Epoxidation of phosphinoyl alkenes with hydrogen peroxide

Article abstract of DOI:10.1016/j.tetlet.2005.11.083

The epoxidation of alkenylphosphorus compounds with hydrogen peroxide was systematically studied, revealing that while alkenylphosphine oxides failed to produce the corresponding epoxides, alkenylphosphonates, or phosphinates having a phenyl group at α-po

Full text of DOI:10.1016/j.tetlet.2005.11.083

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 421–424
Epoxidation of phosphinoyl alkenes with hydrogen peroxide
Yutaka Ono and Li-Biao Han*
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
Received 18 October 2005; revised 15 November 2005; accepted 17 November 2005
Available online 2 December 2005
Abstract—The epoxidation of alkenylphosphorus compounds with hydrogen peroxide was systematically studied, revealing that
while alkenylphosphine oxides failed to produce the corresponding epoxides, alkenylphosphonates, or phosphinates having a phenyl
group at a-position reacted with H2O2/K2CO3 or alkenylphosphonic acids or phosphinic acids having an aliphatic group at a- or
b-positions reacted with H2O2/Na2WO4/Et3N to produce high yields of the corresponding epoxides.
Ó 2005 Elsevier Ltd. All rights reserved.
Phosphinoyl epoxides 1 are an important class of com-
[P]
R
pounds in bioorganic chemistry. For example, fosfo-
mycin (R2 = Me; R1 = R3 = H; [P] = P(O)(OH)2) is a
famous antibiotic, which is widely used clinically.1 They
are also important synthetic intermediates for the prepa-
ration of various bioactive compounds.2 A straightfor-
ward method for their preparation is the direct
epoxidation of the corresponding alkenyl phosphorus
compounds.3 Thus, epoxidation of some alkenyl phos-
phorus compounds with NaOCl,4 carboxylic peracid,5
R
[P]
2: [P] = P(O)(OMe)2
3: [P] = P(O)(OH)2
4: [P] = P(O)Ph2
5: [P] = P(O)Ph(OEt)
6: [P] = P(O)Ph(OH)
2′: [P] = P(O)(OMe)2
3′: [P] = P(O)(OH)2
4′: [P] = P(O)Ph2
5′: [P] = P(O)Ph(OEt)
6′: [P] = P(O)Ph(OH)
a: R = Ph, b: R = n-C6H13, c: R = H
Scheme 1. A series of alkenylphosphorus compounds.
t
CF3CO3H,6 dioxirane,7 BuOOH,8 etc.9 have been
reported. However, a systematic investigation on the
epoxidation of alkenyl phosphorus compounds (phos-
phonates, phosphinates, and phosphine oxides) has not
been performed, partly due to the lack of these chemi-
cals. For example, the epoxidation of alkenylphosphi-
nates is not known. Hydrogen peroxide H2O2 is a
clean oxidant.10 The epoxidation of alkenyl phosphinoyl
compounds using H2O2, however, is rather limited.11
We have recently developed a catalytic method for the
selective preparation of alkenylphosphorus com-
pounds.12 Now we wish to report a systematic study
on the epoxidation of these phosphorus compounds
with H2O2 (Scheme 1), revealing that the epoxidation
is strongly structure depending.
The epoxidation of alkenylphosphonic acids and their
esters with H2O2 was investigated first. In the case of
the gem-alkenes (2), we found that dimethyl (1-phenyl-
ethenyl)phosphonate (2a; [P] = P(O)(OMe)2, R = Ph)
could be successfully epoxidized by a mixture of 30%
H2O2 (8.8 equiv) and K2CO3 (1 equiv) in EtOH at room
temperature to give the desired epoxide in 70% yield
(Scheme 2).11a–e,13 Similar reactions using other bases
such as NaOH, NaHCO3, and Et3N did not give satis-
factory results.
Ph
Ph
H2O2, K2CO3
O
P(O)(OMe)2
P(O)(OMe)2
1a, 70% yielda
EtOH
R2
R1
[P]
R3
room temperature
2a
NaOH, noneb; NaHCO3, nonec; Et3N, nonec
O
1, [P] = a phosphinoyl (P(O)) group
Scheme 2. Epoxidation of dimethyl (1-phenylethenyl)phosphonate.
Conditions: 2a (1 mmol), base (1 mmol), 30% aqueous H2O2 (1 mL,
8.8 mmol), EtOH (1 mL), room temperature, 16 h: (a) determined by
31P NMR; (b) EtOCH2CH(Ph)P(O)(OMe)2 was formed quantitatively;
(c) no reaction.
Keywords: Phosphinoyl epoxide; Epoxidation; Hydrogen peroxide.
Corresponding author. Tel.: +81 29 861 4855; fax: +81 29 861
4511; e-mail: libiao-han@aist.go.jp
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.083

422
Y. Ono, L.-B. Han / Tetrahedron Letters 47 (2006) 421–424
Surprisingly, when the Ph group of 2a was replaced by
an alkyl group n-C6H13 (2b; [P] = P(O)(OMe)2, R = n-
C6H13), the epoxidation did not proceed at all under
similar reaction conditions. Compound 2b remained
unchanged even after heating at 60 °C for 2 days. This
difference in reactivity between 2a and 2b might be due
to the electron-donating character of n-C6H13 and the
lack of its ability for stabilizing the intermediate anion
formed via the nucleophilic attack of HOOꢀ to the dou-
ble bond.11a–e,13
that this tungstate can catalyze the epoxidation of phos-
phonic acids but not their esters, that is, a similar treat-
ment of 2b resulted in a complete recovery of the
substrate.15
The reactions of the trans-alkenes 20 did not completely
comply with the reaction patterns of their corresponding
gem-alkene counterparts 2. Thus, no epoxidation took
place with dimethyl (2-phenylethenyl)phosphonate
(20a; [P] = P(O)(OMe)2, R = Ph) and dimethyl (1-octen-
yl)phosphonate (20b; [P] = P(O)(OMe)2, R = n-C6H13)
under the reaction conditions of Scheme 2.16 For these
substrates, the H2O2/Na2WO4/Et3N system (Table 1)
was also not effective. Although the tungstate catalyzed
epoxidation of phosphonic acid 30b ([P] = P(O)(OH)2,
R = n-C6H13) under the reaction conditions of Table 1
(run 11) could produce (2-hexyloxiranyl)phosphonic
acid (1b0) in 97% yield,17 a similar reaction with
30a ([P] = P(O)(OH)2, R = Ph) gave a complicated
mixture.
Since a tungstate is a common catalyst for the epoxida-
tion of electron-rich alkenes with H2O2,14 we thought
that this tungstate-catalyzed epoxidation should be
applicable to that of 2b. Disappointingly, however, this
strategy did not work at all. Remarkably, however,
instead of 2b, when its corresponding phosphonic acid
(3b; [P] = P(O)(OH)2, R = n-C6H13) was employed as
the substrate, the epoxidation proceeded efficiently.
Thus, 3b reacted with 1 equiv of 30% aqueous H2O2 in
the presence of Na2WO4 (1 mol %) and a catalytic
amount of Et3N (0.5 equiv) at room temperature to give
the corresponding epoxide in 93% yield (Table 1, run
11). The reaction is highly affected by the amounts of
tungstate, Et3N and H2O2 used as shown in Table 1.
For example, when an equimolar ratio of Et3N was
employed (run 5), the epoxidation became sluggish,
although a similar reaction using 20 mol % tungstate
catalyst and 1 equiv of Et3N gave 99% yield of 1b (run
1). On the other hand, reducing the amount of Et3N
to 0.1 mol equiv lowers the yields of 1b, particularly in
cases when less H2O2 was employed (compare runs 6,
9, and 11 with runs 7, 10, and 12). High loadings of
the tungstate catalyst did not always give good results.
As the loading of tungstate increased (>5 mol %), the
yields of 1b decreased (runs 2–4), probably due to the
decomposition of the epoxide formed. It is noted again
Finally, unsubstituted vinylphosphonate 2c ([P] = P(O)
(OEt)2, R = H) reacted quite differently (Scheme 3).
Thus, diethyl vinylphosphonate under the reaction con-
ditions of Scheme 2 (H2O2/base) only gave a trace
amount of epoxide. The main product (up to 87% yield)
was, interestingly, a monoester of hydroxyethylphos-
phonic acid 7.18 Changing the solvent to MeOH, iPrOH,
tBuOH, H2O, THF, and acetone, or changing the
base to K2CO3, NaOMe, NaOEt, NaOtBu, Ca(OH)2,
CaCO3, and CaO, all gave a similar result.
Phosphinates 5–60 display a similar reaction pattern to
their phosphinates counterparts. Thus, ethyl phenyl-
(1-phenylethenyl)phosphinate (5a; [P] = P(O)Ph(OEt),
R = Ph), but not 2-octenylphosphinate (5b; [P] = P(O)-
Ph(OEt), R = n-C6H13), was successfully epoxidized
under the conditions of Scheme 2 to give 70% yield of
phenyl(1-phenyloxiranyl)phosphinate (1c) as a 1:1 dia-
stereomeric mixture.19 To the best of our knowledge,
this is the first synthesis of such a phosphinyloxirane.
In a similar manner, treatment of alkenylphosphinic
acids having a a-n-C6H13 (6b) or b-n-C6H13 group
(60b) under the conditions of H2O2/Na2WO4/Et3N sys-
tem (Table 1, run 11) gave the corresponding epoxides
1d and 10d in 62% and 71%, respectively. However, simi-
lar to phosphonic acids, b-Ph phosphinic acid 60a did
not give the corresponding epoxide by the treatment
with H2O2/Na2WO4/Et3N.20
a
Table 1. Epoxidation of 3b with H2O2
C6H13
P(O)(OH)2
3b
C6H13
30% H2O2
O
P(O)(OH)2
Na2WO4
base
1b
tBuOH, RT, 16 h
Run
Na2WO4
(mol %)
Et3N
(equiv)
H2O2
(equiv)
Conversionb
(%)
Yieldb
(%)
1
2
3
4
5
6
7
8
20
20
10
5
1
1
1
1
1
1
1
9
9
9
9
9
9
9
9
4
4
1
1
100
100
100
100
7
100
99
82
99
5
15
44
0
83
75
33
73
26
93
57
0.5
0.5
0.5
1
0.5
0.1
0.05
0.5
0.1
0.5
0.1
In sharp contrast to these alkenylphosphonates and
alkenylphosphinates, alkenyl phosphine oxides (4 and
40; [P] = P(O)Ph2, R = Ph or n-C6H13) did not react with
H2O2 under similar reaction conditions. The unsubsti-
9
95
97
94
10
11
12
30% H2O2
NaOH
O
P
HO
OR'
OH
P(O)(OR')2
1
1
92
2c
7
a Conditions: 3b (0.5 mmol) in tBuOH (0.5 mL), room temperature,
16 h.
b The conversion of the starting material and the yield of the product
were determined by 31P NMR.
Yield: R = Me, 72%; R = Et, 87%; R = i-Pr, 65%
Scheme 3. Conditions: 2c (1 mmol), NaOH (1 mmol), 30% H2O2
(1 mL, 8.8 mmol), EtOH (1 mL), room temperature, 20 h.

Y. Ono, L.-B. Han / Tetrahedron Letters 47 (2006) 421–424
423
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In summary, the epoxidation of alkenylphosphorus
compounds with H2O2 is highly affected by the substit-
uents of the phosphorus compounds. By using H2O2/
K2CO3, epoxidation takes place efficiently with alken-
ylphosphonates or phosphinates having a phenyl group
at a-position (2a and 5a, R = Ph), and by using H2O2/
Na2WO4/Et3N, epoxidation takes place efficiently with
alkenylphosphonic acids21 or phosphinic acids having
an aliphatic group at a- or b-positions (3b, 30b, 6b,
and 60b, R = n-C6H13). Alkenylphosphine oxides did
not produce the corresponding epoxides under similar
conditions. These results, to some extent, resemble the
early observations on the epoxidation of a,b-unsatu-
rated carbonyl compounds,15 which deserve future
mechanistic exploration.
11. Hydrogen peroxide epoxidation of the vinylphospho-
¨
nates bearing carbonyl group: (a) Ohler, E.; Zbiral, E.;
El-Badawi, M. Tetrahedron Lett. 1983, 24, 5599; (b)
¨
Ohler, E.; El-Badawi, M.; Zbiral, E. Chem. Ber. 1985,
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McKenna, C. E. J. Org. Chem. 1995, 60, 7080; (e) Page,
P. C. B.; McKenzie, M. J.; Gallagher, J. A. Synth.
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Glamkowski, E. J.; Gal, G.; Purick, R.; Davidson, A. J.;
Sletzinger, M. J. Org. Chem. 1970, 35, 3510; (g) Wang,
X.-Y.; Shi, H.-C.; Sun, C.; Zhang, Z.-G. Tetrahedron
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Acknowledgements
This work was supported by New Energy and Industrial
Technology Development Organization (NEDO) of
Japan (Industrial Technology Research Grant Program
in 2004).
12. Han, L.-B.; Zhang, C.; Yazawa, H.; Shimada, S. J. Am.
Chem. Soc. 2004, 126, 5080, and references cited therein.
13. Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665.
14. (a) Mimoun, H. In The Chemistry of Functional Groups,
Peroxides; Patai, S., Ed.; John Wiley and Sons: Chiches-
ter, 1983, Chapter 15; (b) Jorgensen, K. A. Chem. Rev.
1989, 89, 431. Although the reaction mechanism for the
tungstate catalyzed epoxidation with H2O2 is quite com-
plicated and details have not been fully understood, the
reaction is believed to proceed via intermediates of peroxo
tungsten complexes (see also Ref. 10).
Supplementary data
1
Detailed experimental procedures and copies of H and
13C spectra of the phosphinoyl epoxides. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2005.11.083.
15. Similar tungstate catalyzed epoxidation of a,b-unsatu-
rated carboxylic acids with H2O2 is known to be affected
by a lot of factors such as pH (the addition of a base) and
concentration, under which a complex of different tung-
state species exhibiting different catalytic activities are
believed to be produced (a) Payne, G. B.; Williams, P. H.
J. Org. Chem. 1959, 24, 54; (b) Kirshenbaum, K. S.;
Sharpless, K. B. J. Org. Chem. 1985, 50, 1979; (c) Shi,
H.-C.; Chen, G.; Wang, X.-Y.; Zhang, Z.-G. J. Mol.
Catal. A: Chem. 2004, 216, 29.
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16. The difference of the reactivity between 2a and 20a may be
due to the fact that the resulting anionic intermediate
ꢀ
generated by the addition of HO2 could be more
stabilized in case of 2a. However, a steric effect may be
also contributing since DFT calculations (HF/
6-311G(2d,p)//B3LYP/6-31G(d) level of theory) showed
lower LUMO of 20a (1.96 eV) than that of 2a (2.58 eV)
which excludes the possibility of lacking of electrophilicity
of 20a.
17. Retention of the trans configuration during present
3
reaction was confirmed on the basis of JHH value
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Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1982,
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(ꢁ3 Hz) of two adjacent oxirane ring protons on the
products, which are typical of trans-substituted phos-
phoryl oxiranes (Ref. 7b) (see Supplementary data).
18. It was noted, however, that in the absence of H2O2 no
reaction took place between 2c and NaOH, indicating
that H2O2 is necessary for the formation of 7 under the
present conditions. Thus, the b-addition of HOOꢀ to the
carbon–carbon double bond must proceed. The inter-
mediate might be unstable or decomposed before the
oxirane ring was formed. Vinylphosphonic acid could
be epoxidized in the presence of a tungstate salt (40%
yield).
7. (a) Cristau, H.-J.; Mbianda, X. Y.; Geze, A.; Beziat, Y.;
Gasc, M.-B. J. Organomet. Chem. 1998, 571, 189; (b)
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424
Y. Ono, L.-B. Han / Tetrahedron Letters 47 (2006) 421–424
19. The 31P NMR spectrum of the product in CDCl3 displays
two peaks at d 32.8 and 35.7 with an integral ratio of 1:1
(see Supplementary data).
was formed directly from the oxidation of the alkene.
Transition metal-catalyzed oxidation of alkenes to ketones
with H2O2 is well known (Ref. 14).
20. Instead, ketone 8 was obtained.
O
21. The trisubstituted alkenes (trans-phosphinic acids) are also
successfully epoxidided to the corresponding oxiranes
under the conditions of run 11 Table 1.
Ph
Ph
P
OH
O
R
R
8
30% H2O2
O
Although a pinacol type rearrangement of epoxyphosph-
onates to the aldehydes via phosphorus migration medi-
ated by an acid or heat is known ( Churi, R. H.; Griffin, C.
E. J. Am. Chem. Soc. 1966, 88, 1824), we assume that 8
R
R
P(O)(OH)2
P(O)(OH)2
Na2WO4
Et3N
R = nC3H7: 81%
R = Ph: 87%