Convenient and regioselective one-pot solvent-free synthesis of β-hydroxyphosphonates

Article abstract of DOI:10.1080/00397910601033757

A simple, efficient, regioselective, and solvent-free method has been developed for the synthesis of β-hydroxyphosphonates from epoxides and triethyl phosphite using ZnCl2 in high yields under mild conditions. Copyright Taylor & Francis Group, LLC.

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Convenient and Regioselective
One‐Pot Solvent‐Free Synthesis of
ß‐Hydroxyphosphonates
A. R. Sardarian a & Z. Shahsavari‐Fard a
a Chemistry Department, College of Science, Shiraz University, Shiraz, Iran
Published online: 25 Jul 2007.
To cite this article: A. R. Sardarian & Z. ShahsavariFard (2007) Convenient and Regioselective One‐Pot
Solvent‐Free Synthesis of ß‐Hydroxyphosphonates, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:2, 289-295, DOI: 10.1080/00397910601033757
To link to this article: http://dx.doi.org/10.1080/00397910601033757
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Synthetic Communicationsw, 37: 289–295, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601033757
Convenient and Regioselective One-Pot
Solvent-Free Synthesis of
ß-Hydroxyphosphonates
A. R. Sardarian and Z. Shahsavari-Fard
Chemistry Department, College of Science, Shiraz University
Shiraz, Iran
Abstract: A simple, efficient, regioselective, and solvent-free method has been
developed for the synthesis of b-hydroxyphosphonates from epoxides and triethyl
phosphite using ZnCl2 in high yields under mild conditions.
Keywords: epoxides, b-hydroxyphosphonates, triethyl phosphite, ZnCl2
Phosphonic acid and analogues of naturally occurring phosphonates have
attracted considerable interest as potential regulators, mediators, or inhi-
bitions of metabolic processes.[1] b-Hydroxyphosphonates have a number
of properties that make them attractive as herbicides, horticulture agents,
antioxidants, and moisture-resistant compounds.[2] These properties have
simulated a recent resurgence of interest in the chemistry of such
compounds.
The easy availability of epoxides from polyhydroxylic and unsaturated
compounds, and the stereochemistry of their reactions, make them among
the most attractive starting materials in organic synthesis. Although a
number of reports have appeared on ring-opening reactions of epoxides
involving carbon, nitrogen, oxygen, and sulfur nucleophiles, surprisingly
very few examples are known in the literature about ring opening of
epoxides with trialkyl phosphites and dialkyl phosphite salts.
Received in the U.K. February 2, 2006
Address correspondence to A. R. Sardarian, Chemistry Department, College of
Science, Shiraz University, Shiraz 71454, Iran. E-mail: sardarian@susc.ac.ir
289

290
A. R. Sardarian and Z. Shahsavari-Fard
Although alkylphosphonates are easily accessible by the Arbuzov
reaction of alkyl halides with phosphite esters,[3] a similar methodology
fails to provide the title compounds from the reaction of phosphite esters
with epoxides because they tend to undergo elimination reactions leading to
the formation of olefins and cyclopropanes.[4] The methods for preparing
these compounds including reduction of b-ketophosphonates,[5] oxidation of
b-H in alkylphosphonates,[6] hydrolysis of acyl derivatives,[7] reaction of
some Grignard reagents with b-ketophosphonates,[8] and nucleophilic ring-
opening reaction of epoxides by trialkyl phosphite[9] and lithium diethyl
phosphite.[10] All these methods suffer from some drawbacks: multistep
reactions, low yields, hard workup, side products, and use of excess of
epoxides, strong bases, and solvents.
In this report, the b-hydroxyphosphonates are obtained by complete
regioselective phosphorylation of epoxides with triethyl phosphite in the
presence of ZnCl2 under mild conditions, (Scheme 1).
Various epoxides with different substitutents on the 2 and 3 positions are
studied, and the results, in Table 1, show that triethyl phosphite attacks the
epoxide ring even in the presence of functional groups susceptible to
Arbuzov reaction and Micheal addition, the epoxides of 1b, c, respectively.
Also, it preferentially attacks the less crowded position on the epoxide ring
in all cases, and olefin is not observed as by-product.
This regioselectivity may be interpreted on the basis of less stability of the
transition state of B in comparison to the transition state of A due to the steric
repulsion between the ethoxy groups of triethyl phosphite and the substituents
on the more substituted carbon atom in the former (Scheme 2).
The general procedure followed is addition of ZnCl2 to an equimolar
amount of triethyl phosphite and epoxide. The mixture is stirred for 5–
150 min at 608C. After cooling, 30 mL of ethyl acetate is added to the
reaction mixture, which is then filtered. The desire products are purified by
plate chromatography with n-hexane and ethyl acetate to give the pure
product as a viscous liquid in quantitative yields. All products give satisfac-
tory spectral data in accordance with the assigned structures and known litera-
ture data.[8b,10c,11a–b]
In summary, regioselective one-pot reaction, solvent-free conditions,
high yields, simple workup, mild conditions, relatively ease, low cost, and
cleanliness makes this method an attractive and useful contribution to the
Scheme 1.

Solvent-Free Synthesis of ß-Hydroxyphosphonates
291
Table 1. Reaction of (EtO)3P with epoxides in the presence of ZnCl2 at 608C via
Scheme 1
Reaction
time
(min.)
Yielda
(%)
Entry
a
Starting materials
Products
5
94
b
c
15
10
95
90
d
e
30
35
86
90
f
120
95
g
h
120
120
90
97
i
150
89
aIsolated yields.
present methodologies. Indeed, a wide range of epoxides are converted to the
corresponding b-hydroxyphosphonates using this method. Further investi-
gations on this reaction are now in progress.
EXPERIMENTAL
General
1H NMR and 13C NMR spectra were measured on a Bruker Advance DPX FT
250 instrument at 62.9 MHz with TMS as an internal standard. IR spectra were
obtained on Perkin-Elmer or FTIR-800 instruments. Mass spectra were
obtained on a Shimadzu GCMS0QP 1000EX at 20 and/or 70 eV.

292
A. R. Sardarian and Z. Shahsavari-Fard
Scheme 2.
Preparation of b-Hydroxyphosphonates (2)
ZnCl2 (2 mmol) is added to a mixture of (EtO)3P (2 mmol) and epoxide
(2 mmol). The mixture is stirred at 608C for 5–150 min. After cooling,
30 mL of ethyl acetate is added to the reaction mixture, which is then
filtered. The product is purified by plate chromatography with n-hexane and
ethyl acetate (5 : 5–1 : 9) to give the pure product as a viscous liquid in 86–
95% yield.
Diethyl 2-Hydroxy-2-phenylethylphosphonate (2a)[8b]
1
Bp: 1888C; H NMR (CDCl3): d 1.29 [6H, m, PO(OCH2CH3)2], 2.35 (1H,
ddd, J ¼ 6.4, 15.3, 18.9, CHHP), 3.05 (1H, ddd, J ¼ 6.1, 15.2, 18.4, CHHP)
and 4.18 [5H, m, PO(OCH2CH3) 2, CHOH], 7.31 (5H, m, H aroma);
13C NMR (CDCl3): d 16.44 [PO(OCH2CH3)2], 35.92 (d, J ¼ 136, CH2P),
64.53 (CHOH), 67.13 [PO(OCH2CH3)2], 125.50, 128.19, 128.51, 133.44 (C
aroma); IR (neat, cm21): 3363.6 (-OH), 2985.6 (Ar), 1242.1 (P55O), 1049.2
and 972.1 (Et-O), 794.6 (P-O); MS (EI): m/z (%) 258 (Mþ, 5.6), 257
(M 2 1, 40.8), 240, 201, 185, 167, 138, 104, 77 (100), 64, 43.
Diethyl 2-Hydroxy-3-phenoxypropylphosphonate (2b)[10a]
1
Bp: 1798C; H NMR (CDCl3): d 1.36 [6H, m, PO(OCH2CH3)2], 2.28 (1H,
ddd, J ¼ 5.9, 15.4, 18.8, CHHP), 2.36 (1H, ddd, J ¼ 6.1, 15.5, 18.7,
CHHP), 3.99 (2H, m, OCH2CHOH), 4.22 [4H, m, PO(OCH2CH3)2], 4.47
(1H, m, CHOH), 6.97 (3H, m, H aroma), 7.26 (2H, m, H aroma); 13C NMR
(CDCl3): d 16.14 [PO(OCH2CH3)2], 30.2 (d, J ¼ 143.65, CH2P), 63.76
(CH-OH), 65.05 [PO(OCH2CH3)2], 71.37 (CH2OPh), 114.55, 121.21,
129.50, 158.27 (C aroma); IR (neat, cm21): 3426.8(-OH), 2986.5 (Ar),
1422.0 (P55O), 1150.0 and 1095.0 (Et-O), 900.0 (P-O); MS (EI): m/z (%)
289 (M þ 1, 11.7), 288 (Mþ, 0.6), 270, 181, 138, 153, 125 (100), 94, 77, 43.

Solvent-Free Synthesis of ß-Hydroxyphosphonates
293
3-(Diethylphosphoryl)-2-hydroxypropyl methacrylate (2c)
Bp: 1458C; 1H NMR (CDCl3): d 1.34 [6H, m, PO(OCH2CH3)2], 1.96 (3H, s,
C55CCH3), 2.24 (1H, ddd, J ¼ 6.4, 15.1, 18.5, CHHP), 2.63 (1H, ddd,
J ¼ 6.4, 15.2, 18.7, CHHP), 3.66 (1H, m, CHOH), 4.27 [4H, m,
PO(OCH2CH3)2], 4.46 (2H, m, OCH2CHOH), 5.62 (1H, s, C55CHH), 6.17
(1H, s, C55CHH); 13C NMR (CDCl3): d 15.09 [PO(OCH2CH3)2], 17.15
(C55CCH3), 35.70 (d, J ¼ 144.7, CH2P), 64.19 [PO(OCH2CH3)2], 76.65
(OCH2CHOH), 123.61 (C55CCH3), 135.55 (C55CCH3), 168.23 (C55O); IR
(neat, cm21): 3386.8 (-OH), 1720.4 (C55O), 1635.5 (C55C), 1180.4 (P55O),
1026.1 and 970.0 (Et-O): MS (EI): m/z (%) 280 (Mþ, 0.8), 279, 262, 143,
137, 64, 43 (100).
Diethyl 3-Chloro-2-hydroxypropylphosphonate (2d)
1
Bp: 1618C; H NMR (CDCl3): d 1.36 [6H, m, PO(OCH2CH3)2], 2.23 (1H,
ddd, J ¼ 6.1, 15.3, 17.8, CHHP), 2.29 (1H, ddd, J ¼ 5.80, 15.4, 17.5,
CHHP), 3.61 (1H, J ¼ 5.25, 7.8, ClCHH), 3.66 (1H, dd, J ¼ 5.25, 7.8,
ClCHH), 4.22 [4H, m, PO(OCH2CH3)2], 4.43 (1H, m, CHOH); 13C NMR
(CDCl3): d 15.01 [PO(OCH2CH3)2], 29.43 (d, J ¼ 144.5, CH2P), 49.2
(CH2Cl), 63.70 (CHOH), 66.01 [PO(OCH2CH3)2]; IR (neat, cm21): 3433.1
(-OH), 1396.4 (CH2-Cl), 1195.8 (P55O), 1026.1 and 972.1 (Et-O), 833.2
(P-O), 694.3 (C-Cl); MS (EI): m/z (%) 231 (M þ 1, 0.3), 230 (Mþ), 195,
213, 125 (100), 107, 81, 65, 41.
Diethyl 2-Hydroxycyclohexylphosphonate (2e)[9c]
1
Bp: 1428C; H NMR (CDCl3): d 1.25 [8H, m, PO(OCH2CH3)2], CH2), 1.68
(2H, m, CH2), 1.86 (2H, m, CH2), 2.01 (2H, m, CH2), 3.65 (1H, m, CHP),
4.13 [4H, m, PO(OCH2CH3)2], 4.43 (1H, m, CHOH); 13C NMR (CDCl3):
d 16.34 [PO(OCH2CH3)2], 22.91, 25.12, 25.21, 34.87 (C cyclohexyl), 43.22
(d, J ¼ 138.5, CHP), 62.74 (CHOH), 68.97 [PO(OCH2CH3)2]; IR (neat,
cm21): 3425.3 (-OH), 1226.6 (P55O), 1026.1 and 972.1 (Et-O), 794.6
(P-O); MS (EI): m/z (%) 236 (Mþ,4.7), 218, 165, 137, 109, 82, 44 (100).
Diethyl 2-Hydroxy-3-isopropoxypropylphosphonate (2f)[10]
Bp: 1528C; 1H NMR (CDCl3): d 0.98 [6H, d, J ¼ 5.95, CH (CH3)2], 1.15 [6H,
m, PO(OCH2CH3)2], 1.95 (1H, ddd, J ¼ 5.9, 15.1, 17.8, CHHP), 2.02 (1H,
ddd, J ¼ 6.0, 15.3, 17.9, CHHP), 3.26 (1H, d, J ¼ 5.7), 3.42 (1H, m,
CHOH), 4.02 [4H, m, PO(OCH2CH3)2], 4.32 (2H, m, OCH2CHOH);
13C NMR (CDCl3): d 16.03 [PO(OCH2CH3)2], 21.78 (CH(CH3)2], 29.64

294
A. R. Sardarian and Z. Shahsavari-Fard
(d, J ¼ 142.78, CH2P), 63.45 (CHOH), 65.39 [PO(OCH2CH3)2], 71.17
[OCH(CH3)2], 72.22 (OCH2CHOH); IR (neat, cm21): 3426.3 (-OH), 1369.4
(P55O), 1165.9 and 1028.0 (Et-O), 807.2 (P-O); MS (EI): m/z (%) 255
(M þ 1, 12.6), 236, 181, 153, 125, 81, 64, 43 (100).
Diethyl 3-(Allyloxy)-2-hydroxypropylphosphonate (2g)
1
Bp: 1598C; H NMR (CDCl3): d 1.35 [6H, m, PO(OCH2CH3)2], 2.18 (1H,
ddd, J ¼ 6.46, 15.4, 17.5, CHHP), 2.25 (1H, ddd, J ¼ 6.47, 15.3, 17.7,
CHHP), 3.47 (2H, d, J ¼ 5.0, OCH2CHOH), 3.72 (1H, m, CHOH), 4.04
(2H, d, J ¼ 5.6, C55CCH2O), 4.27 [4H, m, PO(OCH2CH3)2], 5.19 (1H, dd,
J ¼ 1.8, 11.25, HHC55C), 5.27 (1H, dd, J ¼ 2.0, 17.25, HHC55C), 5.86
(1H, m, HC55CH2); 13C NMR (CDCl3): d 16.19 [PO(OCH2CH3)2], 30.06
(d, J ¼ 143.8, CH2P), 63.93 (CHOH), 65.35 [PO(OCH2CH3)2], 72.27
(C55CCH2), 73.75 (OCH2CHOH), 117.52(CH255CH), 134.22 (H2C55CH);
IR (neat, cm21): 3400.0 (-OH), 1452.5 (P55O), 1020.8 and 978.0 (Et-O),
920.0 (P-O); MS (EI): m/z (%) 252 (Mþ, 0.1), 234, 167, 149 (100), 138,
80, 57, 43.
Diethyl 2-Hydroxy-1-methoxy-2-methylpropylphosphonate (2h)
Bp:1818C; 1H NMR (CDCl3): d 1.01 [6H, m, C(CH3)2], 1.13 [6H, m,
PO(OCH2CH3)2], 2.94 (1H, d, J ¼ 39.82, CHP), 3.58 [4H, m,
PO(OCH2CH3)2], 4.66 (3H, s, OCH3); 13C NMR (CDCl3): d 15.10
[PO(OCH2CH3)2], 17.15 [C(CH3)2], 65.34 [C(CH3)2], 65.57 (OCH3), 67.95
[PO(OCH2CH3)2], 76.95 (d, J ¼ 141.5, CHP); IR (neat, cm21): 3241.2
(-OH), 1210.2 (P55O), 1027.0 and 978.8 (Et-O), 798.0 (P-O); MS (EI): m/z
(%) 240 (Mþ, 0.2), 239, 222, 103, 85, 64 (100), 43.
Diethyl 2-Hydroxydec-9-enylphosphonate (2i)
Bp: 1698C; 1H NMR (CDCl3): d 1.27–1.75 [18H, m, PO(OCH2CH3)2,
-(CH2)6-], 1.98 (2H, m, CH2P), 4.21 [4H, m, PO(OCH2CH3)2], 3.75–4.48
(1H, m, CHOH), 4.82 (1H, d, J ¼ 10.28, HHC55CH), 4.87 (1H, d,
J ¼ 15.28, HHC55CH), 5.86 (1H, m, HHC55CH); 13C NMR (CDCl3):
d 15.06 [PO(OCH2CH3)2], 17.08 (CH2), 26.71 (CH2), 26.82 (CH2), 28.67
(CH2), 29.69 (d, J ¼ 125.35, CH2P), 33.50 (CH2), 33.94 (CH2), 61.30
(CHOH), 63.66 [PO(OCH2CH3)2], 114.03 (CH255CH), 137.53 (CH255CH);
IR (neat, cm21): 3452.3 (-OH), 1190.0 (P55O), 1028.0 and 980.0 (Et-O),
720.0 (P-O); MS (EI): m/z (%) 292 (Mþ, 0.2), 274, 181, 155, 125, 81, 64,
41 (100).

Solvent-Free Synthesis of ß-Hydroxyphosphonates
ACKNOWLEDGMENT
295
We gratefully acknowledge the support of this work by the Shiraz University
research council.
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