Dioxirane oxidation of 2-Aryl-1-vinyl-1, 1-diphosphane dioxide: A convenient approach for the synthesis of novel 1,2-epoxy-2-aryl ethylgembisphosphonates

Article abstract of DOI:10.1002/hc.21084

The synthesis of tetraethyl 1,2-epoxy-2-aryl ethylgembisphosphonates by direct epoxidation of 2-aryl,vinyl-1,1-diphosphonate derivatives with ethyl methyldioxirane generated in situ from potassium hydrogen monopersulfate (caroate) and butanone in a phase

Full text of DOI:10.1002/hc.21084

Heteroatom Chemistry
Volume 24, Number 3, 2013
Dioxirane Oxidation of 2-Aryl-1-vinyl-1,
1-diphosphane Dioxide: A Convenient
Approach for the Synthesis of Novel
1,2-Epoxy-2-aryl Ethylgembisphosphonates
Marthe Carine Djuidje Fotsing,1 Neil Coville,2
and Xavier Yangkou Mbianda1
1Department of Applied Chemistry, University of Johannesburg, Doornfontein Campus,
Johannesburg 2028, South Africa
2Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
Johannesburg 2050, South Africa
Received 25 October 2012; revised 11 February 2013
particular importance owing to their use as valu-
ABSTRACT: The synthesis of tetraethyl 1,2-epoxy-2-
able building blocks in the synthesis of bioac-
aryl ethylgembisphosphonates by direct epoxidation of
tive substances [4] and as polymer modifiers [
2-aryl,vinyl-1,1-diphosphonate derivatives with ethyl
5, 6]. One of the most general and convenient ap-
methyldioxirane generated in situ from potassium hy-
proaches for the preparation of these compounds is
drogen monopersulfate (caroate) and butanone in a
through the direct oxidation of the corresponding
phase transfer system is reported. The epoxides were
vinylphosphonates [7]. However, the epoxydation
isolated in excellent yields and fully characterized by
of 1,2-alkenyl phosphonates using the traditional
ꢀC
spectral and microanalytical data. 2013 Wiley Pe-
epoxidation reagents (electrophilic peracids or nu-
cleophilic peroxides) generally gives poor results,
due to the electron-withdrawing effect of the phos-
phoryl group on the carbon in the α-position, re-
sulting in a relatively weak electrophilicity of the
double bond and also to the appearance of compet-
ing side reactions (Michael addition, ring opening
of the formed epoxide, isomerization, etc.) [5–7].
As an alternative method free from these limita-
tions, we previously proposed the oxidation reac-
tion with dioxiranes as a simple and efficient route
for the obtention of 1,2-epoxyalkylphosphonates [
8]. The reaction proceeded regioselectively in mild
conditions, with moderate to good yield. We have
now applied this reaction to the epoxidation of
substituted vinylgembisphosphonates, and we wish
to report here our preliminary results on the syn-
thesis of 2-aryl-1,2-epoxyethylgembisphosphonate.
To the best of our knowledge, the epoxidation of
riodicals, Inc. Heteroatom Chem 24:234–241, 2013;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21084
INTRODUCTION
Epoxides are interesting versatile intermediate
reagents in organic synthesis, because the open-
ing of their ring with different nucleophiles read-
ily leads to diverse 1,2-difunctional systems in a
regioselective manner [1–3]. Epoxides with phos-
phoryl substituents on the α-carbon atom are of
Correspondence to: X. Y. Mbianda; e-mail: mbianday@uj.ac.za.
Contract grant sponsor: Organization for Women in Science for
the Developing World.
Contract grant sponsor: National Research Foundation.
ꢀC
2013 Wiley Periodicals, Inc.
234

Dioxirane oxidation of 2-Aryl-1-vinyl-1,1-diphosphane dioxide 235
SCHEME 1 Synthesis of 2-aryl-1-vinyl-1,1-diphosphane dioxide.
substituted vinylgembisphosphonates has never
been reported and spectroscopic data featuring this
class of epoxides have never been described in the
literature. These new structures are of great bio-
logical interest, since they might serve as valuable
precursors for the preparation of biologically active
amino bisphosphonic acids used in the treatment
of various human pathologies including cancer [9];
bone- and joint-related diseases such as ostereoporo-
sis, rheumatoid arthritis, Paget’s disease [10–12] and
parasitic disorders such as malaria, leishmaniasis,
and Chaga’s disease [13–16].
the literature [18]. Other interesting spectroscopic
features of these compounds are listed in Table 1.
These include the signal in 13C NMR spectra of the
geminal carbon C1 that appears as a triplet around
1
120 ppm with very large JP-C coupling constant
(around 170 Hz); the signal of the aromatic ipso car-
bon that appears as a doublet of doublets around
134 ppm with cis and trans 3JP-C coupling constants
ranging from 7.60 to 8.70 Hz and 16.00 to 22.60 Hz,
respectively. Previous investigators [17] wrongly as-
signed this signal to the ethylenic carbon C2. In fact,
carbon C2 appears as a singlet in the downfield re-
gions (156–161 ppm). The very large value of the 1JP-C
2
coupling constant for C1 and the zero value of JP-C
for C2 are common characteristic of the P(V)–C=C–
bonding system [19].
RESULTS AND DISCUSSION
Synthesis of Aryl-Substituted
Vinylgembisphosphonates
Synthesis of 1,2-Epoxy-2-aryl
Ethylgembisphonates
Aryl-substituted vinylgembisphosphonates were syn-
thesized by α-P-addition of diethyl phosphate a
to readily available alkynylphosphonates 1 using
tributylphosphine as a catalyst, according to a
method described by Leclercle´ and coworkers [17]
(Scheme 1).
The epoxidation was carried out through dioxirane
that was generated in situ from buffered potas-
sium hydrogen monopersulfate (caroate) solution
and methylethylketone in a phase transfer system
facilitated by the catalytic activity of tetrabutylam-
monium hydrogensulfate [8] (Scheme 2).
The reaction progress was monitored by FT-IR
spectroscopy, and the reaction completion rested on
the appearance of the vinyl (C=C) band (between
1570 and 1678 cm−1), and the total disappearance
of the alkyne (C≡C) band at 2200 cm−1 in the IR
spectra. The regioselective nature of this addition
reaction was established by the 31P NMR spectra of
the crude products, where only a pair of doublets
(around 12 and 17 ppm) with a two-bond P–P cou-
pling of 50 Hz was observed. This clearly indicates
that the two phosphorus atoms on carbon C1 were
nonequivalent: each being a doublet resulting from
coupling with the other. The reaction selectivity was
The pH of the reaction was kept strictly between
7.3 and 7.5 to avoid a Bayer–Villiger side reaction
involving the ketone [20]. To achieve this, our reac-
tion setup was equipped with a pH control system
connected to a pump that maintains the pH range
by a controlled addition of a 0.1 mol KOH solution
to the reaction mixture. The completion of the reac-
tion was monitored by 31P NMR spectroscopy, where
the epoxy gembisphosphonates spectra featured a set
of two doublets (around 13 and 15 ppm) similar to
those observed in the corresponding vinylbisphos-
2
phonates, but with a bigger JP-P coupling constant
1
further substantiated by the H NMR signal of the
(around 70 Hz) that reflects the change in the elec-
tronic nature of carbon C1.
ethylenic proton that appears as a doublet of dou-
blets in downfield region (around 8.20 ppm), with
cis and trans 3JP-H vinylic coupling constants ranging
from 28.00 to 29.20 Hz and from 46.80 to 48.00 Hz,
respectively. These values of the JP-H vinylic cou-
pling constants are consistent with those reported in
The reaction data shown in Table 2 reveals that
a 100% conversion (based on 31P NMR) was ob-
tained after 92 h, with a maximum of four addi-
tions of caroate solution for all the compounds.
These results suggest a relatively faster reaction of
3
Heteroatom Chemistry DOI 10.1002/hc

236 Fotsing, Coville, and Mbianda
C)
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Heteroatom Chemistry DOI 10.1002/hc

Dioxirane oxidation of 2-Aryl-1-vinyl-1,1-diphosphane dioxide 237
SCHEME 2 Synthesis of 1-2, epoxyarylbisphosphonates.
the vinylbisphosphonates when compared to their
monophosphonate counterparts for which a period
of 144 h (six additions of the caroate solution)
was required for a total conversion [8]. This supe-
rior reactivity of the vinyl bisphosphonates could
be explained by an increase in the nucleophilic-
ity of the double bond owing to the electron-
withdrawing effect brought about by the second
phosphoryl group. For two cases (entry 2c and 2f),
in which the nucleophilicity of the double bonds
was further enhanced by the presence of strong
electron-withdrawing substituents (CF3 and F) on
the phenyl ring, the reaction was even faster (48 and
73 h, respectively). These observations confirmed
the fact that dioxiranes are very efficient oxygen-
transfer agents for the epoxydation of electron-poor
alkenes under mild conditions [20]. The reaction
was chemo- and regioselective, since no by-products
were observed in the 31P NMR of the crude prod-
ucts and the compounds were easily isolated in high
yields except for two cases (entry 2d and 2f), where
the products decomposed during the purification
process.
The structure of the final product was verified
by a combination of 1H, 31P, and 13C NMR and
mass spectroscopy (Table 3). Interesting features ob-
1
served include the H NMR signal of the proton H2
that appears as a triplet around 4.57 ppm with a
3JP-H coupling constant ranging from 4.8 to 5.2 Hz.
The large upfield shift of this signal, relative to the
TABLE 2 Epoxidation of 2-Substituted 1,1-Vinylbisphosphonates
Entry
R1
Yield (%)
Conversion Rate (%)
Number of Caroate Additions
Reaction Time (h)
3a
3b
72
86
100
100
4
4
96
96
3c
92
100
2
48
3d
3e
59
79
100
100
4
4
96
96
3f
42
58
100
100
3
4
72
96
3g
Heteroatom Chemistry DOI 10.1002/hc

238 Fotsing, Coville, and Mbianda
TABLE 3 Some Typical Data of Epoxyalkylbisphosphonates
δ
13C NMR (ppm) J (Hz)
1
δ
31P NMR (ppm)
2JP–P (Hz)
δ H NMR (ppm)
Entry
3JP–H (Hz) H2
C1
C2
Cipso
m/z
392
3a
13.43 (d), 15.25 (d)
72.00
4.66 (t)
4.80
55.15 (t)
182.10
60.90 (s)
131.53 (s)
3b
3c
3d
3e
3f
12.30 (d), 13.80 (d)
66.56
12.85 (d), 14.46 (d)
68.80
13.58 (d), 15.38 (d)
68.80
13.57 (d), 15.45 (d)
73.60
13.39 (d), 14.94 (d)
72.00
13.55 (d), 15.34 (d)
72.00
4.51 (t)
4.80
4.67 (t)
4.80
4.63 (t)
5.20
4.56 (t)
5.20
4.61 (t)
5.20
4.59 (t)
5.20
54.89 (t)
179.80
55.62 (t)
184.00
55.83 (t)
182.30
55.44 (t)
184.00
55.93 (t)
182.60
55.73 (t)
182.00
61.43 (m)
60.85 (s)
61.97 (s)
60.78 (s)
61.32 (s)
61.68 (s)
137.83 (s)
136.15 (s)
137.96 (s)
135.65 (s)
128.86 (s)
137.06 (s)
393
460
406
406
410
406
3g
corresponding vinylbisphosphonates, could be ex-
plained by the fact that the proton is now bonded
to a sp3 carbon linked to an heteroatom. Also note-
worthy in the 13C NMR spectrum is the upfield shift
of all the signals compared to their vinyl analogs. For
which were synthesized in our laboratory, following
a procedure described by Aguiar and Chatta [21]. All
reactions in nonaqueous solvents were conducted in
flame-dried glassware under a positive pressure of
argon and with magnetic stirring. IR spectra (film)
were recorded using a Nicolet 380 FTIR spectrom-
eter. The NMR spectra were obtained in CDCl3 on
a Bruker 400 instrument (1H NMR at 400 MHz,
13C NMR at 100 MHz, and 31P NMR at 160 MHz).
1H NMR and 13C NMR chemical shifts refer to
signals of residual peaks as internal standard. 31P
NMR chemical shifts values are given in ppm rel-
ative to 85% H3PO4 as external standard. Abbrevia-
tions of coupling patterns are as follows: s, singlet; d,
doublet; t, triplet; q, quatruplet; m, multiplet. Mass
spectra were obtained using a Pegasus 4D GCxGC
TOFMS mass spectrometer. TLC was conducted on
thin Merck silica gel sheets with ethyl acetate as
a mobile phase, and 4-(p-nitrobenzylpyridine) and
tetraethylenepentamine as a revelator [22].
instance, the geminal carbon C1 appears as a triplet
1
around 55 ppm with a coupling constant JP-C
=
182 Hz and the carbons C2 and Cipso appear as sin-
glets around 60.90 and 131.53 ppm, respectively.
CONCLUSIONS
In conclusion, we have described
a
simple
and practical method to synthesize 2-aryl 1,2-
epoxyethyl gembisphosphonates in good yields
through dioxirane oxidation of the corresponding
vinylgembisphosphonates. This new class of com-
pounds has been fully characterized by NMR and
mass spectral analysis. They are valuable tools that
can give access to a wide range of substituted 1-
hydroxymethylene-1,1-bisphosphonates with potent
biological applications.
Synthesis of Aryl-Substituted
Vinylgembisphosphonates, 2
EXPERIMENTAL PROCEDURES AND
METHODS
To a solution of phenylethynyl-phosphonic acid di-
ethyl ester (1) (119 mg, 0.5 mmol) and diethylphos-
phite (7 μL, 0.55 mmol) in ethanol (5 mL), n-PBu3
(25 μL, 0.1 mmol) under argon was added. The
General Experimental Conditions
The starting materials and solvents were commer-
cially available, except for the alkynylphosphonates,
Heteroatom Chemistry DOI 10.1002/hc

Dioxirane oxidation of 2-Aryl-1-vinyl-1,1-diphosphane dioxide 239
mixture was heated under reflux for 8 h and then
evaporated. The resulting residue was purified by
flash column chromatography on silica gel with the
system (acetone-hexane 7:3) as eluent to yield the
expected product.
Tetraethyl (2-p-tolyl)vinyl Bisphosphonate 2d.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.36 (t, 6H4,
3JHH = 7.20 Hz); 1.33 (t, 6H4, 3JHH = 6.80 Hz); 2.33 (s,
3H); 3.97–4.02 (m, 4H3); 4.12–4.17 (m, 4H3); 7.15 (d,
2Har, 3JHH = 7.60 Hz); 7.65 (d, 2Har, 3JHH = 7.60 Hz);
8.22(dd, 1H2, 3JPH = 29.20 Hz, 3JPH = 48.00 Hz). 13
C
NMR (CDCl3, 100 MHz) δ (ppm): 15.19 (d, C4, 3JPC
=
Tetraethyl(2-phenyl)vinyl Bisphosphonate 2a.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.11 (t,
6H4, 3JHH = 6.80 Hz); 1.35 (t, 6H4, 3JHH = 7.20 Hz);
3.95–4.09 (m, 4H3); 4.11–4.20 (m, 4H3); 7.35–7.27
(m, 3Har); 7.70–7.71 (m, 2Har); and 8.27 (dd, 1H2,
3JPH = 29.20 Hz, 3JPH = 47.60 Hz). 13C NMR (CDCl3,
3
7.00 Hz); 15.48 (d, C4, JPC = 6.00 Hz); 20.63 (s, C);
2
, 2
61.56 (d, C3, JPC = 6.00 Hz); 61.75 (d, C3
J
PC
=
1
5.00 Hz); 118.29 (t, C1, JPC = 167.00 Hz); 127.90
,
(d, Car JPC = 14.00 Hz), 130.03(s, Car); 130.84 (dd,
Cipso, JPC = 8.00 Hz, JPC = 21.00 Hz); 140.44 (s, Car);
160.62 (s, C2). 31P NMR (CDCl3, 160 MHz) δ (ppm):
12.55 (d, JPP = 51.20 Hz); 17.92 (d, JPP = 48.00 Hz).
IR (film, cm−1): 3440, 2930, 2866, 2844, 1726, 1615,
1581, 1510, 1250, 1033, 955, 832.
3
100 MHz) δ (ppm): 15.21 (d, C4, JPC = 7.00 Hz);
3
2
15.99 (d, C4, JPC = 6.00 Hz); 61.68 (d, C3, JPC
=
, 2
6.30 Hz), 61.92 (d, C3
J
PC
= 5.60 Hz), 120.30 (t, C1,
1JPC = 169.20 Hz); 127.29 (s, Car); 129.53 (s, Car);
129.77 (s, Car); 133.85 (dd, Cipso, JPC = 8.60 Hz, JPC
=
22.60 Hz); 160.51 (s, C2). 31P NMR (CDCl3, 160 MHz)
Tetraethyl (2-o-tolyl)vinyl Bisphosphonate 2e.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.02 (t, 6H4,
3JHH = 7.20 Hz); 1.32 (t, 6H4, 3JHH = 7.20 Hz); 2.22
(s, 3H); 3.77–3.93 (m, 4H3); 4.08–4.19 (m, 4H3); 7.10–
δ (ppm): 12.02 (d, JPP = 51.20 Hz); 17.25 (d, JPP
=
51.20 Hz). IR (film, cm−1): 3480, 2980, 2360, 1648,
1497, 1570, 1391, 1257, 1020, 776.
3
7.15 (m, 2Har); 7.20 (t, 1Har, JHH = 7.60 Hz); 7.51
3
3
(d, 1Har, JHH = 8.00 Hz); 8.33 (dd, 1H2, JPH
=
Tetraethyl(3-pyridine)vinyl Bisphosphonate 2b.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.31–1.22 (m,
6H4); 1.37–1.41 (t, 6H4, 3JHH = 7.20 Hz); 4.02–4.13
(m, 4H3); 4.15–4.24 (m, 4H3); 8.25 (s, 1Har); 8.26
(dd, 1H2, 3JPH = 28.2 Hz, 3JPH = 46.80); 8.31 (t, 2Har,
3JHH = 5.2Hz); 8.71 (s, 1Har). 13C NMR (CDCl3, 100
3
28.00 Hz, JPH = 47.60 Hz). 13C NMR (CDCl3, 100
3
MHz) δ (ppm): 15.17 (d, C4, JPC = 7.00 Hz); 15.54
3
(d, C4, JPC = 3.00 Hz); 19.05 (s, C); 61.49 (d, C3,
2JPC = 6.00 Hz); 61.91 (d, C3, 2JPC = 6.00 Hz); 124.53
1
(t, C1, JPC = 170.40 Hz); 124.62 (s, Car); 128.18 (s,
3
Car); 128.93 (s, Car); 134.24 (dd, Cipso, JPC = 8.30 Hz,
JPC = 20.50 Hz); 134.98 (s, Car); 160.30 (s, C2). 31P
MHz) δ (ppm): 15.69 (d, C4, JPC = 6.00 Hz); 15.94
(d, C4, 3JPC = 6.00 Hz); 62.29 (d, C3, 2JPC = 7.00 Hz),
2
NMR (CDCl3, 160 MHz) δ (ppm): 11.75 (d, JPP
=
62.53 (d, C3, JPC = 6.00 Hz), 115.76 (s, Car); 122.52
51.80 Hz); 16.38 (d, JPP = 52.80 Hz). IR (film, cm−1):
3459, 2978, 2911, 2866, 1659, 1581, 1458, 1391, 1245,
1044, 787.
(s, Car); 124.26 (t, C1, 1JPC = 168.00 Hz); 130.37 (dd,
Cipso, JPC = 9.00 Hz, JPC = 22.00 Hz); 136.76 (s, Car);
156.66 (s, C2). 31P NMR (CDCl3, 160 MHz) δ (ppm):
11.16 (d, JPP = 48.00 Hz); 15.98 (d, JPP = 48 Hz).
IR (film, cm−1): 3480, 2980, 2360, 1648, 1497, 1570,
1391, 1257, 1020, and 776.
Tetraethyl (4-fluorophenyl)vinyl Bisphosphonate
2f. 1H NMR (CDCl3, 400 MHz) δ (ppm): 1.17 (t,
3
6H4, JHH = 6.80 Hz); 1.35 (t, 6H4, 3JHH = 7.20 Hz);
Tetraethyl [4-(Trifluoromethyl) Phenyl])vinyl Bis-
phosphonate 2c. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 1.21 (t, 6H4, 3JHH = 7.20 Hz); 1.33 (t,
6H4, 3JHH = 7.20 Hz); 3.72–3.87 (m, 4H3); 4.11–4.19
3.98–4.11 (m, 4H3); 4.14–4.20 (m, 4H3); 7.05 (t, 2Har,
3JHH = 8.40 Hz); 7.77–7.81 (m, 2Har); 8.23 (dd, 1H2,
3JPH = 29.20 Hz, 3JPH = 47.60 Hz). 13C NMR (CDCl3,
3
100 MHz) δ (ppm): 15.37 (d, C4, JPC = 7.00 Hz);
3
3
2
(m, 4H3); 7.46 (d, 2Har, JHH = 8.00 Hz); 7.74 (d,
15.63 (d, C4, JPC = 7.00 Hz); 61.89 (d, C3, JPC
=
3
3
2
2Har, JHH = 8 Hz); 8.24(dd, 1H2, JPH = 28.80 Hz,
3JPH = 46.80). 13C NMR (CDCl3, 100 MHz) δ (ppm):
7.00 Hz); 62.08 (d, C3, JPC = 6.00 Hz); 113.62 (d,
Car, J = 21 Hz); 114.54 (d, Car, J = 21 Hz); 115.27 (d,
2
1
15.69–15.69 (m, C4); 62.36 (d, C3, JPC = 6.00 Hz),
Car, J = 22.00 Hz); 119.93 (t, C1, JPC = 167.40 Hz);
2
62.60 (d, C3, JPC = 5.00 Hz), 119.43 (s, Car); 122.16
129.04 (d, Car, J = 8.80 Hz); 136.40 (d, Car, J =
8.00 Hz); 133.46 (t, Cipso, JPC = 8.00 Hz); 159.30 (s,
C2); and 163.35 (d, Car, J = 397.10 Hz). 31P NMR
(CDCl3, 160 MHz) δ (ppm): 12.56 (d, JPP = 48.00 Hz);
17.28 (d, JPP = 48.00 Hz). 19F NMR (CDCl3, 376
MHz) δ (ppm): −108.60. IR (film, cm−1): 3482, 2990,
2900, 2866, 1603, 1536, 1447, 1413, 1245, 1011,
966, 832.
1
(s, Car); 124.35 (t, C1, JPC = 165.00 Hz); 124.84
(s, Car); 128.71 (s, Car); 129.56 (s, Car); 130.62 (m,
Car); 131.94 (s, Car); 133.61 (s, Car); 137.98 (m, Cipso);
158.47(s, C2). 31P NMR (CDCl3, 160 MHz) δ (ppm):
11.84 (d, JPP = 48.00 Hz); 16.07 (d, JPP = 48 Hz).
IR (film, cm−1): 3482, 2990, 2922, 1626, 1581, 1492,
1447, 1380, 1335, 1257, 1156, 1134, 1033, 865.
Heteroatom Chemistry DOI 10.1002/hc

240 Fotsing, Coville, and Mbianda
IR (film, cm−1): 3488, 2980, 2937, 2913, 1640, 1457,
1396, 1261, 1163, 1028, 808. MS: m/z 392.
Tetraethyl (2-m-tolyl)vinyl Bisphosphonate 2g.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.09 (t, 6H4,
3JHH = 7.20 Hz); 1.31 (t, 6H4, 3JHH = 7.20 Hz); 2.30 (s,
3H); 3.90–4.01 (m, 4H3); 4.09–4.15 (m, 4H3); 7.13 (d,
1Har, 3JHH = 8.00 Hz); 7.21 (t, 1Har, 3JHH = 8.00 Hz);
Tetraethyl 1,2-Epoxy-2-(3-pyridine)bisphosphon-
ate 3b. 1H NMR (CDCl3, 400 MHz) δ (ppm): 1.15
(m, 6H4); 1.34 (m, 6H4); 4.04 (m, 4H3); 4.24 (m,
7.48 (d, 2Har, 3JHH = 7.20 Hz); 8.22 (dd, 1H2, 3JPH
=
3
3
28.80 Hz, JPH = 47.80 Hz). 13C NMR (CDCl3, 100
4H3); 4.51 (t, 1H2, JP-H = 4.80 Hz); 7.25 (m, 3Har);
8.14 (s, 1Har).). 13C NMR (CDCl3, 100 MHz) δ (ppm):
3
MHz) δ (ppm): 15.65 (d, C4, JPC = 7.00 Hz); 15.96
3
3
15.23 (m, C4,); 15.40 (m, C4, JPC = 6.00 Hz); 54.89
(d, C4, JPC = 6.00 Hz); 20.89 (s, C); 62.65 (d, C3,
1
2JPC = 7.00 Hz); 62.31 (d, C3, 2JPC = 5.00 Hz); 120.20
(t, C1, JP-C = 179.80 Hz); 61.43 (m, C2); 62.43 (d,
2
2
1
C3, JP-C = 6.30); 63.22 (d, C3, JP-C = 6.40); 124.15
(t, C1, JPC = 170.00 Hz); 121.08 (s, Car); 127.61
(s, Car) 124.56 (s, Car); 131.63 (s, Car); 136.80 (s, Car);
(s, Car); 130.57 (s, Car); 130.94 (s, Car); 134.22 (dd,
Cipso, JPC = 9.00 Hz, JPC = 22.00 Hz); 137.25 (s, Car);
161.37(s, C2). 31P NMR (CDCl3, 160 MHz) δ (ppm):
12.23 (d, JPP = 49.60 Hz); 17.43 (d, JPP = 49.60 Hz).
IR (film, cm−1): 3471, 2978, 2922, 1648, 1589, 1480,
1402, 1245, 1167, 1033, 787.
137.83 (s, Cipso). 31P NMR (CDCl3, 160 MHz) δ (ppm):
12.30 (d, 1P, JP-P = 67.20 Hz); 13.74 (d, 1P, 2JP-P
=
2
67.20 Hz). IR (film, cm−1): 3427, 2956, 2925, 2876,
1665, 1469, 1383, 1242, 1163, 1028, 789. MS: m/z
393.
Tetraethyl 1,2-Epoxy-2-[4-(trifluoromethyl)phen-
yl] Bisphosphonate 3c. 1H NMR (CDCl3, 400 MHz)
δ (ppm): 1.23 (m, 6H4); 1.36 (m, 6H4); 4.08 (m, 4H3);
Synthesis of 1,2-Epoxy-2-aryl
Ethylgembisphosphonates 3 (Typical Procedure)
3
4.26 (m, 4H3); 4.67 (t, 1H2, JP-H = 4.80); 7.49 (m,
4 mmol of vinylgembisphosphonates (2a), 100 mL of
butanone, 100 mL of CH2Cl2, phosphate buffer (pre-
pared by dissolving 0.177 g (1.30 mmol) of KH2PO4
and 0.648 g (4.6 mmol) of HNa2PO4 in 150 −mL of
water) and 0.5 g (1.7 mmol) of nBu4N+HSO4 were
introduced in a flask fitted with a vigorous mechanic
stirrer. Then a solution of aqueous caroate (25 g
(77 mmol) in 100 mL H2O) was slowly added (over
6 h). The pH of the mixture was maintained between
7.3 and 7.5 by a solution of KOH (5%). Stirring was
maintained for 18 h, then a new batch of aqueous
caroate solution was slowly added (over 6 h) and the
reaction mixture was stirred for an additional period
of 18 h. After completion, solid NaCl was added to
the cloudy reaction mixture until saturation. The or-
ganic phase was separated by decantation, and the
aqueous phase was extracted with CH2Cl2 (4×100
mL). The combined organic layers were dried over
MgSO4, filtered, and then evaporated. The crude
product was purified by chromatography on silica
gel with ethyl acetate as eluent.
2Har); 7.56(m, 2Har).). 13C NMR (CDCl3, 100 MHz)
δ (ppm): 15.48 (m, C4,); 15.85 (m, C4); 55.62 (t,
1
C1, JP-C = 184.00 Hz); 60.85 (s, C2); 61.88 (d, C3,
2JP-C = 5.80); 62.82 (m, C3,); 63.83 (m, C3); 124.56
(s, Car); 124.16 (m, Car); 124.36 (m, Car); 127.19 (s,
Car); 128.76 (d, Car); 130.25 (m, C); 136.15 (s, Cipso).
31P NMR (CDCl3, 160 MHz) δ (ppm): 12.85 (d, 1P,
2JP-P = 68.80 Hz); 14.46 (d, 1P, 2JP-P = 68.80 Hz).
IR (film, cm−1): 3507, 2980, 2925, 2827, 1720, 1622,
1445, 1389, 1255, 1132, 1016, 789. MS: m/z 460.
Tetraethyl 1, 2-Epoxy-2-p-tolylbisphosphonate 3d.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.12 (m, 6H4);
1.37 (m, 6H4); 3.37 (m, 4H3); 4.28 (m, 4H3); 4.63 (t,
3
3
1H2, JP-H = 5.20); 7.11 (d, 2Har, JH-H = 7.60 Hz);
7.29 (d, 2Har, 3JH-H = 8.00 Hz). 13C NMR (CDCl3, 100
3
MHz) δ (ppm): 15.88 (d, C4, JP-C = 6.00 Hz); 16.19
1
(m, C4); 21.02 (s, C); 55.83 (t, C1, JPC = 182.30 Hz);
61.97 (s, C2); 62.70 (m, C3,); 63.73(d, C3,2 JP-C
=
6.30 Hz); 126.68(s, Car); 128.21(s, Car); 129.14(s, Car);
137.96 (s, Cipso). 31P NMR (CDCl3, 160 MHz) δ (ppm):
13.59 (d, 1P, JP-P = 72.00 Hz); 15.38 (d, 1P, 2JP-P
=
2
Tetraethyl 1,2-Epoxy-2-phenylbisphosphonate 3a.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.11 (m, 6H4);
1.37 (m, 6H4); 3.90 (m, 4H3); 4.27 (m, 4H3); 4.66
72.00 Hz). IR (film, cm−1): 3507, 2980, 2931, 2864,
1732, 1647, 1451, 1383, 1261, 1022, 802. MS: m/z
406.
3
(t, 1H2, JP-H = 4.80 Hz); 7.29 (m, 2Har); 7.41 (m,
3
2Har, JH-H = 7.20 Hz). 13C NMR (CDCl3, 100 MHz)
3
δ (ppm): 15.09 (d, C4, JPC = 6.00 Hz); 15.40 (m, C4,
Tetraethyl 1,2-Epoxy-2-o-tolylbisphosphonate 3e.
1H NMR (CDCl3, 400 MHz) δ (ppm): 1.20 (m, 6H4);
1.37 (m, 6H4); 3.94 (m, 4H3); 4.29 (m, 4H3); 4.56
3JP-C = 6.00 Hz); 55.15 (t, C1, JP-C = 182.10 Hz);
1
2
60.90 (s, C2); 61.77 (d, C3, JP-C = 6.10 Hz); 61.93
2
3
(d, C3, JP-C = 6.40 Hz); 62.94 (m, C3); 126.04 (m,
(t, 1H2, JP-H = 5.20 Hz); 7.15 (m, 3Har); 7.33 (d,
4
Car); 126.76 (s, Car); 127.42 (s, Car); 131.53 (s, Cipso).
31P NMR (CDCl3, 160 MHz) δ (ppm): 13.43 (d, 1P,
2JP-P = 72.00 Hz); 15.25 (d, 1P, 2JP-P = 72.00 Hz).
1Har, JH-H = 7.60 Hz). 13C NMR (CDCl3, 100 MHz)
δ (ppm): 15.58 (d, C4, J = 6.00); 15.80 (m, C4); 18.12
1
(s, C); 55.44 (t, C1, JP-C = 184.00 Hz); 60.78 (s, C2);
Heteroatom Chemistry DOI 10.1002/hc

Dioxirane oxidation of 2-Aryl-1-vinyl-1,1-diphosphane dioxide 241
2
2
[4] Hendlin, D.; Stapley, E.; Jackson, M.; Wallick, H.;
Miller, A.; Wolf, F.; Miller, T.; Chaiet, L.; Kahan,
F.; Foltz, E.; Woodruff, H.; Mata, J.; Hernandez, S.;
Mochales, S. Science 1969, 166, 122–123.
[5] Savignac, P.; Iorga, B. Modern Phosphorus Chem-
istry; CRC Press: Boca Raton, FL, 2003.
[6] (a) Troev, K.; Tsacheva, I. Bulg Chem Commun 2006,
40, 54–58; (b) Troev, K. D. In Chemistry and Appli-
cation of H-Phosphonates; Elsevier: Amsterdam, the
Netherlands, 2006.
62.10 (d, C3, JP-C = 6.50 Hz); 62.38 (d, C3, JP-C
=
6.10 Hz); 63.27 (dm, C3); 124.36 (s, Car); 125.99 (s,
Car); 127.66 (s, Car); 128.74 (s, Car); 130.66 (s, Car);
135.65 (s, Cipso).). 31P NMR (CDCl3, 160 MHz) δ
2
(ppm): 13.57 (d, 1P, JP-P = 75.20 Hz); 15.45 (d,
1P, 2JP-P = 75.20 Hz). IR (film, cm−1): 3501, 2974,
2925, 2864, 1659, 1457, 1371, 1261, 1169, 1010, 802.
MS: m/z 406.
[7] (a) Redmore D. Chem Rev 1971, 71, 315–326; (b)
Iorga, B.; Eymery, F.; Savignac, P. Synthesis 1999,
207–224.
Tetraethyl 1,2-Epoxy-2-(4-fluorophenyl)bisphos-
phonate 3f. 1H NMR (CDCl3, 400 MHz) δ (ppm):
1.12 (m, 6H4); 1.36 (m, 6H4); 3.92 (m, 4H3); 4.25 (m,
[8] Cristau, H.-J.; Mbianda, X. Y.; Geze, A.; Beziat, Y.;
Gasc, M.-B. J Organomet Chem 1998, 571, 189–193.
[9] (a) Licata, A. Ann Pharmacother 2005, 39, 668–677;
(b) Guise, T. A. Cancer Treat Rev 2008, 34, S19-S24.
[10] Fleisch, H. Eur Spine J 2003, 12, S142–S146.
[11] (a) Russell, R. G. G.; Rogers, M. J.; Bone 1999, 25, 97;
(b) Russell, R. G. G.; Rogers, M. J. Br J. Rhumatol
1997, 36(Suppl. 1), 10–14
[12] Rodan, G. A.; Martin, T. J. Science 2000, 289, 1508–
1514.
[13] Szajnman, S. H.; Montalvetti, A.; Wang, Y.; Ro-
driguez, J. B. Bioog Med Chem Lett 2003, 13, 3231–
3235.
[14] Yardley, V.; Khan, A.; Martin, M.; Slifer, T.; Araujo,
F.; Moreno, S.; Docampo, R.; Croft, S.; Oldfield, E.
Synthesis 2002, 46, 929–931.
[15] Sherman, I. W. in Malaria: Parasite Biology, Patho-
genesis and Protection; ASM Press: Washington, DC,
1998.
[16] Kioy, D.; Jannin, J.; Mattock, N. Nat Rev Microbiol
2004, 2, 186–187.
[17] (a) Lecercle´, D.; Sawicki, M.; Taran, F. Org Lett 2006,
8, 4283–4285; (b) Lecercle, D., in Ph.D. Thesis, Uni-
versite de Paris XI Orsay. 2007.
3
4H3); 4.61 (t, 1H2, JP-H = 5.20 Hz); 7.00 (m, 2Har);
7.37 (m, 2Har). 13C NMR (CDCl3, 100 MHz) δ (ppm):
15.99 (d, C4, 3JP-C = 5.90 Hz,); 16.28 (m, C4); 55.93 (t,
Ca, JP-C = 182.60); 61.32 (s, C2); 63.27 (t, C3, 2JP-C
=
1
6.10 Hz); 64.01 (m, C3,); 114.67 (d, Car, J = 21.70 Hz);
128.10 (s, Car); 128.78 (s, Car); 128.86 (s, Cipso); 162.45
(d, Car, J = 245.80 Hz). 13C NMR (CDCl3, 100 MHz)
2
δ (ppm): 13.39 (d, 1P, JP-P = 72.00 Hz); 14.94 (d,
1P, 2JP-P = 72.00 Hz). IR (film, cm−1): 3488, 2968,
2925, 2852, 1726, 1610, 1518, 1463, 1383, 1261, 1157,
1022, and 802. MS: m/z 410.
Tetraethyl
1,2-Epoxy-2-m-tolylbisphosphonate
3g. 1H NMR (CDCl3, 400 MHz) δ (ppm): δ 1.04–1.10
(m, 6H4); 1.31–1.36 (m, 6H4); 2.36 (s, 3H); 3.79–3.98
3
(m, 4H3); 4.19–4.29 (m, 4H3); 4.59 (t, 1H2, JPH
=
5.20 Hz); 7.04–7.05 (m, 1Har); 7.15–7.19 (m, 3Har).
13C NMR (CDCl3, 100 MHz) δ (ppm): 15.83 (d, C4,
J = 6.00 Hz); 16.19 (d, C4, J = 5.00 Hz); 21.06 (s, C);
1
55.73 (t, C1, JPC = 182.00 Hz); 61.68 (s, C2); 63.61
[18] (a) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gasc,
M.-B. J Organomet Chem 1997, 529, 301–311; (b)
Benezra, C. Tetrahedron Lett 1961, 51, 4471–4474;
(c) Sainz-Diaz, C. I.; Galvez-Ruaro, E.; Hernadez-
Laguna, A.; Bellanato, J. J Org Chem 1995, 60, 74–
83.
[19] Quin L. D.; Verkade J. G. In Phosphorus-31 NMR
Spectroscopy in Stereochemical Analysis; VCH: New
York, 1987.
(m, C3); 63.71 (d, C3, 2JPC = 6.00 Hz); 123.80 (s, Car);
127.29 (s, Car); 127.43 (s, Car); 128.86 (s, Car); 132.05
(s, Car); 137.06 (s, Cipso). 13C NMR (CDCl3, 100 MHz)
2
δ (ppm): 13.55 (d, 1P, JPP = 72.00 Hz); 15.34 (d,
1P, 2JPP = 73.60 Hz). IR (film, cm−1): 2979,2931,
2873, 1610, 1591, 1476, 1444, 1391, 1254, 1163,
1014, 974, 886, 830, 789, 696. MS: m/z 406.
[20] (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Synthesis
1992, 1/2, 41–51; (b) Adam, W.; Golsh, D.; Hadjiara-
poglou, L.; Patonay, T. Tetrahedron Lett 1991, 32,
1041–1044.
[21] Chatta, M. S.; Aguiar, A. M. J Org Chem 1971, 36,
2719–2720.
REFERENCES
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Heteroatom Chemistry DOI 10.1002/hc