InBr3-catalyzed reduction of ketones with a hydrosilane: Deoxygenation of aromatic ketones and selective synthesis of secondary alcohols and symmetrical ethers from aliphatic ketones

Article abstract of DOI:10.1016/j.tetlet.2011.04.029

An InBr₃-Et₃SiH reducing system was developed to selectively convert aliphatic ketones to a variety of secondary alcohols in moderate to good yields. An initial mixing of InBr₃ and PhSiH ₃ was followed by the addition of aliphatic ketones and a solvent to afford the symmetrical ether derivatives.

Full text of DOI:10.1016/j.tetlet.2011.04.029

Tetrahedron Letters 52 (2011) 3133–3136
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Tetrahedron Letters
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InBr3-catalyzed reduction of ketones with a hydrosilane: deoxygenation of
aromatic ketones and selective synthesis of secondary alcohols and
symmetrical ethers from aliphatic ketones
⇑
Norio Sakai , Ken Nagasawa, Reiko Ikeda, Yumi Nakaike, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An InBr3–Et3SiH reducing system was developed to selectively convert aliphatic ketones to a variety of
secondary alcohols in moderate to good yields. An initial mixing of InBr3 and PhSiH3 was followed by
the addition of aliphatic ketones and a solvent to afford the symmetrical ether derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 March 2011
Revised 31 March 2011
Accepted 6 April 2011
Available online 12 April 2011
Keywords:
Reduction
Indium
Silane
Ether
Alcohol
The reductive deoxygenation of an aromatic ketone to the cor-
responding hydrocarbon derivative holds a central and important
position in functional group conversion.1 Clemmensen reduction
under acidic conditions and Wolff–Kishner reduction via hydra-
zones have generally been employed to achieve this on a labora-
tory scale.2,3 Another frequently used method consists of direct
hydrogenation using H2 gas on Pd-C4 and Raney Ni,5 and a metal
hydride generated from a combination of boron hydrides,6 alumi-
num hydrides7 and hydrosilanes8 with a Lewis or Brønsted acid.
On the other hand, the preparation of ether derivatives is one of
the most widely investigated methods in organic synthesis.
Williamson ether synthesis and its modification under basic condi-
tions have been extensively developed for this purpose.1a,9 As a
further extension of this method, several research groups have
demonstrated acid-promoted reductive coupling of carbonyl
compounds with a hydrosilane, which led to the preparation of
symmetrical or unsymmetrical ethers.10 In this context, during
research on the reductive transformation of a carbonyl group on
aliphatic ketones using a reducing system that combined InBr3
with a hydrosilane, one of us found that selective synthesis of a
secondary alcohol and an ether from the same aliphatic ketone
could be accomplished by changing the order of addition of the re-
agents.11,12 In this paper, we report the scope and limitations of
this selective preparation, as well as the finding that this reducing
system promoted the deoxygenation of a variety of aryl ketones to
produce the corresponding alkyl benzene derivatives.
The reduction of benzylacetone (1a) with an indium catalyst
and a silane compound was initially examined as a model reaction
(Table 1).13 Based on previous research,14 when the reaction was
conducted with 5 mol % of InBr3 and 4 equiv (Si-H) of Et3SiH in
chloroform at room temperature, the expected reduction
Table 1
Examination of reductive conditions for aliphatic ketonesa
Run
InX3
Silane
Yielda (%)
2a
3a
1
2
3
InBr3
InCl3
In(OAc)3
InBr3
InBr3
Et3SiH
Et3SiH
Et3SiH
Et3SiH
PhMe2SiH
PhSiH3
(87)
24
(11)
NDc
NDc
79
67
97
NDc
14
4b
5b
6b
28
Trace
InBr3
a
NMR (Isolated) yield.
InBr3 (5 mol %) and a hydrosilane (4 equiv) were initially stirred at room tem-
b
perature for 1 h, followed by the addition of ketone 1a and chloroform with addi-
⇑
Corresponding author. Tel.: +81 4 7122 1092; fax: +81 4 7123 9890.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
tional stirring of the resultant mixture.
c
ND = Not detected.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.029

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N. Sakai et al. / Tetrahedron Letters 52 (2011) 3133–3136
Table 2
Table 3
Selective conversion from aliphatic ketones to secondary alcoholsa,b
Selective synthesis of symmetrical ethers from aliphatic ketonesa
a
Isolated yield.
Et3SiH was used instead of PhSiH3.
Product was obtained as mixture of diastereomer.
b
c
a
Isolated yield.
b
The yield of the corresponding ether was in parenthesis.
ND = Not detected.
Diastereomer ratio was determined by NMR.
c
(Table 4).16 For example, when reduction with 4-methylacetophe-
none (4a) was conducted with 5 mol % of InBr3 and 4 equiv of
Et3SiH in chloroform at 60 °C, deoxygenation proceeded preferen-
tially to produce the corresponding 4-methylethylbenzene (5a) in
82% yield as good as the conventional result with the InCl3–Me2-
SiHCl system.8g The halogen substituent such as a bromo and iodo
group on the benzene ring was tolerant to this reducing system.
When reduction was conducted with 10 mol % of InBr3 and 8
equiv of the silane, 1,4-diacetylbenzene (4j) was quantitatively
converted to 1,4-diethylbenzene (5j) within 1 h. Surprisingly, for
the substrates having either an electron-withdrawing group on
the benzene ring or a substituent next to the carbonyl group, the
corresponding silyl ether products 5k–m were selectively obtained
instead of the deoxygenative product. These results imply that the
electron-withdrawing effect such as a nitro or cyano group, made a
transient benzyl cation intermediate less stable, which obstructed
the subsequent elimination of the siloxy group to finally isolate the
silyl ether products. Also steric hindrance and an electron-with-
drawing effect of a bromomethylene moiety may have an effect
d
proceeded cleanly to produce the corresponding secondary alcohol
derivative 2a in 87% yield with 11% of the ether product 3a (run 1).
Unlike a related study with InCl3 and Me2SiHCl,8g this reducing
system did not form the deoxygenated product, which is the alkyl-
benzene derivative. InCl3 and In(OAc)3 were ineffective for the
reduction, and most starting material was recovered (runs 2 and
3). Consequently, only InBr3 showed outstanding catalytic activity
for reductive conversion of an aliphatic ketone to a secondary
alcohol. However, when a catalytic amount of InBr3 and 4 equiv
of Et3SiH were initially stirred at room temperature for 1 h,
followed by the addition of the ketone 1a and chloroform, the
symmetrical ether 3a rather than the alcohol 2a was obtained
unexpectedly as a major product in 79% yield (run 4).15 PhMe2SiH
showed a similar tendency for the product ratio (run 5). Finally, a
reducing procedure that combined a catalytic amount of InBr3 with
4 equiv (Si-H) of PhSiH3 successfully converted the aliphatic ketone
to a symmetrical ether (run 6).
Under the optimized conditions shown in Table 1, the prepara-
tion of a variety of secondary alcohols was first examined with
aliphatic ketones (Table 2). With the exception of ketone 1a–c,
reductions proceeded selectively, producing the corresponding
secondary alcohol derivatives 2 in moderate to good yields. In par-
ticular, functional groups such as a double bond or a cyano group
were tolerant of this reducing system. In addition, although a hy-
droxy group on the benzene ring 2c was silylated by the reducing
agent, the use of tetrabuthylammonium fluoride (TBAF) removed
the protecting group to convert to the corresponding unsubstituted
phenol.
Table 4
Selective reduction of aromatic ketonesa
Next, the selective synthesis of a symmetrical ether from an ali-
phatic ketone was examined using InBr3 and PhSiH3 (Table 3).
When 5 mol % of InBr3 and 4 equiv (Si-H) of PhSiH3 were initially
stirred at room temperature for 1 h, followed by the addition of
benzylacetone derivatives 1 and chloroform, the expected ethers
3 were selectively produced in good yields. Cyclohexanones 1d,e
were also selectively and successfully converted to the desired
ether derivatives 3d,e in practical yields. An ether moiety, a
fluoride or a hydroxy group on the benzene ring did not affect on
this reducing system, although the hydroxy group was partially
silylated.
To extend the application of this reducing system, the reaction
was examined using an aromatic ketone and an acetophenone
derivative under the standard conditions described above
a
Isolated yield.
InBr3 (0.1 equiv), Et3SiH (8 equiv).
b

N. Sakai et al. / Tetrahedron Letters 52 (2011) 3133–3136
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Scheme 1.
on formation of the product 5m. When a substrate with a hydroxy
group on the benzene ring was treated under standard conditions,
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To better understand the reaction path that produces a sym-
metrical ether, a control experiment was conducted. When the
reaction with benzylacetone (1a) and the silyl ether 6a prepared
was carried out with 5 mol % of InBr3 and 4 equiv (Si-H) of Et3SiH
in chloroform at room temperature, the corresponding ether 3a
was unexpectedly obtained in only 15% GC yield.17 Since the
formation of a similar ether derivative by a reducing system
containing Me3SiI–Et3SiH, TrClO4–Et3SiH and BiBr3–Et3SiH was
reported,10b–d reaction of the silyl ether, which was formed by
hydrosilylation, with an activated ketone was expected to initially
produce a silylated hemiacetal, followed by desiloxylation of the
acetal with another hydrosilane to afford the corresponding sym-
metrical ether (Scheme 1).18–21 However, as yet there is no reason-
able explanation for the selective synthesis of a secondary alcohol
and an ether from the same aliphatic ketone, with the only differ-
ence being the order of addition of the reagents used.
An InBr3–Et3SiH reducing system was used to selectively con-
vert aliphatic ketones to a variety of secondary alcohols in moder-
ate to good yields. In another experimental procedure, the mixing
of InBr3 and PhSiH3 (or Et3SiH) was followed by the addition of an
aliphatic ketone and a solvent to afford symmetrical ether deriva-
tives in good yields. This indium catalytic system successfully
accommodated the deoxygenation of a variety of aryl ketones to
produce the corresponding alkyl benzene derivatives. Further
investigation into the reaction mechanism for the preparation of
symmetrical ether derivatives is now in progress.
13. General procedure for reductive preparation of
a secondary alcohol from an
aliphatic ketone: To a freshly distilled CHCl3 solution (0.6 mL) in a screw-
capped vial under N2 atmosphere, InBr3 (10.6 mg, 0.0300 mmol) and aliphatic
ketone 1 (0.6 mmol) was successively added. After the process, Et3SiH (383 lL,
2.4 mmol) was added. The resulting mixture was stirred at 60 °C (bath
temperature) or room temperature, and monitored by TLC or GC analysis until
consumption of the starting ketone. The reaction was quenched with H2O. The
aqueous layer was extracted with CH2Cl2 (5 mL Â 3), the organic phases were
dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by
a silica gel column chromatography
(hexane/AcOEt = 19/1) to give the corresponding secondary alcohol 2. 4-(1,3-
Benzodioxol-5-yl)-2-butanol (2b): 98% yield; yellow oil; 1H NMR (500 MHz,
CDCl3) d 1.21–1.27 (m, 3H), 1.57 (br s, 1H), 1.69–1.77 (m, 2H), 2.56–2.70 (m,
Acknowledgments
2H), 3.78–3.82 (m, 1H), 5.91 (s, 2H), 6.63–6.65 (m, 1H), 6.69–6.73 (m, 2H); 13
C
This work was partially supported by a grant from the Japan Pri-
vate School Promotion Foundation supported by MEXT and by a
grant from CCIS program supported by MEXT. The authors thank
Shin-Etsu Chemical Co., Ltd, for the gift of hydrosilanes.
NMR (125 MHz, CDCl3) d 23.5, 31.8, 41.0, 67.2, 100.7, 108.1, 108.8, 121.0, 135.9,
145.5, 147.5; MS (EI): m/z 194 (M+).
14. (a) Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007, 72, 5920–5922; (b)
Sakai, N.; Moriya, T.; Fujii, K.; Konakahara, T. Synthesis 2008, 3533–3536; (c)
Sakai, N.; Fujii, K.; Konakahara, T. Tetrahedron Lett. 2008, 49, 6873–6875; (d)
Sakai, N.; Moritaka, K.; Konakahara, T. Eur. J. Org. Chem. 2009, 4123–4127; (e)
Sakai, N.; Fujii, K.; Nabeshima, S.; Ikeda, R.; Konakahara, T. Chem. Commun.
2010, 46, 3173–3175.
Supplementary data
15. General procedure for reductive preparation of an ether from an aliphatic ketone: A
Supplementary data (NMR spectra for the prepared com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.04.029.
mixture of InBr3 (10.6 mg, 0.0300 mmol) and PhSiH3 (99
lL, 0.80 mmol) was
initially stirred in screw-capped vial under N2 atmosphere at room
a
temperature. After 1 h, a freshly distilled CHCl3 solution (0.6 mL) and an
aliphatic ketone 1 (0.6 mmol) was successively added. The resulting mixture
was stirred at room temperature, and monitored by TLC or GC analysis until
consumption of the starting ketone. The reaction was quenched with H2O. The
aqueous layer was extracted with CH2Cl2 (5 mL Â 3), the organic phases were
dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by silica chromatography (hexane/AcOEt = 19/
1) to give the corresponding symmetrical ether 3. Bis[(1,3-benzodioxol-5-yl)-
2-butyl]ether (3b): 88% yield; colorless oil; 1H NMR (500 MHz, CDCl3) d 1.12–
1.17 (m, 6H), 1.61–1.81 (m, 4H), 2.51–2.69 (m, 4H), 3.43–3.48 (m, 2H), 5.88–
5.92 (m, 4H), 6.61–6.73 (m, 6H); 13C NMR (125 MHz, CDCl3) d 20.4, 21.1, 31.7,
31.7, 39.0, 39.3, 72.0, 72.8, 100.7, 100.7, 108.0, 108.1, 108.7, 108.8, 120.9, 121.0,
136.2, 136.3, 145.4, 145.5, 147.5, 147.5; MS (ESI): m/z 393 (M++Na); HRMS
(ESI): Calcd for C22H26O5Na: 393.1678, Found: 393.1651.
References and notes
1. (a) Larock, R. C., Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH:
New York, 1999.; (b) Yamamura, S.; Nishiyama, S. Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8,
pp 307–325.; (c) Hutchins, R. O.; Hutchins, M. K.; Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8,
pp 327–362.
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16. General procedure for reductive preparation of an alkylbenzene from an aromatic
ketone: To a freshly distilled CHCl3 solution (0.6 mL) in a screw-capped vial

3136
N. Sakai et al. / Tetrahedron Letters 52 (2011) 3133–3136
under N2 atmosphere, InBr3 (10.6 mg, 0.0300 mmol), aromatic ketone
4
MS (ESI): m/z 284 (M++Na); HRMS (ESI): Calcd for C15H23NNaOSi: 284.1447,
(0.6 mmol) and Et3SiH (383
l
L, 2.40 mmol) was successively added. The
Found: 284.1407.
resulting mixture was stirred at 60 °C (bath temperature) or room
temperature, and monitored by TLC or GC analysis until consumption of the
starting ketone. The reaction was quenched with H2O. The aqueous layer was
extracted with CH2Cl2 (5 mL Â 3), the organic phases were dried over
anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The
crude product was purified by a silica gel column chromatography (hexane/
AcOEt = 19/1) to give the corresponding alkylbenzene 5. 1-Cyano-4-[1-
(triethylsiloxy)ethyl]benzene (5k): 85% yield; colorless oil; 1H NMR
17. Formation of the corresponding alcohol derivative (65%) and the silyl ether
(11%) was observed by GC.
18. Kira, M.; Hino, T.; Sakurai, H. Chem. Lett. 1992, 21, 555–558.
19. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1979, 20, 4679–4680.
20. Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000,
65, 6179–6186.
21. One reviewer suggested use of CH3CN as an solvent to in-situ generate Br2InH
and Et3SiBr. However, CH3CN was ineffective for this reduction. Therefore, the
authors showed not the reaction path through Br2InH but the simple reaction
path described in Scheme 1.
(500 MHz, CDCl3)
d 0.54–0.62 (m, 6H), 0.90–0.93 (m, 9H), 1.41 (d, 3H,
J = 6 Hz), 4.90 (q, 1H, J = 6 Hz), 7.45 (d, 2H, J = 8 Hz), 7.61 (d, 2H, J = 8 Hz); 13C
NMR (125 MHz, CDCl3) d 4.7, 6.7, 27.0, 69.9, 110.5, 119.0, 125.8, 132.0, 152.3;