Published on Web 05/27/2007
Indirect ortho Functionalization of Substituted Toluenes
through ortho Olefination of N,N-Dimethylbenzylamines Tuned
by the Acidity of Reaction Conditions
Guixin Cai, Ye Fu, Yizhou Li, Xiaobing Wan, and Zhangjie Shi*
Contribution from Beijing National Laboratory of Molecular Sciences (BNLMS), PKU Green
Chemistry Center and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, People’s
Republic of China, and Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
East China Normal UniVersity, Shanghai 200062, People’s Republic of China
Received January 26, 2007; E-mail: zshi@pku.edu.cn
Abstract: Highly regioselective olefination of substituted N,N-dimethylbenzylamines was developed by tuning
the acidity of reaction conditions based on analysis of their features. The ortho-functionalized N,N-
dimethylbenzylamines were further transformed into 3-(2′-tolyl)propanoic acid and its derivatives under
mild conditions. These two transformations could be combined into one pot, and 3-(2′-tolyl)propanoic acid
and its derivatives were obtained in moderate to good yields. Mechanistic studies indicated that electrophilic
attack on the phenyl ring by the Pd(II) ion assisted by the N,N-dimethylaminomethyl group was a key step
during this catalytic transformation, which was controlled by the acidity of the reaction conditions.
Introduction
acetamino, oxazolyl, pyridyl, and imino groups, have been
broadly utilized to provide either stoichiometric or catalytic
In the past several decades, many efforts have been made to
direct functionalization of a variety of C-H bonds.1 Aromatic
C-H activation through different chemical processes has been
studied.2 Direct functionalization of aromatic C-H bonds by
electrophilic attack of metal ions is one of the most important
pathways.3 Functional groups containing heteroatoms, such as
ortho-metalation of aromatic rings to construct C-C4a-f and
C-X (X ) halides, N, etc.) bonds.4g-jPrevious synthetic work
on functionalization of N,N-dimethylbenzylamine generally
utilized n-BuLi to ortho lithiate the N,N-dimethylbenzylamine,
which limited the tolerance of functional groups in the sub-
strates.5 Although the N,N-dimethylaminomethyl group has been
used as a directing group to realize the ortho-metalation by
transition metal complexes to form metallocycles and further
construct C-C bonds in a stoichiometric manner under basic
conditions,6 the catalytic version of ortho functionalization of
an aromatic C-H bond directed by an N,N-dimethylaminom-
ethyl group has rarely been reported, except one case reported
by Murai and co-workers, in which achieved ortho silylation
catalyzed by Ru(0) was initiated through oxidative addition.7
(1) (a) Murai, S. ActiVation of UnreactiVe Bonds and Organic Synthesis;
Springer-Verlag: Berlin, 1999; pp 48-78. (b) Shilov, A. E.; Shul’pin, G.
B. Chem. ReV. 1997, 97, 2879. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (d) Arndtsen, B. A.; Bergman, R. G.; Mobley, T.
A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (e) Cho, J.-Y.; Tse, M.
K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305. (f)
Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
2685. (g) Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J. Am. Chem. Soc.
2003, 125, 7506. (h) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.; Inoue,
Y. J. Am. Chem. Soc. 2003, 125, 12102. (i) Davies, H. M. L.; Hansen, T.;
Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (j) Crabtree, R. H. J.
Organomet. Chem. 2004, 689, 4083. (k) Sen, A. Acc. Chem. Res. 1998,
31, 550. (l) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (m) Stahl,
S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37,
2180. (n) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (o) Chen, H. Y.;
Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. (p)
Brown, S. H.; Crabtree, R. H. J. Am. Chem. Soc. 1989, 111, 2935. (q)
Solari, E.; Musso, F.; Ferguson, R.; Floriani, C.; Villa, A. C.; Rizzoli, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1510. (r) Dick, A. R.; Sanford, M.
S. Tetrahedron 2006, 62, 2439.
(2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529. (b) Shi, Z.; He, C. J. Am. Chem.
Soc. 2004, 126, 13596. (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005,
7, 3657. (d) Ishiyama, T.; Sato, K.; Nishio, Y.; Miyaura, N. Angew. Chem.,
Int. Ed. 2003, 42, 5346. (e) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.
2003, 3485. (f) Zhao, J.; Campo, M.; Larock, R. C. Angew. Chem., Int.
Ed. 2005, 44, 1873. (g) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.
(4) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (b) Boele, M. D.
K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries,
J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (c)
Tremont, S. J.; ur Rahman, H. J. Am. Chem. Soc. 1984, 106, 5759. (d)
Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156. (e) Kalyani,
D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 7330. (f) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2006, 128, 9048. (h) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2005, 44, 2112. (i) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang,
S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. (j) Tsang, W. C. P.; Zheng,
N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
(5) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Saa, J. M.; Llobera, A.;
Garcia-Raso, A.; Costa, A.; Deya, P. M. J. Org. Chem. 1988, 53, 4263.
(6) (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (b) Holton, R. A.; Davis, R. G.
J. Am. Chem. Soc. 1977, 99, 4175. (c) Dunina, V. V.; Kuz’mina, L. G.;
Kazakova, M. Y.; Gorunova, O. N.; Grishin, Y. K.; Kazakova, E. I. Eur.
J. Org. Chem. 1999, 1029. (d) Grove, D. M.; van Koten, G.; Ubbels, H. J.
C. J. Am. Chem. Soc. 1982, 104, 4285. (e) Holton, R. A. Tetrahedron Lett.
1977, 4, 355. (f) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K.
J. Chem. Soc., Perkin Trans. 2 1983, 1511.
(3) (a) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633. (c) Hennessy, E.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 12084. (d) Hashmi, A. S. K.; Schwarz, L.; Choi, J. H.;
Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (e) Wang, X.; Lane,
B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (f) Alexakis, A.;
Tomassini, A.; Andrey, O.; Bernardinelli, G. Eur. J. Org. Chem. 2005,
1332.
(7) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai,
S. Chem. Lett. 2002, 396.
9
7666
J. AM. CHEM. SOC. 2007, 129, 7666-7673
10.1021/ja070588a CCC: $37.00 © 2007 American Chemical Society