A novel procedure for conversion of epoxides to α -hydroxyphosphonates with a trialkylphosphite mediated by LiClO4

Article abstract of DOI:10.1016/j.tetlet.2003.09.002

A new method has been developed for the direct conversion of epoxides to α-hydroxyphosphonates by the reaction of a trialkylphosphite with the epoxide in 5 M lithium perchlorate in diethyl ether (LPDE). The reaction is highly regioselective and efficient with excellent yields under mild and neutral conditions.

Full text of DOI:10.1016/j.tetlet.2003.09.002

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7933–7935
A novel procedure for conversion of epoxides to
a-hydroxyphosphonates with a trialkylphosphite mediated
by LiClO4
Najmoddin Azizi and Mohammad R. Saidi*
Department of Chemistry, Sharif University of Technology, PO Box 11365-9516 Tehran, Iran
Received 19 July 2003; revised 21 August 2003; accepted 1 September 2003
Abstract—A new method has been developed for the direct conversion of epoxides to a-hydroxyphosphonates by the reaction of
a trialkylphosphite with the epoxide in 5 M lithium perchlorate in diethyl ether (LPDE). The reaction is highly regioselective and
efficient with excellent yields under mild and neutral conditions.
© 2003 Published by Elsevier Ltd.
Phosphonic acids and their phosphonate derivatives are
of great interest in synthetic organic chemistry due to
their biological activities.1 They are employed in syn-
thetic operations leading to carbonꢀcarbon bond
formation2 and as transition state analogues in produc-
tion of antibody catalysts for a wide variety of reac-
tions.3 a-Hydroxyphosphonates, especially enantio-
merically pure a-hydroxyphosphonates,4 have been
used for the preparation of a-substituted phosphonates
such as a-halophosphonates, and are important inter-
mediates in organic synthesis.5,6 They have been used
for the preparation of a-ketophosphonates,7 1,2-dike-
tones from acid chlorides, a-aminophosphonates, and
ing materials in organic synthesis, due to their high
reactivity9 and easy access. There are many reports on
Lewis acid catalyzed ring-opening reactions of epoxides
with carbon,10 nitrogen,11 phosphite,12 oxygen13 and
other nucleophiles14 in the literature.
Recently, concentrated solutions of lithium perchlorate
in diethyl ether (LPDE) have gained importance as
versatile reaction media for various organic transforma-
tions at room temperature, which are otherwise difficult
to carry out under mild conditions. Several organic
reactions are faster in this medium compared with other
solvents. Moreover, high chemo-, regio-, and stereose-
lectivities have been observed in this medium. The mild
Lewis acidity of the lithium ion in donor solvents such
as diethyl ether is responsible for these selectivities.15 In
continuation of our interest in the application of etheral
solutions of lithium perchlorate,16 as well as in the
chemistry of phosphonate derivatives,17 herein we
are widely used for pharmaceutical applications.8
A
number of synthetic methods for a-hydroxyphospho-
nates have been reported.3,4,8 Although these methods
are useful, to the best of our knowledge, there is no
report in the literature on the conversion of epoxides to
a-hydroxyphosphonates. Epoxides are attractive start-
Scheme 1.
Keywords: epoxide; a-hydroxyphosphonates; trialkylphosphite; lithium perchlorate.
* Corresponding author. Fax: +98-21-601-2983; e-mail: saidi@sharif.edu
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.002

7934
N. Azizi, M. R. Saidi / Tetrahedron Letters 44 (2003) 7933–7935
describe a simple and new protocol for the direct
conversion of epoxides to a-hydroxyphosphonates by
reaction with trialkylphosphites in a 5 M solution of
LPDE under neutral conditions. It has been well estab-
lished that epoxides rearrange to produce carbonyl
compounds15 using 5 M LPDE under neutral reaction
conditions. Thus, when an epoxide was reacted with an
equimolar amount of trimethylsilyl chloride (TMSCl)
and a trialkylphosphite in 5 M LPDE, the a-hydroxy
phosphonate was produced as the sole product. In the
presence of LiClO4/TMSCl, the epoxide would appear
to rearrange faster than nucleophilic addition to the
epoxide (Scheme 1).
various structurally diverse epoxides and trialkylphos-
phite. These results are summarized in Table 1.18,19 The
data in Table 1 clearly shows that different epoxides
were successfully converted into a-hydroxyphospho-
nates in high yields at room temperature with high
regioselectivity and short reaction times. The reactions
were clean and the products were obtained without the
formation of any side-products, such as the direct
nucleophilic addition products that are normally
observed under the influence of Lewis acids.
In conclusion, we present a straightforward LPDE
mediated methodology for the conversion of epoxides
to a-hydroxyphosphonates by reaction with a tri-
alkylphosphite using inexpensive and readily available
reagents under very mild conditions. The present proce-
dure provides a novel, efficient and simple methodology
for the preparation of a-hydroxyphosphonates. Fur-
thermore LiClO4 is not expensive and is stable to
moisture so that it can be recovered and reused after
activation.
In order to optimize the reaction conditions, we investi-
gated the stoichiometry of the reaction. a-Hydroxy-
phosphonate formation was observed almost quantita-
tively by stirring the epoxide (1 equiv.), trimethylsilyl
chloride (1.1 equiv.) and trialkylphosphite (1.2 equiv.)
at room temperature for 15–45 min. The yield of the
a-hydroxyphosphonate was reduced drastically and the
formation of undesired products was observed in the
absence of trimethylsilyl chloride. To show the general-
ity and scope of the LPDE promoted a-hydroxyphos-
phonate synthesis, the reaction was examined with
Further investigations to broaden the scope, synthetic
applications and mechanistic aspects are now underway
in our laboratories.
Table 1. LDPE-promoted synthesis of a-hydroxyphosphonates from epoxides

N. Azizi, M. R. Saidi / Tetrahedron Letters 44 (2003) 7933–7935
7935
Caution: Although we did not have any accident while
using LiClO4, it is advisable to dry lithium perchlorate
in a fume hood using a suitable lab-shield.
14. (a) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Reddy, Ch.
S.; Yadav, J. S. Tetrahedron Lett. 2001, 42, 3955; (b)
Berlin, S.; Ericsson, C.; Engman, L. Org. Lett. 2002, 4, 3.
15. Sankararaman, S.; Nesakumar, J. E. Eur. J. Org. Chem.
2000, 2003.
16. (a) Saidi, M. R.; Azzizi, N.; Naimi-Jamal, M. R. Tetra-
hedron Lett. 2001, 42, 8111; (b) Saidi, M. R.; Azzizi, N.
Tetrahedron: Asymmetry 2002, 13, 2523; (c) Saidi, M. R.;
Azzizi, N. Tetrahedron: Asymmetry 2003, 14, 389; (d)
Azzizi, N.; Saidi, M. R. Tetrahedron Lett. 2002, 43, 4305.
17. (a) Saidi, M. R.; Azzizi, N. Synlett 2002, 1347; (b) Azizi,
N.; Saidi, M. R. Phosphorus Sulfur Silicon 2003, 178,
1255; (c) Azizi, N.; Saidi, M. R. Tetrahedron 2003, 59,
5329.
Acknowledgements
We are grateful to the Sharif University of Technology
Research Council for financial support of this research.
We also thank ‘Volkswagen-Stiftung, Federal Republic
of Germany’ for financial support towards the purchase
of chemicals.
18. Typical procedure: A mixture of the epoxide (2 mmol),
trimethylphosphite or triethylphosphite (2.4 mmol),
TMSCl (2.2 mmol) and 3 mL of 5 M LiClO4 in diethyl
ether were placed in a 50 mL flask under argon and
stirred at room temperature for 15–45 min. After the
reaction was complete, CH2Cl2 (15 mL) was added and
the resulting precipitated LiClO4 was separated by filtra-
tion. The organic layer was washed with water (2×15
mL), dried over MgSO4, and the solvent was removed.
Almost pure product was obtained, further purification
was carried out by column chromatography on basic
alumina eluting with ethyl acetate/hexane, if needed. All
compounds were characterized on the basis of spectro-
scopic data (IR, NMR, MS) and by comparison with
those reported in the literature.
19. Dimethyl 1-(trimethylsiloxy)-2-phenylethanephosphonate:
Oil; IR (CH2Cl2): 1490, 1462, 1258, 1041, cm−1; 1H NMR
(CDCl3, 500 MHz): l 0.25 (s, 9H), 2.94–2.99 (m, 1H),
3.10–3.27 ( m, 1H), 3.72–3.84 (m, 6H), 4.10–4.16 (m, 1H),
7.24–7.40 (m, 5H); 13C NMR (CDCl3, 125 MHz): l 53.1
(d, Jcp=6.9 Hz), 54.2 (d, Jcp=6.8 Hz), 59.1 (d, Jcp=162.2
Hz), 128.6, 129.3, 132.1, 134.2.
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