RuCl3-catalyzed alkenylation of aromatic C-H bonds with terminal alkynes

Article abstract of DOI:10.1021/ol802262r

(Chemical Equation Presented) RuCl₃-catalyzed regio- and/or stereoselective alkenylation reactions of a variety of arylpyridines proceeded efficiently with terminal alkynes or allylic compounds in the presence of benzoyl peroxide or benzoic acid.

Full text of DOI:10.1021/ol802262r

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5309-5312
RuCl3-Catalyzed Alkenylation of
Aromatic C-H Bonds with Terminal
Alkynes
Kai Cheng, Bangben Yao, Jinlong Zhao, and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic of China
yhzhang@zju.edu.cn
Received September 29, 2008
ABSTRACT
RuCl3-catalyzed regio- and/or stereoselective alkenylation reactions of a variety of arylpyridines proceeded efficiently with terminal alkynes or
allylic compounds in the presence of benzoyl peroxide or benzoic acid.
Transition metal-catalyzed C-H activation has currently
aroused considerable interest since it avoids the otherwise
necessary prefunctionalization such as halogenation and
metalation.1,2 In particular, the chelation-assisted cleavage
of C-H bonds at the ortho-position of directing groups has
been recognized as one of the most powerful strategies
applicable to the functionalization of unreactive C-H bonds.
For example, the chelation-assisted reactions of aromatic
compounds bearing oxygen- or nitrogen-containing groups
with organohalides, organometals, and internal alkynes
have been successfully developed.3 Alkenylation of arenes
is among the most important transformations in organic
synthesis. The first example of carbonyl-directed alkenyla-
tion of R-tetralone with internal alkynes catalyzed by
Ru(H)2(CO)(PPh3)3 was reported by Murai and co-workers.4
Later, Miura et al. reported the iridium-catalyzed reactions
of 1-naphthols and internal alkynes, in which alkenylation
occurs regioselectively at the spatially neighboring position
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013–1025. (b) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int.
Ed. 2008, 47, 7497–7500. (c) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc.
2008, 130, 2926–2927. (d) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 2448–2449. (e) Lewis, J. C.; Berman, A. M.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493–2500.
(f) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075–7078. (g)
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848–10849. (h) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem.
Soc. 2008, 130, 10510–10511. (i) Ueda, S.; Nagasawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 6411–6413. (j) Murahashi, S.-I.; Nakae, T.; Terai, H.;
Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005–11012. (k) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238. (l) Roy, A. H.;
Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082–2093.
(m) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742–7743. (n) Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007,
129, 7768–7769. (o) Li, L.; Jones, W. D. J. Am. Chem. Soc. 2007, 129,
10707–10713. (p) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem.
Soc. 2007, 129, 14106–14107. (q) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2007, 129, 12404–12405. (r) Stuart, D. R.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 12072–12073. (s) Li, Z.; Cao, L.; Li, C.-J.
Angew. Chem., Int. Ed. 2007, 46, 6505–6507. (t) Kanyiva, K. S.; Nakao,
Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007, 46, 8872–8874. (u) Li, Z.;
Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007, 46,
5184–5186. (v) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am.
Chem. Soc. 2007, 129, 15372–15379. (w) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172–1175. (x) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org.
Lett. 2008, 10, 3607–3609. (y) Basle´, O.; Li, C.-J. Org. Lett. 2008, 10,
(2) (a) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9,
825–828. (b) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V.
Org. Lett. 2007, 9, 2333–2336. (c) Li, R.; Wang, S. R.; Lu, W. Org.
Lett. 2007, 9, 2219–2222. (d) Tobisu, M.; Yamaguchi, S.; Chatani, N. Org.
Lett. 2007, 9, 3351–3353. (e) Niwa, T.; Yorimitsu, H.; Oshima, K.
Org. Lett. 2007, 9, 2373–2375. (f) Yip, S. F.; Cheung, H. Y.; Zhou, Z.;
Kwong, F. Y. Org. Lett. 2007, 9, 3469–3472. (g) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137–3139. (h)
Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927–
4930. (i) Westermaier, M.; Mayr, H. Org. Lett. 2006, 8, 4791–4794. (j)
Godula, K.; Sames, D. Science 2006, 312, 67–72. (k) Yanagisawa, S.; Sudo,
T.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748–11749. (l)
Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem. Soc.
2006, 128, 12376–12377. (m) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 16496–16497. (n) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005,
127, 17000–17006. (o) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int.
Ed. 2005, 44, 4046–4048. (p) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077–1101. (q) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem.
Res. 2001, 34, 633–639. (r) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698–1712.
3661–3663
.
10.1021/ol802262r CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

of phenolic function to give the corresponding 8-substituted
1-naphthol derivatives.5 They also found recently that the
carboxylate group was a good directing group for the
alkenylation of internal alkynes at an ortho C-H bond in
benzoic acids in the presence of rhodium/copper catalyst.6
Very recently, the nickel-catalyzed alkenylation of N-
protected 3-cyanoindoles was described by Nakao and co-
workers7 and the ruthenium-catalyzed reaction of arylpyri-
dine and alkenyl ester gave rise to site-selective alkenylation
at an ortho C-H bond in the aryl ring.8 Despite these
important advances, terminal alkynes are rarely used as
alkenylation substrates in chelation-assisted aromatic C-H
bond reactions,9 and they were reported to be inactive in
ruthenium-catalyzed carbonyl directed alkenylation
reactions.4b To the best of our knowledge there is no example
of alkenylation in chelation-assisted C-H bond activation
using terminal alkynes. Herein, we report our efforts to
develop a new catalytic method for the alkenylation of
arylpyridines at the ortho C-H bond in the aryl ring with
terminal alkynes in the presence of 5 mol % of RuCl3 and 1
equiv of benzoyl peroxide or/and benzoic acid. Markedly
high stereoselectivity was obtained in good to high yields
with (E)-stereoisomers as the predominant alkenylation
products. The catalytic system could also be extended to the
alkenylation of arylpyridines with allylic compounds, which
provide new protocols for the synthesis of arylalkenes.
We first examined the effects of various additives toward
the reaction of 2-phenylpyridine and phenylacetylene in the
Table 1. The Optimization of Reaction Conditionsa
a Reaction conditions: 2-phenylpyridine (1 mmol), phenylacetylene (1.2
mmol), catalyst (5 mol %), additives (1 mmol), base (2 mmol), NMP (5
mL), 150 °C, 6 h. b Isolated yields.
¨
(3) (a) Ozdemir, I.; Demir, S.; C¸ etinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157.
(b) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 5858–5859. (c) Zhao, X.; Yu, Z. J. Am. Chem. Soc. 2008,
130, 8136–8137. (d) Larive´e, A.; Mousseau, J. J.; Charette, A. B. J. Am.
Chem. Soc. 2008, 130, 52–54. (e) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (f) Deng, G.; Zhao, L.; Li,
C.-J. Angew. Chem., Int. Ed. 2008, 47, 6278–6282. (g) Vogler, T.; Studer,
A. Org. Lett. 2008, 10, 129–131. (h) Kozhushkov, S. I.; Yufit, D. S.;
Ackermann, L. Org. Lett. 2008, 10, 3409–3412. (i) Wang, G.-W.; Yuan,
T.-T.; Wu, X.-L. J. Org. Chem. 2008, 73, 4717–4720. (j) Yang, S.; Li, B.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066–6067. (k) Chiong,
H. A.; Pham, Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879–9884.
(l) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi,
F. J. Am. Chem. Soc. 2007, 129, 9858–9859. (m) Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2007, 129, 11904–11905. (n) Kuninobu, Y.;
Nishina, Y.; Takeuchi, T.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 6518–
6520. (o) Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833–
2836. (p) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006, 128, 9048–
9049. (q) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634–12635. (r) Martinez, R.; Chevalier, R.; Darses, S.; Genet, J.-P.
Angew. Chem., Int. Ed. 2006, 45, 8232–8235. (s) Ackermann, L.; Altham-
mer, A.; Born, R. Angew. Chem., Int. Ed. 2006, 45, 2619–2622. (t) Chen,
X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790–6791. (u) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211–5213.
(v) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229–2231. (w)
Ackermann, L. Org. Lett. 2005, 7, 3123–3125. (x) Shabashov, D.; Daugulis,
O. Org. Lett. 2005, 7, 3657–3659. (y) Kalyani, D.; Deprez, N. R.; Desai,
L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (z) Oi, S.;
Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett. 2001,
3, 2579–2581.
presence of 5 mol % of RuCl3 in NMP at 150 °C for 6 h. It
was found that additive and solvent played the crucial role
in the reaction efficiency (Table 1). In the absence of
additives, no alkenylated product was observed (Table 1,
entry 1). Promising results were obtained upon examining a
variety of commercially available peroxides and a remarkable
positive effect was observed when 1 equiv of benzoyl
peroxide was presented in the reaction (Table 1, entries 2-4).
Under these conditions, a satisfactory 76% isolated yield of
the alkenylated product 2-(2-styrylphenyl)pyridine was ob-
tained (Table 1, entry 2). With RuCl2(PPh3)3 as catalyst, the
yield was decreased to 55% (Table 1, entry 5). The palladium
catalysts had a poor effect on the alkenylation reaction (Table
1, entries 6 and 7). The use of NMP as solvent proved to be
the most adequate compared to other solvents tested such
as CH3CN, toluene, DME, and THF. GC-MS analysis
revealed that excellent stereoselectivity was obtained with
this transformation, in which only (E)-stereoisomers were
observed. In addition, the reaction was highly regioselective
to give the monoalkenylated product without the suffering
of double alkenylation.
(4) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. (b) Kakiuchi, F.;
Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett. 1995, 681–682.
(5) Satoh, T.; Nishinaka, Y.; Miura, M.; Nomura, M. Chem. Lett. 1999,
615–616.
In an earlier paper, we reported the RuCl3-catalyzed
arylation of arylpyridines with aryl iodides in the presence
of peroxides in NMP.10 We established that the decomposi-
tion of benzoyl peroxide to Ar• radicals was supressed under
the reaction conditions, and quantitive amounts of benzoic
acid were generated rapidly. Therefore, it became interesting
(6) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407–1409.
(7) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem. Soc.
2006, 128, 8146–8147.
(8) Oi, S.; Tanaka, Y.; Inoue, Y. Organometallics 2006, 25, 4773–4778.
(9) Lim, Y.-G.; Lee, K.-H.; Koo, B. T.; Kang, J.-B. Tetrahedron Lett.
2001, 42, 7609–7612.
(10) Cheng, K.; Zhang, Y.; Zhao, J.; Xie, C. Synlett 2008, 1325–1330.
Org. Lett., Vol. 10, No. 22, 2008
5310

Table 2. Scope of the Alkenylation Reactiona
a Reaction conditions: arylpyridine (1 mmol), alkyne (1.2 mmol), RuCl3 (5 mol %), benzoyl peroxide (1 mmol), K2CO3 (2 mmol), NMP (5 mL), 150 °C,
6 h. b Isolated yields. The yields with benzoic acid (1 mmol) in place of benzoyl peroxide are in parentheses. c E/Z ) 62/38. d E/Z ) 52/48.
to examine the effect of benzoic acid on the reaction.
Significantly, we discovered that benzoic acid indeed pro-
moted the transformation and a 62% isolated alkenylation
product was obtained (Table 1, entry 8). The combination
of RuCl3 catalyst and benzoic acid also allowed the arylation
of arylpyridines under the reaction conditions. Although the
replacement of benzyl peroxide with benzoic acid led to the
lower yields, the results were still valuable considering the
benzoyl peroxide was not easy to handle at high tempera-
tures.
arylpyridines as shown in Table 2. The electron-donating
and electron-withdrawing substituents in the aryl ring of aryl
alkynes were well tolerated to give moderate to high yields
(Table 2, entries 1-5 and 9-13). The conjugated enyne
smoothly underwent a selective reaction and afforded the
diene derivative (Table 2, entries 6 and 14). The electronic
properties of the substituents on arylpyridines proved to have
little effect on the alkenylation processes, and good yields
were obtained (Table 2, entries 15-19). 3-Methyl-2-phe-
nylpyridine showed a relatively better reactivity (Table 2,
entries 1-8). The alkenylation reaction was highly stereo-
selective and only (E)-alkenylated products were isolated.
We then proceeded to evaluate the generality of these
reaction conditions with a variety of terminal alkynes and
Org. Lett., Vol. 10, No. 22, 2008
5311

Scheme 1
Scheme 2
Scheme 1. A proton abstract by the benzoic anion coodinated
to ruthenium results in intermediate 2 and the exchange of
benzoic acid with terminal alkynes to form intermediate 3.
The subsequent migratory insertion leads to intermediate 4,
which liberates the alkenylated product and ruthenium
catalyst by protodemetalation.
Finally, this catalytic system was extended to the alkeny-
lation of arylpyridine with allylic compounds such as allyl
chloride, allyl bromide, and allyl acetate (Scheme 2). In these
cases, however, the regioisometric products of a and b were
isolated, while the alkenylated isomer a was the major
product.
In conclusion, we have developed a new selective RuCl3-
catalyzed C-H functionalization process that can alkenylate
arylpyridines without the use of ligands with high regiose-
lectivity and/or stereoselectivity. The scope of the alkeny-
lation and arylation is broad and tolerates a variety of
functional groups. Mechanistic studies toward the detailed
understanding of the activation pathways are in progress in
our laboratory.
The alkyl alkynes were also suitable for the alkenylation
reaction as revealed with the two examples in entries 7 and
8, generating the desired products in good yields (Table 2).
However, in these cases, (Z)-stereoisomers was observed
although (E)-stereoisomers were the major products (Table
2, entries 7 and 8). As depicted in Table 2, the arylpyridine-
related substrates, including naphthalenepyridine, phenylpy-
rimidine, and phenylpyridazine, proved to be adaptable to
these conditions, producing the alkenylation products in
comparable yields (Table 2, entries 20-22). In general, the
replacement of benzoyl peroxide with benzoic acid led to
lower yields (Table 2, entries 1-22, the yields in parenthe-
ses). The internal alkynes were inactive under the reaction
conditions.
There is little experimental evidence at present to elucidate
the exact reaction pathway for the direct alkenylation
processes. Since arylpyridines with electron-withdrawing
substituents (Table 2, entries 18 and 19) also give good
alkenylation yields, an electrophilic aromatic substitutioin
mechanism is not favored. Recently, Echavarren and Maseras
proposed a proton abstract mechnism, which provides a
satisfactory explanation for the Pd-catalyzed arylation via
C-H bond activation.11 On the basis of this C-H bond
activation chemistry and our results, a plausible mechanism
for the alkenylation process was suggested as shown in
Acknowledgment. Funding from Zhejiang Provincial
Natural Science Foundation of China (R407106) and Natural
Science Foundation of China (No. 205710631) is acknowl-
edged.
Supporting Information Available: The experimental
procedure and spectroscopic data (1H NMR, 13C NMR, and
HRMS) for the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067. (b) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496–16497.
OL802262R
5312
Org. Lett., Vol. 10, No. 22, 2008