Green regioselective azidolysis of epoxides catalyzed by multi-site phase-transfer catalyst

Article abstract of DOI:10.1002/jccs.200900088

A facile synthesis of 1,2-azidoalcohols from their epoxides using α,α',α''-N-hexakis(triethylammoniummethylene chloride)-melamine as amulti-site phase-transfer catalyst in water was developed. By this eco-friendly and highly atom-economic method, a variety of 1,2-azidoalcohols was obtained in high yields with excellent regioselectivity and in short reaction times. Application of this six-site PTC in the ring opening of epoxides by cyanide, acetate and chloride anions was also studied. The catalyst can be recovered after completion of the reaction and can be recycled without affecting the catalytic property.

Full text of DOI:10.1002/jccs.200900088

594
Journal of the Chinese Chemical Society, 2009, 56, 594-599
Green Regioselective Azidolysis of Epoxides Catalyzed by Multi-site
Phase-Transfer Catalyst
Ali Reza Kiasat,* Roya Mirzajani, Haji Shalbaf, Tahereh Tabatabaei and Mehdi Fallah-Mehrjardi
Chemistry Department, College of Science, Shahid Chamran University, Ahvaz 61357-4-3169, Iran
A facile synthesis of 1,2-azidoalcohols from their epoxides using a,a¢,a¢¢-N-hexakis(triethylammo-
niummethylene chloride)-melamine as a multi-site phase-transfer catalyst in water was developed. By this
eco-friendly and highly atom-economic method, a variety of 1,2-azidoalcohols was obtained in high
yields with excellent regioselectivity and in short reaction times. Application of this six-site PTC in the
ring opening of epoxides by cyanide, acetate and chloride anions was also studied. The catalyst can be re-
covered after completion of the reaction and can be recycled without affecting the catalytic property.
Keywords: Multi-site phase-transfer catalyst; Atom economic; 1,2-Azidoalcohol; Epoxide;
Ring opening; Regioselectivity.
INTRODUCTION
For processes in which one reactant is lipophilic and
tations, a number of alternative procedures have been re-
ported over the past few years using a variety of cata-
lysts.9-20
the other is hydrophilic, high reaction rates can be attained
only if the immiscibility of the reactions can be overcome.
Phase-transfer catalysis is a simple solution, especially for
reactions involving anionic reactants.1,2 The paramount
considerations in the selection of the catalyst are economy
of scale and efficiency of the PTC, particularly on the ex-
plicit industrial scale preparation of organic compounds.
With a view to satisfy these requirements, researchers have
developed novel “multi-site” phase transfer catalysts
(MPTC) which consist of more than one catalytic site. It is
expected that the increased number of catalytic active sites
present in a molecule should enhance its catalytic effi-
ciency and the reaction yield and hence the economy of the
reaction process.3
Although significant advances have been made in this
area, low regioselectivity, longer reaction time, strongly
acidic conditions, high catalyst loading, toxic solvents and
lower substrate compatibility limit their applications. Thus
there is a need to develop an efficient catalytic protocol for
ring opening of various epoxides with azide anions under
mild and more convenient conditions.
RESULTS AND DISCUSSION
In 2004, a report by Balakrishnan2 outlined the prepa-
ration of an efficient multi-site phase-transfer catalyst,
a,a¢,a¢¢-N-hexakis(triethylammoniummethylene chlo-
ride)-melamine. They found that this MPTC catalyst has
higher activity than the commercially available single-site
phase transfer catalyst in the alkylation of phenylaceto-
nitrile with 1-bromobutane. With this in mind and as a part
of our research to develop green chemistry by using water
as reaction medium,21-25 we report herein our results on
regioselective ring opening of various epoxides with azide
ion using a,a¢,a¢¢-N-hexakis(triethyl-ammoniummethyl-
ene chloride)-melamine as an efficient multi-site phase-
transfer catalyst, in water (Scheme I). As described here, a
variety of azidoalcohols can be synthesized in an atom-eco-
nomical manner with high regioselectivity under mild and
non-toxic conditions.
Vicinal azidoalcohols not only constitute components
of biologically active natural products, they also serve as
essential intermediates in the synthesis of amino sugar,2-4
carboxylic nucleosides,5 lactames,6 oxazolines7 and amino-
alcohols.8 Consequently, the development of novel syn-
thetic methods for their synthesis has attracted sustained
interest in organic synthesis. The most common method
for the preparation of azidohydrins is the ring opening of
epoxides by using different azides in suitable solvents.
Even though the classical protocol uses sodium azide and
ammonium chloride, the azidolysis reaction requires a long
reaction time (12-48 h), and the azidohydrin is often ac-
companied by isomerization, epimerization, and rearrange-
ment of products. In order to overcome some of these limi-
Scheme II describs the three-step process for facile
preparation of a,a¢,a¢¢-N-hexakis(triethylammoniummeth-

Regioselective Azidolysis of Epoxides
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 595
Scheme I Regioselective azidolysis of epoxides in the presence of multi-site phase-transfer catalyst
Scheme II Three-step process for preparation of a,a¢,a¢¢-N-hexakis(triethylammoniumm-ethylene chloride)-mela-
mine
ylene chloride)-melamine using inexpensive starting mate-
rials.
1). As shown in Tables 1 and 2, interestingly this catalyst
acted very efficiently in water, and it was observed that 0.2
g of the catalyst is enough to convert 1 mmol of different
epoxides carrying electron donating or withdrawing groups
to their corresponding b-azido alcohol in high isolated
yields. It is noteworthy that no evidence for the formation
of diol as a by-product of the reaction was observed.
As shown in Table 2, using the optimized reaction
condition (3/1 molar ratio of NaN3: epoxide and 0.2 g cata-
We examined the catalytic ability of a,a¢,a¢¢-N-hexa-
kis(triethylammoniummethylene chloride)-melamine for
conversion of 2,3-epoxypropyl phenyl ether (1 mmol) to
the corresponding azidoalcohol with NaN3 (3 mmol) in
various solvents. TLC analysis of the reaction mixture
clearly showed that in organic solvents and under reflux
conditions the reaction was not complete after 5 hrs (Table

596 J. Chin. Chem. Soc., Vol. 56, No. 3, 2009
Kiasat et al.
lished from their spectral (1H and 13C NMR and MS) data.
Furthermore, cyclohexene oxide as a cycloalkyl epoxide
reacted smoothly in an SN2 fashion with NaN3 and in the
presence of MPTCto afford the corresponding azidohydrin
in high yield. The stereochemistry of the ring opening
product was found to be trans from the coupling constants
of the ring protons in 1H NMR spectrum.
Table 1. Efficiency of solvents on azidolysis of epoxidesa
Entry
Solvent
Time (min)
Result
1
2
3
4
5
dicholoromethane
n-hexane
300
300
300
300
30
Not completed
Not completed
Not completed
Not completed
completed
acetonitrile
ethyl acetate
water
a 2,3-epoxypropyl phenyl ether (1 mmol), NaN3 (3 mmol) and
0.2 g of MPTC were used under reflux conditions.
The most ideal synthetic methodology could be de-
fined as a system wherein 100% atom economy is pre-
served, the solvent is recycled to the fullest extent and the
catalyst or excess of reagent remains throughout in the sol-
vent medium and without losing activity for several runs.
In general, the methodology worked well independently on
the nature of the epoxide, furnishing the corresponding
azidoalchols in high yields. The MPTC and the additional
sodium azide (2 mmol) were conveniently separated from
the reaction mixture by simple extraction of product in
ether phase. The aqueous phase was reused five consecu-
tive times with only slight variation in the yields of the cor-
lyst/mmol epoxide) styrene oxide afforded the product of
opening at the benzylic position as the major product, while
2-alkylepoxides gave the products just formed by cleavage
at the terminal position. These observations demonstrated
that in the former case, the product is generated through the
formation of a stabilized benzylic cation during the reac-
tion and in the second case, they are formed by predomi-
nant attack of the azide ion on the less hindered carbon of
the epoxide. The structures of the products were estab-
Table 2. Reaction of different epoxides with NaN3 using MPTC in water
Time Yields
(min)
(%)b
Entry
Substrate
O
Product(s)a
N3
OH
1
2
3
30 85 (19:1)c
OH
N3
+
Ph
Ph
Ph
O
OH
30
30
85
75
PhO
N3
OH
PhO
O
O
N3
O
O
OH
O
N3
4
5
45
30
80
88
O
OH
N3
O
O
OH
O
N3
O
6
7
45
60
83
75
O
O
O
OH
O
N3
O
a All of the products were known compounds and identified by comparison of their physical
and spectral data with those of authentic samples.
b Isolated yields.
c According to GC analysis.

Regioselective Azidolysis of Epoxides
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 597
Scheme III Nucleophilic ring-opening of epoxides with sodium azide in the atom-economical method
responding products. Scheme III describes the facile nu-
cleophilic ring-opening of epoxides with sodium azide in
the atom-economical method.
catalyst under similar reaction conditions for ring opening
of styrene oxide and 2,3-epoxypropyl phenyl ether with ac-
etate, cyanide and chloride anions. The obtained results are
shown in Table 4 and clearly show the generality of this cat-
alyst for nucleophilic ring opening of epoxides.
The advantage of using this multi-site phase transfer
catalyst for the synthesis of 1,2-azidoalcohols using azide
ion is shown by comparing our results with those previ-
ously reported in the literature (Table 3).
In conclusion, in this study we have introduced a sim-
ple, rapid and mild procedure for the regioselective prepa-
ration of 1,2-azidoalcohols using a,a¢,a¢¢-N-hexakis(tri-
ethyl-ammoniummethylene chloride)-melamine as a multi-
site phase-transfer catalyst in water. The advantages of the
present protocol, such as being an environmentally friendly
While establishing the advantages of a,a¢,a¢¢-N-hex-
akis-(triethyl-ammoniummethylene chloride)-melamine
as a multi-site phase-transfer catalyst for ring opening of
epoxide by azide anion in water, we continued to apply this
Table 3. Comparison of azidolysis of styrene oxide with different methods
Regioselectivity (%)
a-attack (I) b-attack (II)
95
Entry
Reagent and reaction conditions
Time (h)
Yield (%) Ref.
1
2
3
4
5
6
NaN3/MPTC/H2O/90 °C
NaN3/NH4Cl/MeOH-H2O/reflux
LiN3/CH3CN/80 °C
0.5
5
5
85
90
94
65
45
90
a
81
79
78
-
19
21
22
-
26
26
27
28
29
20
42
5
TMGA/Hf(OTf)4/CH3CN/r.t
TMSN3/b-CD/H2O/37 °C
NaN3/H2O(pH = 9.5)/30 °C
13
97
3
a Present method.

598 J. Chin. Chem. Soc., Vol. 56, No. 3, 2009
Kiasat et al.
Table 4. Ring opening of styrene oxide and 2,3-epoxypropyl phenyl ether with acetate,
cyanide and chloride anion
No
Epoxide
Catalyst/Reagent/Solvent
Time (h)
Yield (%)
O
1
MPTC/NaCN/H2O
MPTC/NaOAC/H2O
MPTC/NH4Cl/H2O
MPTC/NaCN/H2O
MPTC/NaOAC/H2O
MPTC/NH4Cl/H2O
0.5
2
83
85
75
87
75
80
Ph
1.5
1.5
2
O
2
PhOCH2
2
a Reactions were carried out under similar conditions which applied to preparation of azido
alcohols.
alternative, short reaction times, simplicity in operation,
Selected spectroscopic data
the low cost of reagent, highly regioselectivity, and high
yields of products, make this new process an attractive al-
ternative to current methodologies.
2-Azido-2-phenyl-1-ethanol: IR (neat): n N3 (2102
cm-1); 1H-NMR (400 MHz, CDCl3): d 3.37 (s, 1H), 3.74
(m, 2H), 4.67 (m, 1H), 7.34-7.44 (m, 5H). 13C-NMR (100
MHz, CDCl3): d 66.37, 68.03, 127.49, 128.46, 128.61,
136.47.
EXPERIMENTAL
General
2-Azidocyclohexan-1-ol: IR (neat): n N3 (2097
cm-1); 1H-NMR (400 MHz, CDCl3): d 1.20-1.36 (m, 4H),
1.72-1.78 (m, 2H), 2.00-2.07 (m, 2H), 2.52 (s, 1H), 3.10-
3.22 (m, 1H), 3.28-3.42 (m, 1H). 13C-NMR (100 MHz,
CDCl3): d 24.38, 24.48, 24.51, 33.14, 62.14, 73.79.
1-Azido-3-butoxypropan-2-ol: IR (neat): n N3
(2102 cm-1); 1H-NMR (400 MHz, CDCl3): d 0.87 (t, 3H),
1.31-1.35 (m, 2H), 1.50-1.53 (m, 2H), 3.14 (s, 1H), 3.30
(m, 2H), 3.39 (t, 2H), 3.41 (d, 2H), 3.86 (m, 1H). 13C-NMR
(100 MHz, CDCl3): d 13.78, 19.16, 30.74, 53.52, 69.74,
70.59, 70.71.
Epoxides and other chemical materials were pur-
chased from Fluka and Merck in high purity. MPTC was
prepared according to a previously reported procedure.2
All of the azidohydrin compounds were prepared by our
procedure and their spectroscopic and physical data were
compared with those of authentic samples. NMR spectra
were recorded in CDCl3 on a Bruker Avance DPX 400
MHz instrument spectrometer using TMS as internal stan-
dard. IR spectra were recorded on a BOMEM MB-Series
1998 FT-IR spectrophotometer. The purity determination
of the products and reaction monitoring were accomplished
by TLC on silica gel polygram SILG/UV 254 plates.
General procedure for the preparation of 1,2-azido-
alcohols from epoxides
1-Azido-3-phenoxypropan-2-ol: IR (neat): n N3
(2102 cm-1); 1H-NMR (400 MHz, CDCl3): d 3.50 (d, 2H),
3.89-3.97 (m, 1H), 4.00 (d, 2H), 4.18 (s, 1H), 6.95-7.00 (m,
2H), 7.02-7.06 (m, 1H), 7.27-7.36 (m, 2H). 13C-NMR (100
MHz, CDCl3): d 53.51, 69.22, 69.30, 114.30, 121.16,
129.42, 158.37.
NaN3 (3 mmol) was dissolved in water (5 mL) fol-
lowed by the addition of MPTC (0.2 g) and epoxide (1
mmol) and the whole was stirred at 90 °C for the lengths of
time shown in Table 2. The progress of the reaction was
monitored by TLC. After completion of the reaction, the
mixture was extracted with ether (2 ´ 10 mL). The com-
bined organic extracts (dried over CaCl2) were evaporated
under reduced pressure. The desired azidohydrin was ob-
tained in good to excellent isolated yields (75-88%). For
styrene oxide, further purification was achieved by pre-
parative TLC or by silica gel column chromatography. The
aqueous layer containing MPTC and excess sodium azide
was utilized in further runs by an addition of epoxide (1
mmol) and NaN3 (1 mmol).
2-Methyl acrylic acid-3-azido-2-hydroxy propyl
1
ester: IR (neat): n N3 (2103 cm-1); H-NMR (400 MHz,
CDCl3): d 1.9 (m, 3H), 3.1 (br s, 1H), 3.70 (d, 2H), 3.90 (d,
2H), 4.12 (m, 1H), 5.62 (m, 1H), 6.15 (m, 1H). 13C-NMR
(100 MHz, CDCl3): d 17.20, 56.44, 68.65, 70.36, 124.12,
136.71, 169.45.
ACKNOWLEDGMENT
The authors are thankful to the Shahid Chamran Uni-
versity Research Council for financial support of this work.
Received October 16, 2008.

Regioselective Azidolysis of Epoxides
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 599
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