First synthesis of S,S-dialkyl difluorophosphonodithioates and difluorophosphonotrithioates

Article abstract of DOI:10.1016/j.tetlet.2003.09.195

Several dialkyl difluoromethylphosphonodithioates and difluoromethylphosphonotrithioates have been prepared from difluoromethylphosphonyl dichloride and two equivalents of alkanethiols under basic conditions. Treatment of these species with LDA at low temperatures mainly resulted in decomposition, and to the low-yield isolation of difluorophosphinates or phosphine oxides, thus reflecting the lability of the P-S bond. The desired difluorophosphonodithioates and difluorophosphonotrithioates can be efficiently prepared by reversing the sequence of reactions.

Full text of DOI:10.1016/j.tetlet.2003.09.195

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8837–8840
First synthesis of S,S-dialkyl difluorophosphonodithioates
and difluorophosphonotrithioates
Chrystel Lopin, Ge´raldine Gouhier and Serge R. Piettre*
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, UMR 6014 CNRS, Universite´ de Rouen, rue Tesnie`re,
F-76821 Mont Saint Aignan, France
Received 15 July 2003; revised 16 September 2003; accepted 23 September 2003
Abstract—Several dialkyl difluoromethylphosphonodithioates and difluoromethylphosphonotrithioates have been prepared from
difluoromethylphosphonyl dichloride and two equivalents of alkanethiols under basic conditions. Treatment of these species with
LDA at low temperatures mainly resulted in decomposition, and to the low-yield isolation of difluorophosphinates or phosphine
oxides, thus reflecting the lability of the P–S bond. The desired difluorophosphonodithioates and difluorophosphonotrithioates
can be efficiently prepared by reversing the sequence of reactions.
© 2003 Elsevier Ltd. All rights reserved.
The ubiquitous presence of the phosphate group 1 in
biomolecules is the main reason behind the consider-
able amount of effort devoted to the search for the
ideal mimic of this function (Fig. 1). Among the vari-
ous molecular units that have been introduced in poten-
tially bioactive molecules, the phosphonates 2,
phosphonothioates 3 and phosphonodithioates 4 have
been much used in pharmaceuticals and agrochemicals,
with various results.1 The introduction of two fluorine
atoms a to the phosphorus by Blackburn in the early
eighties gave a new impetus to the chemistry of phos-
phonates and resulted in an upsurge of interest for
enzyme inhibitors featuring the difluorophosphonate
unit 5.2 Thus, many synthetic methodologies have been
worked out that allow either the construction of this
functional group or its introduction into more complex
structures.3 We recently introduced a new variant, the
difluorophosphonothioates 6.4 Beside being a new
isostere to phosphate, reagents derived from molecules
featuring a phosphorus–sulfur double bond often bear
a clear synthetic advantage over their oxygenated coun-
terparts. Thus, for instance, while the reported sensitive
lithium reagent 5e is stable at or below −78°C and
readily decomposes at higher temperatures, its sulfur
analogue 6e is stable at temperatures of −40°C.3d,4,5 In
the course of a program dedicated to the search for new
mimics of the phosphate group, we became interested in
the, as yet, unreported difluorophosphonodithioates 7
and difluorophosphonotrithioates 8, incorporating two
and three sulfur atoms, respectively, and in the corre-
sponding lithioderivatives 7e and 8e.
Dialkyl difluoromethylphosphonates and dialkyl
difluoromethylphosphonothioates (e.g. 5a and 6a,
respectively) are routinely prepared by interacting phos-
Figure 1.
phites
9
or thiophosphites 10 with chlorodifl-
uoromethane under basic conditions (Fig. 2).3d,4a
A
similar approach relying on the use of dithiophosphites
11 or trithiophosphites 12 was thwarted by the reported
low stabilities of these species. Thus, the much less
stable P–S bond (45–50 kCal/mol versus 90–100 kCal/
Keywords: difluorophosphonodithioate; difluorophosphonotrithioate;
Lawesson’s reagent.
* Corresponding author. Fax: +33 (0)235 52 29 71; e-mail:
serge.piettre@univ-rouen.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.195

8838
C. Lopin et al. / Tetrahedron Letters 44 (2003) 8837–8840
A second approach based on heteroatomic manipula-
tion on phosphorus proved to be more successful.
Transformation of diethyl difluoromethylphosphonate
(5a) into the corresponding phosphonyl dichloride 14a
can be achieved efficiently in excess refluxing thionyl
chloride (Scheme 1).8 Treatment of 14a with two equiv-
alents of thiols 15a–c or one equivalent of propan-1,3-
dithiol 15d under basic conditions delivered the desired
difluorophosphonothioates 7a–d in fair to good isolated
yields. Exposure of difluoromethylphosphonodithioates
7a–c to Lawesson’s reagent allowed the clean conver-
sion of the PꢀO bond into a PꢀS bond and delivered the
corresponding difluoromethylphosphonotrithioates 8a–
c in good to excellent yields.9 Interestingly, the interac-
tion of diethyl difluoromethylphosphonothioate (6a)
with an excess of thionyl chloride under similar condi-
tions resulted in the formal replacement of the sulfur
atom with an oxygen and led exclusively to the isola-
tion of phosphonyl dichloride 14a.10
Figure 2.
Clean alkylation of 5a and 6a have been reported to
occur at −78°C and −40°C, respectively, upon sequen-
tial treatment with LDA and various alkyl halides.3d,4a
When S,S-diethyl difluoromethylphosphonodithioate
(7a) was reacted with LDA and benzyl bromide, two
compounds, identified as 17 and 18, were formed in
variable amounts (Scheme 2). Modification of the reac-
tion conditions did not lead to any improvement in
yield.11 Purification by chromatography allowed the
isolation of the two compounds in low yields (17:
3–15%; 18: 4–5%).12 Evaporation of the aqueous phase
resulting from the work-up furnished S-ethyl
difluoromethylphosphonothioic acid (20).
Scheme 1.
These experiments clearly show that the intermediate
lithium reagent 7e is formed at −78°C, but seems to
undergo a rapid transformation into 16, followed by a
fast reaction with unreacted 7a (competitive with
deprotonation by LDA) to produce 17 and 19; the
latter would generate 20 upon hydrolysis and air oxida-
tion of the tautomeric P(III) intermediate during the
work-up. Alternatively, 7a and 7e could also react
together to give 17 and 19. Neither the desired deriva-
tive 21, nor any of the possible compounds resulting
from a polyalkylation process (23 or 25) were detected.
Additional experiments conducted at –100°C led to
analogous results.
Difluoromethylphosphonodithioates 7b, 7c and 7d, and
difluoromethylphosphonotrithioate 8a behaved simi-
larly under analogous conditions. Thus, the low stabili-
ties of lithium reagents 7e and 8e, as well as of other
related dialkyl analogues, led us to consider a new
approach.
Scheme 2.
mol for the PꢁO bond) results in the rapid hydrolysis of
dithiophosphites 11, rendering their preparation
difficult.6 Attempts to synthesize the reportedly more
stable 1,2,3-dithiaphosphinane-2-oxide 11a were con-
ducted by hydrolysing the chloride 13 (1 equiv. H2O, 1
equiv. triethylamine) or interacting it with an equimolar
amount of tert-butanol and triethylamine, but were
unsuccessful. In addition, both dithiophosphites 11 and
trithiophosphites 12 have been reported to readily dis-
proportionate, dimerize or oligomerize.7
Reversing the sequence of reactions, i.e. alkylating
phosphonate 5a first, then applying the above described
protocol, successfully led to the isolation of the desired
a,a-difluorophosphonodithioates
7
and
a,a-
difluorophosphonotrithioates 8 (Scheme 3). Thus, gen-
eration of diethyl difluorophosphonates 5f, 5g and 5h
from lithium salt 5e and benzyl bromide, n-pentyl
bromide or 1-bromo-4-chlorobutane, respectively, and

C. Lopin et al. / Tetrahedron Letters 44 (2003) 8837–8840
8839
even at −100°C, and undergo transformations into a
variety of compounds.
Difluorophosphonodithioates and difluorophosphono-
trithioates constitute new isosteres of the phosphate
group and may find applications in the context of
analogues of natural phosphates as inhibitors of bio-
chemical processes.
References
1. See for instance: (a) Kazama, H.; Matsuoka, S. JP
Patent, 1992, 04,330,083 [92,330,383]; (b) Kazama, H.;
Matsuoka, S. JP Patent, 1993, 05 39,296 [93 39,296]; (c)
Nakanishi, H.; Kuribayashi, T. JP Patent, 1993, 05
09,490 [93 09,490]; (d) Ra¨sa¨nen, J. P.; Pohjala, E.; Pak-
kanen, T. A. J. Chem. Soc., Perkin Trans. 2 1994, 2485–
2490; (e) Tang, C. C.; Ma, F. P.; Zhang, K.; He, Z. J.;
Jin, Y. C. Heteroat. Chem. 1995, 6, 413–417; (f)
Rodriguez, O. P.; Thompson, C. M. Phosphorus, Sulfur
Silicon Relat. Elem. 1996, 117, 101–110; (g) Jingzen, Y.;
Chambers, H. W. Pestic. Biochem. Physiol. 1996, 54,
210–219; (h) Kalir, H.; Kalir, H. H. In The Chemistry of
Organophosphorus Compounds; Hartley, F. R., Ed.; Wiley
& Sons: Chichester, 1996; pp. 767–780.
2. (a) Blackburn, G. M.; Kent, D. E. J. Chem. Soc., Chem.
Commun. 1981, 511–513; (b) Blackburn, G. M.; England,
D. A.; Kolmann, F. J. Chem. Soc., Chem. Commun. 1981,
930–932; (c) Blackburn, G. M.; Kent, D. E.; Kolkmann,
F. J. Chem. Soc., Chem. Commun. 1981, 1188–1190; (d)
Blackburn, G. M.; Kent, D. E. J. Chem. Soc., Perkin
Trans. 1 1986, 913–917; (e) Chambers, R. D.; Jaouhari,
R.; O’Hagan, D. Tetrahedron 1989, 45, 5101–5108; (f)
Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jain, S.
C. J. Chem. Soc., Chem. Commun. 1990, 1053–1054; (g)
Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J.
A. K. Tetrahedron 1996, 52, 165–176.
Scheme 3.
treatment of the resultant alkylated compounds first
with thionyl chloride, then with two equivalents of
ethanethiol in the presence of triethylamine led to the
isolation of the desired difluorophosphonodithioates
7f–h in fair to good yields (Table 1). Reacting these
species with Lawesson’s reagent efficiently achieved
their conversion into the corresponding difluorophos-
phonotrithioates 8f–h. Even diethyl bromodifl-
uoromethylphosphonate (5i) (R1=Br, R2=CH3CH2)
was converted into the dichloride and the difluorophos-
phonodithioate 7i, albeit in low overall yield, pre-
sumably because of the sensitivity of both the
intermediate bromodifluoromethylphosphonyl dichlo-
ride and the product itself (Entry 4).13 Conversion to
the phosphonotrithioate 8i occurred smoothly to deliver
the desired compound in very good yield. Both families
of compounds are reasonably stable, and can be easily
chromatographed on silica without undergoing notice-
able decomposition.14
3. (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578; (b)
Burton, D. J.; Takei, R.; Shin-Ya, S. J. Fluorine Chem.
1981, 18, 197–202; (c) Burton, D. J.; Ishihara, T.;
Maruta, M. Chem. Lett. 1982, 755–758; (d) Obayashi,
M.; Ito, E.; Kondo, K. Tetrahedron Lett. 1982, 23, 2323–
2326; (e) Obayashi, M.; Ito, E.; Kondo, K. Tetrahedron
Lett. 1982, 23, 2327–2328; (f) Burton, D. J.; Sprague, L.
G.; Pietrzyk, D. J.; Edelmuth, S. H. J. Org. Chem. 1984,
49, 3438–3440; (g) Blackburn, G. M.; Brown, D.; Martin,
S. J.; Parratt, M. J. J. Chem. Soc., Perkin Trans. 1 1987,
181–186; (h) Burton, D. J.; Sprague, L. G. J. Org. Chem.
1988, 53, 1523–1527; (i) Burton, D. J.; Sprague, L. G. J.
Org. Chem. 1989, 54, 613–617; (j) Bigge, C. F.; Drum-
Conclusion
Difluorophosphonates can be transformed into
difluorophosphonodithioates and difluorophosphono-
trithioates by applying to the substrates a sequence of
reactions involving (i) chlorination; and (ii) the interac-
tion with two equivalents of alkanethiol under basic
conditions, and, for the difluorophosphonotrithioates;
(iii) treatment with Lawesson’s reagent. The lithium
salts of diethyl difluoromethylphosphonodithioate and
difluorophosphonotrithioate appear to be unstable,
Table 1.
Entry
R1
R2
Yields (%)a
Yields (%)
1
2
3
4
C6H5CH2−
CH3CH2−
CH3CH2−
CH3CH2−
CH3CH2−
7f
7g
7h
7i
87
42
8f
8g
8h
8i
99
92
97
86
n-C5H11
−
Cl(CH2)4−
Br
52
19b
a Isolated yields from 5f–i and 15a.
b See Ref. 13.

8840
C. Lopin et al. / Tetrahedron Letters 44 (2003) 8837–8840
mond, J. T.; Johnson, G. Tetrahedron Lett. 1989, 30,
V. Zh. Obshch. Khim. 1974, 44, 1694–1697; (d) Nifant’ev,
E. E.; Chechetkin, A. S.; Blagoveshchenskii, V. S.;
Sokurenko, A. M. Zh. Obsch. Khim. 1983, 53, 2695–2697.
8. Bergstrom, D. E.; Shum, P. W. J. Org. Chem. 1988, 53,
3953–3958.
9. Piettre, S. R. Tetrahedron Lett. 1996, 37, 4707–4710.
10. There are precedents for this kind of transformation:
Pelchowicz, Z. J. Chem. Soc. 1961, 238–240.
7013–7016; (k) Yang, Z.-Y.; Burton, D. Tetrahedron Lett.
1991, 32, 1019–1022; (l) Differding, E.; Duthaler, R. O.;
Krieger, A.; Ru¨egg, G. M.; Schmit, C. Synlett 1991,
395–396; (m) Yang, Z.-Y.; Burton, D. J. J. Org. Chem.
1992, 57, 4676–4683; (n) Martin, S. F.; Dean, D. W.;
Wagman, A. S. Tetrahedron Lett. 1992, 33, 1839–1842;
(o) Smyth, M. S.; Ford, H.; Burke, T. R. Tetrahedron
Lett. 1992, 33, 4137–4140; (p) Hu, C.-M.; Chen, J. J.
Chem. Soc., Perkin Trans. 1 1993, 327–330; (q) Berkow-
itz, D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J. Org.
Chem. 1993, 58, 6174–6176; (r) Burke, T. R.; Smyth, M.
S.; Otaka, A.; Roller, P. P. Tetrahedron Lett. 1993, 34,
4125–4128; (s) Smyth, M. S.; Burke, T. R. Tetrahedron
Lett. 1994, 35, 551–554; (t) Berkowitz, D. B.; Sloss, D. G.
J. Org. Chem. 1995, 60, 7047–7050; (u) Matulic-Adamic,
J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995, 60,
2563–2569; (v) Lequeux, T. P.; Percy, J. M. J. Chem.
Soc., Chem. Commun. 1995, 2111–2112; (w) Li, A.-R.;
Chen, Q.-Y. Synthesis 1996, 606–608; (x) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 2233–2236; (y) Herpin, T. F.;
Houlton, J. S.; Motherwell, W. B.; Roberts, B. P.; Wei-
bel, J.-M. J. Chem. Soc., Chem. Commun. 1996, 613–614;
(z) Yokomatsu, T.; Sato, M.; Shibuya, S. Tetrahedron:
Asymmetry 1996, 7, 2743–2754; (aa) Matulic-Adamic, J.;
Haeberli, P.; Usman, N. J. Org. Chem. 1995, 60, 2563–
2569; (bb) Blades, K.; Cockerill, G. S.; Easterfield, H. J.;
Lequeux, T. P.; Percy, J. M. Chem. Commun. 1996,
1615–1616; (cc) Blades, K.; Lequeux, T. P.; Percy, J. M.
Chem. Commun. 1996, 1457–1458; (dd) Solas, D.; Hale,
R. L.; Patel, D. V. J. Org. Chem. 1996, 61, 1537–1539;
(ee) Blades, K.; Lequeux, T. P.; Percy, J. M. Tetrahedron
1997, 53, 10623–10632; (ff) Waschbu¨sch, R.; Samadi, M.;
Savignac, P. J. Organomet. Chem. 1997, 529, 267–278;
(gg) Kovensky, J.; McNeil, M.; Sinay¨, P. J. Org. Chem.
1999, 64, 6202–6205; (hh) Berkowitz, D. B.; Bhuniya, D.;
Peris, G. Tetrahedron Lett. 1999, 40, 1869–1872; (ii) Butt,
A. H.; Percy, J. M.; Spencer, N. S. Chem. Commun. 2000,
1691–1692; (jj) Vayron, P.; Renard, P.-Y.; Valleix, A.;
Mioskowski Chem. Eur. J. 2000, 6, 1050–1063; (kk)
Lequeux, T.; Lebouc, F.; Lopin, C.; Yang, H.; Gouhier,
G.; Piettre, S. R. Org. Lett. 2001, 3, 185–188; (ll) Yoko-
matsu, T.; Katayama, S.; Shibuya, S. Chem. Commun.
2001, 1878–1879.
11. These included temperatures, number of equivalents of
base and electrophile or addition of HMPA (see: Ref.
3kk).
12. Complete consumption of the starting phospho-
nodithioate was observed (1H, 19F and 31P NMR spec-
trometries).
13. 19F NMR spectroscopic data of 14e and 7i indicated 70%
and 48% yields, respectively, for the two steps.
14. Representative procedure for compounds 7f and 8f: To a
stirring mixture of diethyl 2-phenyl-1,1-difluoroethyl-
phosphonate (5f) (1 g, 3.6 mmol) and freshly distilled
pyridine (0.045 mL, 0.55 mmol) under argon was added
thionyl chloride (2.7 mL, 36 mmol). The resultant solu-
tion was refluxed for 72 h, cooled down to room temper-
ature, and the excess thionyl chloride was distilled off
under reduced pressure (50–60°C/50 mbar; Kugelrohr) to
give the desired phosphonyl chloride 14b. 19F NMR (188
MHz, CDCl3) l=55.96 (dt, 2F, J=20.3 Hz, J=138.8
Hz). This material was used in the next step without
further purification. A solution of 14b (0.93 g, 3.6 mmol)
in dry ether (7.3 mL) was added dropwise to a cooled
solution (0°C) of triethylamine (0.9 g, 1.24 mL, 8.87
mmol) and ethanethiol (0.445 g, 0.533 mL, 7.17 mmol) in
dry ether (14 mL). Stirring was continued at room tem-
perature for 16 h, after which period of time the volatiles
were removed under vacuum. A Kugelrohr distillation
afforded 7f as a colorless oil (0.96 g, 87%, 2 steps). 1H
NMR (200 MHz, CDCl3) l 7.40–7.15 (m, 5H), 3.49 (td,
2H, J=20.5, 2.9 Hz), 3.10–2.90 (m, 4H), 1.41 (t, 6H,
J=7.3 Hz). 13C NMR (75 MHz, CDCl3) d=131.39,
128.80, 128.15 (3s, 5C), 39.05 (dt, 1C, J=20.1, 16.2 Hz),
25.83 (d, 2C, J=3.5 Hz), 16.89 (d, 2C, J=4.9 Hz). 19F
NMR (188 MHz, CDCl3) l 54.42 (dt, 2F, J=20.3, 105.1
Hz). 31P NMR (81 MHz, CDCl3) l 59.93 (t, 1P, J=102.3
Hz). Exact mass (CI, 200 eV) m/z calcd for
C12H17F2OPS2. M+ 310.0427. Found 310.0423. A stirring
solution of phosphonodithioate 7f (0.96 g, 3.1 mmol) and
Lawesson’s reagent (1.26 g, 3.1 mmol) in dry toluene (13
mL) was refluxed under argon for 2 h. The mixture was
then cooled to room temperature and evaporated. The
residual oil was diluted in heptane (20 mL) and filtered,
and the filtrate was evaporated. Purification on silica gel
eluting with heptane/ethyl acetate (7:3) furnished 8f as a
4. (a) Piettre, S. R.; Raboisson, P. Tetrahedron Lett. 1996,
37, 2229–2232; (b) Yokomatsu, T.; Takechi, H.; Murano,
T.; Shibuya, S. J. Org. Chem. 2000, 65, 5858–5861.
5. (a) Burton, D. J. J. Fluorine Chem. 1983, 23, 339–345; (b)
Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189–
275.
6. (a) Hudson, R. F.; Keay, L. J. Chem. Soc. 1956, 3269–
3271; (b) Kardanov, N. A.; Provotorova, N. P.; Petro-
vskii, P. V.; Godoviloc, N. N.; Kabachnik, M. I. Izv.
Akad. Nauk. SSSR 1983, 2114–2121; (c) Al’fonsov, V. A.;
Trusenev, A. G.; Batyeva, E. S.; Pudovic, M. A. Ivz.
Akad. Nauk. SSSR 1991, 2103–2111.
7. (a) Nifant’ev, E. E.; Zavalishina, A. I.; Sorokina, S. F.;
Chernyak, S. M. Dolk. Akad. Nauk. SSSR 1972, 203,
593–595; (b) Sorokina, S. F.; Zavalishina, A. I.; Nifan-
t’ev, E. E. Zh. Obshch. Khim. 1973, 43, 750–752; (c)
Nifant’ev, E. E.; Zavalishina, A. I.; Sorokina, S. F.;
Blagoveshchenskii, V. S.; Yakovleva, O. P.; Esenina, E.
1
yellowish oil (1 g, 99%). H NMR (200 MHz, CDCl3) l
7.40–7.20 (m, 5H), 3.60 (dt, 2H, J=19.7, 2.9 Hz), 3.10–
2.90 (m, 4H), 1.39 (t, 6H, J=7.3 Hz). 13C NMR (75
MHz, CDCl3) l 129.93, 127.33, 126.63 (3s, 5C), 36.85 (dt,
1C, J=20.4, 18.4 Hz), 26.59 (d, 2C, J=3.5 Hz), 14.82 (d,
2C, J=5.6 Hz). 19F NMR (188 MHz, CDCl3) l 55.90 (dt,
2F, JF-H=16.9, 101.7 Hz). 31P NMR (81 MHz, CDCl3) l
88.00 (t, 1P, J=98.7 Hz). Exact mass (CI, 200 eV) m/z
calcd for C12H17F2PS3. M+ 326.0198. Found 326.0188.