Construction of the 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine ring system

Article abstract of DOI:10.1071/CH05190

The novel 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine ring system has been prepared by reaction of the sodium salt of diethyl mercaptomethylphosphonate with nitrile oxides, followed by cyclization of the resulting hydroximinoyl sulfide. The stability

Full text of DOI:10.1071/CH05190

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CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 834–836
www.publish.csiro.au/journals/ajc
Construction of the 1,2,3,4-Tetrahydro-1,4,6,2-oxathiazaphosphorine
Ring System
Wynona M. JohnsonA,B and Kathleen A. TurnerA
A CSIRO Molecular and Health Technologies, Clayton South VIC 3169, Australia.
B Corresponding author. Email: noni.johnson@csiro.au
The novel 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine ring system has been prepared by reaction of the
sodium salt of diethyl mercaptomethylphosphonate with nitrile oxides, followed by cyclization of the resulting
hydroximinoyl sulfide. The stability of the new ring system is investigated.
Manuscript received: 16 August 2005.
Final version: 21 October 2005.
O
O
N
Heterocyclic ring systems continue to play a pivotal role in
the development of new pharmaceuticals and agrochemi-
cals. New ring systems can provide scaffolds and building
blocks for the exploration of chemical space free of patent
competition.
Cl
NOH
Cl
Cl
N
P
OEt
OEt
OEt
P
ϩ
Ph
N
H
O
Cl
Cl
Ph
2d
3
1
As part of our interest in constructing novel ring sys-
tems for this purpose, we have investigated the synthesis of
oxadiaza- and oxathiaza-phosphorines.
Scheme 1. Synthesis of 1,2,3,4-tetrahydro-1,4,6,2-oxadiazaphos-
phorine ring system 1.
We reported[1] the first preparation of the 1,2,3,4-
tetrahydro-1,4,6,2-oxadiazaphosphorine ring system 1 by
a one-step process from 2,6-dichlorobenzonitrile oxide
generated in situ from the corresponding hydroximinoyl
chloride 2d and diethyl benzylaminomethylphosphonate 3
(Scheme 1).
It was envisaged that a similar process could be used
to prepare the related 1,2,3,4-tetrahydro-1,4,6,2-oxathiaza-
phosphorine ring system shown in compound 6.
R
NOH
S
R
NOH
Cl
OEt
OEt
OEt
OEt
Et3N, THF
EtOH
P
ϩ
NaS
P
O
O
R1
R1
2a–2e
4
5a–5e
NaOH
C6H6
O
O
N
OH
R
P OEt
R
N
O
The sodium salt of diethyl mercaptomethylphosphonate 4
can be readily prepared from S-bromomethyl thioacetate.[2]
Treatment of 4 with nitrile oxides in the presence of several
bases did not, however, produce the corresponding tetrahy-
drooxathiazaphosphorine 6 but the intermediate hydroximi-
noyl sulfide 5, Scheme 2.∗
Cyclization of hydroximinoyl sufide 5 in the presence of
several bases was investigated with little success: Nitroge-
nous bases, such as collidine and diisopropylethylamine,
returned starting material, and piperidine resulted in the salt
of the corresponding phosphonic acid. Sodium ethoxide,
sodium hydride, and lithium diisopropyl amide did not react
under mild conditions, and under more forcing conditions
gave a mixture of unidentified products.
S
P
MeOH
OEt
OMe
R1
R1
7a
6a–6e
R
R1 Yield [%]
of 5 of 6
48
77
a
H
H
H
H
F
67
57
56
26
45
b
c
d
e
Br 76
Cl Cl 71
Cl 53
F
Scheme 2. Synthesis of 2-ethoxy-1,2,3,4-tetrahydro-1,4,6,2-oxathia-
zaphosphorine 2-oxides 6.
Residual moisture on the sodium hydroxide was removed
as the benzene azeotrope before addition of the sulfide 5.
Failure to remove this moisture resulted in only the hydrolysis
product being obtained.
Cyclization of 5 was ultimately effected by treatment with
anhydrous powdered sodium hydroxide in benzene to give the
desired 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorines 6.
∗ This reaction was not investigated under the specific conditions ultimately used to provide the oxathiazaphosphorines 6.
© CSIRO 2005 10.1071/CH05190
0004-9425/05/120834

1,2,3,4-Tetrahydro-1,4,6,2-oxathiazaphosphorine Ring System
835
This ring system demonstrates similar stability to the oxa-
diazaphosphorine system.[1] The oxathiazaphosphorine ring
compounds can be stored for extended periods in a sealed
container in the freezer. Some examples of compounds 6
were not stable to recrystallization and consequently accurate
melting points could not be obtained in these cases. It was
found that compound 6a remained unchanged after stirring
at room temperature or at 50◦C for seven days with a two-
fold excess of water in acetonitrile. After stirring for seven
days in dry methanol ∼10% of the heterocyclic ring system
had been opened, whereas the ring system was completely
opened after 18 h in dry methanol at 60◦C to give compound
7a as a mixture of E and Z isomers.
In conclusion, we have developed a short, efficient syn-
thesis of 1,4,6,2-oxathiazaphosphorines. Their instability to
ring-opening limits their use as building blocks for pharma-
ceuticals and agrochemicals containing the six-membered
ring system. However, their susceptibility to nucleophilic
attack at phosphorus could make them useful intermediates
for preparation of a wide variety of substituted phosphorus
species.
Diethyl S-Benzohydroximinoylthiomethylphosphonate 5a
White crystals, 48% yield, mp 75–77◦C. (Found: C 47.8, H 5.9,
N 4.9%. C12H18NO4PS requires C 47.5, H 6.0, N 4.6%.) νmax
(KBr)/cm−1 3207 (OH), 1232 (P=O). δH 7.48–7.60 (2H, m, ArH),
7.35–7.45 (3H, m, ArH), 4.12 (4H, dq, J 7, 8, 2 × CH2O), 3.00 (2H,
d, J 14, CH2P), 1.30 (6H, t, J 7, CH3). δC 152.4 (JPC 6.5), 132.9, 129.8,
128.8, 128.6, 63.0 (JPC 5.1), 25.1 (JPC 149.0), 16.3 (JPC 5.8). δP 23.8.
m/z (APCI) 326 (38%, [M + Na]+), 207 (100), 130 (69).
Diethyl S-2ꢀ-Fluorobenzohydroximinoylthiomethylphosphonate 5b
White crystals, 77% yield, mp 104–105◦C. (Found: C 45.1, H
5.4, N 4.6%. C12H17FNO4PS requires C 44.9, H 5.3, N 4.4%.) νmax
(KBr)/cm−1 3201 (OH), 1233 (P=O). δH 7.31–7.47 (2H, m, ArH),
7.04–7.23 (2H, m, ArH), 4.09 (4H, dq, J 7, 8, 2 × CH2O), 2.79 (2H,
d, J 15, CH2P), 1.27 (6H, t, J 7, CH3). δC 159.8 (JFC 250.7), 149.2 (JPC
8.0), 131.9 (JFC 8.7), 131.6 (JFC 2.2), 124.6 (JFC 3.6), 120.2 (JFC 15.6),
116.0 (JFC 21.0), 63.2 (JPC 6.5), 24.3 (JPC 147.5, JFC 1.5), 16.2 (JPC
5.9). δP 23.2. m/z (APCI) 344 (77%, [M + Na]+), 207 (100), 130 (21).
Diethyl S-2ꢀ-Bromobenzohydroximinoylthiomethylphosphonate 5c
White crystals, 76% yield, mp 150–152◦C. (Found: C 37.6, H 4.6,
N 3.9%. C12H17BrNO4PS requires C 37.7, H 4.5, N 3.7%.) νmax
(KBr)/cm−1 3220 (OH), 1244 (P=O). δH 7.60 (1H, m, J 8, ArH),
7.22–7.41 (3H, m, ArH), 4.09 (4H, dq, J 7, 8, 2 × CH2O), 2.66 (2H, d, J
16, CH2P), 1.28(6H, t, J7, CH3). δC 153.4(JPC 9.5), 133.1, 133.0, 131.8,
131.3, 127.8, 123.3, 63.1 (JPC 6.5), 24.2 (JPC 146.1), 16.3 (JPC 6.5). δP
23.2. m/z (APCI) 785 (17%, [2M + Na]+), 404 (38%, [M + Na]+), 207
(100), 130 (39).
Experimental
Melting points were determined on a Bausch & Lomb hot-stage melt-
ing point apparatus and are uncorrected. Microanalyses were performed
by the Campbell Microanalytical Laboratory (Dunedin, New Zealand).
Infrared spectra were measured on a Perkin–Elmer 842 infrared spec-
trophotometer. 1H, 13C, and 31P NMR spectra were recorded on a Bruker
AC200 at 200, 50.3, and 81.0 MHz respectively, or on a Bruker AV400
at 400 and 100.6 MHz, respectively, or a Bruker DRX500 at 500 and
125.8 MHz, respectively. Chemical shifts were measured in ppm rela-
tive to CDCl3 and then related to tetramethylsilane (1H, 13C). H3PO4
was used as an external standard for 31P NMR spectra. Positive- and
negative-ion atmospheric pressure chemical ionization (APCI) mass
spectra were acquired with a VG Platform mass spectrometer using
a cone voltage of 50V and the source was maintained at 100◦C. High-
resolution electron impact mass spectra (HR-EIMS) were recorded on
a ThermoQuest MAT 95XL, using an ionization energy of 70 eV. Accu-
rate mass measurements were obtained with a resolution of 5000–10 000
using perfluorokerosene (PFK) as the reference compound.
Diethyl S-2ꢀ,6ꢀ-Dichlorobenzohydroximinoylthiomethyl-
phosphonate 5d
White crystals, 71% yield, mp 144–145◦C. (Found: C 38.9, H 4.4,
N 3.9%. C12H16Cl2NO4PS requires C 38.7, H 4.3, N 3.8%.) νmax
(KBr)/cm−1 3212 (OH), 1243 (P=O). δH 7.27–7.42 (3H, m, ArH), 4.13
(4H, dq, J 7, 8, 2 × CH2O), 2.66 (2H, d, J 18, CH2P), 1.32 (6H, dt, J
0.7, 7, CH3). δC 150.5 (JPC 12.4), 135.7, 131.6, 130.0, 128.3, 63.2 (JPC
5.8), 23.7 (JPC 143.8), 16.3 (JPC 6.0). δP 23.8. m/z (APCI) 393 (100%,
[M + Na]+), 207 (67).
Diethyl S-2ꢀ-Chloro-6ꢀ-fluorobenzohydroximinoylthiomethyl-
phosphonate 5e
White crystals, 53% yield, mp 139–141◦C. (Found: C 40.7, H 4.7,
N 4.1%. C12H16ClFNO4PS requires C 40.5, H 4.5, N 3.9%.) νmax
(KBr)/cm−1 3143 (OH), 1218 (P=O). δH 7.22–7.43 (2H, m, ArH), 7.07
(1H, dt, J 1, 8, ArH), 4.11 (4H, dq, J 7, 8, 2 × CH2O), 2.70 (2H, d, J 16,
CH2P), 1.30 (6H, t, J 7, CH3). δC 160.8 (JFC 253.6), 146.9 (JPC 10.2),
135.3 (JFC 3.8), 132.0 (JFC 9.4), 125.6 (JFC 3.6), 119.8 (JFC 20.4), 114.6
(JFC 21.8), 63.2 (JPC 6.5), 23.9 (JPC 145.3), 16.2 (JPC 6.5). δP 22.7. m/z
(APCI) 378 (47%, [M + Na]+), 207 (100), 129 (35).
Synthesis of Diethyl S-Benzohydroximinoylthiomethylphosphonates 5
A solution of diethyl S-acetylthiomethylphosphonate[2] (20 mmol) in
anhydrous ethanol (8 mL) was added to a stirred solution of sodium
ethoxide (20 mmol) in ethanol (8 mL) maintained under nitrogen. The
resulting mixture was stirred at room temperature for 2 h. A solution
of the hydroximinoyl chloride (20 mmol) in anhydrous tetrahydro-
furan (100 mL) was prepared. Half of this solution was added to
that of the phosphonate, followed by triethylamine (20 mmol). The
remainder of the hydroximinoyl chloride solution (50 mL) was then
added and the resulting mixture was stirred at room temperature (1–6
days) before being concentrated under reduced pressure. The residue
was taken up in ethyl acetate (500 mL) and water (250 mL). The
organic layer was removed and washed with water (250 mL) and brine
(250 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was dissolved in boiling ether, the solution was
allowed to cool and the crystals were filtered off to give the diethyl
S-benzohydroximinoylthiomethylphosphonate 5. Additional material
was obtained by radial thin-layer chromatography of the filtrate on
4 mm layers of Merck Kieselgel 60 PF254 using successive elution with
dichloromethane, 1% methanol in dichloromethane, and 2% methanol
in dichloromethane.
Synthesis of 1,2,3,4-Tetrahydro-1,4,2,6-oxathiazaphosphorines 6
Sodium hydroxide pellets (ground and weighed under nitrogen;
0.6 mmol) were added under a stream of nitrogen to anhydrous benzene
(50 mL) contained in a flask connected to a Dean–Stark trap main-
tained under nitrogen. The suspension was heated at reflux until 5 mL
of benzene had collected, and was then allowed to cool a little before
the hydroximinoylphosphonate (0.6 mmol) was added under a stream of
nitrogen. The resulting mixture was heated at reflux for 2 h and the first
5 mL of benzene in the Dean–Stark trap was discarded. The suspension
was cooled and filtered through glass-fibre paper. The filter cake was
washed with dry benzene and the combined filtrates were concentrated
under reduced pressure.
2-Ethoxy-5-phenyl-1,2,3,4-tetrahydro-1,4,6,2-
oxathiazaphosphorine 2-Oxide 6a
White crystals, 67% yield, mp 65–68◦C. (HR-EIMS found: 257.026.
C10H12NO3PS requires 257.027.) δH 7.71–7.80 (2H, m, ArH), 7.37–
7.59 (3H, m, ArH), 4.18–4.43 (2H, m, CH2O), 3.49 (1H, dd, J 14, 17,

836
W. M. Johnson and K. A. Turner
CH2P), 3.20 (1H, dd, J 14, 14, CH2P), 1.39 (3H, t, J 7, CH3). δC 163.5
(JPC 20.4), 132.2, 131.7, 128.8, 128.0, 63.6 (JPC 6.5), 21.0 (JPC 137.3),
16.1 (JPC 5.8). δP 12.3. m/z (EI) 257 (36%, M+•), 119 (100).
15, CH2P), 1.40 (3H, t, J 7, CH3). δC 160.4 (JFC 254.3), 155.5 (JPC
26.1), 134.7 (JPC 2.9), 132.9 (JFC 10.2), 125.8 (JFC 3.6), 119.3 (JFC
21.1), 114.6 (JFC 21.1), 63.7 (JPC 6.5), 21.0 (JPC 135.9), 16.1 (JPC 6.5).
δP 5.4. m/z (EI) 309 (11%, M+•), 173 (49), 171 (100), 155 (51), 93 (49).
2-Ethoxy-5-(2-fluorophenyl)-1,2,3,4-tetrahydro-
1,4,6,2- oxathiazaphosphorine 2-Oxide 6b
Ethyl Methyl S-Benzohydroximinoylthiomethylphosphonate 7a
White semi-solid, 57% yield. (HR-EIMS found: 275.017.
C10H11FNO3PS requires 275.017.) δH 7.42–7.68 (2H, m, ArH), 7.10–
7.31 (2H, m, ArH), 4.26–4.46 (2H, m, CH2O), 3.55 (1H, dd, J 14, 17,
CH2P), 3.21 (1H, dd, J 14, 15, CH2P), 1.44 (3H, t, J 7, CH3). δC 159.7
(JFC 252), 158.4 (JFC 2, JPC 24), 133.3 (JFC 8.3), 130.8 (JFC 2), 124.6
(JFC 4), 119.7 (JFC 2), 116.6 (JFC 22.2), 63.7 (JPC 6.5), 21.5 (JPC 135.9),
16.1 (JPC 6.5). δP 7.6. m/z (EI) 275 (27%, M+•), 137 (100), 121 (40).
2-Ethoxy-5-phenyl-1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine
2-oxide 6a (10 mg, 0.04 mmol) was heated in dry methanol (1 mL) at
60◦C for 18 h. The solvent was removed and the product was isolated by
preparative HPLC on anAlltima C18 5u column, using 50% methanol in
water as the mobile phase, to give two products, E and Z oxime isomers
[2 mg (E isomer), 5 mg (Z isomer), 64%]. Z isomer: White crystals. δH
7.54 (1H, br s, NOH), 7.43 (2H, d, J 8, ArH), 7.33 (2H, t, J 8, ArH), 7.14
(1H, t, J 8, ArH), 4.15–4.23 (2H, m, CH2O), 3.81 (3H, d, J 11, CH3O),
3.33 (2H, d, J 13, CH2P), 1.35 (3H, t, J 7, CH3). δC 132.9, 129.9, 129.0,
128.6, 63.3 (JPC 6), 53.4 (JPC 7), 22.7 (JPC 152), 16.4 (JPC 6). δP 25.2.
m/z (APCI) 312 (100, [M + Na]+), 193 (36).‡ E isomer: (HR-EIMS
found: 289.053. C11H16NO4PS requires 289.053.) δH 7.52–7.58 (2H,
m, ArH), 7.40–7.46 (3H, m, ArH), 4.08–4.17 (2H, m, CH2O), 3.74 (3H,
d, J 11, CH3O), 2.96 (2H, d, J 14, CH2P), 1.32 (3H, t, J 7, CH3). δC
132.2, 129.9, 129.0, 128.7, 63.1 (JPC 6), 53.2 (JPC 6), 24.8 (JPC 149),
16.3 (JPC 6). δP 23.6. m/z (APCI) 312 (100, [M + Na]+), 272 (100), 244
(46), 193 (91), 169 (66).
5-(2-Bromophenyl)-2-ethoxy-1,2,3,4-tetrahydro-
1,4,6,2-oxathiazaphosphorine 2-Oxide 6c
White crystals, 56% yield.† δH 7.60–7.70 (1H, m, ArH), 7.29–7.44
(3H, m,ArH), 4.28–4.48 (2H, m, CH2O), 3.56 (1H, dd, J 14, 17, CH2P),
3.24 (1H, dd, J 14, 15, CH2P), 1.46 (3H, t, J 7, CH3). δC 162.1 (JPC
24.4), 133.7, 132.6, 132.2, 131.0, 127.6, 122.8, 63.7 (JPC 6.8), 21.6 (JPC
136.6), 16.3 (JPC 5.9). δP 7.7. m/z (EI) 319 (71%, [M − 18]), 317 (68),
199 (100), 197 (90), 185 (81), 183 (86).
5-(2,6-Dichlorophenyl)-2-ethoxy-1,2,3,4-tetrahydro-
1,4,6,2-oxathiazaphosphorine 2-Oxide 6d
References
White crystals, 26% yield. (HR-EIMS found: 324.949. C10H10
Cl2NO3PS requires 324.949.) δH 7.24–7.37 (3H, m, ArH), 4.20–4.41
(2H, m, CH2O), 3.57 (1H, dd, J 14, 17, CH2P), 3.21 (1H, dd, J 14, 15,
CH2P), 1.38 (3H, t, J 7, CH3). δC 158.8 (JPC 25.4), 135.3, 132.2, 129.3,
128.4, 63.7 (JPC 7.3), 21.0 (JPC 136.6), 16.2 (JPC 5.8). δP 6.5. m/z (EI)
325 (12%, M+•), 189 (81), 187 (100).
[1] W. M. Johnson, A. Faux, G. Fallon, Heterocycles 1999, 51, 2479.
[2] G. K. Farrington, A. Kumar, F. C. Wedler, Org. Prep. Proc. Intl
1989, 21, 390.
5-(2-Chloro-6-fluorophenyl)-2-ethoxy-1,2,3,4-tetrahydro-
1,4,6,2-oxathiazaphosphorine 2-Oxide 6e
Colourless oil, 45% yield. (HR-EIMS found: 308.979. C10H10
ClFNO3PS requires 308.979.) δH 6.97–7.65 (3H, m, ArH), 4.20–4.42
(2H, m, CH2O), 3.53 (1H, dd, J 14, 17, CH2P), 3.19 (1H, dd, J 14,
† A molecular ion was not observed for this compound.
‡ This compound was unstable to EI conditions so we were unable to obtain HRMS data.