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Chemistry Letters Vol.36, No.4 (2007)
One-pot Synthesis of ꢀ-Alkoxy Azides from Carbonyl Compounds
Catalyzed by Iron(III) Chloride
Megumi Omura, Katsuyuki Iwanami, and Takeshi OriyamaÃ
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received January 25, 2007; CL-070088; E-mail: tor@mx.ibaraki.ac.jp)
In the presence of alkoxytrimethylsilane and a catalytic
Table 1. Optimization of the reaction conditionsa
amount of iron(III) chloride, the reaction of various carbonyl
compounds with trimethylsilyl azide afforded the corresponding
ꢀ-alkoxy azides. This reaction could be suitable especially
for azidation of aromatic aldehydes and proceeds under mild
conditions in a convenient one-pot manner.
OBn
N3
BnOTMS, FeCl3
CHO
+ TMSN3
Ph
Ph
Run
Solvent
Temp.
Time/h
Yield/%b
1
2
3
4
5
6
7
8
MeNO2
MeNO2
MeNO2
CH2Cl2
MeCN
MeCN
EtCN
rt
0 ꢀC
1
1
52
71
85
74
79
91
84
47
À20 ꢀC
À20 ꢀC
À20 ꢀC
À40 ꢀC
À40 ꢀC
À78 ꢀC
1
1
1
1
1
24
The azide group has been used extensively in organic syn-
thesis. Several methods for the introduction of the azide group
have been reported.1 Trimethylsilyl azide has been frequently
employed for this purpose because of its handy property.2
There are some reports on the reactivity of trimethylsilyl azide
toward carbonyl compounds. Addition of trimethylsilyl azide
to aldehydes in the presence of a catalytic amount of zinc(II)
chloride provided ꢀ-siloxy azides, but these reactions were
applied only to aliphatic aldehydes.3 After that, ꢀ-siloxy azides
derived from aromatic aldehydes were reported to be very unsta-
ble and difficult to isolate.4 ꢀ-Alkoxy azides were synthesized
starting from acetals with hydrazoic acid in the presence of a
stoichiometric amount of magnesium(II) bromide.5 Aliphatic
aldehydes were reacted with an excess of hydrazoic acid in
the presence of alcohol and a catalytic amount of titanium(IV)
chloride to afford ꢀ-alkoxy azides, but a similar reaction of
aromatic aldehydes has not occurred.6 On the other hand, we
have recently demonstrated hybrid transformations including
‘‘nucleophilic addition to a carbonyl group’’ and ‘‘O-protection
of a hydroxy group’’ in a simple one-pot procedure. These
reactions of carbonyl compounds with various silyl nucleophiles
and alkoxytrimethylsilane were effectively promoted by
iron(III) chloride.7
EtCN
aMolar ratio of aldehyde:BnOTMS:TMSN3:FeCl3 = 1:1.2:
1.5:0.05. bIsolated yield of purified product.
Table 2. Synthesis of ꢀ-benzyloxy azides from various aliphat-
ic aldehydesa
OBn
N
BnOTMS, FeCl
3
RCHO
+ TMSN
3
R
MeCN, −40 °C, 1 h
3
Run
RCHO
Yield/%b
1
2
3
4
5
PhCH2CH2CHO
(CH3)2CHCH2CHO
i-PrCHO
cyclo-C6H11CHO
t-BuCHO
91
90
97
93
57
aMolar ratio of aldehyde:BnOTMS:TMSN3:FeCl3 = 1:1.2:
1.5:0.05. bIsolated yield of purified product.
In this communication, we wish to describe the first example
of the direct conversion of various carbonyl compounds to the
corresponding ꢀ-alkoxy azides under the influence of a catalytic
amount of iron(III) chloride.
various alkoxytrimethylsilanes to give the corresponding ꢀ-
alkoxy azides as summarized in Table 3. Reaction with allyl-
oxytrimethylsilane gave ꢀ-allyloxy azide in 63% yield (Run
2). Silyl ethers of primary and cyclic secondary alcohols gave
the corresponding ꢀ-alkoxy azides in high yields (Runs 3 and
4). However, when t-butoxytrimethylsilane was used, the corre-
sponding product was obtained in only 12% yield (Run 5).
Next, the reaction was conducted with various aromatic al-
dehydes (Table 4). We examined the reaction of benzaldehyde
under the same reaction conditions as that of aliphatic aldehydes,
and the corresponding product was obtained in 52% yield. How-
ever, the reaction of aromatic aldehydes proceeded smoothly
to give the corresponding ꢀ-benzyloxy azides in high yields
via in situ formation of acetal according to the procedure report-
ed in our previous paper7b (Run 1).9 Aromatic aldehydes having
electron-donating (Runs 2–4, 6) or -withdrawing (Runs 7 and 8)
groups, and naphthaldehydes (Runs 9 and 10) reacted readily
under the above reaction conditions in good to excellent yields.
Although mesitaldehyde did not react (Run 5), cinnamaldehyde
First, we examined the reaction of 3-phenylpropanal with
1.5 equiv. of trimethylsilyl azide and 2.4 equiv. of benzyloxytri-
methylsilane in the presence of 5 mol % of iron(III) chloride in
nitromethane at room temperature according to the procedure
reported in our previous paper,7c and the desired product was
obtained in 52% yield (Table 1, Run 1). After a preliminary in-
vestigation, we found that the reaction proceeded in acetonitrile
at À40 ꢀC to give the highest yield of the product (Run 6).8
Next, various aliphatic aldehydes were tested under these
optimized reaction conditions (Table 2). 3-Methylbutanal, iso-
butanal, and cyclohexanecarbaldehyde were uniformly trans-
formed into the corresponding ꢀ-benzyloxy azides in excellent
yields (Runs 2–4). Even in the case of sterically hindered
pivalaldehyde, the desired product was obtained in 57% yield
(Run 5).
Furthermore, this reaction was similarly effective for
Copyright ꢀ 2007 The Chemical Society of Japan