A straightforward one-pot synthesis of biologically important imidazolyl alcohols via catalytic epoxide ring-opening reactions

Article abstract of DOI:10.1016/j.tetlet.2012.04.019

A general and efficient method for the preparation of biologically important imidazolyl alcohols via ring-opening of epoxides with N-silylated imidazole catalyzed by LiBr under solvent-free conditions is reported.

Full text of DOI:10.1016/j.tetlet.2012.04.019

Tetrahedron Letters 53 (2012) 3049–3051
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A straightforward one-pot synthesis of biologically important imidazolyl
alcohols via catalytic epoxide ring-opening reactions
M. Abdul Jalil a, , Shah Md. Masum b
⇑
a School of Engineering, Presidency University, 10 Kemal Ataturk Avenue, Banani, Dhaka 1213, Bangladesh
b Department of Applied Chemistry and Chemical Engineering, University of Dhaka, Dhaka 1000, Bangladesh
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient method for the preparation of biologically important imidazolyl alcohols via ring-
opening of epoxides with N-silylated imidazole catalyzed by LiBr under solvent-free conditions is
reported.
Received 20 February 2012
Revised 25 March 2012
Accepted 4 April 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Imidazolyl alcohol
Antifungal
Epoxide
Catalyst
Solvent-free
The imidazole group is an important residue found in a wide
variety of biologically active and medicinally significant molecules,
comprising several classes of derivatives that can be found in fun-
gicides,1 histamine H2-receptor antagonists,2 and anticancer
agents.3 Among bioactive imidazole derivatives, imidazolyl alco-
hols are a very important class of compounds that show a wide
spectrum of activity and are used as important building blocks
for drug synthesis. For instance, metronidazole, ornidazole, and
secnidazole (Fig. 1) are effective antiprotozoal drugs of this family,
which have been used for the treatment of amebic dysentery and
other fungal infections. Miconazole and econazole are clinically
used representative antifungal drugs derived from imidazolyl
alcohols and several related compounds are currently undergoing
clinical trials.4
Apart from their excellent bioactivities, imidazolyl alcohols are
also used as ligands for catalytic reactions.5 Some of them are used
as bidentate N-heterocyclic carbene ligands (NHC) after alkylating
the imidazole ring.6 Also, higher oxidation state complexes provide
enhanced stabilities to metal catalysts.7 Moreover, their use as
ionic liquids have also been reported.8 Therefore, the development
of an efficient route that can be applied to the large scale synthesis
of this important class of molecules is an important goal.
accessible in optically pure form.9 Catalytic ring-opening of epox-
ides by amines is a straightforward method to prepare b-amino
alcohols.10 Surprisingly, no effective catalytic methods for the
ring-opening reaction of an epoxide with an imidazole have been
described to date. Only a few uncatalyzed methods for the prepa-
ration of imidazolyl alcohols via ring-opening of an epoxide by
imidazole are reported.5,11 However, these methods suffer from
one or more disadvantages such as long reaction times, elevated
temperature and pressure, moderate yields, are not viable industri-
ally, and lack generality. Here we report an efficient and general
epoxide ring-opening reaction, using silylated imidazole catalyzed
by LiBr at room temperature under solvent-free conditions, to
afford a cost-effective and environmentally friendly process for
the synthesis of imidazolyl alcohols. It has been established that
solvent-free reactions are generally fast, give high selectivity and
yields, and usually require easier work-up procedures and simpler
equipment.12 We chose four different epoxide systems as repre-
sentatives, alkyl, aryl, functional and internal, to generalize our
method.
N
N
N
OH
OH
Epoxides are very useful synthons in organic synthesis because
they are susceptible to attack by nucleophiles and are readily
Cl
N
N
N
OH
O2N
O2N
O2N
⇑
metronidazole
ornidazole
secnidazole
Corresponding author. Tel.: +880 2 9899049x114; fax: +880 2 8831184.
E-mail addresses: drmajalil@yahoo.com, jalil_a@presidency.edu.bd (M. Abdul
Jalil).
Figure 1. Examples of antiprotozoal drugs.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.019

3050
M. Abdul Jalil, S. Md. Masum / Tetrahedron Letters 53 (2012) 3049–3051
Me3Si
OH
O
N
N
O
5 mol% LiBr
neat, rt, 6 h
KF
N
N
Cl
Cl
N
N
+
Cl
MeOH, 3 h
1
2 (82%)
SiMe3
Scheme 1. Synthesis of imidazolyl alcohol from epichlorohydrin.
Me3Si
OH
O
N
O
KF
MeOH,3 h
5 mol% LiBr
N
N
N
N
+
Ph
N
neat, 60 °C, 4 h
Ph
Ph
SiMe3
3
4 (78%)
Scheme 2. Synthesis of imidazolyl alcohol 4 using an aryl-substituted unsymmetric epoxide.
Me3Si
O
To initiate our study we first chose the synthetically more
O
important functionalised epoxide epichlorohydrin. The reaction
of neat epichlorohydrin with an equimolar amount of silylated
imidazole in the presence of a catalytic amount of LiBr (5 mol %)
resulted in clean conversion into the ring-opened product 1, which
on treatment with KF in wet methanol gave the respective alcohol
2 in 82% isolated yield (Scheme 1). Similarly, we also prepared the
optically pure imidazolyl alcohol (R)-2 which was isolated as a
white solid by starting from (R)-epichlorohydrin.13 In contrast,
the racemic imidazolyl alcohol 2 was a viscous colorless liquid.
The progress of the reaction was monitored by 1H NMR spec-
troscopy and showed that 1 was the sole product resulting from
nucleophilic attack at the terminal carbon of the epoxide. No prod-
uct arising from nucleophilic displacement of chlorine could be
detected through NMR and GC–MS analyses of the reaction mix-
ture. We conducted the same reaction in the absence of LiBr to
ascertain its role in the reaction. No significant amount of imidaz-
olyl silyl ether 1 was formed in the absence of LiBr under the same
reaction conditions even after prolonged stirring. It has been
reported that the strong oxophilicity of a lithium ion can activate
oxygen-containing electrophiles to nucleophilic attack.14 We also
conducted the LiBr-catalyzed reaction using 1H-imidazole instead
of silylated imidazole under both solvent-free conditions and in
anhydrous DMF. In both cases the conversion was rather disap-
pointing. Yields of only 20–25% imidazolyl alcohol were obtained
after purification. Therefore, silylated imidazole proved to be a
more effective nucleophile than 1H-imidazole for efficient ring-
opening of epoxides. This might be due to the enhanced nucleophi-
licity of the silylated imidazole. The other advantages in using sily-
lated imidazole are: (i) it is widely soluble in most organic solvents,
(ii) the reaction can be carried out conveniently under solvent-free
conditions, and (iii) it is easy to convert the O-silylated product
into its respective alcohol. We found that a significant amount of
the imidazole silyl ethers were hydrolyzed to their respective alco-
hols during column chromatography using silica gel. Therefore, it
was better to conduct the desilylation step on the crude product
before performing column chromatography in order to obtain the
pure imidazolyl alcohol as the sole product.
R
N
N
LiBr
R
Silyl transfer
LiBr
LiBr
O
O
N
N
R
R
SiMe3
TS 1
-
TS II
-
N
N
SiMe3
Figure 2. A plausible mechanism.
corresponding alcohol 4. The 1H and 13C NMR spectra for 4 were
identical to those reported.5 The formation of the regioisomer 4
was further confirmed by determining the MS (EI) of the crude imid-
azolyl alcohol. In the MS, the presence of a daughter ion at m/z (M+
106) due to the loss of PhCHO from 4 and the absence of a daughter
ion at (M+ 31), a diagnostic feature of the alternative regioisomer,
due to loss of CH2OH, revealed the formation of regioisomer 4,
exclusively. Although the phenyl group in styrene oxide assists in
the stabilization of the carbocationic character at the benzylic
carbon in transition state TS-I (Fig. 2), the preferential attack at
the terminal carbon of styrene oxide can be explained due to the
enhanced nucleophilicity and hard nature of the silylated imidazole
favoring a more SN2-like process.
We next turned our attention to the conversion of an alkyl-
substituted unsymmetric epoxide into the corresponding imidazo-
lyl alcohol using propylene oxide as our model substrate. Reaction
of propylene oxide with silylated imidazole in the presence of a
catalytic amount of LiBr followed by desilylation with KF gave
the corresponding ring-opened product 6 in 68% yield (Scheme
3). Spectroscopic analysis confirmed that no regioisomer was
formed in this reaction.
Next, we evaluated the regioselective outcome of the LiBr-cata-
lyzed epoxide ring- opening with silylated imidazole using styrene
oxide as a representative unsymmetrical epoxide. The reaction un-
der mild heating at 60 °C gave only regioisomer 4 in 78% isolated
yield (Scheme 2). At room temperature the reaction was slow
and required 40 h to complete.
No regioisomer was formed as a result of attack of the nucleo-
phile at the benzylic position. The regioselectivity was determined
by 1H NMR spectroscopy of the crude imidazolyl silyl ether and its
respective alcohol. In both cases, only one set of signals was
Finally, we examined the efficiency of this method to prepare an
imidazolyl alcohol by using a symmetric internal epoxide. An
excellent 81% yield of product 8 was obtained from cyclohexene
oxide on treatment with silylated imidazole under mild heating
at 60 °C in the presence of 5 mol % LiBr (Scheme 4).
observed and that was identified as regioisomer
3 and its

M. Abdul Jalil, S. Md. Masum / Tetrahedron Letters 53 (2012) 3049–3051
3051
Me3Si
OH
O
O
N
N
KF
5 mol% LiBr
neat, rt, 30 h
N
N
+
N
N
Me
Me
Me
SiMe3
MeOH,3 h
5
6 (68%)
Scheme 3. Synthesis of imidazolyl alcohol 6 using an alkyl-substituted unsymmetric epoxide.
SiMe3
OH
O
O
N
N
KF
5 mol% LiBr
+
N
N
MeOH,3 h
neat, 60 °C, 8 h
SiMe3
N
N
7
8 (81%)
Scheme 4. Synthesis of an imidazolyl alcohol using a symmetric internal epoxide.
Process Res. Dev. 2001, 5, 467–471; (d) Pouget, C.; Fagnere, C.; Basly, J. P.;
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The stereochemistry of the ring-opened product 8 was found to
be trans. The spectral data (1H and 13C) were similar to those of the
reported compound.5,15
A plausible mechanism for the LiBr-catalyzed epoxide ring-
opening with silylated imidazole is depicted in Figure 2.
Coordination of the epoxide oxygen to Li+ (TS-I) renders the
epoxide susceptible to nucleophilic attack by the silylated imidaz-
ole leading to TS-II. Subsequent intra or intermolecular silyl trans-
fer resulted in formation of the imidazolyl silyl ether and liberation
of the catalyst.
In conclusion, we have described an efficient general catalytic
method for the preparation of biologically important imidazolyl
alcohols via an epoxide ring-opening reaction. The advantages of
this method are that the reactions are carried out under mild con-
ditions in short times, with excellent stereo- and regioselectivity,
using an inexpensive, user friendly, non-toxic catalyst. The sol-
vent-free reaction conditions combined with simple experimental
and product isolation procedures is expected to contribute to the
development of an environmentally friendly (assuming no toxic
organic solvents are used in the work-up/column chromatography)
process for the synthesis of biologically and catalytically important
imidazolyl alcohols.
7. (a) Arnold, P. L.; Scarisbrick, A. C.; Black, A. J.; Rodden, M.; Wilson, C. Chem.
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9. (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, 1993. Chapter 4.1; (b) Jacobsen, E. N. Ibid. Chapter 4.2.
10. See for examples: (a) Yamamoto, Y.; Asao, N.; Meguro, M.; Tsukade, N.;
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Acknowledgment
11. Glas, H.; Thiel, W. R. Tetrahedron Lett. 1998, 38, 5509.
12. (a) Tanaka, K.; Toda, F. In Solvent-free Organic Synthesis; Wiley-VCH, 2003; (b)
Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159–2169; (c)
Varma, R. S. Pure Appl. Chem. 2001, 73, 193–198; (d) Tanaka, K.; Toda, F. Chem.
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Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975–2978.
We gratefully thank Dr. Tapan Kumar Chakraborti of the Presi-
dency University for his support.
13. Synthesis of (R)-2: A 2-necked flask equipped with a stopper and a rubber
septum was charged with LiBr (0.022 g, 5 mol %) in a glove box. It was then
Supplementary data
connected to
a vacuum line and heat applied using a heating gun with
Supplementary data (synthetic and spectroscopic data for com-
pounds 2, 4, 6, and 8) associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.019.
occasional shaking of the flask in order to accumulate LiBr at the bottom of the
flask. The flask was then filled with N2 and epichlorohydrin (0.46 g, 2.5 mmol)
was added via syringe and the mixture stirred for 10 min. Silyl imidazole
(0.70 g, 2.5 mmol) was added via syringe and stirring was continued for 6 h at
room temperature. KF (2.7 mmol) and MeOH (10 ml) were added and the
mixture stirred for 3 h. The solvents were removed in vacuo and the remaining
oily residue was purified by column chromatography using silica gel (CH2Cl2/
References and notes
MeOH = 9:1). Yield 82% (white solid); mp 89.0–91.0 °C; IR (KBr, cmÀ1
) m; 3117,
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