Efficient method for the one-pot azidation of alcohols using bis(p-nitrophenyl)
phosphorazidate
Masanori Mizunoa,b and Takayuki Shioiri*a
a Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467, Japan
b Research and Development Department, Eisai Chemical Co. Ltd, Sunayama, Hasaki, Kashima-gun, Ibaraki 314-02, Japan
The direct stereoselective conversion of various alcohols and
hexopyranoses into the corresponding alkyl azides and
glycosyl azides, respectively, is efficiently accomplished by
using bis(p-nitrophenyl) phosphorazidate and DBU.
This method was extended to the preparation of glycosyl
azides, key intermediates in the synthesis of glycosyl amino
acids.8 The results summarized in Table 2 demonstrate that this
method selectively gives 1,2-trans-glycosyl azides. The stereo-
chemical outcome of these direct azidations may be rationalized
on grounds similar to those proposed by Sabesan and Neira9 for
the preparation of anomerically enriched glycosyl phosphates
from hexopyranoses, i.e. probably the azidation occurs via
initial formation of the thermodynamically stable 1,2-cis-
glycosyl phosphate which subsequently undergoes the azide
displacement with inversion of configuration.
Azides have been used extensively in organic synthesis,
especially for the introduction of primary amino groups and the
construction of heterocyclic structures.1 In most cases, aliphatic
azides are prepared by nucleophilic substitution of the corre-
sponding halides or sulfonates by the azide anion.2 The only
known methods for the direct conversion of alcohols into azides
are the Mitsunobu reaction,3 in which removal of the by-
products is troublesome, and the diphenyl phosphorazidate
(DPPA)–DBU method4 which is effective only for activated
alcohols. In the course of our investigation on the reactivity of
some analogs of DPPA, we have discovered that bis(p-
nitrophenyl) phosphorazidate (p-NO2DPPA), prepared easily
by nitration of DPPA,5 in combination with DBU is quite useful
and efficient for the direct conversion of alcohols into azides, as
shown in Scheme 1.
In summary, compared to other methods2–4 that have been
reported, this present method for the stereoselective synthesis of
Table 1 Azidation of alcoholsa
Entry
1
Alcohol
Solvent t/h
Azide
Yield (%)
76
N3
OH
toluene 16
2
1
2b
3b
4b
toluene
toluene
toluene
6
6
6
81
87
90
N3
OH
4
6
3
5
HO
R1
H
+
(p-NO2C6H4O)2P(O)N3
N3
+
DBU
R2
N3
OH
H
+
(p-NO2C6H4O)2P(O)OH•DBU
R1
R2
N3
OH
8 (96.3% ee)c
7 (96.5% ee)c
Scheme 1
N3
OH
Treatment of decan-1-ol 1 or decan-2-ol 3 with p-NO2DPPA
(1.2 equiv.) and DBU (1.2 equiv.) in toluene (1 mol l21
5
THF
1
94
)
10 (100% ee)d
9 (100% ee)d
smoothly afforded the corresponding azides 2 and 4 in good
yield. Superior features of this method are that the reactions
proceed with considerably faster rates than when DPPA–DBU
is used (5 and 3% yields, respectively), and there are fewer
byproducts to struggle with than in the Mitsunobu reaction. In
the azidation of decan-2-ol 3, DBU (81% yield) was much
superior to triethylamine (28%), triethylamine with 0.1 part of
DMAP (44%) and diisopropylethylamine (32%) under analo-
gous reaction conditions. Toluene was the solvent of choice
though THF and DMF can also be used.
Various azides prepared from alcohols according to this
method are listed in Table 1. High stereoselectivity was
observed in the reaction of optically active alcohols; for
instance, (R)-(2)-octan-2-ol 7 and (R)-(+)-1-phenylethanol 9
afforded (S)-(+)-2-azidooctane 8 and (S)-(2)-1-phenylethyl
azide 10, respectively, in good yield with inversion of
configuration without loss of stereochemical integrity.
(R)-(+)-2-Phenyl-1-(thiazol-2-yl)ethanol 11 was also conven-
iently converted to the (S)-azide 12, which was an intermediate
for the synthesis of dolaphenine [(S)-(2)-2-phenyl-1-(thiazol-
2-yl)ethylamine],6 the C-terminal unit of dolastatin 10 having
strong anticancer activity. Allylic alcohols gave a mixture of the
isomeric azides (entries 8–11 and 13) due to rapid 1,3-re-
arrangement of the allylic azides.7 However, the azidation of
alicyclic alcohols such as cyclohexanol 31 and (2)-menthol 32
were unsuccessful under the same reaction conditions.
N3
S
OH
S
6
7
8
THF
3
2
2
91
82
N
N
12 (95.6% ee)e
11 (95.9% ee)e
N3
OH
THF
14 (81.3% ee)f
13 (100% ee)c
toluene
94
(9:5:2)g
N3
OH
16a
16b
15
N3
N3
16c
16a + 16b + 16c
9
toluene 0.5
95
17
(3:4:1)g
30
OH
OH
16a + 16b + 16c
10
11
toluene
toluene
2
2
(7:10:3)g
Sm 61h
18
82
(1:1)g
N3
19 OH
20a
20b
N3
continued
Chem. Commun., 1997
2165