the viewpoint of handling, workup, and environmental impact,
development of a highly simple reductive procedure of esters,
which proceeds under milder conditions, is needed. On the other
hand, several groups have recently reported that a combination
of a trivalent indium salt and a milder reducing reagent, a
hydrosilane, is an effective reagent system for the reductive
conversion of a functional group involving dehalogenation of
organic halides, reduction of an alcohol, 1,4-reduction of enones,
and reductive aldol reaction.8 In this context, the reductive C-O
bond cleavage of propargylic acetates using InBr3-Et3SiH to
produce an internal alkyne was demonstrated.9 During ongoing
investigations on the development of the selective deacetoxy-
lation of several organic compounds using the InBr3-Et3SiH
system, remarkably it was found that, unlike our previous result,9
the InBr3-Et3SiH reducing system causes the reduction of the
carbonyl function of esters under milder conditions, resulting
in the preparation of unsymmetrical ethers.10,11 Thus, we report
herein on a further study of the present reductive procedure.
Initially, the reduction of phenethyl acetate (1a) with Et3SiH
in the presence of 0.05 equiv of InBr3 as a model reaction was
studied.12 Table 1 shows the results of the search for optimized
conditions. It was found that chloroform was the best solvent
for this reaction (run 1). Benzene and toluene also showed a
similar effect (runs 2 and 3). However, when the reaction was
conducted in THF, the reaction did not proceed (run 4), and
the use of acetonitrile also resulted in decreased yields (run 5).
On the other hand, it was noted that when the similar reaction
was carried out using InCl3, In(OAc)3, and In(OTf)3, the desired
ether product was not obtained, resulting in the recovery of the
starting acetate (runs 6-8). Then, running this reaction with
(EtO)3SiH, instead of Et3SiH, produced a low yield (run 9). In
contrast, a reducing reagent, such as PhMe2SiH, was effective
for this reaction (run 10). Consequently, it was found that the
combination of 0.05 equiv of InBr3 and 4 equiv of Et3SiH in
chloroform gave the best results for the reaction.13
An Efficient One-Pot Synthesis of Unsymmetrical
Ethers: A Directly Reductive Deoxygenation of
Esters Using an InBr3/Et3SiH Catalytic System
Norio Sakai,* Toshimitsu Moriya, and Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo UniVersity of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
ReceiVed April 18, 2007
This study describes a novel one-pot procedure for a directly
reductive conversion of the carbonyl function of esters to
the corresponding ethers by Et3SiH in the presence of a
catalytic amount of InBr3.
Previous methods for the preparation of ethers involved the
reaction of an alkoxy anion with an alkyl halide/sulfonate under
basic conditions (Williamson synthesis) and the acid-promoted
dehydrogenate condensation of alcohols.1 Since the 1960s, the
representative preparation of ethers has been a direct reduction
of a carbonyl function of esters and thioesters.1 Although a
number of protocols for the direct reduction of esters and
thioesters have been developed, most were accomplished
through treatment with stronger reducing agents, such as
LiAlH42 and DIBAL,3 or a more toxic reagent, such as organotin
hydride,4 or by use of a complicated transition-metal complex.5
In addition, these require γ-ray6 or UV irradiation.7 Thus, from
To generalize this reaction, the reduction of various esters 1
was carried out under optimized conditions with the reactions
typically run at 60 °C in a CHCl3 solution. The results are
displayed in Table 2. In most cases, the reduction of esters with
no relation to the length of the alkyl chain was completed in a
(1) For selected reviews for the preparation of ethers, see: (a) Greene,
T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis, 3rd ed.;
Wiley-VCH: New York, 1999. (b) Larock, R. C. ComprehensiVe Organic
Transformations, 2nd ed.; Wiley-VCH: New York, 1999.
(2) (a) Pettit, G. R.; Kasturi, T. R. J. Org. Chem. 1960, 25, 875. (b)
Pettit, G. R.; Ghatak, U. R.; Green, B.; Kasturi, T. R.; Piatak, D. M. J.
Org. Chem. 1961, 26, 1685. (c) Pettit, G. R.; Kasturi, T. R. J. Org. Chem.
1961, 26, 4553. (d) Pettit, G. R.; Piatak, D. M. J. Org. Chem. 1962, 27,
2127.
(8) For selected papers of a reductive reaction using a combination of
an indium(III) catalyst and a silane, see: (a) Miyai, T.; Ueba, M.; Baba, A.
Synlett 1999, 182. (b) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba,
A. J. Org. Chem. 2001, 66, 7741. (c) Shibata, I.; Kato, H.; Ishida, T.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711. (d) Miura,
K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985. (e) Hayashi,
N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981. (f) Miura, K.; Tomita,
M.; Yamada, Y.; Hosomi, A. J. Org. Chem. 2007, 72, 787.
(9) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2005,
46, 6407.
(3) Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J.;
Neuenschwander, K. J. Org. Chem. 1981, 46, 2417.
(4) (a) Nicolaou, K. C.; Sato, M.; Theodorakis, E. A.; Miller, N. D. J.
Chem. Soc., Chem. Commun. 1995, 1583. (b) Jang, D. O.; Song, S. H.;
Cho, D. H. Tetrahedron 1999, 55, 3479.
(5) (a) Raney-Ni: Baxter, S. L.; Bradshaw, J. S. J. Org. Chem. 1981,
46, 831. (b) Mn complex: Mao, Z.; Gregg, B. T.; Cutler, A. R. J. Am.
Chem. Soc. 1995, 117, 10139. (c) Ti complex: Hansen, M. C.; Verdaguer,
X.; Buchwald, S. L. J. Org. Chem. 1998, 63, 2360. (d) Ti-Si: Yato, M.;
Homma, K.; Ishida, A. Tetrahedron 2001, 57, 5353. (e) Ru complex:
Matsubara, K.; Iura, T.; Maki, T.; Nagashima, H. J. Org. Chem. 2002, 67,
4985.
(10) Buchwald and Ohta groups reported titanocene- or rhodium-
catalyzed reduction of esters with a silane producing the corresponding
primary alcohols, respectively; see: (a) Berk, S. C.; Kreutzer, K. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1991, 113, 5093. (b) Berk, S. C.;
Buchwald, S. L. J. Org. Chem. 1992, 57, 3751. (c) Barr, K. J.; Berk, S. C.;
Buchwald, S. L. J. Org. Chem. 1994, 59, 4323. (d) Ohta, T.; Kamiya, M.;
Kusui, K.; Michibata, T.; Nobutomo, M.; Furukawa, I. Tetrahedron Lett.
1999, 40, 6963.
(11) Baba’s group reported that an ester group is tolerant to the InCl3-
Ph2SiHCl system; see ref 8b.
(6) Nakao, R.; Fukumoto, T.; Tsurugi, J. Bull. Chem. Soc. Jpn. 1974,
47, 932 and references cited therein.
(7) (a) Baldwin, S. W.; Doll, R. J.; Haut, S. A. J. Org. Chem. 1974, 39,
2470. (b) Baldwin, S. W.; Haut, S. A. J. Org. Chem. 1975, 40, 3885.
(12) See details in Supporting Information.
(13) When the reaction was carried out using 2 and 3 equiv of Et3SiH,
the product 2a was obtained in 67 and 91% yields, respectively. Using
more than 3 equiv of Et3SiH led to complete reduction.
10.1021/jo070814z CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/28/2007
5920
J. Org. Chem. 2007, 72, 5920-5922