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Chemistry Letters Vol.33, No.9 (2004)
Preparation of Nitriles from Primary Alcohols by a New Type of Oxidation-reduction
Condensation Using 2,6-Dimethyl-1,4-benzoquinone and Diethyl Cyanophosphonate
Teruaki Mukaiyama,ꢀy;yy Kouta Masutani,y;yy and Yoshiaki Hagiwaray;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received May 21, 2004; CL-040584)
Cyanation of alkoxydiphenylphosphines, in situ prepared
from nBuLi and various primary alcohols, with 2,6-dimethyl-
1,4-benzoquinone (DMBQ) and diethyl cyanophosphonate pro-
vided the corresponding nitriles in high yields.
Table 1. Cyanation of benzyl alcohol with various cyanides and
DMBQ
n
BuLi, Ph PCl
XCN (1.0 equiv.)
2
BnOPPh
BnCN
BnOH
2
o
DMBQ
THF, 0 C, 1 h
Solvent, rt, 24 h
Oxidation-reduction condensation is known as one of very
convenient and useful synthetic reactions in organic synthesis.1
Various esters and ethers can be prepared in excellent yields un-
der mild conditions by the combined use of alkoxydiphenylphos-
phines and quinones.2 Further, successful syntheses of tertiary
alkyl esters3 and dialkyl ethers4 were performed by the above
procedure although it had been known difficult to work them
out by conventional oxidation-reduction condensations. Then,
some new versatile synthetic methodologies for carbon–oxygen
bond formation were requested. In order to extend the scope of
condensation reaction, our attention was next focused on
carbon–carbon bond formation by using cyanide ion which is
the most simple carbon nucleophile.
Preparation of nitriles from the corresponding alcohols is
important in organic synthesis from the viewpoint of carbon
chain elongation. In order to perform the above transformation,
two-step procedure which involves prior conversion of alcohols
into their halides or sulfonates and the following substitution
with inorganic cyanides has generally been employed. When
secondary and tertiary alcohols were used in this reaction, how-
ever, some reaction conditions such as high temperature and the
use of strong bases often caused undesirable elimination reac-
tion. Therefore, procedures such as one-pot cyanation of alco-
hols by using Mitsunobu reaction were devised to let the trans-
formation go through under mild conditions.5,6 Very recently,
a conversion of alcohols into nitriles by using PPh3/DDQ/
nBu4NCN system was reported.7 However, there are some limi-
tations in applying this system to other cyanation since it was too
strong to use DDQ as an oxidant and too difficult to use extreme-
ly hygroscopic nBu4NCN. Here, a new type of oxidation-reduc-
tion condensation using a combination of milder oxidizing
agent, 2,6-dimethyl-1,4-benzoquinone (DMBQ), and easy-to-
handle cyanating agent, diethyl cyanophosphonate, is described
for the preparation of nitriles from primary alcohols.
BnOPPh
/equiv.
Solvent
/mL
a
DMBQ
/equiv.
2
Yield /%
Entry
XCN
CH Cl
2
2
2
2
1
2
1.0
TMSCN
1.0
1.0
0
/0.50
CH Cl
HO CN
2
1.0
1.0
20
/0.50
CH Cl
O
2
3
4
35
49
1.0
1.0
/0.50
(EtO) PCN
2
O
CHCl
/0.50
3
1.0
(EtO) PCN
2
O
CHCl
/0.50
3
5
6
1.5
1.5
1.5
1.5
73
82
(EtO) PCN
2
O
CHCl
/1.5
3
(EtO) PCN
2
aA small amount of DMBQ was contained. Yield was deter-
mined by 1H NMR analysis.
yield when 1.5 equiv. of benzyloxydiphenylphosphine and 1.5
equiv. of DMBQ in CHCl3 were used (Table 1, Entries 4–6).
Next, cyanation of several primary alcohols using DMBQ
and diethyl cyanophosphonate was tried (Table 2). When benzyl
alcohols having various substituents were used, the correspond-
ing nitriles were obtained in good yields (Table 2, Entries 1–4).
Non-benzylic, hindered primary alcohols, and monoprotected
diols having p-methoxybenzyl group or tetrahydropyranyl group
also provided the desired nitriles in satisfactory yields (Table 2,
Entries 5–9). On the other hand, substrates shown in Entries 8
and 9 did not provide the corresponding nitriles when subjected
to the methods reported by Iranpoor7 and Untch6b at all.
A proposed reaction mechanism is shown in Scheme 1: alk-
oxydiphenylphosphine reacted initially with DMBQ to form the
adduct,2 which in turn transformed to the phosphonium cyanide
by the interaction with diethyl cyanophosphonate. Attack of the
cyanide anion to a carbon atom adjacent to oxygen atom of the
alkoxy group afforded the corresponding nitrile.
In the first place, cyanation reaction of benzyloxydiphenyl-
phosphine, in situ formed from nBuLi-treated benzyl alcohol and
chlorodiphenylphosphine, with TMSCN by using DMBQ was
tried in CH2Cl2. The desired nitrile, however, was not obtained
at all (Table 1, Entry 1). When acetone cyanohydrin was used as
a cyanating agent, the yield of nitrile was still 20% (Table 1,
Entry 2). While the use of diethyl cyanophosphonate also gave
it in 35% yield (Table 1, Entry 3). After screening several
reaction conditions, the nitrile was obtained eventually in 82%
Copyright Ó 2004 The Chemical Society of Japan
Mukaiyama, Teruaki
