produce a 1,1-diarylethene derivative 3e in
63% yield, along with a minor amount of normal product
3e0 (entry 4). From a terminal alkyne, tris(isopropyl)-
silylacetylene (2f), the corresponding hydroarylation
product 3f was obtained, albeit with a low yield (entry 5).
A series of N,N-disubstituted benzamides having a
cyclic- or diphenylamino group, 1bꢀd, reacted with 2a
to form products 3gꢀi, respectively, in 47ꢀ79% yields
(entries 6ꢀ8).
(12) (a) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 13, 706. After our report, related
Ru-catalyzed oxidative coupling reactions were also disclosed: (b) Li,
B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14, 736.
(c) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci 2012, 3, 177. (d) Li,
B.; Feng, H.; Xu, S.; Wang, B. Chem.;Eur. J. 2011, 17, 12573. (e)
Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548. (f) Ackermann, L.;
Pospech, J. Org. Lett. 2011, 13, 4153. (g) Ackermann, L.; Lygin, A. V.;
Hofmann, N. Org. Lett. 2011, 13, 3278. (h) Arockiam, P. B.; Fischmeister,
C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13, 3075. (i) Hashimoto,
Y.; Ueyama, T.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1165.
(13) For reactions using Ru/Ag or related cationic Ru catalysts, see:
(a) Hashimoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.; Miura,
M. Chem. Lett. 2012, 41, 118. (b) Chinnagolla, R. K.; Jeganmohan, M.
Eur. J. Org. Chem. 2012, 417. (c) Ackermann, L.; Pospech, J.; Graczyk,
K.; Rauch, K. Org. Lett. 2012, 14, 930. (d) Ackermann, L.; Lygin, A. V.
Org. Lett. 2012, 14, 764. (e) Ackermann, L.; Wang, L.; Wolfram, R.
Lygin, A. V. Org. Lett. 2012, 14, 728. (f) Chinnagolla, R. K.; Jeganmohan,
M. Chem. Commun. 2012, 48, 2030. (g) Kwon, K.-H.; Lee, D. W.; Yi, C. S.
Organometallics 2012, 31, 495. (h) Padala, K.; Jeganmohan, M. Org. Lett.
2011, 13, 6144. (i) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics
2010, 29, 5748. (j) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett.
2004, 6, 581.
A plausible mechanism for the reaction of 1 with 2 is
illustrated in Scheme 1. First, ortho-metalation of 1 takes
Org. Lett., Vol. 14, No. 8, 2012
2059

Table 2. Reaction of Benzamides 1 with Alkynes 2a
Scheme 1
Scheme 2
a Reaction conditions: [1]/[2]/[{Ru(p-cymene)Cl2}2]/[AgSbF6]/[AcOH] =
0.25:0.5:0.0125:0.05:1 (in mmol), in dioxane (3 mL) at 100 °C for 5 h under N2.
b Isolated yield based on the amount of 1 used. c A separable byproduct, N,N-
dimethyl-2-(1-phenyl-2-(trimethylsilyl)vinyl)benzamide (3e0), wasalsoformed
in 17% yield.
For further mechanistic information, deuterated N,N-
dimethylbenzamide (1a-d5) was subjected to the reaction
conditions (Scheme 2a). In the early stage, deuterium
incorporation in the olefinic position of the product could
not be detected by 1H NMR. The fact excludes the
possibility of a reaction pathway via oxidative addition
of an ortho CꢀH bond, which should lead to deuterium
incorporation at the position.10a,d In addition, no signifi-
cant deuterium loss at the ortho positions of recovered 1a-
d5 as well as at the 6-position of product 3a-d4 was
observed. This result indicates that the ortho-metalation
step to form A is likely irreversible. Next, an intermole-
cular competition reaction of 1a-d0/1a-d5 with 2a was
conducted. As shown in Scheme 2b, a considerable primary
isotope effect of 2.1 was observed, which suggests that the
rate-determining step involves CꢀH(D) bond cleavage.
place to give a five-membered ruthenacycle intermediate A
accompanied by loss of a proton.14 Subsequently, alkyne
insertion into the resulting RuꢀC bond to form an inter-
mediate B and protonolysis may occur to produce 3.
(14) It was recently reported that AcOH promotes the CꢀH bond
activation of 2-phenylpyridine: Flegeau, E. F.; Bruneau, C.; Dixneuf,
P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161 and references
therein.
2060
Org. Lett., Vol. 14, No. 8, 2012

at the 20-and60-positions to afford 5in 85% yield (Scheme 3).
In contrast, N-methyl-2-phenylimidazole (6) coupled with 2a
in a 1:1 manner to produce 7 selectively.
Scheme 3
In summary, we have demonstrated that the ruthenium-
catalyzed hydroarylationofalkyneswithbenzamidestakes
place efficiently. The procedure is also applicable to phe-
nylazoles. The present catalyst system and related ones are
expected to be applicable to other hydroarylation reac-
tions. Work is underway toward further development of
the catalysis.
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan.
Supporting Information Available. Standard experi-
mental procedure and characterization data of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The catalyst system was found to be applicable to the
reactions of phenylazoles. Thus, 1-phenylpyrazole (4)
underwent 2-fold coupling with 2a via CꢀH bond cleavage
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2061