A novel one-pot synthesis of cyanohydrin alkyl ethers from aldehydes catalyzed by iron(III) chloride

Article abstract of DOI:10.1246/cl.2004.1324

A variety of cyanohydrin alkyl ethers were readily prepared from aldehydes with trimethylsilyl cyanide and alkoxy-trimethylsilane under the influence of a catalytic amount of iron(III) chloride in a convenient one-pot procedure.

Full text of DOI:10.1246/cl.2004.1324

1324
Chemistry Letters Vol.33, No.10 (2004)
A Novel One-pot Synthesis of Cyanohydrin Alkyl Ethers
from Aldehydes Catalyzed by Iron(III) Chloride
Katsuyuki Iwanami and Takeshi OriyamaÃ
Department of Environmental Sciences, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received August 6, 2004; CL-040932)
A variety of cyanohydrin alkyl ethers were readily prepared
directly from aldehyde in a convenient one-pot procedure.
After the preliminary investigations, for aromatic aldehydes,
we found that employment of 2.4 equiv. of benzyloxytrimethyl-
from aldehydes with trimethylsilyl cyanide and alkoxy-trimeth-
ylsilane under the influence of a catalytic amount of iron(III)
chloride in a convenient one-pot procedure.
1.2 equiv.
2.4 equiv.
2 mol%
OBn
TMSCN
BnOTMS / FeCl
3
PhCHO
o
o
Ph
CN
73%
neat / 0 C / 2 h CH NO / 0 C / 1 h
3
2
O-Protected cyanohydrins are known as versatile synthetic
intermediates in organic synthesis,1 and several straightforward
methods have been reported so far. Cyanohydrin silyl ethers are
obtained conveniently from the parent carbonyl compounds with
trialkylsilyl cyanide under the influence of Lewis acids,2 Lewis
bases,3 or organo-catalysts.4 Cyanohydrin esters are prepared
from aldehydes with acyl cyanide5 in the presence of a base such
as potassium carbonate6a and 1,4-diazabicyclo[2.2.2]octane.6b
Recently, we also developed cyanobenzoylation of aldehydes
with benzoyl cyanide without a catalyst.7 On the other hand, cy-
anohydrin alkyl ethers can be prepared directly from acetals in-
stead of from aldehydes.8 However, methyl or ethyl ethers of cy-
anohydrins which are formed from dimethyl or diethyl acetals do
not function appropriately as a protecting group, due to difficulty
of their ether bond-cleavage.
Herein we wish to report a novel one-pot preparation of var-
ious cyanohydrin alkyl ethers, namely, O-alkyl protected cyano-
hydrins, including benzyl ether which is one of the most impor-
tant and popular protecting groups for the hydroxy function.9
In the course of our exploration of the usefulness of the
reactions promoted by iron(III) chloride,10,11 we discovered a
general and facile synthesis of dibenzyl acetals from aldehydes
using benzyloxytrimethylsilane catalyzed by iron(III) chloride
(Scheme 1).11
Scheme 2. One-pot synthesis of cyanohydrin benzyl ether.
Table 1. Optimization of the reaction conditions of the second
step for aromatic aldehydea
OBn
BnOTMS / FeCl
TMSCN
1 h
3
PhCHO
o
Ph
CN
0 C / 2 h
Equiv. of
TMSCN
Run
Solvent
Temp
Yield/%b
1
2
CH3NO2
neat
neat
neat
neat
0 ꢀC
0 ꢀC
0 ꢀC
0 ꢀC
rt
1.2
1.2
1.2
1.5
1.5
1.5
73
89
70
93
98
57
3c
4
5
6d
a
neat
rt
Molar ratio of PhCHO:BnOTMS:FeCl3 = 1:2.4:0.02.
Isolated yield of purified product.
b
c
d
TMSCN was added immediately after adding PhCHO.
1.2 equiv. of BnOTMS were used.
Table 2. Synthesis of cyanohydrin benzyl ethers from aromatic
aldehydesa
2.4 equiv.
2 mol%
OBn
OBn
OBn
OBn
OBn
BnOTMS / FeCl3
neat / 0 oC / 2 h
TMSCN
1 h
BnOTMS / FeCl
3
ArCHO
RCHO
RCHO
o
Ar
0 C / 2 h
R
CN
Run
RCHO
Temp
Yield/%b
2.4 equiv.
5 mol%
BnOTMS / FeCl3
CH2Cl2 / rt / 2 h
1
2
3
4
5
6
7
8c
9
PhCHO
rt
rt
rt
0 ꢀC
0 ꢀC
rt
0 ꢀC
rt
0 ꢀC
rt
98
96
70
95
88
83
87
51d
70
87
R
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
2,4,6-Me3C6H2CHO
4-MeOC6H4CHO
4-BrC6H4CHO
4-MeO2CC6H4CHO
2-Naphthaldehyde
(E)-PhCH=CHCHO
Scheme 1. Dibenzyl acetalizaion of aldehydes.
In the first place, we undertook to examine one-pot prepara-
tion of O-benzyl cyanohydrin via dibenzyl acetal in situ-formed
from the corresponding aldehydes. A mixture of benzaldehyde
and 2 mol % amount of iron(III) chloride was treated with 2.4
equiv. of benzyloxytrimethylsilane (BnOTMS) at 0 ꢀC, after
2 h, 1.2 equiv. of trimethylsilyl cyanide (TMSCN) in nitro-
methane was added and stirred for additional 1 h at the same
temperature. The usual work-up of the reaction mixture afforded
the desired product, ꢀ-(benzyloxy)phenylacetonitrile in 73%
yield (Scheme 2). To the best of our knowledge, this is the first
example in which O-benzyl-protected cyanohydrin was obtained
10
a
Molar ratio of aldehyde:BnOTMS:FeCl3:TMSCN = 1:2.4:
0.02:1.5.
Isolated yield of purified product.
b
c
Nitromethane was used as a solvent.
34% of dibenzyl acetal was recovered.
d
Copyright ꢀ 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.10 (2004)
1325
silane and 1.5 equiv. of trimethylsilyl cyanide without solvent
gave the best result as shown in Table 1 (Run 5). The reaction
was conducted with various aromatic aldehydes,12 and the
successful results are summarized in Table 2. In the case of sub-
stituted benzaldehyde with an electron-donating group such as
tolualdehydes and p-anisaldehyde, the corresponding cyanohy-
drin benzyl ethers could be obtained in good to excellent yields
(Runs 2–6). Especially, a sterically hindered aldehyde, mesit-
aldehyde, gave the corresponding cyanohydrin benzyl ether in
88% yield (Run 5). As regards benzaldehyde having an elec-
tron-withdrawing group, 4-bromobenzaldehyde also gave the
corresponding ether in 87% yield (Run 7), but for 4-methoxycar-
bonylbenzaldehyde, the desired product was obtained in 51%
yield (Run 8). Similarly, 2-naphthaldehyde and cinnamaldehyde
afforded benzylated cyanohydrin in 70% and 87% yield, respec-
tively (Runs 9 and 10).
using p-methoxybenzyloxytrimethylsilane as an alkyl silyl ether,
no reaction occurred (Run 2). Silyl ethers of primary and cyclic
secondary alcohols gave the corresponding alkyl ethers of cya-
nohydrin in good yields (Runs 3–5).
In conclusion, we have developed a novel one-pot synthesis
of O-alkyl protected cyanohydrins starting from a variety of pa-
rent aldehydes. This reaction has the following synthetic advan-
tages: 1) in contrast to the known cyanations of aldehyde, this
novel one-pot procedure promotes both cyanation and O-alkyla-
tion, 2) various alkyl-ether types of a protecting group for the hy-
droxyl function are obtained by using the corresponding alkoxy-
trimethylsilane, 3) extremely mild reaction conditions, 4) exper-
imental convenience. Further investigations to broaden the scope
and synthetic applications of this efficient cyanoalkylation are
under way in our laboratory.
References and Notes
1
Table 3. Synthesis of cyanohydrin benzyl ethers from aliphatic
aldehydesa
R. J. H. Gregory, Chem. Rev., 99, 3649 (1999); J.-M. Brunel
and I. P. Holmes, Angew. Chem., Int. Ed., 43, 2752 (2004).
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and A. Umani-Ronchi, Tetrahedron Lett., 42, 3041 (2001);
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H. Zhou, F.-X. Chen, B. Qin, X. Feng, and G. Zhangb, Synlett,
2004, 1077.
OBn
2
TMSCN
BnOTMS / FeCl3
CH2Cl2 / 2 h
RCHO
CH2Cl2 / 1 h
R
CN
Run
RCHO
Temp
Yield/%b
1
2c
3
4
5
PhCH2CH2CHO
PhCH2CH2CHO
PhCH2CH2CHO
n-BuCHO
cyclo-C6H11CHO
t-BuCHO
rt
0 ꢀC
24
22
73
80
74
47
À20 ꢀC
À20 ꢀC
À20 ꢀC
À20 ꢀC
6
3
a
Molar ratio of aldehyde:BnOTMS:FeCl3:TMSCN = 1:2.4:
0.05:1.5.
Isolated yield of purified product.
2 mol % of FeCl3 was used and the reaction was performed
in no solvent.
b
c
4
5
6
S. Hunig and R. Schaller, Angew. Chem., Int. Ed. Engl., 21, 36
¨
(1982).
Next, for aliphatic aldehydes, 3-phenylpropanal was select-
ed as a test compound, and we tentatively chose the reaction
temperature of À20 ꢀC (Table 3, Run 3). n-Pentanal and cyclo-
hexanecarbaldehyde were transformed into the corresponding
cyanohydrin benzyl ethers in good yields (Runs 4 and 5). Even
in the case of sterically hindered pivalaldehyde, the desired
product was obtained in 47% yield (Run 6).
Furthermore, this reaction was similarly effective for vari-
ous trimethylsilyl ethers of alcohols as illustrated in Table 4.
Reaction with allyloxytrimethylsilane gave the corresponding
cyanohydrin allyl ether in 95% yield (Run 1). On the other hand,
a) M. Okimoto and T. Chiba, Synthesis, 1996, 1188. b)
H. M. R. Hoffman, Z. M. Ismail, R. Hollwag, and A. R. Zein,
Bull. Chem. Soc. Jpn., 63, 1807 (1990).
T. Watahiki, S. Ohba, and T. Oriyama, Org. Lett., 5, 2679
(2003).
T. Mukaiyama, T. Soga, and H. Takenoshita, Chem. Lett.,
1989, 997.
T. W. Greene and P. G. M. Wuts, in ‘‘Protective Groups in
Organic Synthesis,’’ 3rd ed., John Wiley & Sons, New York
(1999), p 76.
7
8
9
Table 4. Synthesis of various cyanohydrin alkyl ethersa
10 T. Watahiki and T. Oriyama, Tetrahedron Lett., 43, 8959
(2002).
11 T. Watahiki, Y. Akabane, S. Mori, and T. Oriyama, Org. Lett.,
5, 3045 (2003).
OR
ROTMS / FeCl3
0 oC / 2 h
TMSCN
PhCHO
0 oC / 1 h
Ph
CN
12 Typical procedure: To a suspension of anhydrous iron(III)
chloride (1.8 mg, 0.011 mmol) and benzyloxytrimethylsilane
(292 mL, 1.48 mmol), was added benzaldehyde (63 mL, 0.62
mmol) and stirred at 0 ꢀC under argon atmosphere. After 2 h,
trimethylsilyl cyanide (124 mL, 0.93 mmol) was added and
stirred for 1 h at room temperature. The reaction mixture was
diluted with CH2Cl2 and quenched with a phosphate buffer
(pH 7). The organic materials were extracted with CH2Cl2,
washed with brine, and dried over Na2SO4. ꢀ-(Benzyloxy)-
phenylacetonitrile (135.2 mg, 98%) was isolated by thin-layer
chromatography on silica gel.
Run
ROTMS
Yield/%b
1
2
3
4
5
CH2=CHCH2OTMS
PMBOTMS
PhCH2CH2CH2OTMS
n-BuOTMS
cyclo-C6H11OTMS
95
0
66
91
77
a
Molar ratio of PhCHO:ROTMS:FeCl3:TMSCN = 1:2.4:
0.02:1.5.
Isolated yield of purified product.
b
Published on the web (Advance View) September 11, 2004; DOI 10.1246/cl.2004.1324