Ionic liquids/H2O systems for the reaction of epoxides with NaN3: A new protocol for the synthesis of 2-azidoalcohols

Article abstract of DOI:10.1016/j.tetlet.2005.07.074

Oxiranes undergo ring opening rapidly with sodium azide in a [bmim]BF ₄/H₂O or [bmim]PF₆/H₂O (2:1) solvent system, under mild and neutral reaction conditions to afford the corresponding 2-azidoalcohols in high t

Full text of DOI:10.1016/j.tetlet.2005.07.074

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6559–6562
Ionic liquids/H2O systems for the reaction of epoxides with NaN3:
a new protocol for the synthesis of 2-azidoalcohols
J. S. Yadav,* B. V. S. Reddy, B. Jyothirmai and M. S. R. Murty
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 April 2005; revised 7 July 2005; accepted 15 July 2005
Abstract—Oxiranes undergo ring opening rapidly with sodium azide in a [bmim]BF4/H2O or [bmim]PF6/H2O (2:1) solvent system,
under mild and neutral reaction conditions to afford the corresponding 2-azidoalcohols in high to quantitative yields. The remark-
able features of this procedure are improved yields, enhanced reaction rates, high regioselectivity and ease of recyclability of ionic
liquids (ILs). The recovered ionic liquid can be reused for four to five times but with gradual decrease in activity.
ꢀ 2005 Published by Elsevier Ltd.
2-Azidoalcohols are important precursors for the syn-
thesis of b-aminoalcohols,1 some of which are of signifi-
cance as b-adrenergic blocking agents, as highly
effective antagonists for the treatment of cardiovascular
diseases, cardiac failure and asthma, and are also useful
as chiral auxiliaries in asymmetric synthesis.2 They are
also useful intermediates for the synthesis of amino sug-
ars and carbocyclic nucleosides.3 The simple and the
most straightforward synthetic method for the prepara-
tion of 2-azidoalcohols involves the regioselective ring
opening of oxiranes with sodium azide under various
reaction conditions.1 These epoxide opening reactions
are, however, generally carried out under either acidic
or basic conditions1,3,4 and they usually require high
temperatures and/or long reaction times, and side reac-
tions, such as isomerization, epimerization and rear-
rangements may be induced by the alkaline conditions.
Furthermore, high temperatures are not only detrimen-
tal to certain functional groups, but also to the control
of regioselectivity. A variety of activators or promoters
have been reported to assist epoxide ring-opening reac-
tions with sodium azide under mild conditions.5–7 Since
2-azidoalcohols have become increasingly useful and
important in drugs and pharmaceuticals, the develop-
ment of simple, efficient and environmentally friendly
processes for their synthesis is desirable.
In recent years, ionic liquids have emerged as alterna-
tive reaction media for the immobilization of transition
metal based catalysts, Lewis acids and enzymes.8 They
are solvents with unique properties such as tunable
polarity, high thermal stability, immiscibility with a
number of organic solvents, negligible vapour pressure
and ease of recyclability. They are referred to as Ôde-
signer solventsÕ as their properties such as hydrophilic-
ity, hydrophobicity, Lewis acidity, viscosity and density
can be altered by the fine-tuning of parameters such as
the choice of organic cation, inorganic anion and the
length of alkyl chain attached to the organic cation
(Fig. 1).
+
+
( )n
N
N
-
N
N
-
PF6
BF4
[bmim]BF4
n = 5 = [octmim]PF6
n = 1 = [bmim]PF6
n = 3 = [hmim]PF6
Figure 1. Chemical structure of the ionic liquids.
Keywords: Ionic liquids (ILs); Oxiranes; Azidoalcohols.
*
Corresponding author. Fax: +91 40 27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.074

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J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 6559–6562
N3
OH
[bmim]PF /H2O (2:1)
6
O
+
OH
NaN3
N3
+
R
R
R
65 °C
2
3
Scheme 1.
These structural variations offer flexibility to the chemist
to find the best solvent, catering to the needs of any par-
ticular process. As a result of their green credentials and
potential to enhance reaction rates and selectivities,
ionic liquids are finding increasing applications in
organic synthesis.9
Treatment of 3-phenoxy-1,2-epoxypropane with sodium
azide in a 1-butyl-3-methylimidazolium hexafluorophos-
phate/water (2:1) solvent system for 3 h afforded the cor-
responding 2-azidoalcohol 2 (R = PhOCH2) in 95%
yield. The product was isolated by simple extraction
with diethyl ether. The rest of the ionic liquid was
washed further with ether and reused in successive runs
without further purification. Encouraged by the results
obtained with 3-phenoxy-1,2-epoxypropane, we exam-
ined several other epoxides (Table 1). Various 3-aryl-
oxy-1,2-epoxypropanes and aliphatic oxiranes reacted
In this article, we report the use of ionic liquids as novel
and recyclable reaction media for the synthesis of 2-azido-
alcohols from oxiranes and sodium azide under mild
and neutral conditions (Scheme 1).
Table 1. Synthesis of 2-azidoalcohols in 1-butyl-3-methylimidazolium ionic liquids
Entry
a
Epoxide
Producta
[bmim]PF6–H2O
Time (h)
Yield (%)b
[bmim]BF4–H2O
Time (h)
Yield (%)b
OH
N3
OH
4a
3.0
95
4.5
89
O
b
c
4b
4c
4d
5.0
3.5
4.0
87
90
94
6.0
5.5
5.0
81
85
87
O
O
N3
OH
O
N3
N3
OH
d
N3
N3
O
Ph
OH
e
5e
3.5
93
4.5
88
Ph
Ph
Ph
Ph
O
f
3f
3.0
4.5
4.0
91(5)
90(8)
89(9)
5.5
6.0
4.5
84(11)
87(9)
OH
Ph
OH
O
O
g
h
2g
2h
N3
N3
OH
85(12)
( )3
( )3
OH
O
RO
RO
N3
i
j
R = phenyl
R = p-Cl-phenyl
R = benzyl
R = p-MeO-phenyl
R = p-Me-phenyl
R = p-isopropylphenyl
R = 2-naphthyl
R = phenyl
R = p-Cl-phenyl
R = benzyl
R = p-MeO-phenyl
R = p-Me-phenyl
R = p-isopropylphenyl
R = 2-naphthyl
2i
3.0
4.5
5.0
4.0
3.5
4.0
5.0
95
93
90
94
96
92
90
5.0
6.0
6.5
5.5
4.0
5.5
7.0
89
85
87
82
85
89
84
2j
k
l
m
n
o
2k
2l
1m
1n
1o
2m
2n
2o
a All the products have been reported previously.12
b Yields refer to isolated pure products after purification by column chromatography. Yields in parentheses refer to the other regioisomer as
determined by GLC analysis.

J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 6559–6562
6561
recovered ionic liquid, the products obtained were of
the same purity as in the first run. In terms of efficiency
and selectivity, this procedure has advantages over
either protic or Lewis acid catalyzed procedures. The
scope and generality of this process is illustrated with
respect to various epoxides and sodium azide11 and
the results are presented in Table 1.
[bmim]PF6/H2O (2:1)
65 °C
OH
O +
NaN3
( )n
( )n
N3
n = 1, 2, 4
4
n = 1, 2, 4
Scheme 2.
smoothly with sodium azide under similar reaction con-
ditions to produce the corresponding 2-azidoalcohols in
excellent yields. Styrene epoxide and tetrahydronaphtho-
[1,2-b]oxirane underwent cleavage with sodium azide
with preferential attack at the benzylic position to give
the corresponding azidohydrins in 94% and 91% yields,
respectively10 (Table 1, entries d and f). The stereochem-
istry of the product 4d was found to be trans based on
In summary, an ionic liquid/water solvent system was
proved to be an effective reaction medium for the syn-
thesis of 2-azidoalcohols from epoxides by playing the
dual role of solvent as well as promoter. The epoxides
showed a significant increase in reactivity thereby reduc-
ing the reaction times and improving the yields substan-
tially. Simple experimental and product isolation
procedures combined with ease of recovery and reuse
of this reaction media is expected to contribute to the
development of green strategy for the preparation of
2-azidoalcohols.
1
1
the H NMR coupling constants. The H NMR coup-
ling constants of 4d are d 4.41 (d, J = 7.1 Hz, 1H) for
(–CHN3). The large coupling constant values are in
accordance with trans stereochemistry. The product 5e
(Table 1, entry e) obtained from cis-stilbene was the
1
anti-isomer based on the H NMR coupling constants
Acknowledgements
d 4.50 (d, J = 6.5 Hz, 1H) for (–CHN3) and d 4.65 (d,
J = 6.5 Hz, 1H) for (–CHOH). Bicyclic oxiranes such
as cyclopentene, cyclohexene and cyclooctene epoxides
also underwent cleavage with sodium azide to produced
2-azidoalcohols 4 in high yields (Scheme 2).
B.V.S. and B.J. thank CSIR, New Delhi for the award
of fellowships.
Except for the reactions of styrene oxide, hexene oxide
and octene oxide, which produced minor amounts of
the other regioisomer (5%, 8% and 9%), the reactions
of other epoxides were found to be highly regioselective
affording a single product in high to quantitative yield.
The stereochemistry of the ring-opened products from
bicyclic epoxides was found to be trans from the cou-
pling constants of the ring hydrogens as has been
observed in most epoxide ring-opening reactions.5–7
The direction of ring opening is that characteristically
observed for terminal epoxides under SN2 conditions,
probably dictated by steric and electronic factors. In
the absence of the ionic liquid, the reactions were very
slow in water, resulting in low yields. The addition of
ionic liquid significantly improved the reaction rates
and yields. This is probably due to activation of the
epoxide by the acidic nature of the ring hydrogen of
the imidazole moiety. Thus, the combination of ionic
liquid and water as solvent system (2:1) was found to
be an effective reaction media for this conversion. The
cleavage of epoxides with sodium azide was performed
in both hydrophilic [bmim]BF4 and hydrophobic
[bmim]PF6 ionic liquids, the latter being superior in
terms of conversion. The main advantage of the use of
ionic liquids is that these molten salts can be easily
recovered on work-up. Since the products were fairly
soluble in the ionic liquids, they could be easily sepa-
rated by simple extraction with ether. The remaining
ionic liquid was thoroughly washed with ether and
reused for four to five subsequent runs, but with a grad-
ual decrease in activity. For example, treatment of
3-phenoxy-1,2-epoxypropane with sodium azide in
[bmim]PF6 afforded the 2-azidoalcohol in 95%, 90%,
87%, 83% and 79% yields over five runs. Even though,
the yields decreased gradually in runs performed using
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11. Experimental procedure: Epoxide (1 mmol) and sodium
azide (1.5 mmol) in 1-butyl-3-methylimidazolium hexaflu-
orophosphate/water (2:1, 3 mL) were stirred at 65 ꢁC for
an appropriate time (Table 1). After completion of the
reaction, as indicated by TLC, the reaction mixture was
extracted with diethyl ether (3 · 10 mL). The combined
ether extracts were concentrated in vacuo and the resulting
product was directly charged onto a small silica gel
column and eluted with a mixture of ethyl acetate/
n-hexane (2:8) to afford the pure 2-azidoalcohol. The
remainder of the ionic liquid was washed with ether and
recycled in subsequent runs. The azidoalcohols thus
obtained were identified by comparison of their NMR,
IR Mass, TLC, mixed TLC analysis and physical data
with authentic samples. The spectral data of all the
products were identical with those of the authentic
samples.12
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