A convenient synthesis of phosphonothioic acids

Article abstract of DOI:10.1016/S0040-4020(02)01616-2

A method for the convenient synthesis of phosphonothioates, or phosphonothioic acids, is reported. A significant advantage of the method is the alleviation of the need for purification of intermediates, other than washing with water. No chromatography is needed and the only purification step is the crystallization of the final product. The method uses standard reagents and should be applicable to the synthesis of phosphonothioic acids bearing a range of functional groups.

Full text of DOI:10.1016/S0040-4020(02)01616-2

Tetrahedron 59 (2003) 595–599
A convenient synthesis of phosphonothioic acids
†
Krzysztof Swierczek, John W. Peters and Alvan C. Hengge
*
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
Received 31 July 2002; revised 12 December 2002; accepted 12 December 2002
Abstract—A method for the convenient synthesis of phosphonothioates, or phosphonothioic acids, is reported. A significant advantage of
the method is the alleviation of the need for purification of intermediates, other than washing with water. No chromatography is needed and
the only purification step is the crystallization of the final product. The method uses standard reagents and should be applicable to the
synthesis of phosphonothioic acids bearing a range of functional groups. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Thiophosphonates, or phosphonothioates acids and their
salts (1), have been the subject of a number of patents and
publications involving various uses including antiviral
compounds,1–4 plant growth regulators,5 inhibitors of a
number of different enzymes,6,7 and as lubricants,8 among
others. The reported methods of preparation vary consider-
ably. While these methods are suitable for specific
compounds they often utilize conditions that would
preclude application to the synthesis of derivatives bearing
different or more labile functional groups. Methyl and, to a
lesser extent, ethyl esters have often been used as protecting
groups during syntheses of phosphates and phosphonates.
However, while typically dimethyl or diethyl groups of
phosphonate esters can be removed by treatment with
trimethylsilyl iodide or trimethylsilyl bromide, this method
fails or gives low yields of thio derivatives like 1.9
Deprotection of the dibenzyl esters of a,a-difluoromethyl-
enephosphonothioic acids has been reported using sodium
in liquid ammonia.10 Recently the deprotection of diethyl
a,a-difluoromethylenephosphonothioic acids via a thiono–
thiolo rearrangement followed by Pd-catalyzed deallylation
has been reported.11
We sought a synthetic approach that would be convenient,
used standard reagents and that would allow the use of the
commonly used methyl ester protecting group, which would
aid the generality of the method. We report a synthetic
approach that combines a number of steps consisting of
reactions which have been individually reported before but
which, when combined, gives an approach that is con-
venient and that also offers a significant practical advantage
in that purification of intermediates is unnecessary. The
multistage synthesis for the compounds reported here
requires only a single purification step, namely, a simple
crystallization of the final product. The phosphonothioic
acids shown in Scheme 1 were prepared using this method.
The general method involves the Michaelis–Becker alkyl-
ation by an alkyl halide of the anion of dimethyl
phosphonothioate 3,12 which can be easily made by treating
dimethyl phosphite with Lawesson’s reagent. While
synthetic approaches have been reported that perform this
oxo–thio conversion at later stages,10 the susceptibility of
other functional groups to Lawesson’s reagent led us to do
this at the earliest stage possible in order to favor the
generality of the approach.
We found the dimethyl esters 4 to be difficult to
deprotect, as has been reported for other dialkyl esters
of phosphonothioic acids.9 In our hands, for example,
propylphosphonothioic acid O,O-dimethyl ester 4a did
not react with iodotrimethylsilane at room temperature or
in boiling dichloromethane, and in refluxing tetrachloro-
methane decomposition resulted. However we found
that a two-step rearrangement involving mono-deprotec-
tion using trimethylamine under mild conditions to give
5 followed by reaction with methyl iodide gives the
Keywords: phosphonothioic acid; phosphonothioate ester; thiono-thiolo
rearrangement.
*
Corresponding author. Tel.: þ1-4357973442; fax: þ1-4357973390;
O,S-dimethyl ester 7 which, in contrast to the
O,O-dimethyl ester, readily undergoes deprotection by
e-mail: hengge@cc.usu.edu
On leave from the Silesian University of Technology, Gliwice, Poland.
†
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01616-2

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K. Swierczek et al. / Tetrahedron 59 (2003) 595–599
Scheme 1. Intermediates 4–7 were used in crude form and were not characterized. PTC, phase transfer catalysis.
trimethylsilyl iodide to give the disilyl ester 6. This in
turn is easily and rapidly hydrolyzed to give the final
product.
butylamine,16 thiourea17 or sodium iodide.11 Specifically,
refluxing 4a with n-butylamine in benzene for 24 h gave
11% of recovered substrate, and, after alkylation with
iodomethane, only 24% of propylphosphonothioic acid O,S-
dimethyl ester 7a was obtained. A similar reaction with
thiourea in boiling ethanol gave 14% recovered substrate
and, after alkylation, 22% of 7a. An attempt carried out with
sodium iodide in refluxing 2-butanone gave only decompo-
sition products.
In practice only the most rudimentary purification of
intermediates is necessary. The crude O,O-dimethyl esters
4 are mono-deprotected with trimethylamine13 to give the
intermediates 5; two of them precipitate from solution. The
crude salts of 5 (or their water solutions) are treated with
iodomethane to form the corresponding O,S-dimethyl ester
7.14,15 Again, this intermediate need not be purified beyond
simple washing with water, drying, and removal of
volatiles. The O,S-dimethyl ester 7 is easily di-dealkylated
by iodotrimethylsilane under mild conditions. After
removal of volatile materials under reduced pressure the
silyl esters 6 are hydrolyzed with either methanol or water.
This crude material, after removal of volatiles, is dissolved
in acetone and treated with either trimethyl amine or with
aniline to give the salts of the final products, which
crystallize from the reaction mixture.
3. Conclusion
Each of the individual steps in this synthetic approach has
literature precedent, but the combination affords a method
that is convenient, uses only standard and mild reagents, and
that should be general. Even the product with the lowest
final yield (24.8%) implies an average yield for the five
steps of about 76%. A significant advantage of this approach
is the alleviation of the need for purification of inter-
mediates, and the absence of the need for chromatographic
separations.
Although the demethylation with trimethylamine13 is slow it
was found to be superior to other methods utilizing n-

K. Swierczek et al. / Tetrahedron 59 (2003) 595–599
597
4. Experimental
chloride (1.81 g, 7.94 mmol) in CH2Cl2 (200 mL) was
cooled on an ice bath and a solution of NaOH (32 g,
0.8 mol) in water (32 mL) was added slowly with vigorous
stirring. The ice bath was removed and the reaction mixture
was stirred overnight. The reaction mixture was then
washed with water, dried (MgSO4) and solvent was
removed under reduced pressure to afford crude 4a
(9.4 g). This material was dissolved in acetone (50 mL),
liquid Me3N (20 mL) was added, and the mixture left at
room temperature for 7 days. Precipitated white crystals
were filtered off, washed with acetone, and dried over P4O10
to give extremely hygroscopic crude 5a (7.40 g). This
material was dissolved in CH2Cl2 (250 mL), MeI (9 mL)
was added (a precipitate formed immediately) and the
suspension was refluxed for 3 h. The mixture was cooled
and washed with water, dried (MgSO4), and solvent was
removed under reduced pressure to give crude 7a (4.48 g).
This material was dissolved in CH2Cl2 (20 mL), cooled on
an ice bath, and Me3SiI (12.36 g) was added. After 1 h the
ice bath was removed and the solution was left overnight.
Volatiles were then removed under reduced pressure, and
the residual red oil was dissolved in MeOH (50 mL).
Solvent was then removed under reduced pressure, the
residual red oil was dissolved in acetone (20 mL) and
saturated with gaseous Me3N (the solution became color-
less). After removal of solvent under reduced pressure the
colorless oil slowly crystallized to give the trimethylam-
monium salt of 1a (5.54 g, 35% total yield from dimethyl
thiophosphite). An analytical sample was recrystallized
4.1. General
All chemicals and solvents were purchased from commer-
cial sources and used without purification. All melting
points are uncorrected. All reactions with thiophosphorus
compounds were carried out under a nitrogen atmosphere.
Elemental analyses were performed by Atlantic Microlabs.
1H NMR spectra were recorded at 400 MHz in DMSO-d6
solutions using TMS as an internal standard. 13C NMR
spectra were recorded at 100 MHz in D2O using 3-(tri-
methylsilyl)propionic-2,2,3,3-d4 acid sodium salt as an
internal standard or in DMSO-d6 solutions using TMS as
internal standard. 31P NMR spectra were recorded at
162 MHz in DMSO-d6 solutions using 85% phosphoric
acid as an external standard.
4.2. Starting materials
Lawesson’s reagent was prepared from anisole and P4S10.18
Freshly prepared reagent gave better results than the
commercial product. 2a and 2b were commercial products.
6-Bromohexanoic acid tert-butyl ester 2c was synthesized
by passing isobutylene through solution of 6-bromo-
hexanoic acid in CH2Cl2 in presence of concentrated
19
H2SO4 and used directly without purification in the next
stage. Dimethyl thiophosphite 3 was obtained by refluxing
dimethyl phosphite with Lawesson’s reagent in benzene.20
7-Methylnaphthalene-1-carboxylic acid was prepared by
acetylation of 2-methylnaphthalene to 1-(7-methyl-naph-
thalen-1-yl)-ethanone followed by oxidation with
bromine.21
1
from acetone–Et2O mixture. Mp 96–1008C. H NMR d
C
2.64 (s, 9H), 1.62–1.48 (m, 4H), 0.92 (t, J¼7.1 Hz, 3H). 13
NMR (D2O) d 47.6 (s, N–CH3), 42.5 (d, J¼100.7 Hz,
P–CH2), 20.1 (d, J¼3.8 Hz, CH3), 17.5 (d, J¼18.3 Hz,
CH2). 31P NMR d 75.0. Anal. Calcd for C6H18NO2PS: C,
36.17; H, 9.11; N, 7.03. Found: C, 36.10; H, 9.01; N, 6.94.
4.2.1. 7-Bromomethylnaphthalene-1-carboxylic acid. A
suspension of N-bromosuccinimide (6.23 g, 0.035 mol) in a
solution of 7-methylnaphthalene-1-carboxylic acid (6.2 g,
0.033 mol) in CCl4 (200 mL) was refluxed in the presence
of a trace of benzoyl peroxide for 2 h. The resulting white
suspension was evaporated to dryness under reduced
pressure, washed with hot water and dried to give the
crude product (8.46 g, 96%). An analytical sample was
recrystallized from benzene–ethanol mixture. Mp 209.5–
2118C. 1H NMR d 13.20 (bs, 1H), 8.91 (bs, 1H), 8.30–7.95
(m, 3H), 7.72–7.54 (m, 2H), 4.92 (s, 2H). MS m/e: 266 (7,
Mþ), 185 (100, M2Br), 139 (30), 129 (13). Anal. Calcd for
C12H9BrO2: C, 54.37; H, 3.42. Found: C, 54.45; H, 3.44.
4.2.4. Benzylphosphonothioic acid (1b), trimethyl-
ammonium salt. A mixture of 3 (10.02 g, 79.5 mmol), 2b
(11.07 g, 87.5 mmol), dibenzo-18-crown-6 (1.43 g,
4 mmol) and anhydrous K2CO3 (16.49 g, 0.119 mol) in
acetonitrile (240 mL) was vigorously stirred for 3 days.
Insoluble material was filtered off, acetonitrile was removed
by rotary evaporation, and the residue dissolved in CH2Cl2
(100 mL). This solution was washed with water, dried
(MgSO4), and the solvent was removed under reduced
pressure. The residual material was dissolved in warm
acetone (100 mL), cooled, and a precipitate of crown ether
(1.08 g) was filtered off. Removal of acetone from the
filtrate yielded crude 4b (14.24 g) contaminated mainly with
remaining crown ether and dibenzyl sulfide (according to
GCMS). The crude 4b was dissolved in acetone (50 mL),
liquid Me3N (30 mL) was added, and the mixture was left in
room temperature for 7 days. Precipitated white crystals
were filtered off, washed with acetone, and dried over P4O10
to give crude 5b (12.30 g). This material was dissolved in
CH2Cl2 (300 mL), MeI (14 mL) was added (a precipitate
formed immediately) and the resulting suspension was
refluxed for 3 h. After cooling the mixture was washed with
water, dried (MgSO4), and the solvent removed under
reduced pressure to give crude 7b (8.37 g) as white crystals.
A portion of this material (3.67 g) was dissolved in CH2Cl2
(20 mL), cooled with an ice bath, and Me3SiI (7.87 g) was
added. After 1 h the ice bath was removed and the solution
4.2.2. 7-Bromomethylnaphthalene-1-carboxylic acid
tert-butyl ester (2d). Isobutylene was passed through
suspension of 7-bromomethylnaphthalene-1-carboxylic
acid (10.4 g, 39.2 mmol) in CH2Cl2 (150 mL) in presence
of concentrated H2SO4 (1 mL) for 3 h, then mixture was
stirred overnight. The resulting deep green solution was
washed with a saturated solution of NaHCO3, dried
(MgSO4) and the solvent was removed under reduced
pressure to give crude 2d (11.2 g, 88.8%) as a deep green
oil. This compound was directly used for the subsequent
Michaelis–Becker alkylation without further purification.
4.2.3. Propylphosphonothioic acid (1a), trimethyl-
ammonium salt. A solution of 3 (10.00 g, 79.4 mmol), 2a
(11.71 g, 95.2 mmol) and triethylbenzylammonium

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K. Swierczek et al. / Tetrahedron 59 (2003) 595–599
was left overnight. Volatiles were removed under reduced
pressure, and the residual red oil was dissolved in MeOH
(50 mL). Solvent was then removed under reduced pressure,
the residual red oil dissolved in acetone (20 mL) and
saturated with gaseous Me3N (the solution became color-
less). After removal of solvent under reduced pressure the
colorless oil slowly crystallized to give the trimethylam-
monium salt of 1b (3.49 g, 41% total yield from 3). An
analytical sample was recrystallized from acetone. Mp
4.2.6. 6-Thiophosphonohexanoic acid (1c), p-methyl-
anilinium salt. Using the same procedure as described
above from 3 (9.12 g, 72.4 mmol), an aqueous solution
(100 mL) of crude 5c was obtained. To this solution EtOH
(200 mL) and MeI (20 mL) were added, and the mixture
was refluxed for 3 h. Solvents were then removed by rotary
evaporation, and the residue was dissolved in AcOEt
(200 mL). This mixture was extracted with water dried
(MgSO4) and solvents were removed under reduced
pressure to give crude 7d (10.33 g). A portion of this
material (3.22 g) was reacted with Me3SiI as described for
1c, then treated with cold water (10 mL) instead of MeOH,
volatiles were removed under vacuum, and the residue was
dissolved in Et2O (10 mL) and p-toluidine (3.5 g) in ether
(10 mL) was added. The resulting white precipitate was
collected by filtration, washed repeatedly with ether, and
dried to give the p-methylanilinium salt of 1d (2.42 g, 34%
total yield from dimethyl thiophosphite). An analytical
sample was recrystallized from EtOH–acetone–Et2O
1
152–1548C (with decomposition). H NMR d 7.32–7.09
(m, 5H), 3.03 (d, J¼18.3 Hz), 2.48 (s, 9H). 13C NMR (D2O)
d 137.9 (d, J¼8.4 Hz, Caromatic), 132.8 (d, J¼5.3 Hz,
CHaromatic), 131.2 (d, J¼3.8 Hz, CHaromatic), 129.2 (d,
J¼3.8 Hz, CHaromatic), 47.9 (d, J¼95.4 Hz, P–CH2), 47.6
(s, N–CH3). 31P NMR d 68.1. IR (KBr, cm21) 1599, 1478,
1452, 1066, 1028, 900, 784, 697, 594. Anal. Calcd for
C10H18NO2PS: C, 48.57; H, 7.34; N, 5.66. Found: C, 48.66;
H, 7.36; N, 5.69.
4.2.5. 6-Thiophosphonohexanoic acid methyl ester (1c0),
anilinium salt. A solution of 3 (4.56 g, 36.2 mmol), 2c
(10.00 g, 39.8 mmol) and triethylbenzylammonium
chloride (0.82 g, 3.62 mmol) in CH2Cl2 (100 mL) was
cooled on an ice bath and a solution of NaOH (14.5 g,
0.362 mol) in water (14.5 mL) was added slowly with
vigorous stirring. The ice bath was removed and the mixture
was stirred for 3 days, then washed with water, dried
(MgSO4), and the solvent removed under reduced pressure
to give crude 4c (8.00 g). This material was dissolved in
acetone (30 mL), liquid Me3N (20 mL) was added, and the
mixture was left at room temperature for 2 weeks. The
solvent was removed by rotary evaporation and the residue
was dissolved in water (30 mL), then extracted with
CH2Cl2. The aqueous solution of 5c was concentrated to
small volume and mixed with CH2Cl2 (100 mL). MeI
(10 mL) was added (a precipitate formed immediately) and
the suspension was refluxed for 3 h. After cooling the
mixture was washed with water, dried (MgSO4), and the
solvent was removed under reduced pressure to give crude
7c (4.06 g). This material was dissolved in CH2Cl2 (20 mL),
cooled on ice bath, and Me3SiI (8.96 g) was added. After 1 h
the bath was removed and the solution was left overnight.
Volatiles were removed under vacuum, and the residual red
oil was boiled with MeOH (50 mL). Solvent was then
removed under reduced pressure, the red residual oil
dissolved in MeOH (10 mL) and aniline (4 g) was added
(the solution became colorless). After removing the solvent
under vacuum, Et2O (20 mL) was added and the resulting
white precipitate was collected by filtration, washed with
ether, and dried to give the anilinium salt of 1c0, (2.87 g,
25% total yield from 3). An analytical sample was
recrystallized from acetone–Et2O mixture. Mp 107–
1088C. 1H NMR d 7.03–6.97 (m, 2H), 6.58–6.45 (m,
3H), 3.58 (s, 3H), 2.28 (t, J¼7.4 Hz), 1.80–1.68 (m, 2H),
1.60–1.46 (m, 4H), 1.40–1.26 (m, 2H). 13C NMR (DMSO-
d6) d 173.4 (s, CvO), 148.3 (s, Caromatic), 128.9 (s,
CHaromatic), 116.0 (s, CHaromatic), 114.1 (s, CHaromatic),
51.2 (s, O–CH3), 35.9 (d, J¼106.0 Hz, P–CH2), 33.2 (s,
CH2), 29.1 (d, J¼17.5 Hz, CH2), 24.1 (s, CH2), 22.9 (d,
J¼3.1 Hz, CH2). 31P NMR d 87.0. IR (KBr, cm21) 1735
(CvO), 1497, 1210, 1022, 915, 742, 689, 594, 502. Anal.
Calcd for C13H22NO4PS: C, 48.89; H, 6.94; N, 4.39. Found:
C, 49.02; H, 6.91; N, 4.31.
mixture. Mp 167–1688C (with decomposition). H NMR
1
d 6.82 (d, J¼7.6 Hz, 2H), 6.49 (d, J¼8.1, 2H), 2.19 (t,
J¼7.4 Hz, 2H), 2.12 (s, 3H), 1.80–1.68 (m, 2H), 1.60–1.45
(m, 4H), 1.39–1.29 (m, 2H). 13C NMR (DMSO-d6) d 174.5
(s, CvO), 145.5 (s, Caromatic), 129.3 (s, CHaromatic), 124.5 (s,
Caromatic), 114.4 (s, CHaromatic), 36.0 (d, J¼106.0 Hz,
P–CH2), 33.5 (s, CH2), 29.2 (d, J¼17.5 Hz, CH2), 24.2 (s,
CH2), 22.9 (d, J¼3.8 Hz, CH2), 20.1 (s, CH3). 31P NMR d
87.0. IR (KBr, cm21) 1710 (CvO), 1510, 1224, 1014, 928,
808, 637, 591, 493. Anal. Calcd for C13H22NO4PS: C,
48.89; H, 6.94; N, 4.39. Found: C, 48.80; H, 6.98; N, 4.35.
4.2.7. 7-Thiophosphonomethylnaphthalene-1-carboxylic
acid (1d), p-methylanilinium salt. A solution of 3 (3.84 g,
30.5 mmol), crude 2d (11.2 g, 34.9 mmol) and triethyl-
benzylammonium chloride (0.72 g, 3.17 mmol) in CH2Cl2
(100 mL) was cooled on ice bath and a solution of NaOH
(12.7 g, 0.317 mol) in water (12.7 mL) was added slowly
with vigorous stirring. The ice bath was removed and the
mixture was stirred overnight, then washed with water,
dried (MgSO4), and the solvent was removed under reduced
pressure to give crude 4d (10.38 g) as an orange oil. This
material was dissolved in acetone (30 mL) and liquid Me3N
(25 mL) was added, and this mixture left at room
temperature for 2 weeks. Solvent was then removed by
rotary evaporation and the residue was dissolved in water
(50 mL). This solution was extracted with AcOEt, then to
the aqueous layer EtOH (150 mL) and MeI (10 mL) were
added and the mixture refluxed for 3 h. Solvents were
removed by rotary evaporation, the residue dissolved in
AcOEt (125 mL) and extracted with water. The organic
layer was dried (MgSO4) and the solvent removed under
reduced pressure to give crude 7d (4.44 g) as a thick orange
oil. This material was reacted with Me3SiI (8.00 g) in
CH2Cl2 (25 mL) as above. Then a water–dioxane mixture
(1:1, 20 mL) was added, after which volatiles were removed
under vacuum. The residue was dissolved in a Et2O–
acetone mixture (4:1, 50 mL) and p-toluidine (3.9 g) in ether
(20 mL) was added. The resulting white precipitate was
collected by filtration, washed with ether and dried to give
the p-methylanilinium salt of 1d (4.39 g, 37% total
yield from 3). An analytical sample was recrystallized
from an EtOH–acetone–Et2O mixture. Mp 200–2018C
(with decomposition). 1H NMR d 8.75–8.71 (m, 1H),

K. Swierczek et al. / Tetrahedron 59 (2003) 595–599
599
Bongartz, J.-P.; Starnes, M. C.; Cheng, Y.-C. Phosphorus,
Sulfur Silicon 1990, 49/50, 183–186.
8.13–8.07 (m, 2H), 7.91 (d, J¼8.6 Hz, 1H), 7.58–7.49 (m,
2H), 6.85 (d, J¼7.6 Hz, 2H), 6.54 (d, J¼8.1 Hz, 2H), 3.42
(d, J¼18.8 Hz, 2H), 2.13 (s, 3H). 13C NMR (DMSO-d6) d
168.7 (s, CvO), 144.9 (s, Cphenyl), 133.5 (d, J¼8.4 Hz,
Cnaphthyl), 132.6 (d, J¼1.5 Hz, CHnaphthyl), 132.2 (d,
J¼3.1 Hz, Cnaphthyl), 130.6 (d, J¼3.1 Hz, Cnaphthyl), 129.8
(s, CHnaphthyl), 129.3 (s, CHphenyl), 129.0 (d, J¼4.6 Hz,
CHnaphthyl), 127.9 (d, J¼3.1 Hz, CHnaphthyl), 127.5 (d,
J¼1.5 Hz, Cnaphthyl), 126.3 (d, J¼8.4 Hz, CHnaphthyl),
125.0 (s, Cphenyl), 124.3 (s, CHnaphthyl), 114.7 (s, CHphenyl),
44.7 (d, J¼99.9 Hz, P–CH2), 20.2 (s, Hz, CH3). 31P NMR d
79.7. IR (KBr, cm21) 1663 (CvO), 1507, 1285, 1250,
1003, 941, 840, 653, 578, 488.Anal. Calcd for
C19H20NO4PS: C, 58.60; H, 5.18; N, 3.60. Found: C,
58.48; H, 5.21; N, 3.41.
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Acknowledgements
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This work was supported by NIH grant GM47297 to A. C.
H. and by an ARA award to J. W. P. The authors gratefully
acknowledge the use of equipment in the Shimadzu
Analytical Sciences Laboratory at Utah State University,
created with equipment donated by Shimadzu Scientific
Instruments, Inc. (Columbia, MD).
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