The lack of influence of electronic effects on the stereochemistry of the oxidation of aryl thiophosphates

Article abstract of DOI:10.1039/a800849c

A series of epimeric six-membered cyclic aryl thiophosphates 1-7 were oxidized to their corresponding phosphates by means of a mixture of aqueous hydrogen peroxide (30%) and hydrogen chloride. The oxidation, under these conditions, is highly stereospecifi

Full text of DOI:10.1039/a800849c

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The lack of influence of electronic effects on the stereochemistry
of the oxidation of aryl thiophosphates
Barbara Gordillo,* Magali Salas and Javier Hernández
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional, 14-740, México, D. F., Mexico
Received (in Gainesville, FL) 12th December 1997, Revised 27th January 1999,
Accepted 14th February 1999
A series of epimeric six-membered cyclic aryl thiophosphates 1–7 were oxidized to their corresponding phosphates
by means of a mixture of aqueous hydrogen peroxide (30%) and hydrogen chloride. The oxidation, under these
conditions, is highly stereospecific so that the products were obtained in quantitative yields with retention of
configuration at the phosphorus center. Our results do not support the participation of pentacoordinate species
as plausible intermediates of the oxidation reaction.
Table 1 Stereoselectivity in the oxidation of thiophosphoryl com-
pounds
Organophosphorus compounds play a ubiquitous role in
metabolic oxidation processes.1,2 The widespread biological
activity of phosphate derivatives, as thiophosphates,3 which are
active not only as insecticides4 but also as antiviral drugs,5 has
prompted their investigation, particularly in relation to the
stereochemistry and mechanism of their oxidation.
Phosphono
thionates
Cyclic thio
phosphates
Phosphine
sulfides
R2
Phosphino
thionates
R2
OR3
R3
OR3
OR3
O
R2O
P
P
P
P
R1
R1
R1
O
S
S
S
S
Dramatic variations of the stereochemical outcome of the
oxidation of thiophosphoryl compounds were reported earlier.6
I
II
IV
III
As
a consequence, several research laboratories became
R1, R2, or R3 = alkyl substituents
involved in the problem, and very interesting results were
derived from these studies.7–16 A brief summary of the findings
is as follows. The stereochemistry of the oxidation process
depends mainly on the nature of the oxidizing agent, on the
structures of the thio derivatives, on pH, on solvent; and least,
on temperature and reaction times. A list of oxidizing agents
and the stereochemistry with which the oxidation of several
thiophosphoryl compounds was carried out are summarized in
Table 1.
As observed, phosphine sulfides react with conventional
neutral or acidic oxidizing agents with overall inversion of con-
figuration, whereas cyclic thiophosphates are converted into
their corresponding oxo derivatives with net retention of con-
figuration. More striking is the behavior of phosphino and
phosphono thionates, which are oxidized with either inversion
or retention of configuration even though the same type of
oxidizing agents are used, i.e. peroxy acids.6 A rationale of the
results for the oxidation of thiophosphoryl compounds by
hydrogen peroxide has been provided by Stec and Michalski13
who postulated that the first step in the reaction was the nucleo-
philic attack of sulfur on hydrogen peroxide with the concomi-
tant formation of a thiophosphonium intermediate. The second
step was then the formation of a pentacoordinate intermediate
which determined the stereochemical course of the reaction. An
in line arrangement of the attacking–departure groups in the
apical positions of the pentacovalent intermediate produces
the oxo product with inversion of configuration, and an apical–
equatorial arrangement leads to the product with retention
of configuration due to the participation of pseudorotation
(Scheme 1).
Oxidizing
agent
Thio
derivative
Overall
stereoselectivity
Reference
KMnO4–py
HNO3
HNO3
HNO3
N2O4–CF3CO2H
N2O4
MCPBA
MCPBA–CF3CO2H
O3
I
I
III
IV
I
III
II
II
III
IV
I
IV
Retention
Inversion
Inversion
Retention
Inversion
Retention
Retention
Inversion
Retention
Retention
Inversion
Retention
Inversion
Inversion
Inversion
Racemization
Inversion
Inversion
Retention
Inversion
Retention
Retention
7
8
8
9
8
9
6
6a
10
10
11a
11b
11c
11d
11e
12
13
13
13
14
14
15
O3
DMSO–H2SO4
DMSO–H2SO4
DMSO–HNO3
DMSO–I2
DMSO–I2
TFAA
H2O2
H2O2–CF3CO2H
H2O2
I
I
IV (R3 = H)
I
I
I
IV
I
IV
IV
Me2Se᎐O
᎐
Me2Se᎐O
᎐
Cl3CCHO
phorus containing heterocycles, the electronic environment at
phosphorus can be modified by the presence of electron releas-
ing or electron withdrawing groups in the aromatic residue.
Therefore, as an additional proof of the participation of penta-
coordinate intermediates in the oxidation of thiophosphoryl
compounds, we planned to study the stereochemical course of
the oxidation of the epimeric thiophosphates 1–7 (Scheme 2)
with hydrogen peroxide in acidic media. If participation of
pentacoordinate intermediates occurs a mixture of retention
and inversion products which varies with the electronic charac-
teristics of the aryloxy group may be anticipated (see below).
The results of these studies are discussed herein.
It is pertinent to emphasize that in several reactions of
organophosphorus compounds in which pentacovalent species
are postulated as intermediates, for example the alkaline
hydrolysis of phosphates,17 it has been found that the partici-
pation of pseudorotation depends highly on the electronic
characteristics of the phosphorus atom. For aryloxy phos-
J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286
1281

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a
a
+
P
b
OH –
SOH
P
S
+
HO-OH
b
c
c
a
a
a
+
P
b
SOH OH –
HO
P
SOH
+ S + H2O
O
P
a, b, c =
alkyl groups
b
c
c
b
c
inversion
a or b or
c = OR
a
OH
P
a
one BPR
or TR
HO
P
OR
b
SOH
b
P
O
+ S + H2O
SOH
OR
b
a
RO
retention
Scheme 1 6
the solid phosphates were purified by recrystallization; liquids
were purified by flash column chromatography using a 50%
hexanes–ethyl acetate solution as eluent.
OAr
S
P
P
O
O
S
OAr
O
O
cis
trans
Stereochemistry of the oxidation reactions
a
σp
Thiophosphates (1–7) were reacted with hydrogen peroxide in
hydrogen chloride following the procedure described above.
Crude materials were analyzed by 31P NMR spectroscopy of an
aliquot of the reaction solution. Complete disappearance of the
starting material was observed [31P NMR: δ(trans) = 54.3 to 56.2
ppm; δ(cis) = 59.2 to 61.0 ppm]. Only one oxo product was
formed [31P NMR: δ(trans) = Ϫ12.2 to Ϫ15 ppm; δ(cis) = Ϫ9.7 to
Ϫ12.2 ppm]. The stereochemistry of the products was assigned
for the isolated materials, according to the NMR properties of
phosphates reported in refs. 17, 21 and 22. See Tables 2 and 3.
1, Ar = p-MeO-C6H4- –0.27
2, Ar = p-Me-C6H4- –0.17
3, Ar = p-Ph-C6H4- –0.01
0
4, Ar = C6H5-
0.23
0.66
0.78
5, Ar = p-Br-C6H4-
6, Ar = p-CN-C6H4-
7, Ar = p-NO2-C6H4-
a Values in ref. 18.
Scheme 2
Experimental
Melting points were obtained in a Mel-Temp II apparatus with
an open capillary tube. Microanalyses were performed by
Galbraith Laboratories, Inc. Unless otherwise stated, H and
Oxidations-in-competition experiments
1
A solution of 0.01 g of aryl thiophosphate (1, 4 or 7) in 0.22 mL
of 1,4-dioxane was added to an NMR tube. A 30% aqueous
solution of hydrogen peroxide (50 equiv.) was then added fol-
lowed by 8 equiv. of hydrogen chloride (37% aqueous solution).
The NMR tube was capped and introduced into the NMR
equipment immediately. The reaction was followed by 31P NMR
until no starting material was observed. The spectra were regis-
tered in accord with the times reported in Table 4. Only one oxo
product was detected (see chemical shifts in Tables 2 and 3).
The area ratio of the thiophosphate/phosphate was calculated
electronically.
13C NMR spectra were recorded in CDCl3 solutions on a Jeol
GSX-270 spectrometer (at 270 and 67.5 MHz, respectively) and
on a Jeol Eclipse 400 (at 399.8 and 100.5 MHz respectively).
Chemical shifts (δ) are referenced to internal (CH3)4Si. 31P
NMR spectra were recorded, in CDCl3, at 109.25 MHz on the
Jeol GSX-270 spectrometer and at 161.83 MHz on the Jeol
Eclipse 400 spectrometer. Chemical shifts are reported in ppm
downfield (ϩ) from external 85% H3PO4. The mass spec-
trometry analyses were obtained on a Hewlett Packard 5989A
spectrometer.
r-2-(p-Methoxyphenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-8)†
cis- and trans-Aryl thiophosphates (1–7)
These compounds were prepared from meso-pentane-2,4-diol19
by the stereospecific approach described in ref. 20.
Purification by flash column chromatography gave 0.090 g
(95.7%) of a solid, mp 75–77 ЊC. The NMR spectral data for
this compound are in agreement with those reported in the
literature.17,21
General procedure for the oxidation of cis- or trans-aryl
thiophosphates (1–7)
In a 100 mL round-bottomed flask, equipped with a magnetic
stirrer, were placed 0.1 g of the aryl thiophosphate and 5 mL of
1,4-dioxane. The mixture was stirred until the thiophosphate
was totally dissolved, and then 100 equiv. of hydrogen peroxide
(30% aqueous solution) followed by 8 equiv. of hydrogen chlor-
ide (37% aqueous solution) were added. The reaction mixture
was stirred for an additional 12 h at ambient temperature and
then a solution of saturated sodium bicarbonate was added
until pH = 7 was reached. The organic layer was extracted with
20 mL of dichloromethane, dried over anhydrous sodium sulf-
ate, filtered, and concentrated in a rotary evaporator. Most of
r-2-(p-Methoxyphenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (cis-8)
Purification by flash column chromatography resulted in 0.088
g (93.6%) of a yellow oil. The NMR spectral data for this
compound are in accordance with those reported in the
literature.17,21
† Phosphinanes were previously called phosphorinanes (the change is
in accord with recommendation RB-1.1 Hantsch–Widman System,
IUPAC, 1993).
1282
J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286

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r-2-(p-Methylphenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-9)
(39.4%) of a solid, mp 88–90 ЊC. The NMR spectral data for
this compound are in agreement with those reported in the
literature.21,22
Recrystallization from ethyl acetate afforded 0.064 g (68.1%)
of colorless crystals, mp 85–87 ЊC. 1H NMR: δ 1.40 (dd,
JHCCH = 6.2 Hz, JHCCOP = 2.5 Hz, 6 H, CH3’s at C4 and C6), 1.75
(dt, Jgem = 13.9 Hz, Janti = 9.6 Hz, 1 H, H5 ax.), 1.85 (~dq,
Jgem = 13.9 Hz, Jgauche = 2.7 Hz, JHCCOP = 2.2 Hz, 1 H, H5 eq.),
2.31 (s, 3 H), 4.70 (m, 2 H, H4,6), 7.12 (br s, 4 H, Harom.); 13C
NMR: δ 20.70 (s, 1 C), 22.07 (d, 2 C), 40.45 (d, 1 C), 76.45 (d,
2 C), 119.15 (d, 2 C), 130.24 (s, 2 C), 134.41 (s, 1 C), 148.37 (d,
1 C); MS: m/z 256 (Mϩ), 215 (Mϩ Ϫ 41), 188 (Mϩ Ϫ 68), 108
(Mϩ Ϫ 148), 90 (Mϩ Ϫ 166), 69 (Mϩ Ϫ 187), 41 (Mϩ Ϫ 215).
Anal. Calcd for C12H17O4P: C, 56.23; H, 6.69. Found: C, 56.28;
H, 6.86%.
r-2-(Phenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxaphosphinane
(cis-11)
Purification by flash column chromatography resulted in 0.040
g (42.6%) of a yellow oil. The NMR spectral data for this
compound are in accordance with those reported in the
literature.21,22
r-2-(p-Bromophenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-12)
Recrystallization from ethyl acetate gave 0.090 g (94.7%) of
colorless crystals, mp 137–139 ЊC. 1H NMR: δ 1.40 (dd,
JHCCH = 6.2 Hz, JHCCOP = 2.5 Hz, 6 H, CH3’s at C4 and C6), 1.78
(dt, Jgem = 14.6 Hz, Janti = 9.3 Hz, 1 H, H5 ax.), 1.86 (~dq,
Jgem = 14.6 Hz, Jgauche = 4.1 Hz, JHCCOP = 2.5 Hz, 1 H, H5 eq.),
4.67 (m, 2 H, H4,6), 7.16 (~d, JHCCH = 8.8 Hz, 2 H, Harom.), 8.43
(d, 2H, Harom.); 13C NMR: δ 23.16 (d, 2 C), 41.5 (d, 1 C), 78.07
(d, 2 C), 118.86 (s, 1 C), 122.48 (d, 2 C), 133.85 (s, 2 C), 150.86
(d, 1 C); MS: m/z 320 (Mϩ), 281 (Mϩ Ϫ 39), 253 (Mϩ Ϫ 67), 234
(Mϩ Ϫ 86), 172 (Mϩ Ϫ 148), 68 (Mϩ Ϫ 252), 41 (Mϩ Ϫ 279).
Anal. Calcd for C11H14O4PBr: C, 41.25; H, 4.41. Found: C,
41.02; H, 4.54%.
r-2-(p-Methylphenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-
dioxaphosphinane (cis-9)
Recrystallization from ethyl acetate gave 0.071 g (75.5%) of
1
colorless crystals, mp 79–81 ЊC. H NMR: δ 1.36 (dd, JHCCH
=
6.2 Hz, JHCCOP = 2.5 Hz, 6 H, CH3’s at C4 and C6), 1.66 (dt,
Jgem = 14.6 Hz, Janti = 9.6 Hz, 1 H, H5 ax.), 1.83 (~dq, Jgem = 14.6
Hz, Jgauche = 4.0 Hz, JHCCOP = 2.2 Hz, 1 H, H5 eq.), 2.32 (s, 3 H),
4.77 (m, 2 H, H4,6), 7.12 (br s, 4 H, Harom.); 13C NMR: δ 20.76 (s,
1 C), 22.21 (d, 2 C), 40.28 (d, 1 C), 75.87 (d, 2 C), 120.06 (d,
2 C), 130.02 (s, 2 C), 134.74 (s, 1 C), 148.56 (d, 1 C); MS: m/z
256 (Mϩ), 215 (Mϩ Ϫ 41), 188 (Mϩ Ϫ 68), 108 (Mϩ Ϫ 148), 90
(Mϩ Ϫ 166), 69 (Mϩ Ϫ 187), 41 (Mϩ Ϫ 215). Anal. Calcd for
C12H17O4P: C, 56.23; H, 6.69. Found: C, 56.08; H, 6.99%.
r-2-(p-Bromophenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (cis-12)
r-2-(p-Phenylphenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-10)
Recrystallization from ethyl acetate afforded 0.080 g (73%)
of colorless crystals, mp 49–51 ЊC. 1H NMR: δ 1.30 (dd,
JHCCH = 6.2 Hz, JHCCOP = 2.6 Hz, 6 H, CH3’s at C4 and C6), 1.61
(dt, Jgem = 14.6 Hz, Janti = 9.9 Hz, 1 H, H5 ax.), 1.80 (dq,
Jgem = 14.6 Hz, Jgauche = 2.6 Hz, JHCCOP = 2.6 Hz, 1 H, H5 eq.),
4.73 (m, JHCOP = 2.6 Hz, 2 H, H4,6), 7.05 (dd, JHCCH = 8.6 Hz,
JHCCOP = 1.3 Hz, 2 H, Harom.), 7.38 (d, 2 H, Harom.); 13C NMR:
δ 21.17 (d, 2 C), 39.19 (d, 1 C), 75.21 (d, 2 C), 117.14 (s, 1 C),
121.14 (d, 2 C), 131.28 (s, 2 C), 148.79 (d, 1 C); MS: m/z 320
(Mϩ), 281 (Mϩ Ϫ 39), 253 (Mϩ Ϫ 67), 234 (Mϩ Ϫ 86), 172
(Mϩ Ϫ 148), 68 (Mϩ Ϫ 252), 41 (Mϩ Ϫ 279). Anal. Calcd for
C11H14O4PBr: C, 41.25; H, 4.41. Found: C, 41.34; H, 4.60%.
Recrystallization from ethyl acetate gave 0.072 g (75.8%) of
colorless crystals, mp 145–146 ЊC. 1H NMR: δ 1.39 (dd,
JHCCH = 6.2 Hz, JHCCOP = 2.5 Hz, 6 H, CH3’s at C4 and C6), 1.74
(dt, Jgem = 14.6 Hz, Janti = 9.5 Hz, 1 H, H5 ax.), 1.85 (dq,
Jgem = 14.6 Hz, Jgauche = 2.2 Hz, JHCCOP = 2.2 Hz, 1 H, H5 eq.),
4.70 (m, 2 H, H4,6), 7.31 (~d, JHCCH = 7.3 Hz, 2 H, Harom.), 7.31
(~t, JHCCH = 7.3 Hz, 1 H, Harom.), 7.45 (t, JHCCH = 7.5 Hz, 2H,
Harom.), 7.56 (m, 4H, Harom.); 13C NMR: δ 21.93 (d, 2 C), 40.31
(d, 1 C), 76.60 (d, 2 C), 119.66 (d, 2 C), 126.85 (s, 2 C), 127.19 (s,
1 C), 128.37 (s, 2 C), 128.70 (s, 2 C), 137.9 (s, 1 C), 140.05 (s,
1 C), 149.96 (d, 1 C); MS: m/z 318 (Mϩ), 276 (Mϩ Ϫ 42), 250
(Mϩ Ϫ 68), 232 (Mϩ Ϫ 86), 170 (Mϩ Ϫ 148), 141 (Mϩ Ϫ 177),
41 (Mϩ Ϫ 277). Anal. Calcd for C17H19O4P: C, 64.13; H, 6.02.
Found: C, 63.54; H, 5.70%.
r-2-(p-Cyanophenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-13)
Recrystallization from a mixture of 90% hexanes–methylene
chloride gave 0.040 g (42.6%) of colorless crystals, mp 87–
r-2-(p-Phenylphenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (cis-10)
1
89 ЊC. H NMR: δ 1.42 (dd, JHCCH = 6.2 Hz, JHCCOP = 2.5 Hz,
6 H, CH3’s at C4 and C6), 1.82 (dt, Jgem = 14.6 Hz, Janti = 10.9
Hz, 1 H, H5 ax.), 1.89 (dq, Jgem = 14.6 Hz, Jgauche = 2.5 Hz,
JHCCOP = 2.5 Hz, 1 H, H5 eq.), 4.79 (m, 2 H, H4,6), 7.36 (~d,
JHCCH = 8.4 Hz, 2 H, Harom.), 8.43 (d, 2H, Harom.); 13C NMR:
δ 22.05 (d, 2 C), 40.3 (d, 1 C), 77.3 (d, 2 C), 108.75 (s, 1 C),
118.19 (s, 1 C), 120.51 (d, 2 C), 134.23 (s, 2 C), 153.94 (d, 1 C);
MS: m/z 267 (Mϩ), 226 (Mϩ Ϫ 41), 200 (Mϩ Ϫ 67), 181
(Mϩ Ϫ 86), 119 (Mϩ Ϫ 148), 68 (Mϩ Ϫ 199), 41 (Mϩ Ϫ 226).
Anal. Calcd for C12H14O4PN: C, 53.92; H, 5.28. Found: C,
54.01; H, 5.43%.
Purification by flash column chromatography gave 0.070 g
(73.7%) of a solid which was recrystallized from a mixture
of 80% hexanes–methylene chloride to afford colorless
1
crystals, mp 93–95 ЊC. H NMR: δ 1.33 (dd, JHCCH = 6.2 Hz,
JHCCOP = 2.2 Hz, 6 H, CH3’s at C4 and C6), 1.66 (dt, Jgem = 14.6
Hz, Janti = 10.9 Hz, 1 H, H5 ax.), 1.80 (~dq, Jgem = 14.6 Hz,
Jgauche = 2.5 Hz, JHCCOP = 2.2 Hz, 1 H, H5 eq.), 4.75 (m,
JHCOP = 2.5 Hz, 2 H, H4,6), 7.29 (dd, JHCCH = 8.0 Hz, JHCCOP
=
1.1 Hz, JHCCH = 7.3 Hz, 3 H, Harom.), 7.34 (t, JHCCH = 7.3 Hz,
2 H, Harom.), 7.55 (d, 4H, Harom.); 13C NMR: δ 22.06 (d, 2 C),
40.22 (d, 1 C), 76.06 (d, 2 C), 120.56 (d, 2 C), 126.97 (s, 2 C),
127.26 (s, 1 C), 128.24 (s, 2 C), 128.77 (s, 2 C), 138.24 (s, 1 C),
140.17 (s, 1 C), 150.15 (d, 1 C); MS: m/z 318 (Mϩ), 276
(Mϩ Ϫ 42), 250 (Mϩ Ϫ 68), 232 (Mϩ Ϫ 86), 170 (Mϩ Ϫ 148),
141 (Mϩ Ϫ 177), 41 (Mϩ Ϫ 277). Anal. Calcd for C17H19O4P: C,
64.13; H, 6.02. Found: C, 64.03; H, 6.25%.
r-2-(p-Cyanophenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (cis-13)
Recrystallization from ethyl acetate afforded 0.043 g (45.7%)
of colorless crystals, mp 75–76 ЊC. 1H NMR: δ 1.40 (dd,
JHCCH = 6.2 Hz, JHCCOP = 2.5 Hz, 6 H, CH3’s at C4 and C6), 1.77
(dt, Jgem = 14.6 Hz, Janti = 11.3 Hz, 1 H, H5 ax.), 1.93 (~dq,
Jgem = 14.6 Hz, Jgauche = 2.9 Hz, JHCCOP = 2.5 Hz, 1 H, H5 eq.),
4.81 (m, JHCOP = 2.9 Hz, 2 H, H4,6), 7.35 (dd, JHCCH = 8.4 Hz,
JHCCOP = 2.0 Hz, 2 H, Harom.), 7.65 (d, 2 H, Harom.); 13C NMR:
δ 22.2 (d, 2 C), 40.12 (d, 1 C), 76.66 (d, 2 C), 108.90 (s, 1 C),
r-2-(Phenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxaphosphinane
(trans-11)
Purification by flash column chromatography gave 0.037 g
J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286
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Table 2 Stereochemistry in the oxidation of trans-aryl thiophosphates
(1–7) by H2O2–HCl
Table 3 Stereochemistry in the oxidation of cis-aryl thiophosphates
(1–7) by H2O2–HCl
OAr
P
OAr
P
S
P
O
P
H2O2/HCl
H2O2/HCl
O
S
O
O
O
OAr
O
OAr
O
O
O
O
dioxane-water
dioxane-water
Thiophosphate,
Oxo product,
Thiophosphate,
Oxo product,
Ar
(δ 31P)a
(δ 31P)a
Stereoselectivity
Ar
(δ 31P)a
(δ 31P)a
Stereoselectivity
p-MeOC6H4
p-MeC6H4
p-PhC6H4
C6H5
p-BrC6H4
p-CNC6H4
p-NO2C6H4
1, (55.7)
2, (56.2)
3, (55.8)
4, (55.8)
5, (55.5)
6, (54.5)
7, (54.3)
8, (Ϫ12.2)
9, (Ϫ13.8)
10, (Ϫ12.6)
11, (Ϫ12.7)
12, (Ϫ13.1)
13, (Ϫ15.0)
14, (Ϫ13.7)
Retention
Retention
Retention
Retention
Retention
Retention
Retention
p-MeOC6H4
p-MeC6H4
p-PhC6H4
C6H5
p-BrC6H4
p-CNC6H4
p-NO2C6H4
1, (61.0)
2, (60.9)
3, (60.4)
4, (60.2)
5, (60.1)
6, (59.4)
7, (59.2)
8, (Ϫ9.7)
9, (Ϫ10.1)
10, (Ϫ9.9)
11, (Ϫ10.3)
12, (Ϫ10.4)
13, (Ϫ12.2)
14, (Ϫ10.8)
Retention
Retention
Retention
Retention
Retention
Retention
Retention
a Chemical shifts in ppm (CDCl3).
a Chemical shifts in ppm (CDCl3).
118.15 (s, 1 C), 121.24 (d, 2 C), 133.99 (s, 2 C), 153.91 (d, 1 C);
MS: m/z 267 (Mϩ), 226 (Mϩ Ϫ 41), 200 (Mϩ Ϫ 67), 181
(Mϩ Ϫ 86), 119 (Mϩ Ϫ 148), 68 (Mϩ Ϫ 199), 41 (Mϩ Ϫ 226).
Anal. Calcd for C12H14O4PN: C, 53.92; H, 5.28. Found: C,
53.97; H, 5.42%.
perature and reaction times were kept constant for all the
experiments. The stereoselectivity of the reaction was analyzed
by 31P NMR of the crude material (Tables 2 and 3).
From inspection of Tables 2 and 3, it is deduced that regard-
less of configuration and of the electronic characteristics of the
aryloxy group, the oxidation reaction (which was followed by
31P NMR of the crude material, see the Experimental section
for details) proceeded in quantitative yields with high stereo-
specificity to give the oxo products with retention of configur-
ation at the phosphorus center.
In the case of compound cis-6, the cyano group was also
oxidized to the carboxy group to some extent, after 24 h of
reaction. The oxidation of the cyano group was fully achieved
at 48 h as indicated in the Experimental section of this work.
See also the discussion below.
r-2-(p-Nitrophenoxy)-2-oxo-t-4,t-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (trans-14)
Purification by flash column chromatography gave 0.070 g
(73.7%) of a solid, mp 121–122 ЊC. The NMR spectral data
for this compound are in agreement with those reported in the
literature.17,21
r-2-(p-Nitrophenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-
dioxaphosphinane (cis-14)
Purification by flash column chromatography resulted in 0.030
g (31.6%) of a yellow oil (further recrystallization of this com-
pound from hexanes should result in colorless crystals, mp 78–
79 ЊC as described in the literature17,20). The NMR spectral data
for this compound are in accordance with those reported
previously.17,21
Discussion
It is of importance to note that the fact that the oxidation was
highly stereospecific for all the thiophosphates studied was
unexpected. As stated above, there is a strong dependence of
the electronic environment at the phosphorus atom and the
stability of a pentacoordinate intermediate, thus it was antici-
pated that if the mechanism of the oxidation of epimeric cis
and trans thiophosphates 1–7 by hydrogen peroxide (in hydro-
gen chloride) relies on pentacovalent intermediates (see pro-
posed mechanism in Scheme 3), the stereochemical outcome
should favor either an inversion or a retention process, but not
only one (retention) as observed. The stereomutation of thio-
phosphates may be expected in long-lived pentacovalent
intermediates in which pseudorotation is allowed. In other
words, as shown in Scheme 3, retention of configuration would
have been expected for electron withdrawing groups (X = NO2,
CN, Br) and inversion for electron releasing groups (OMe,
Me, Ph).
Alternatively our results can be explained by proposing a
concerted mechanism (Scheme 4) in which the para-
substituents at the aryloxy group do not alter the stereochemi-
cal outcome but do affect the rate of the oxidation reaction. In
particular, due to the likely participation of the mesomeric ionic
structure (B in Scheme 4), an electron releasing group (ERG) in
the aryloxy substituent is anticipated to increase the rate of
oxidation, whereas an electron withdrawing group (EWG) is
expected to decrease it. The stereochemistry of the thiophos-
phates, though, is not expected to change since in both cases the
favored oxo product is the one that results from retention of
configuration.
r-2-(p-Carboxyphenoxy)-2-oxo-c-4,c-6-dimethyl-1,3,2ë5-dioxa-
phosphinane (cis-15)
This compound was prepared from oxidation of r-2-(p-cyano-
phenoxy)-2-thio-c-4,c-6-dimethyl-1,3,2λ5-dioxaphosphinane
(cis-6) following the general procedure described above and
changing the reaction time to 48 h. Recrystallization from
ethyl acetate afforded 0.031 g (32.6%) of colorless crystals,
mp 156–157 ЊC. 1H NMR (acetone-d6): δ 1.36 (dd, JHCCH
=
6.2 Hz, JHCCOP = 1.8 Hz, 6 H, CH3’s at C4 and C6), 1.81 (dt,
Jgem = 14.8 Hz, Janti = 11.7 Hz, 1 H, H5 ax.), 2.14 (dq, Jgem
=
11.7 Hz, Jgauche = 2.8 Hz, JHCCOP = 2.8 Hz, 1 H, H5 eq.), 4.81
(m, 2 H, H4,6), 7.36 (dd, JHCCH = 8.4 Hz, JHCCOP = 2.7 Hz, 2 H,
Harom.), 8.07 (d, 2H, Harom.); 13C NMR (acetone-d6): δ 21.50 (d,
2 C), 39.33 (d, 1 C), 77.01 (d, 2 C), 120.09 (d, 2 C), 127.41 (s,
1 C), 131.50 (s, 2 C), 154.53 (d, 1 C), 166.05 (s, 1 C); 31P NMR:
δ Ϫ11.55; MS: m/z 286 (Mϩ), 245 (Mϩ Ϫ 41), 219 (Mϩ Ϫ 67),
201 (Mϩ Ϫ 85), 183 (Mϩ Ϫ 103), 68 (Mϩ Ϫ 215), 41 (Mϩ Ϫ
245). Anal. Calcd for C12H15O6P: C, 50.34; H, 5.28. Found: C,
50.59; H, 5.44%.
Results
Stereospecific syntheses of epimeric thiophosphates 1–7 were
performed as described elsewhere.20
The oxidation of thiophosphates was carried out in 1,4-
dioxane by an aqueous solution of hydrogen peroxide (30%).
Hydrogen chloride was used in the reaction to accelerate the
attack of sulfur on hydrogen peroxide (see Scheme 1). The tem-
In this context, to support the proposed mechanism, we per-
formed some oxidations-in-competition experiments (see the
Experimental section for details) with thiophosphates 1, 4
and 7 in both configurations, and the mixture hydrogen per-
1284
J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286

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OH
P
O
P
– S
OAr
O
O
OAr
O
OAr
OAr
O
+
P
P
S
O
H2O2
H +
– H2O
O
SOH
O
inversion
O
SOH
trans
OAr
5
SOH
OAr
P
1
O
4
– S
TR
LP 4,5
LT 1,3,6
O
O
O
P
SOH
P
OAr
O
3
O
– H2O
HO
OH
6
O
retention
SOH
OAr
– S
P
S
P
O
O
O
P
OAr
SOH
O
+
P
O
O
– H2O
OAr
O
H2O2
H +
OH
O
inversion
O
OAr
cis
6
OH
P
O
O
1
O
4
P
– S
TR
OAr
O
O
SOH
O
P
OAr
LP 4,5
LT 1,3,6
O
3
– H2O
HO
OAr
5
SOH
a ERG = electron releasing groups.
b EWG = electron withdrawing groups.
retention
Scheme 3
H3O2 Cl –
+
+
H2O2
HCl
+
..
O
O
O
OAr
OAr
P
P
–
S
S
O
B
A
OAr
OAr
P
+
+
+
OAr
:
OAr
OAr
+
OH2
P
S
–
O
P
S
P
P
¨
O
O
OH
O
O-H
O
O
O
O
O
– S
O
– H +
– H2O
–
O
S
O
S
O
trans
retention
–
–
S
S
O
S
O
P
S
O-H
P
OH
OH2
P
OAr
O
¨
P
O
O
+
P
OAr
O
O
O
– S
O
O
– H +
OAr
+
– H2O
O
:OAr
O
OAr
+
O
+
cis
retention
Scheme 4
oxide–hydrogen chloride in 1,4-dioxane. Here, we observed
that the oxidation was indeed retarded by the nitro sub-
stituent but it was accelerated by the methoxy substituent
(Table 4).
gated bases (ClϪ vs. CH3COOϪ) to stabilize the thiophos-
phonium intermediate which leads to the pentacoordinate
species (Scheme 3).
Evidently, our results are in favor of a higher stabilized
[(RO)3PϩSOH, ϪO(CO)CH3] than [(RO)3PϩSOH, ϪCl] inter-
mediate. Even though this hypothesis may perhaps be sup-
ported by results for oxidation of phosphoryl compounds in the
literature,7a,24 there is no doubt that further analysis of kinetic
and stereochemistry results of the oxidation of aryl thiophos-
phates in different protic acid solutions is warranted. We are
now working on the issue.
In addition, when the oxidation of the p-cyano thiophos-
phate 6 in the cis configuration was allowed to proceed for a
longer period (48 h) the cyano group was fully converted into
the carboxy group. However, the cyano group in the trans
epimer was maintained without change after one month of
reaction under the same oxidizing conditions. These results may
be explained by envisioning that in the concerted mechanism
(Scheme 4) the transition state resembles an ideal tetragonal
pyramid geometry (TP) wherein the oxidizing agent and the
cyano group are necessarily closer in the cis- (86Њ) than in the
trans-isomer (105Њ).23
Finally, in order to study the scope of the methodology pro-
posed here for the oxidation of the thiophosphates, we per-
formed some experiments by using acetic acid as the protic
medium. The results summarized in Table 5 indicate that the
stereoselectivity of the oxidation reaction decreases. We think
that this behavior reflects the differing abilities of the conju-
Conclusion
A highly stereospecific oxidation of cyclic six-membered thio-
phosphates 1–7 in their epimeric cis and trans forms was
achieved using a cheap and commercially available solution of
aqueous 30% hydrogen peroxide in hydrogen chloride, using
1,4-dioxane as solvent. The products were obtained with reten-
tion of configuration regardless of the stereochemistry of the
starting thiophosphate. The lack of a dependence of the stereo-
J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286
1285

View Article Online
Table 4 Oxidations-in-competition experiments with cis- or trans-aryl thiophosphates (1, 4 and 7)
Reaction
time/h
% of
Reaction
time/h
% of
Thiophosphate
conversiona
Thiophosphate
conversiona
trans-1
0.12
0.18
0.25
0.33
0.15
0.27
0.37
0.45
0.25
0.48
0.70
0.92
1.15
1.38
1.62
1.85
2.05
1/0.36
1/1.63
cis-1
0.12
0.18
1/7.43
b
1/21.36
b
trans-4
trans-7
1/0.15
1/0.84
cis-4
cis-7
0.13
0.23
0.32
0.38
0.15
0.42
0.65
0.90
1.17
1.40
1.65
1.88
1/0.38
1/6.33
1/4.00
1/167.36
b
b
1/0.04
1/0.11
1/0.25
1/0.49
1/0.88
1/1.62
1/2.79
1/0.12
1/0.27
1/0.60
1/1.02
1/1.83
1/4.29
1/21.04
b
1/8.83
b
a Values are the area ratio of 31P NMR signals of thiophosphate/phosphate. b No starting material was detected.
Table 5 Stereochemistry in the oxidation of thiophosphates (1, 3, 4, 7)
by H2O2–CH3CO2H in 1,4-dioxane–water as solvent
9 W. J. Stec, A. Okruszek and M. Mikolajczyk, Z. Naturforsch. Teil B,
1971, 26, 856.
10 A. Skowronska and E. Krwczyk, Synthesis, 1983, 509.
11 (a) R. Luckenbach and M. Kern, Chem. Ber., 1975, 108, 3533;
(b) M. Mikolajczyk and L. Luczak, Chem. Ind. (London), 1974, 701;
(c) R. Luckenbach, Synthesis, 1973, 307; (d) M. Mikolajczyk and
L. Luczac, Synthesis, 1975, 114; (e) A. Okruszek and W. J. Stec,
Tetrahedron Lett., 1982, 23, 5203.
12 (a) K. S. Bruzik and W. J. Stec, J. Org. Chem., 1990, 55, 6131;
(b) J. Helinski, Z. Skrzypczynski, J. Wasiak and J. Michalski,
Tetrahedron Lett., 1990, 31, 4081.
Thiophosphate
(series cis)
% of
Thiophosphate
(series trans)
% of
retentiona
retentiona
1
3
4
7
74
75
82
1
2
4
7
86
89
84
100
100
a This percentage was calculated by means of the area ratio of the 31P
NMR signals of each oxo product in the crude material.
13 W. J. Stec, A. Okruszek and J. Michalski, J. Org. Chem., 1976, 41,
233.
14 M. Mikolajczyk and J. Luczak, J. Org. Chem., 1978, 43, 2132.
15 A. Okruszek and W. J. Stec, J. Chem. Soc., Chem. Commun., 1984,
117.
16 See also oxidation of thiophosphoryl nucleotides by oxidative
bromination: B. A. Conolly, F. Eckstein and P. M. Cullis, J. Biol.
Chem., 1982, 257, 3382, or by DMSO, chloral or styrene
oxide: P. Guga and A. Okruszek, Tetrahedron Lett., 1984, 25, 2897;
F. Eckstein, Angew. Chem., Int. Ed., 1983, 22, 423; P. Guga and
J. Stec, Tetrahedron Lett., 1983, 24, 3899.
17 B. Gordillo and E. L. Eliel, J. Am. Chem. Soc., 1991, 113, 2172.
18 C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165.
19 B. Gordillo and J. Hernández, Org. Prep. Proc. Int., 1997, 29, 195.
20 B. Gordillo, C. Garduño, G. Guadarrama and J. Hernández, J. Org.
Chem., 1995, 60, 5180.
21 E. L. Eliel, B. Gordillo, P. White and D. Harris, Heteroatom. Chem.,
1997, 8, 509.
chemical outcome on the electronic characteristics at the phos-
phorus center, along with oxidation reactions in competition,
support a concerted pathway as responsible for the oxidation
mechanism.
References
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Paper 8/00849C
© Copyright 1999 by the Royal Society of Chemistry
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J. Chem. Soc., Perkin Trans. 2, 1999, 1281–1286