Secon d a r y Ben zyla tion Usin g Ben zyl Alcoh ols Ca ta lyzed by
La n th a n oid , Sca n d iu m , a n d Ha fn iu m Tr ifla te
Masahiro Noji, Tomoko Ohno, Koji Fuji, Noriko Futaba, Hiroyuki Tajima, and Keitaro Ishii*
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, J apan
ishiikei@my-pharm.ac.jp
Received February 26, 2003
The combination of a secondary benzyl alcohol and a metal triflate (e.g., La, Yb, Sc, and Hf triflate)
in nitromethane was a highly effective secondary-benzylation system. Secondary benzylation of
carbon (aromatic compounds, olefins, an enol acetate), nitrogen (amide derivatives), and oxygen
(alcohols) nucleophiles was carried out with a secondary benzyl alcohol and 0.01-1 mol % of a
metal triflate in the presence of water. Secondary benzyl alcohols and nucleophiles bearing acid-
sensitive functional groups (e.g., tert-butyldimethylsilyloxy and acetoxy groups and methyl and
benzyl esters) could be used for alkylation. Hf(OTf)4 was the most active catalyst for this alkylation,
and trifluoromethanesulfonic acid (triflic acid, TfOH) was also a good catalyst. The catalytic activity
of metal triflates and TfOH increased in the order La(OTf)3 < Yb(OTf)3 < TfOH < Sc(OTf)3 <
Hf(OTf)4. A mechanistic study was also performed. The reaction of 1-phenylethanol (4a ) in the
presence of Sc(OTf)3 in nitromethane gave an equilibrium mixture of 4a and bis(1-phenylethyl)
ether (54). Addition of a carbon nucleophile to the equilibrium mixture gave alkylated product in
high yield.
In tr od u ction
Friedel-Crafts alkylation using alcohols. Hf(OTf)4 and
Sc(OTf)3 are also effective catalysts8 in the Friedel-
Crafts acylation and alkylation of benzene derivatives
with acid anhydrides, allyl alcohols,9 and benzyl halides.
Sc(OTf)3 is also stable and acts as a Lewis acid in the
presence of water, and a benzylic cation can be generated
from not only benzylic halide but also benzylic alcohol10
and benzylic ether.11
The Friedel-Crafts reaction is a very important method
for introducing alkyl substituents to an aromatic ring.
However, Friedel-Crafts alkylation1 is used less than
Friedel-Crafts acylation in fine organic synthesis. In
many cases, an alkyl halide or olefin is used as the
electrophile source, and large amounts of an aromatic
nucleophile and Lewis or Brønsted acid are necessary for
alkylation. Alcohol is also used as an electrophile for
Friedel-Crafts alkylation,2 and 1 equiv of water is
released as the reaction proceeds; thus, excess sulfuric
acid, polyphosphoric acid,3 or a stoichiometric amount of
Lewis acid4 is required. Therefore, it is difficult to fine
tune Friedel-Crafts alkylation for various functionalized
substrates.5 Recently, lanthanoid triflates have been used
in various synthetic reactions6 and have been shown to
act as catalysts even in the presence of water.7 Therefore,
a catalytic amount of lanthanoid triflate can complete
However, most metal triflate-catalyzed Friedel-Crafts
alkylations require more than 5 mol % of the triflate
(5) (a) Sharman, S. H. J . Am. Chem. Soc. 1962, 84, 2945-2951. (b)
Roberts, R. M.; Shiengthong, D. J . Am. Chem. Soc. 1964, 86, 2851-
2857. (c) Roberts, R. M.; McGuire, S. E. J . Org. Chem. 1970, 35, 102-
107. (d) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1970, 35, 3717-
3721. (e) Roberts, R. M.; McGuire, S. E.; Baker, J . R. J . Org. Chem.
1976, 41, 659-665. (e) Espeel, P. H.; J anssens, B.; J acobs, P. A. J .
Org. Chem. 1993, 58, 7688-7693.
(6) (a) Molander, G. A. Chem. Rev. 1992, 92, 29-68. (b) Kobayashi,
S. Synlett 1994, 689-701. (c) Marshman, R. W. Aldrichimica Acta
1995, 28, 77-84. (d) Inanaga, J .; Sugimoto, Y.; Hanamoto, T. New J .
Chem. 1995, 19, 707-712. (e) Kobayashi, S. In Topics in Organome-
tallic Chemistry; Kobayashi, S. Ed.; Springer: Berlin, 1999; Vol. 2. (f)
Mine, N.; Fujiwara, Y.; Taniguchi, H. Chem. Lett. 1986, 357-360. (g)
Kawada, A.; Mitamura, S.; Kobayashi, S. J . Chem. Soc., Chem.
Commun. 1993, 1157-1158. (h) Kobayashi, S.; Komoto, I. Tetrahedron
2000, 56, 6463-6465.
(7) (a) Kobayashi, S. Chem. Lett. 1991, 2087-2090. (b) Kawada, A.;
Mitamura, S.; Kobayashi, S. Chem. Commun. 1996, 183-184.
(8) (a) Kobayashi, S. Eur. J . Org. Chem. 1999, 15-27. (b) Kawada,
A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545-546. (c) Hachiya,
I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409-412.
(d) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. J pn.
1995, 68, 2053-2060. (e) Matsui, M.; Yamamoto, H. Bull. Chem. Soc.
J pn. 1995, 68, 2663-2668. (f) Kobayashi, S.; Iwamoto, S. Tetrahedron
Lett. 1998, 39, 4697-4700. (g) Kawada, A.; Mitamura, S.; Matsuo, J .;
Tsuchiya, T.; Kobayashi, S. Bull. Chem. Soc. J pn. 2000, 73, 2325-
2333. (h) Shiina, I.; Suzuki, M. Tetrahedron Lett. 2002, 43, 6391-6394.
(9) (a) Matsui, M.; Karibe, N.; Hayashi, K.; Yamamoto, H. Bull.
Chem. Soc. J pn. 1995, 68, 3569-3571. (b) Kato, T.; Nagae, K.;
Hirokawa, M. Tetrahedron Lett. 1999, 40, 1941-1944.
(1) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Carbon-Carbon
σ bond formation. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 293-339.
(2) (a) Ackermann, W.; Heesing, A. Chem. Ber. 1975, 108, 1182-
1187. (b) Laszlo, P.; Mathyl, A. Helv. Chim. Acta. 1987, 70, 577-586.
(c) Shen, Y.-S.; Liu, H.-X.; Wu, M.; Du, W.-Q.; Chen, Y.-Q.; Li, N.-P. J .
Org. Chem. 1991, 56, 7160-7162. (d) Armengol, E.; Cano, M. L.;
Corma, A.; Garc´ıa, H.; Navarro, M. J . Chem. Soc., Chem. Commun.
1995, 519-520.
(3) (a) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1969, 34, 3571-
3574. (b) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1971, 36, 1040-
1044. (c) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1972, 37, 4227-
4235. (d) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1973, 38, 1388-
1395. (e) Sundberg, R. J .; Laurino, J . P. J . Org. Chem. 1984, 49, 249-
254. (f) Davis, B. R.; J ohnson, S. J .; Woodgate, P. D. Aust. J . Chem.
1987, 40, 1283-1299.
(4) Coote, S. J .; Davies, S, G.; Middlemiss, D.; Naylor, A. Tetrahedron
Lett. 1989, 30, 3581-3584.
10.1021/jo034255h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/29/2003
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J . Org. Chem. 2003, 68, 9340-9347