Direct reduction of esters to ethers with an indium(III) bromide/triethylsilane catalytic system

Article abstract of DOI:10.1055/s-0028-1083191

An indium(III) bromide-triethylsilane reagent system promotes direct reduction of esters to produce the corresponding unsymmetrical ethers. This simple catalytic system accommodated other carbonyl compounds, such as a tertiary amide and a carboxylic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083191

PRACTICAL SYNTHETIC PROCEDURES
3533
Direct Reduction of Esters to Ethers with an Indium(III) Bromide/
Triethylsilane Catalytic System
D
irec
t
Reduction
o
o
f
E
sters to E
r
thers io Sakai,* Toshimitsu Moriya, Kohji Fujii, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
E-mail: sakachem@rs.noda.tus.ac.jp
Received 27 June 2008; revised 30 July 2008
PSP
No136
Abstract: An indium(III) bromide–triethylsilane reagent system promotes direct reduction of esters to produce the corresponding unsym-
metrical ethers. This simple catalytic system accommodated other carbonyl compounds, such as a tertiary amide and a carboxylic acid.
Key words: reduction, indium(III) bromide, silane, ether
InBr3 (5 mol%)
Et3SiH (4 equiv)
H
H
O
R2
R1
30–92%
O
R2
R1
O
CHCl3, 60 °C
Scheme 1
Introduction
O
OH
BF3⋅OEt2
DIBAL
Et3SiH
O
R
O
R
O
R
(1)
A number of traditional methods for the preparation of
ethers have been developed; among these are the reaction
of an alkoxy anion with an alkyl halide/sulfonate under
basic conditions (Williamson synthesis) and the acid-pro-
moted dehydration of alcohols.1 Since the 1960s, the typ-
ical preparation of ethers has shifted to the direct
reduction of the carbonyl function of an ester or a
thioester.1 Generally, this has been accomplished by treat-
ment with reducing agents, such as lithium aluminum hy-
dride,2 diisobutylaluminum hydride (Scheme 2, equation
1),3 and organotin hydride (Scheme 2, equation 2),4 by use
of a metal complex5 (Scheme 2, equation 3), and by irra-
diation in the presence of trichlorosilane (Scheme 2, equa-
tion 4).6
BF3⋅OEt2/LiAlH4
Ph3SnH
AIBN (or Et3B)
S
R2
(2)
R2
R1
O
R1
O
Raney-Ni/H2 gas
TiCl4-TMSOTf
R3SiH
O
O
R2
(3)
(4)
R2
R1
O
Mn or Ru complex
R3SiH
R1
O
O
Recently, several groups have reported that a combined
system that uses a trivalent indium salt with a milder re-
ducing reagent, a hydrosilane, is highly effective for the
reductive conversion of functional groups, such as deha-
logenation of organic halides, reduction of alcohols, 1,4-
reduction of enones, and reductive aldol reactions.7 In
2007, we found that the indium(III) bromide–triethylsi-
lane catalytic system selectively reduces the carbonyl
function of esters under mild conditions, leading to the di-
rect preparation of unsymmetrical ethers (Scheme 1).8
Herein, we describe the results of the direct deoxygen-
ation of carbonyl compounds, mainly esters, with a novel
catalytic reducing system.
HSiCl3
R2
R2
R1
O
R1
irradiation
Scheme 2
Table 1 shows the results of the examination for opti-
mized conditions. It is noteworthy that indium salts, such
as indium(III) chloride, acetate, and triflate, are ineffec-
tive in this reduction, with only indium(III) bromide
showing high catalyst activity. We also found that readily
available and economical triethylsilane is one of the opti-
mal reducing reagents for this reaction.9
SYNTHESIS 2008, No. 21, pp 3533–3536
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083191; Art ID: F14308SS
© Georg Thieme Verlag Stuttgart · New York

3534
N. Sakai et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Examinations of Indium Catalysts and Silanes
converted into the corresponding ethers 2 in good yields
(Table 2, entries 1–15).
InX3 (0.05 equiv)
R3SiH (4 equiv)
O
It was found that a nitro group or a bromo group on the
benzene ring are tolerant of the indium(III) bromide–tri-
ethylsilane system (Table 2, entries 3 and 10). The type of
substituted group next to the carbonyl group, other than
the methyl group, could be extended to a branched carbon
chain, or a cyclopropane ring (Table 2, entries 5–8).
Moreover, both the reduction using the linear acetate 1k,
derived from the primary alcohol, and the branched ace-
tate 1l, derived from the secondary alcohol, gave the alkyl
ethers 2k,l in 77% and 69% yields, respectively (Table 2,
entries 11 and 12). Also, linear esters 1m–o, containing
not only a bromo substituent but also a terminal or an in-
ternal alkene moiety, were chemoselectively converted
into the corresponding ethers 2m–o in good yields; it ap-
pears that a halogen atom on the primary carbon and a
double bond are not affected by the reducing reagent
(Table 2, entries 13–15). A heteroaromatic ester 1p with a
thiophene ring also was converted into the corresponding
ether 2p in 55% yield (Table 2, entry 16). This method
proved to be a useful tool for the preparation of cyclic
ethers 2q,r with our catalytic system (Table 2, entries 17
and 18). Thus, this protocol appears to be a highly simple
and practical method for the direct preparation of a variety
of ether frameworks.
Ph
Ph
O
2a
O
CHCl3, 60 °C, 1 h
1a (1 equiv)
Entry
InX3
R3SiH
Yielda (%)
1
InBr3
Et3SiH
99
2
InCl3
Et3SiH
n.r.b
traceb
n.r.b
10
3
In(OTf)3
In(OAc)3
InBr3
Et3SiH
4
Et3SiH
5
(EtO)3SiH
PhMe2SiH
6
InBr3
94
a GC yield.
b Average of two runs.
Scope and Limitations
General reduction of various esters 1 was carried out with
the indium(III) bromide–triethylsilane catalytic system at
60 °C in chloroform solution (Table 2). All esters, with no
relation to the length of the alkyl chain, were smoothly
Table 2 Reduction of Esters 1 to Ethers 2 with an InBr3/Et3SiH Catalytic System
Entry
1
Ester 1
Time (h)
1
Ether 2
Yielda (%)
92
O
H
H
1a
1b
1c
2a
2b
2c
Ph
Ph
O
O
O
H
H
2
3
1
3
69
61
Ph
O
Ph
O
O
H
H
4-NO2C6H4
4-NO2C6H4
O
O
O
H
H
Ph
O
Ph
Ph
O
4
1d
4
2d
89
H
H
O
Ph
O
R
O
R
5
6
7
8
R = n-Pr
R = i-Pr
R = t-Bu
1e
1f
10
1
R = n-Pr
R = i-Pr
R = t-Bu
2e
2f
71
71
30
53
1g
1h
10
10
2g
2h
R = cyclopropyl
R = cyclopropyl
O
H
H
9
1i
1j
1
6
2a
2j
89
62
Ph
Ph
O
O
O
H
H
10
4-BrC6H4
4-BrC6H4
O
O
O
O
11
1k
1
2k
77
H
H
O
Synthesis 2008, No. 21, 3533–3536 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Direct Reduction of Esters to Ethers
3535
Table 2 Reduction of Esters 1 to Ethers 2 with an InBr3/Et3SiH Catalytic System (continued)
Entry
12
Ester 1
Time (h)
1
Ether 2
Yielda (%)
69
O
O
1l
2l
H
H
H
O
O
O
O
13
1m
1
2m
73
H
Br
Br
O
O
14
15
1n
1o
2
2n
2o
72
56
H
H
O
H
O
H
O
10
Me(CH2)7
Me(CH2)7
(CH2)7
(CH2)7
O
O
O
H
H
O
16
17
1p
1q
4
1
2p
2q
55
53
S
S
O
O
H
O
H
H
H
O
O
18
1r
1
2r
84
O
a Isolated yield.
On the other hand, reduction using the ethyl ester derived mide–triethylsilane system reduced the tertiary amide 6 to
from benzoic acid was rather sluggish in its completion. produce the corresponding tertiary amine 7 in 90% isolat-
Also, as shown in Scheme 3, the acetates 3a,b derived ed yield. Also, a carboxylic acid 8 was successfully con-
from diphenylmethanol and a-methylbenzyl alcohol did verted into the corresponding primary alcohol 9 in good
not form the desired ether product, producing instead a yield. On the other hand, treatment of ketone 10 with the
deacetoxylated product 4a,b of the starting materials. reducing system gave the corresponding symmetrical
Similarly, the reaction using an ester with a conjugated ether derivative 11 in 88% yield.10
alkene moiety produced b-ethylstyrene (4c) along with
In conclusion, we have demonstrated that the indium(III)
bromide–triethylsilane reagent system promotes the direct
geometric isomer 5c. Thus, deacetoxylation preferentially
proceeds for the acetoxy group on the secondary carbon
and selective reduction of esters to produce the corre-
vicinal to either a phenyl group or a conjugated double
sponding unsymmetrical ethers. This simple catalytic sys-
bond.
tem appeared to be remarkably tolerant of several
The reduction of alternative types of carbonyl compounds functional groups and was applicable to other important
under optimal conditions was examined, and the results compounds, such as a tertiary amide and a carboxylic
are summarized in Scheme 4. Unfortunately, reductive acid.
deoxygenation using a secondary amide did not form the
desired secondary amine. However, the indium(III) bro-
InBr3 (0.05 equiv)
O
Et3SiH (4 equiv)
Ph
N
O
Ph
Ph
N
CHCl3, 60 °C, 20 h
Bn
InBr3 (0.05 equiv)
Et3SiH (2 equiv)
Bn
7: 90%
O
6
Ph
R
CHCl3, 60 °C, 1 h
InBr3 (0.05 equiv)
Et3SiH (4 equiv)
Ph
R
OH
Ph
OH
4a: 98%
4b: 76%
3a: R = Ph
3b: R = Me
CHCl3, 60 °C, 1 h
O
O
9: 65%
8
InBr3 (0.05 equiv)
Et3SiH (2 equiv)
Ph
InBr3 (0.05 equiv)
Et3SiH (4 equiv)
Ph
4c: 42%
5c: 18%
Ph
Ph
+
O
Ph
O
CHCl3, 60 °C, 1 h
CHCl3, 60 °C, 1 h
Ph
10
O
11: 88%
3c
Scheme 4
Scheme 3
Synthesis 2008, No. 21, 3533–3536 © Thieme Stuttgart · New York

3536
N. Sakai et al.
PRACTICAL SYNTHETIC PROCEDURES
Acknowledgement
Column chromatography was performed using silica gel 60
(Merck). CHCl3 was distilled from P2O5 and stored over 4 A MS.
InBr3, InCl3, and In(OTf)3 were commercially available (Aldrich),
and were used without further purification. All reactions were car-
ried out under an N2 atmosphere, unless otherwise noted. NMR
spectra were recorded using a JEOL ECP-500 (1H: 500 MHz, 13C:
125 MHz) spectrometer with TMS as the internal standard. MS spec-
tra were recorded on a JEOL JNM-700 MStation (FAB, HRMS) us-
ing 3-nitrobenzyl alcohol as a matrix and a JEOL GC-mate (EI).
Reactions were monitored by GC analysis (Shimadzu GC-9A) of
reaction aliquots. Analytical GC was carried out on a gas chromato-
graph equipped with a packed column SE-30 (GL Sciences Inc). GC
yields were determined using decane as the internal standard. Pre-
parative thin-layer chromatography (PTLC) was carried out on a
preparative silica gel PF254 (Merck), and components were located
by observation under UV light. All products were adequately char-
actized.8
This work was partially supported by a fund for the ‘High-Tech Re-
search Center’ Project for Private Universities: a matching fund
subsidy from MEXT, 2000-2004, and 2005-2007. The authors
thank Shin-Etsu Chemical Co., Ltd., for the gift of triethylsilane
(Et3SiH).
References
(1) (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,
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(d) Pettit, G. R.; Piatak, D. M. J. Org. Chem. 1962, 27, 2127.
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N. D. J. Chem. Soc., Chem. Commun. 1995, 1583. (b) Jang,
D. O.; Song, S. H.; Cho, D. H. Tetrahedron 1999, 55, 3479.
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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. (f) Boron complex: Morra, N. A.;
Pagenkopf, B. L. Synthesis 2008, 511.
1-Ethoxy-2-phenylethane (2a); Typical Procedure
To a 30-mL flask under an N2 atmosphere containing CHCl3 (6 mL)
was added successively ester 1a (981 mg, 5.97 mmol), InBr3 (102
mg, 0.288 mmol), and Et3SiH (3.8 mL, 24 mmol). The mixture was
stirred at 60 °C (bath temperature), during which time the soln
turned from colorless to yellow, then to orange. The reaction was
monitored by GC analysis until the starting ester had been con-
sumed. H2O (15 mL) was added and the resulting orange suspension
was stirred continuously until the color disappeared. The aqueous
layer was extracted with CH2Cl2 (3 × 30 mL), the combined organic
phases were dried (anhyd Na2SO4), filtered, and evaporated under
reduced pressure. The crude product was purified by flash column
chromatography (silica gel, hexane–EtOAc, 99: 1) to give ether 2a
(824 mg, 92%) as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.5 Hz, 3 H), 2.90 (t,
J = 7.5 Hz, 2 H), 3.50 (q, J = 7.5 Hz, 2 H), 3.63 (t, J = 7.5 Hz, 2 H),
7.22 (m, 3 H), 7.28 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.2, 36.4, 66.2, 71.6, 126.1,
128.3, 128.9, 139.0.
(6) (a) Nakao, R.; Fukumoto, T.; Tsurugi, J. Bull. Chem. Soc.
Jpn. 1974, 47, 932. (b) Baldwin, S. W.; Doll, R. J.; Haut,
S. A. J. Org. Chem. 1974, 39, 2470. (c) Baldwin, S. W.;
Haut, S. A. J. Org. Chem. 1975, 40, 3885.
(7) For selected papers on the 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.
(8) Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007,
72, 5920; and supporting information.
(9) 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) (a) Kato, J.-i.; Iwasawa, N.; Mukaiyama, T. Chem. Lett.
1985, 743. (b) Sassaman, M. B.; Kotian, K. D.; Prakash,
G. K. S.; Olah, G. A. J. Org. Chem. 1987, 52, 4314.
(c) Komatsu, N.; Ishida, J.; Suzuki, H. Tetrahedron Lett.
1997, 38, 7219. (d) Wada, M.; Nagayama, S.; Mizutani, K.;
Hiroi, R.; Miyoshi, N. Chem. Lett. 2002, 248.
MS (EI): m/z (%) = 150 ([M]+, 65), 105 (100).
N,N-Dibenzylethylamine (7); Typical Procedure
To a screw-capped vial under an N2 atmosphere containing CHCl3
(0.6 mL) was successively added amide 6 (142 mg, 0.593 mmol),
InBr3 (10.5 mg, 0.0300 mmol), and Et3SiH (380 mL, 2.40 mmol).
The mixture was stirred at 60 °C (bath temperature), during which
time the soln turned from colorless to yellow, then to orange. When
the reaction was complete, aq 1 M HCl (5 mL) was added to the re-
sulting mixture. The aqueous layer was basified with aq 1 M NaOH
and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were dried (anhyd Na2SO4), filtered, and evaporated under reduced
pressure to give tertiary amine 7 (120 mg, 90%) as a yellow oil,
which was almost pure.
1H NMR (500 MHz, CDCl3): d = 1.06 (t, J = 7.0 Hz, 3 H), 2.50 (q,
J = 7.0 Hz, 2 H), 3.56 (s, 4 H), 7.22 (m, 2 H), 7.30 (m, 4 H), 7.37
(m, 4 H).
13C NMR (125 MHz, CDCl3): d = 11.9, 47.1, 57.7, 126.7, 128.1,
128.7, 140.0.
MS(FAB): m/z (%) = 226 ([M + H]+, 100).
Synthesis 2008, No. 21, 3533–3536 © Thieme Stuttgart · New York