Iron(III) chloride-catalyzed reductive etherification of carbonyl compounds with alcohols

Article abstract of DOI:10.1246/cl.2007.38

A facile reductive etherification of carbonyl compounds can be performed by the reaction with alcohols and triethylsilane catalyzed by iron(III) chloride. The corresponding alkyl ethers are obtained in good to excellent yields under mild reaction conditions. Copyright

Full text of DOI:10.1246/cl.2007.38

38
Chemistry Letters Vol.36, No.1 (2007)
Iron(III) Chloride-catalyzed Reductive Etherification
of Carbonyl Compounds with Alcohols
Katsuyuki Iwanami, Kentaro Yano, and Takeshi Oriyamaꢀ
Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received September 22, 2006; CL-061104; E-mail: tor@mx.ibaraki.ac.jp)
A facile reductive etherification of carbonyl compounds
pounds with the parent alcohol, not alkoxytrialkylsilane, is more
straightforward and promising. Therefore, we applied this reduc-
tive etherification into the naked and unmodified alcohols.
In the first place, we undertook to examine the reductive
etherification of aldehyde with alcohol and triethylsilane accord-
ing to the procedure reported in a previous paper.8a To a mixture
of benzaldehyde and 1.2 equiv. of 3-phenylpropanol in the pres-
ence of 5 mol % of iron(III) chloride was added 1.2 equiv. of
triethylsilane at 0 ꢁC and stirred at room temperature for 1 h.
The usual work-up of the reaction mixture afforded the desired
product, 1-benzyloxy-3-phenylpropane, in 90% yield (Table 1,
Run 1). On the other hand, when triethylsilane was added at
room temperature, the yield was improved to 97% (Run 2). In
addition, we found that the usage of alcohol needed slightly
longer reaction time compared with the corresponding silyl
ether.8b These results show that the reactivity of unmodified
alcohol is lower than that of silyl ether. A screening of solvents
revealed that nitromethane as a solvent gave the best result.9
Next, the reaction was conducted using various alcohols. Benzyl
alcohol, acyclic and cyclic secondary alcohols also gave the de-
sired product in excellent yields (Runs 3–5). In the case of chiral
secondary alcohol, (S)-2-octanol (>99% ee), the corresponding
(S)-ether (>99% ee) was obtained with complete retention of
stereochemistry (Run 6).10 On the other hand, tertiary alcohol
gave the product in only 25% yield (Run 7). In the case of
phenol, the expected reaction did not proceed at all (Run 8).
The reaction was carried out with various representative
aromatic and aliphatic aldehydes as summarized in Table 2.13
Using this method, all aldehydes tested were uniformly trans-
formed into the corresponding dialkyl ethers in good to excellent
can be performed by the reaction with alcohols and triethylsilane
catalyzed by iron(III) chloride. The corresponding alkyl ethers
are obtained in good to excellent yields under mild reaction
conditions.
Alkyl ether is one of the most important functional groups
for organic synthesis, because it is included in many organic
chemicals, and also it is widely used as a protective group of
the hydroxy function.1 Reductive etherification of carbonyl com-
pounds is known as an alternative method of the Williamson
ether synthesis. In 1972, Doyle et al. reported the synthesis of
ethers by the reduction of carbonyl compounds with triethyl-
silane in alcohol in the presence of excess amounts of sulfuric
acid or trifluoroacetic acid.2 Nicolaou et al. demonstrated
the formation of the oxepane ring from hydroxy ketone using
10 equiv. of triethylsilane and a stoichiometric amount of
TMSOTf.3 Very recently, Izumi and Fukase described a reduc-
tive benzylation of hydroxy functions by using the combination
of benzaldehyde, triethylsilane, and quite an excess molar
TMSCl.4 On the other hand, some methods have been reported
for reductive etherification of carbonyl compounds with triethyl-
silane and alkoxytrimethylsilane under the influence of Lewis
acids.5 However, these reactions require an annoying step-by-
step procedure or a longer reaction time. Although Wada et al.
reported a reductive etherification of carbonyl compounds with
alcohols promoted by bismuth(III) chloride under mild reaction
conditions,6 this involves some substrate limitation; the yields
of the ether products from aliphatic aldehydes and ketones are
unsatisfactory.
In the course of our exploration of the usefulness of the
reactions promoted by iron(III) chloride,7 quite recently, we
have developed a highly efficient reductive etherification of car-
bonyl compounds with alkoxytrialkylsilane and triethylsilane
catalyzed by iron(III) chloride (Scheme 1).8 This includes some
striking features: 1) extremely short reaction time is needed
in contrast to the known methods, 2) not only trimethylsilyl
(TMS) ether but also triethylsilyl (TES) and t-butyldimethylsilyl
(TBS) ethers can be used as the parent silyl ether, 3) various
ethers are obtained from a wide range of aldehydes and ketones,
and 4) high-yielding process. Etherification of carbonyl com-
Table 1. Reductive etherification of benzaldehyde with various
alcoholsa
Et3SiH
PhCHO
ROH
PhCH2OR
+
FeCl3
CH3NO2, rt, 1 h
Run
Alcohol
Yield/%b
1c
2
3
4
5
6
7
8
PhCH2CH2CH2OH
PhCH2CH2CH2OH
BnOH
PhCH2CH2CH(CH3)OH
Cyclohexanol
(S)-2-Octanol
90
97
96
95
97
81d
25
0e
O
OR
R2
Et3SiH
+
ROSi
R1
R2
R1
cat. FeCl3
PhCH2CH2C(CH3)2OH
Phenol
up to 100%
aMolar ratio of PhCHO:alcohol:Et3SiH:FeCl3 = 1:1.2:1.2:0.05.
c
bIsolated yield of purified product. Triethylsilane was added at
(R1= aryl, alkyl; R2 = H, alkyl; Si = TMS, TES, TBS)
0 ꢁC. d>99% ee (Determined by HPLC with chiral column analy-
sis; Daicel Chiralpak IA, t-butyl methyl ether/hexane = 1/1000,
0.1 mL/min). eDibenzyl ether was obtained in 92% yield.
Scheme 1. Iron(III) chloride-catalyzed reductive etherification
of carbonyl compounds with alkoxytrialkylsilane.
Copyright ꢀ 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
39
Table 2. Reductive etherification of various aldehydes with
alcoholsa
sponding ethers in good yields (Table 3, Runs 1 and 2). On the
other hand, aromatic ketone gave the desired ether in only
36% yield (Run 3).
Et3SiH
In conclusion, the present reaction has the following
synthetic advantages: 1) in contrast to the known procedure of
catalytic reductive etherification, this procedure can use free
alcohol; 2) various ethers are obtained from a wide range of
aromatic and aliphatic aldehydes and aliphatic ketones; 3)
extremely mild reaction conditions under the influence of a
catalytic amount of iron(III) chloride; and 4) experimental
convenience. Further investigations to broaden the scope and
synthetic applications of this valuable etherification are under
way in our laboratory.
RCHO
R'OH
RCH2OR'
+
FeCl3
CH3NO2, rt, 1 h
Yield
/%b
Run
Aldehyde
PhCHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
2-MeOC6H4CHO
Alcohol
1
2
3
4
5
PhCH2CH2CH2OH
97
85
82
90
54
77
92
22
43
92
73
87
89
82
90
0
40
87
78
79
84
86
91
86
71
6c 2-MeOC6H4CHO
3-MeOC6H4CHO
4-MeOC6H4CHO
9c 4-MeOC6H4CHO
This paper is dedicated to Professor Teruaki Mukaiyama
on the occasion of his 80th birthday, and for his outstanding
contributions to synthetic organic chemistry.
7
8
10
4-BrC6H4CHO
4-AcC6H4CHO
11
12
13
14
15
16
References and Notes
4-AcOC6H4CHO
4-MeO2CC6H4CHO
1-Naphthaldehyde
2-Naphthaldehyde
(E)-PhCH=CHCHO
1
2
3
T. W. Greene, P. G. M. Wuts, in Protective Groups in Organic
Synthesis, 3rd ed., Wiley-Interscience, New York, 1999, Chap. 2.
M. P. Doyle, D. J. DeBruyn, D. A. Kooistra, J. Am. Chem. Soc.
1972, 94, 3659.
K. C. Nicolaou, C.-K. Hwang, D. A. Nugiel, J. Am. Chem. Soc.
1989, 111, 4136.
M. Izumi, K. Fukase, Chem. Lett. 2005, 34, 594.
a) J.-I. Kato, N. Iwasawa, T. Mukaiyama, Chem. Lett. 1985, 743.
b) M. B. Sassaman, K. D. Kotian, G. K. S. Prakash, G. A. Olah,
J. Org. Chem. 1987, 52, 4314. c) S. Hatakeyama, H. Mori,
K. Kitano, H. Yamada, M. Nishizawa, Tetrahedron Lett.
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hedron Lett. 1997, 38, 7219. e) J. S. Bajwa, X. Jiang, J. Slade,
17c (E)-PhCH=CHCHO
18
19
20
21
22
23
24
25
PhCH2CH2CHO
PhCH2CH2CHO
PhCH2CH2CHO
n-BuCHO
PhCH2CH(CH3)CHOd
cyclo-C6H11CHO
BnOCH2C(CH3)2CHOe
t-BuCHO
4
5
BnOH
PhCH2CH2CH(CH3)OH
PhCH2CH2CH2OH
ˇ
K. Prasad, O. Repic, T. J. Blacklock, Tetrahedron Lett. 2002,
aMolar ratio of aldehyde:alcohol:Et3SiH:FeCl3 = 1:1.2:1.2:0.05.
43, 6709. f) W.-C. Yang, X.-A. Lu, S. S. Kulkarni, S.-C. Hung,
Tetrahedron Lett. 2003, 44, 7837. g) S. Chandrasekhar, G.
Chandrashekar, B. Nagendra Babu, K. Vijeender, K. Venkatram
Reddy, Tetrahedron Lett. 2004, 45, 5497.
bIsolated yield of purified product. CH3CN was used as a solvent.
When nitromethane was used as a solvent, the reaction mixture
c
became complicated. For the preparation of this compound.11 eFor
d
the preparation of this compound.12
6
7
M. Wada, S. Nagayama, K. Mizutani, R. Hiroi, N. Miyoshi,
Chem. Lett. 2002, 248.
Table 3. Reductive etherification of ketones with 3-phenyl-
propanola
a) T. Watahiki, T. Oriyama, Tetrahedron Lett. 2002, 43, 8959.
b) T. Watahiki, Y. Akabane, S. Mori, T. Oriyama, Org. Lett.
2003, 5, 3045. c) K. Iwanami, T. Oriyama, Chem. Lett. 2004,
33, 1324. d) K. Iwanami, M. Aoyagi, T. Oriyama, Tetrahedron
Lett. 2005, 46, 7487. e) K. Iwanami, M. Aoyagi, T. Oriyama,
Tetrahedron Lett. 2006, 47, 4741.
a) K. Iwanami, H. Seo, Y. Tobita, T. Oriyama, Synthesis 2005,
183. b) K. Iwanami, K. Yano, T. Oriyama, Synthesis 2005, 2669.
CH3NO2 (97%), CH3CN (49%), CH2Cl2 (56%), THF (0%).
O
+
Ph
OH
R1
R2
O
Ph
Et3SiH
8
9
R1
R2
FeCl3
CH3NO2, rt
10 ½ꢀꢂD ¼ þ17:1 (c 1.00, CHCl3). (lit. ½ꢀꢂD ¼ þ16:5 (c 0.47,
CHCl3): M. Node, K. Nishide, Y. Shigeta, K. Obata, H. Shiraki,
H. Kunishige, Tetrahedron 1997, 53, 12883.)
Run
Ketone
Time/h
Yield/%b
1
2
3
Benzylacetone
Cyclohexanone
Acetophenone
6
6
24
76
76
36
11 H. Akita, C. Y. Chen, K. Kato, Tetrahedron 1998, 54, 11011.
12 M. C. Stumpp, R. R. Schmidt, Tetrahedron 1986, 42, 5941.
13 Typical procedure: To a suspension of anhydrous iron(III)
chloride (2.4 mg, 0.015 mmol) and benzaldehyde (30 mL, 0.30
mmol) in nitromethane (1.5 mL) was added 3-phenylpropanol
(49.1 mg, 0.36 mmol) and triethylsilane (58 mL, 0.36 mmol)
successively at room temperature under an argon atmosphere.
After stirring for 1 h, the reaction mixture was quenched with
a phosphate buffer (pH 7, 20 mL). The organic materials were
extracted with dichloromethane, washed with brine, and dried
over sodium sulfate. 1-Benzyloxy-3-phenylpropane (64.9 mg,
97%) was isolated by thin-layer chromatography on silica gel.
aMolar ratio of aldehyde:alcohol:Et3SiH:FeCl3 = 1:1.2:1.2:0.05.
bIsolated yield of purified product.
yields. Especially, the protective groups, such as acetate and
methyl ester function were tolerated under these reaction condi-
tions (Runs 12 and 13). Even in the case of sterically hindered
aldehydes, the desired product was obtained in 86 and 71%
yields, respectively (Runs 24 and 25).
Furthermore, we have found that this reaction is similarly
effective for aliphatic and alicyclic ketones to yield the corre-
Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.38