Phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals. Generation and addition onto alkenes and alkynes

Article abstract of DOI:10.1021/jo051511c

Selanylated difluoromethylphosphonates and difluoromethylphosphonothioates are good precursors to phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals, respectively. When generated in the presence of alkenes and a hydrogen donor, the corresponding α,α-difluorinated alkylphosphonates or alkylphosphonothioates are produced in fair to good yields. The use of alkynes results in the formation of α,α-difluorinated allyl derivatives in useful yields. The presence of the sulfur atom in phosphonothiodifluoromethyl radicals usually translates into higher isolated yields.

Full text of DOI:10.1021/jo051511c

Phosphonodifluoromethyl and Phosphonothiodifluoromethyl
Radicals. Generation and Addition onto Alkenes and Alkynes
Se´bastien Pignard, Chrystel Lopin, Ge´raldine Gouhier, and Serge R. Piettre*
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, UMR CNRS 6014, IRCOF-UniVersite´ de
Rouen, Rue Tesnie`res, F-76821 Mont Saint Aignan, France
serge.piettre@uniV-rouen.fr
ReceiVed July 20, 2005
Selanylated difluoromethylphosphonates and difluoromethylphosphonothioates are good precursors to
phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals, respectively. When generated in
the presence of alkenes and a hydrogen donor, the corresponding R,R-difluorinated alkylphosphonates
or alkylphosphonothioates are produced in fair to good yields. The use of alkynes results in the formation
of R,R-difluorinated allyl derivatives in useful yields. The presence of the sulfur atom in phosphono-
thiodifluoromethyl radicals usually translates into higher isolated yields.
Introduction
possibility for carbon-bound fluorine atoms to establish hydro-
gen bonds, much as oxygen atoms, has been suggested.5,6
More recently we have introduced the R,R-difluorophospho-
nothioates 4b, a new variant in which the phosphorus atom is
doubly bonded to sulfur.7 The presence of the sulfur atom may
both help to modulate the binding to metallic enzymes and result
in higher resistance of the functional group toward enzymatic
Increasing the efficacy of a bioactive molecule may be
achieved by fine-tuning its interactions with the biomolecular
target. In this context, the search for the ideal phosphate mimic
has been the focus of many scientists for the past decade. Indeed,
this functional group 1 is involved in many biochemical
processes, including those addressing the replication and
transposition of nucleic acids (Figure 1). Phosphonates 2a,
phosphonothioates 2b, and phosphonodithioates 2c, in which
an esterified oxygen has been replaced with a methylene, as
well as phosphinates 3, featuring two carbon-phosphorus bonds,
have been much studied, and many applications have flourished.1
The generally positive impact of the presence of fluorine in
bioactive molecules led Blackburn and McKenna to indepen-
dently introduce the difluorophosphonates 4a more than 20 years
ago.2 Numerous analogues of natural phosphates encompassing
this fluorinated functional group have since then been prepared
and shown to be bioactive.3 Chambers and O’Hagan underlined
the closer electronic and structural similarities between fluori-
nated phosphonates 4a and the corresponding phosphates.4
Thatcher showed that the apicophilicities of both fluorinated
methylenes, CHF and CF2, are analogous to that of an esterified
oxygen.5 This would translate into similar geometries for the
phosphorus atom in the functional groups 1 and 4. In addition
and despite the fact that this is still subject to debate, the
(1) (a) Edmundson, R. S. The Chemistry of Organophosphorus Com-
pounds. Vol. 4. Ter- and Quinque-Valent Phosphorus Acids and Their
DeriVatiVes; Hartley, F., Ed.; Wiley & Sons: Chichester, 1996; pp 47-
652. (b) Kalir, A.; Kalir, H. H. In The Chemistry of Organophosphorus
Compounds. Vol. 4. Ter- and Quinque-Valent Phosphorus Acids and Their
DeriVatiVes; Hartley, F., Ed.; Wiley&Sons: Chichester, 1996; pp 767-
780. (c) Tang, C. C.; Ma, F. P.; Zhang, K.; Zheng, J.; Jin, Y. C. Heteroat.
Chem. 1995, 6, 413-417. (d) Rodriguez, O. P.; Thompson, C. M.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 117, 101-110. (e) Colling-
wood, S. P.; Taylor, R. J. Synlett 1998, 283-285. (f) Lu, H.; Berkman, C.
E. Bioorg. Med. Chem. 2001, 9, 395-402. (g) An, H.; Wang, T.; Maier,
M. A.; Manoharan, M.; Ross, B. S.; Cook, P. D. J. Org. Chem. 2001, 66,
2789-2801. (h) Dubert, O.; Gautier, A.; Condamine, E.; Piettre, S. R. Org.
Lett. 2002, 4, 359-362. (i) Renard, P.-Y.; Schwebel, H.; Vayron, P.; Josien,
L.; Valleix, A.; Mioskowski, C. Chem. Eur. J. 2002, 8, 2910-2916. (j)
Savignac, P.; Bogdan, I. Modern Phosphonate Chemistry; CRC Press: Boca
Raton, 2003.
(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)
McKenna, C. E.; Shen, P.-D. J. Org. Chem. 1981, 46, 4573-4576. (e)
Blackburn, G. M.; Kent, D. E. J. Chem. Soc., Perkin Trans. 1 1986, 913-
917.
10.1021/jo051511c CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
J. Org. Chem. 2006, 71, 31-37
31

Pignard et al.
hydrolysis when compared to the fully oxygenated analogue.8
In addition, the synthetic methodologies developed to construct
or introduce this functional group have pointed the finger at
the advantages brought by the sulfur atom: increased stability
of the reagents, higher yields in product, reproducibility, and
ease of purification when compared to the fully oxygenated
reagents and products.9 This positive role of sulfur was
highlighted in a successful synthesis of phosphonodifluoro-
methyl analogues of nucleoside-3′-phosphates.7d
Recently, we reported that O,O-dialkylphosphonodifluoro-
methyl radicals 5a generated from selanyl (or sulfanyl) precur-
sors 6a in the presence of a hydrogen donor add to variously
substituted alkenes through a chain-reaction process to deliver
the expected adducts in fair to good yields (Figure 2).10
Phosphonodifluoromethyl radicals have also been postulated as
intermediates in either metal- or oxone-mediated addition of
FIGURE 1. Structures of phosphate and various isosteres such as
phosphonates and phosphinates.
(3) (a) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin
Trans. 1 1984, 1119-1125. (b) Blackburn, G. M.; Guo, M.-J.; Langston,
S. P.; Taylor, G. E. Tetrahedron Lett. 1990, 31, 5637-5640. (c) Blackburn,
G. M.; Langston, S. P. Tetrahedron Lett. 1991, 32, 6425-6428. (d) Burke,
T. R., Jr.; Smyth, M. S.; Nomizu, M.; Otaka, A.; Roller, P. P. J. Org. Chem.
1993, 58, 1336-1340. (e) Matulic-Adamic, J.; Usman, N. Tetrahedron Lett.
1994, 35, 3227-3230. (f) Martin, S. F.; Wong, Y.-L.; Wagman, A. S. J.
Org. Chem. 1994, 59, 4821-4831. (g) Berkowitz, D. B.; Shen, Q.; Maeng,
J.-H. Tetrahedron Lett. 1994, 35, 6445-6448. (h) Matulic-Adamic, J.;
Haeberli, P.; Usman, N. J. Org. Chem. 1995, 60, 2563-2569. (i) Levvy,
S. G.; Wasson, B.; Carson, D. A.; Cottam, H. B. Synthesis 1996, 843-
846. (j) Burke Jr., T. R.; Ye, B.; Akamatsu, M.; Ford, H., Jr.; Yan, X.;
Kole, H. K.; Wolf, G.; Shoelson, S. E.; Roller, P. P. J. Med. Chem. 1996,
39, 1021-1027. (k) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemaker,
R. K. J. Org. Chem. 1996, 61, 4666-4675. (l) Ye, B.; Burke, T. R., Jr.
Tetrahedron 1996, 52, 9963-9970. (m) Qabar, M. N.; Urban, J.; Khan,
M. Tetrahedron 1997, 53, 11171-11178. (n) Hamilton, C. J.; Roberts, S.
M.; Shipitsin, A. J. Chem. Soc., Chem. Commun. 1998, 1087-1088. (o)
Hamilton, C. J.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1051-
1056. (p) Yokomatsu, T.; Abe, H.; Yamagishi, T.; Suemune, K.; Shibuya,
S. J. Org. Chem. 1999, 64, 8413-8418. (q) Butt, A. H.; Percy, J. M.;
Spencer, N. S. Chem. Commun. 2000, 1691-1692. (r) Murano, T.;
Muroyama, S.; Yokomatsu, T.; Shibuya, S. Synlett 2002, 1657-1660. (s)
Burke Jr., T. R.; Lee, K. Acc. Chem. Res. 2003, 36, 426-433. (t)
Yokomatsu, T.; Kato, J.; Sakuma, C.; Shibuya, S. Synlett 2003, 1407-
1410. (u) Yokomatsu, T.; Kato, J.; Sakuma, C.; Shibuya, S. Synlett 2003,
1407-1410. (v) Murano, T.; Yuasa, Y.; Kobayakawa, H.; Yokomatsu, T.;
Shibuya, S. Tetrahedron 2003, 59, 10223-10230. (w) Gautier, A.; Garipova,
G.; Salcedo, C.; Balieu, S.; Piettre, S. Angew. Chem., Int. Ed. 2004, 43,
5963-5967.
FIGURE 2. Structures of radicals 5, their precursors 6, Lawesson
reagent 7, and side products 8 and 9.
either bromo- or iododifluoromethylphosphonates to alkenes and
alkynes, leading to 1:1 adducts.11
We now report an extension of our previous work and show
that addition onto alkynes leads to â,γ-unsaturated-R,R-difluo-
rophosphonates. Not surprisingly, the previously unreported
O,O-dialkylphosphonothiodifluoromethyl radicals 5b can be
generated from the corresponding thioanalogue 6b of precursor
6a: in the presence of alkenes or alkynes, the expected alkyl-
or vinyl-R,R-difluorophosphonothioates, respectively, are pro-
duced.
(8) By analogy, phosphorothioates are more stable than the corresponding
phosphates. See: (a) Eckstein, F. J. Am. Chem. Soc. 1970, 92, 4718-4723.
(b) Eckstein, F. Angew. Chem., Int. Ed. Engl. 1983, 22, 423-506. (c)
Eckstein, F. Annu. ReV. Biochem. 1985, 54, 367-402. (d) Matsukura M.;
Shinozuka, K.; Zon, G.; Mitsuya, H.; Reitz, M.; Cohen, J. S.; Broder, S.
Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 7706-7710. (e) Cooke, A. M.;
Noble, N. J.; Payne, S.; Gigg, R.; Potter, B. V. L. J. Chem. Soc., Chem.
Commun. 1989, 269-271. (f) Uhlmann, E.; Peyman, A. Chem. ReV. 1990,
90, 543-584. (g) Baker, G. R.; Billington, D. C.; Gani, D. Tetrahedron
1991, 47, 3895-3908. (h) Billington, D. C. The Inositol Phosphates; VCH
Weinheim: New York, 1993; p 69. (i) Szczepanik, M. B.; De´saubry, L.;
Johnson, R. A. Tetrahedron Lett. 1998, 39, 7455-7458. (j) Marwic, C. J.
Am. Med. Assoc. 1998, 280, 871. (k) Stix, G. Sci. Am. 1998, 297, 46-50.
(l) Cook, P. D. XIV International Roundtables: Nucleosides, Nucleotides
and Their Biological Applications, Sept. 10-14, 2000, San Francisco, No
34, p 31.
(9) See, for example, refs 7d and 7e. In addition and despite their
complete stability at room temperature, difluorinated phosphonothioates
more readily react with strong oxidants than the corresponding phosphonates,
thereby greatly facilitating the monitoring of both reactions and column
chomatography purifications by TLC.
(10) Lequeux, T.; Lebouc, F.; Lopin, C.; Yang, H.; Gouhier, G.; Piettre,
S. R. Org. Lett. 2001, 3, 185-188.
(4) (a) Chambers, R. D.; Jaouhari, R.; O’Hagan, D. Tetrahedron 1989,
45, 5101-5108. (b) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jain,
S. C. J. Chem. Soc., Chem. Commun. 1990, 1052-1054. (c) Nieschalk, J.;
Batsanov, A. S.; O’Hagan, D.; Howard, J. A. K. Tetrahedron 1996, 52,
165-176.
(5) Thatcher, G. R.; Campbell, A. S. J. Org. Chem. 1993, 58, 2272-
2281.
(6) (a) Smart, B. E. Organofluorine Chemistry: Principles and Com-
mercial Applications; Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New
York, 1994; p 58. (b) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith,
G. T. Tetrahedron 1996, 52, 12613-12622. (c) Burke, T. R.; Ye, B.; Yan,
X.; Wang, S.; Zia, Z.; Chen, L.; Zhang, Z. Y.; Barford, D. Biochemistry
1996, 35, 15989-15996. (d) Berkowitz, D. B.; Bose, M. J. Fluorine Chem.
2001, 112, 13-33. (e) Haufe, G.; Rosen, T. C.; Meyer, O. G. J.; Frohlich,
R.; Rissanen, K. J. Fluorine Chem. 2002, 114, 189-198. (f) Parsch, J.;
Engels, J. E. J. Am. Chem. Soc. 2002, 124, 5664-5672. (g) Kui, S. C. F.;
Zhu, N.; Chan, M. C. W. Angew. Chem., Int. Ed. 2003, 42, 1628-1632.
(h) Olsen, J. A.; Banner, D. W.; Seiler, P.; Sander, U. O.; d’Arcy, A.; Sthle,
M.; Muller, K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 2507-
2511. (i) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. ChemBioChem 2004,
5, 622-627.
(7) (a) Piettre, S. R.; Raboisson, P. Tetrahedron Lett. 1996, 37, 2229-
2232. (b) Piettre, S. R. Tetrahedron Lett. 1996, 37, 2233-2236. (c)
Yokomatsu, T.; Takechi, H.; Murano, T.; Shibuya, S. J. Org. Chem. 2000,
65, 5858-5861. (d) Lopin, C.; Gautier, A.; Gouhier, G.; Piettre, S. J. Am.
Chem. Soc. 2002, 124, 14668-14675. (e) Murano, T.; Yuasa, Y.; Mu-
royama, S.; Yokomatsu, T.; Shibuya, S. Tetrahedron 2003, 59, 9059-9073.
(11) (a) Yang, Z.-Y.; Burton, D. Tetrahedron Lett. 1991, 32, 1019-
1022. (b) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676-4683.
(c) Hu, C.-M.; Chen, J. J. Chem. Soc., Perkin Trans. 1 1993, 327-330. (d)
Li, A.-R.; Chen, Q.-Y. Synthesis 1996, 606-608. (e) Yokomatsu, T.;
Suemune, K.; Murano, T.; Shibuya, S. J. Org. Chem. 1996, 61, 7207-
7211.
32 J. Org. Chem., Vol. 71, No. 1, 2006

Phosphonodifluoromethyl Radicals
SCHEME 1a
6a or 6b and the requisite alkene and of 1.1 equiv of n-Bu3-
SnH. This furnished the desired products 18a and 19a in 45%
and 54%, respectively, as well as 50-40% of reduced precursors
11a or 11b (Table 1, entries 1 and 7). The addition reaction
was then extended to other alkenes 13-17, featuring alkyl,
electron-donating, or electron-withdrawing substituents (Table
1). Both electronic and steric factors play a role in the reaction.
Classic and electron-rich alkenes furnished the products in higher
yields than electron-poor substrates (compare entries 1, 2, 4,
and 5 with 6, and 7, 8, 10 and 11 with 12). The rate of addition
of 1,2-disubstituted alkenes is apparently slowed enough to
mainly induce hydrogen quenching of radicals 5a and 5b (entries
3 and 9); however, replacing one of the alkyl substituent with
an electron-donating atom results in a reversal of this deleterious
steric effect (compare entries 3 and 5, and 9 and 11). Difluo-
rophosphonates 18 and difluorophosphonothioates 19 were
easily separated from tri-n-butyltin selenide 8 by flash chro-
matography. Dimeric species 9 were never isolated from these
reactions nor even observed in the crude samples.
a Reagents and conditions: (a) (i) Na, THF, (ii) HCF2Cl; (b) (i) 1.5 equiv
LDA, THF, -78 °C, (ii) 1.5 equiv PhSeCl, THF, -78 °C; (c) Lawesson
reagent, toluene, 110 °C.
The possibility of carrying out tandem radical additions was
demonstrated by using N-tosyl bisallylamine 20 (Scheme 2).15
Products 21a were isolated in a disappointing 16% yield (a 7:3
mixture of cis and trans diastereomers); however, radical 5b
proved more efficient, affording the corresponding phospho-
nothioate 21b in 51% isolated yield (a 7:3 mixture of cis and
trans diastereomers).16 Despite the lack of kinetic data, the
results are indicative of the probable electrophilic nature of
radicals 5a and 5b. According to the putative radical chain
reaction and the catalytic cycle suggested in Scheme 3, a slower
addition of radicals 5a or 5b onto the reacting alkene would
favor its hydrogen quenching by n-Bu3SnH. Indeed, in reactions
producing less of the desired addition product, more 11a or 11b
was generally isolated. Thus, a high yield of desired product
probably reflects a favorable frontier molecular orbital interac-
tion (and a high addition rate), and conversely, lower yields
may be indicative of less favorable such orbital interactions,
resulting in a competitive reduction of the precursor.
The most salient feature emerging from Table 1 is the
consistently higher yields obtained from precursor 6b when
compared to those of 6a, presumably due to the higher stability
of the phosphonothiodifluoromethyl radical 5b. This observation
is in line with previous data from the literature on the
corresponding anions and on phosphon(othio)yl radicals.7 The
use of tris(trimethylsilyl)silane (TTMSSH), a hydrogen donor
slightly weaker than n-Bu3SnH, resulted in a significant increase
in the isolated yield of 18a, 19a, 18c, and 19c; this could be
the result of the stronger Si-H bond, when compared to Sn-
H, favoring the addition of 5a or 5b onto alkenes over the mere
hydrogen quenching of these radicals.17 However, when enol
ether 16 was used, the main reaction turned out to be the
reduction of both precursors 6a and 6b, possibly due to an
Results and Discussion
Selanylated compounds 6a and 6b were selected as the
precursors of choice of radicals 5a and 5b, respectively. Indeed,
both the weaker C-Se bond, when compared to C-S and C-Br
bonds, for instance, and the high polarizability of selenium were
expected to generate the most efficient homolytic cleavage, and
to decrease the probability of radical addition onto the sp2-
hybridized sulfur atom in 6b, a potentially competitive reac-
tion.12,13 The preparation of precursors 6a and 6b is summarized
in Scheme 1. The fully oxygenated precursor 6a was synthesized
in two steps from commercially available diethyl phosphite 10a
(62% overall yield). Three different preparations of 6b from
10a may be envisioned, depending on the stage at which
Lawesson reagent 7 (LR) is used to transform the PdO bond
into a PdS one.14 Thus, either phosphite 10a (Route A),
difluorophosphonate 11a (Route B), or precursor 6a (Route C)
can be subjected to the action of LR, with different outcomes.
The results clearly indicate that Route B affords the highest
overall yield to precursor 6b (47%, versus 41% and 34% for
Routes A and C, respectively). These syntheses can easily be
carried out on multigram scales.
In accordance with the original procedure, slow addition of
a toluene solution of tri-n-butyltin hydride (1.4 equiv) and
azobisisobutyronitrile (0.5 equiv) to a toluene solution of either
6a or 6b (1 equiv) and n-octene (12) (10 equiv) at 90 °C resulted
in a total consumption of either precursor and the generation
of the desired adducts along with various amount of the reduced
phosphonate 11a or phosphonothioate 11b.10 Optimization of
this first procedure eventually led to the use of a 1:1 mixture of
(15) For examples of such tandem radical processes, see: (a) Hanessian,
S.; Rheinhold, U.; Ninkovic, S. Tetrahedron Lett. 1996, 37, 8967-8970.
(b) Hanessian, S.; Ninkovic, S.; Rheinhold, U. Tetrahedron Lett. 1996, 37,
8971-8974. (c) Parsons, A. F.; Williams, D. A. J. Tetrahedron 1998, 54,
13405-13420. (d) Barks, J. M.; Gilbert, B. C.; Parsons, A. F.; Upeandran,
B. Tetrahedron Lett. 2001, 42, 3137-3140. (e) Gautier, A.; Garipova, G.;
Dubert, O.; Oulyadi, H.; Piettre, S. R. Tetrahedron Lett. 2001, 42, 5673-
5676. (f) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. Tetrahedron
Lett. 2003, 44, 479-483.
(16) Phosphonate 11a and phosphonothioate 11b, resulting from com-
petitive reduction, were the only other products observed by NMR
spectrometry.
(17) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese,
B.; Kopping, B. J. Org. Chem. 1991, 56, 678-683.
(12) Dissociation energies of C-X bonds are as follows: X ) Br, 68
kCal/mol; X ) S, 65 kCal/mol; X ) Se, 58 kCal/mol. See ref 14f.
(13) For an example of a radical addition on a SdP bond, see: Romeo,
R.; Wozniak, L. A.; Chatgilialoglu, C. Tetrahedron Lett. 2000, 41, 9899-
9902.
(14) (a) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. O.
Bull. Soc. Chim. Belg. 1978, 87, 223-228. (b) Scheibye, S.; Pedersen, B.
S.; Lawesson, S. O. Bull. Soc. Chim. Belg. 1978, 87, 229-234. (c) Horner,
L.; Lindel, H. Phosphorus Sulfur 1982, 12, 259-261. (d) Piettre, S. R.;
Raboisson, P. Tetrahedron Lett. 1996, 37, 2229-2232. (e) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 4707-4710. (f) Lopin, C.; Gouhier, G.; Gautier,
A.; Piettre, S. J. Org. Chem. 2003, 68, 9916-9923.
J. Org. Chem, Vol. 71, No. 1, 2006 33

Pignard et al.
TABLE 1. Addition of Radicals 5a and 5b to Alkenes 12-17a
a 5a or 5b (1 equiv), n-Bu3SnH (1.1 equiv), AIBN (0.4 equiv), toluene, 110 °C. b Isolated yields. c Using TTMSSH (1.1 equiv).
SCHEME 2a
and the literature is devoid of the corresponding phosphono-
thioates. Thus, R,R-difluorinated allylphosphonates bearing an
iodine atom on carbon γ to the phosphorus atom have been
prepared by addition of iododifluoromethanephosphonic esters
on terminal alkynes in the presence of sodium dithionite.11d
Shibuya has reported a copper-mediated coupling reaction
between vinyliodides and zinc derivative 40a, and a related
addition across alkynes (Figure 3).11e Alternatively, a sequence
involving (i) the cerium-mediated conjugate addition of lithium
reagent 40b to vinyl sulfoxides and (ii) a thermal syn elimination
of sulfenic acid was developed by Percy.18
a Reagents and conditions: (a) 5a or 5b (1 equiv), n-Bu3SnH (1.1 equiv),
AIBN (0.4 equiv), toluene, 110 °C.
When the above procedure was applied to alkynes, difluori-
nated allylphosphonates and allylphosphonothioates were ob-
tained in fair to good yields (Table 2). Here again, isolated yields
of phosphonothioates 34-39 were found to be higher than in
the case of the corresponding phosphonates 28-33. Alterna-
increase in the HOMO/SOMO gap induced by the Lewis acid
properties of silylated species.
The possibility of adding radicals 5a or 5b onto alkynes was
next considered. Of particular interest was the fact that the
approach might generate a general method of synthesis of R,R-
difluorinated allylphosphonates and allylphosphonothioates. Few
preparations of such phosphonates have been reported so far,
(18) Blades, K.; Percy, J. M. Tetrahedron Lett. 1998, 39, 9085-9088.
34 J. Org. Chem., Vol. 71, No. 1, 2006

Phosphonodifluoromethyl Radicals
SCHEME 3 .
tively, tris(trimethylsilyl)silane (TTMSSH) may be used as
hydrogen donor: addition of radicals 5a or 5b on trimethylsi-
lylacetylene 25, following an otherwise identical procedure, led
to the isolation of adducts 31 and 37, in virtually identical yields
(entries 4 and 10). Decreasing the addition time of the radical
initiator/hydrogen donor solution from 10 to 3 h resulted in a
significant drop in yields, demonstrating the advantage of slow
addition here. In most cases, the E isomer was found to have
formed predominantly, a reflection of the higher stability of
radical-adduct 41, when compared to 42. Interestingly, in the
case of propargyl ether 23, the Z isomer was slightly favored
(entries 2 and 8). Orbital interaction between the phosphorus-
centered functional group and the propargylic oxygen may
explain this apparent aberration. The use of internal alkynes
mainly generated the reduced products 11a and 11b.19
48% and 57%, respectively, and compares favorably with the
literature approach to 43a (39% overall yield).18
Conclusion
Addition of dialkyl phosphonodifluoromethyl and phospho-
nothiodifluoromethyl radicals to alkenes represents a useful
approach to the preparation of R,R-difluorinated alkylphospho-
nates and alkylphosphonothioates. The method can be applied
to alkynes and generates the analogous â,γ-unsaturated adducts
in fair to good yields. The use of these products in cycloaddition
processes is under way in this laboratory, and will be reported
in due course.
Experimental Section
Unless otherwise stated, 1H NMR, 13C NMR, 19F NMR, and 31
P
NMR spectra were recorded in deuterated chloroform on a
spectrometer operating at 200, 50, 188, and 81 MHz, respectively,
and relative to (CH3)4Si, CDCl3, C6F6, and 85% H3PO4, respectively.
Chemical shifts are expressed in parts per million (ppm) and
coupling constants in Hertz (Hz). IR Spectra were recorded on a
FT-IR spectrometer. Chemicals were used without further purifica-
tion. Unless otherwise indicated, all drying of organic extracts were
carried out over magnesium sulfate and all chromatographies were
performed on silica. Abbreviations for the eluents are as follows:
A (AcOEt), C (CH2Cl2), H (n-heptane), and E (Et2O).
O,O-Diethyl difluoromethylphosphonothioate (11b). A solu-
tion of substrate 11a (2.00 g, 7.81 mmol) and Lawesson’s reagent
(3.16 g, 7.81 mmol) in anhydrous toluene (16 mL) is refluxed under
argon for 2 h, cooled to room temperature, and evaporated under
reduced pressure. The crude product is filtered under a mixture of
silica and celite and washed with heptane. The filtrate is evaporated
under reduced pressure. Chromatography and elution with H/A (9:
FIGURE 3. Structures of reagents 40, radicals 41 and 42, and products
43.
1
Adducts 31 and 37 were quantitatively desilylated by treat-
ment with tetra-n-butylammonium fluoride to give R,R-difluo-
roallylphosphonate 43a and R,R-difluoroallylphosphonothioate
43b. The approach developed in this paper thus allows the
preparation of these products with an overall yield, from
difluorophosphonate 11a and difluorophosphonothioate 11b, of
1) give 11b as a colorless oil (1.55 g, 74%) (Rf 0.31). H NMR δ
5.88 (dt, 1H, 2JH-F ) 50.1, 2JH-P ) 20.1), 4.31-4.15 (m, 4H, 3JH-P
) 14.2, 3JH-H ) 7.3), 1.33 (t, 6H, 3JH-H ) 6.9). 31P NMR δ 72.99
(t, 1P, 2JP-F ) 95.2).19F NMR δ 29.62 (dd, 2F, 2JF-P ) 94.7, 2JF-H
2
) 47.2). 13C NMR δ 124.1 (dt, 1C), 65.6 (d, 2C, JC-P ) 6.6),
3
16.0 (d, 2C, JC-P ) 5.4). IR (NaCl) ν cm-1 1120 (C-F), 1046
(P-O), 807 (PdS). Exact mass (EI, 70 eV) m/z calcd for C5H11O2-
PF2S 204.1773, found 204.1801. Anal. Calcd for C5H11O2PF2S: C,
40.37; H, 3.62. Found: C, 40.17; H, 4.27.
(19) For instance, attempted additions of radicals 5a and 5b onto n-oct-
4-yne under otherwise identical conditions resulted in the formation of the
desired adducts in 4% and 8%, respectively, based on 19F NMR spectra of
the crude materials.
The same compound can also be prepared from diethylthiophos-
phite by the following procedure. To a solution of diethylthiophos-
J. Org. Chem, Vol. 71, No. 1, 2006 35

Pignard et al.
TABLE 2. Addition of Radicals 5a and 5b to Alkynes 22-27a
a 5a or 5b (1 equiv), n-Bu3SnH (1.1 equiv), AIBN (0.4 equiv), toluene, 110 °C. b Isolated yields. c Using TTMSSH (1.1 equiv).
phite (22.33 g, 0.145 mol) in anhydrous THF (90 mL) is added
sodium wire (3.5 g, 1.5 mol) in portions. The solution is stirred for
24 h at room temperature. After the disappearance of all of the
sodium, chlorodifluoromethane (40 g, 0.33 mol) is bubbled through
the reaction mixture over a period of time of 3 h. The solution is
stirred under nitrogen for 12 h. Addition of a 1:1 mixture of silica
and celite (100 g), filtration, washing of the solid with heptane
(3 × 100 mL), and evaporation of the filtrate affords a liquid that
is purified as above to give 11b as a colorless oil (18.94 g, 64%).
O,O-Diethyl (phenylselanyl)difluoromethylphosphonate (6a).
A solution of phosphonate 11a (0.42 g, 2.23 mmol; see Supporting
Information) in anhydrous THF (6 mL) is added to a cold (-78
°C) solution of LDA (2.60 mmol, prepared from N,N-diisopropy-
lamine (0.36 mL, 2.60 mmol), THF (10 mL), and n-butyllithium
(1.79 mL of a 1.6 M solution in n-hexane, 2.86 mmol). After 15
min of stirring, a solution of freshly sublimated phenylselanyl
chloride (0.64 g, 3.34 mmol) in anhydrous THF (6 mL) cooled at
-78 °C is added under argon over a period of time of 3 h (cannula).
The resultant mixture is stirred for 4 h at -78 °C, warmed to room
temperature, and quenched with a saturated NaCl aqueous solution.
The mixture is extracted with CH2Cl2 (3 × 10 mL), dried, and
evaporated under reduced pressure. The crude material is chro-
matographed and eluted with a 4:1 mixture of H/A to give 0.55 g
1
(71% yield) of 11a as a colorless oil (Rf 0.2). H NMR δ 7.68-
7.65 (m, 2H), 7.37-7.26 (m, 3H), 4.27-4.14 (m, 4H), 1.28 (t, 6H,
2
3JH-H ) 6.9). 31P NMR δ 4.39 (t, 1P, JP-F ) 95.2). 19F NMR δ
2
77.84 (d, 2F, JF-P ) 94.8). 13C NMR δ 136.6 (s, 2C), 128.8 (s,
1C), 128.1 (s, 2C), 121.7 (dt, 1C), 64.3 (d, 2C, 2JC-P ) 6.6), 15.3
36 J. Org. Chem., Vol. 71, No. 1, 2006

Phosphonodifluoromethyl Radicals
3
(d, 2C, JC-P ) 5.5). IR (NaCl) ν (cm-1) 1270 (PdO), 1042 et
O,O-Diethyl 1,1-difluoro-prop-2-enylphosphonate (43a). At 0
°C, 1.33 mL of tetra-n-butylammonium fluoride (1.33 mmol, 1 M
in THF containing 5% water) is added to 31 (100 mg, 0.33 mmol)
in solution in anhydrous THF (2 mL). The mixture is stirred for 1
h at 0 °C and quenched with NaCl solution (3 mL) at room
temperature. The crude mixture is extracted with ethyl acetate (2
× 5 mL), dried under MgSO4, and evaporated under reduced
1035 (C-F). M. S. (EI) m/z (rel int) 344 (M+ (80Se), 37), 186 (M+
- C6H5Se, 22), 157 (57), 121 (100). Exact mass (CI, 200 eV) m/z
calcd C11H15F2O3PSe (80Se) 344.9970, found 344.9990. Anal. Calcd
for C11H15F2O3PSe: C, 38.50; H, 4.41. Found: C, 38.49; H, 4.42.
O,O-Diethyl (phenylselanyl)difluoromethylphosphonothioate
(6b). Prepared from phosphonothioate 11b by the same procedure;
1
1
obtained as a greenish oil (0.58 g, 72% yield) (Rf 0.34). H NMR
pressure to afford 43a as a pale green oil (75.9 mg, 100%). H
δ 7.72-7.68 (m, 2H), 7.45-7.24 (m, 3H), 4.32-4.20 (m, 4H), 1.32
NMR δ 6.31-6.13 (m, 1H), 6.02-5.85 (m, 1H), 5.63-5.38 (m,
3
2
3
(t, 6H, JH-H ) 6.9). 31P NMR δ 73.01 (t, 1P, JP-F ) 96.4). 19F
1H), 4.32-4.15 (m, 4H), 1.42 (t, 6H, JH-H ) 7.2). 31P NMR δ
2
2
2
NMR δ 79.14 (d, 2F, JF-P ) 94.9). 13C NMR δ 138.0 (s, 2C),
7.55 (t, 1P, JF-P ) 110.3). 19F NMR δ 57.35 (dd, 2F, JF-P
)
2
3
130.1 (s, 1C), 129.5 (s, 2C), 123.4 (dt, 1C), 65.8 (d, 2C, JC-P
)
115.4, JF-H ) 14.5). 13C NMR δ 137.8 (s, 1C), 133.2 (s, 1C),
124.5 (dt, 1C), 64.4 (d, 2C, JC-P ) 6.4), 15.4 (d, 2C, JC-P )
6.7), 16.6 (d, 2C, JC-P ) 5.6). IR (NaCl) ν cm-1 1137 (C-F),
907 (P-O), 753 (PdS). Exact mass (EI, 70 eV) m/z calcd for
C11H15O2PF2SSe 359.2349, found 359.2353. Anal. Calcd for
C11H15O2PF2SSe: C, 36.78; H, 4.21; S, 8.93. Found: C, 36.82; H,
4.24; S, 8.96.
3
2
3
4.8). IR (NaCl) ν cm-1 1187 (PdO), 1092 (C-F), 1069 (P-O).
Exact (EI, 70 eV) m/z calcd for C7H13O3PF2 214.1485, found
214.1533. Anal. Calcd for C7H13O3PF2: C, 39.26; H, 6.12. Found:
C, 39.35; H, 6.08.
Compound 6b can also be prepared from precursor 6a by the
following procedure. A solution of substrate 6a (2.69 g, 7.81 mmol)
and Lawesson’s reagent (3.16 g, 7.81 mmol) in anhydrous toluene
(16 mL) is refluxed under argon for 2 h, cooled to room
temperature, and evaporated under reduced pressure. The crude
product is filtered under a 1:1 mixture of silica and celite and
washed with heptane. The filtrate is evaporated under reduced
pressure. This material is then subjected to chromatography and
elution with a 4:1 mixture of H/A to give 6b as a greenish oil (1.54
g, 55% yield).
Radical Addition of Precursor 6a and 6b onto Alkenes 12-
17 or Alkynes 22-27. General Procedure. To a degassed
refluxing solution of the requisite precursor (1 equiv; 6a or 6b 0.185
mol/L) and the requisite alkene (1 equiv; 12-17 0.185 mol/L) or
alkyne (1 equiv; 22-27 0.185 mol/L) in anhydrous toluene is added
a toluene solution of tri-n-butyltin hydride (1.1 equiv; 0.203 mol/
L) and AIBN (0.4 equiv, 0.074 mol/L) over a period of time of 10
h (syringe pump). After completion of the addition, the resultant
mixture is refluxed for an additional 2 h, cooled to room
temperature, and evaporated under pressure. The crude material is
chromatographed and eluted with the solvents indicated in Sup-
porting Information.
O,O-Diethyl 1,1-difluoro-prop-2-enylphosphonothioate (43b).
The procedure described above is applied to 37 to quantitatively
1
deliver 43b as a colorless liquid. H NMR δ 6.43-6.19 (m, 1H),
6.04-5.82 (m, 1H), 5.59-5.34 (m, 1H), 4.43-4.21 (m, 4H), 1.38
(t, 6H, 3JH-H ) 6.9). 31P NMR δ 78.11 (t, 1P, 2JF-P ) 109.7). 19
F
2
3
NMR δ 59.06 (dd, 2F, JF-P ) 112.9, JF-H ) 15.2). 13C NMR δ
2
140.1 (s, 1C), 135.6 (s, 1C), 122.5 (dt, 1C), 63.8 (d, 2C, JC-P
)
3
6.8), 16.4 (d, 2C, JC-P ) 5.2). IR (NaCl) ν cm-1 1092 (C-F),
1069 (P-O), 836 (PdS). Exact (EI, 70 eV) m/z calcd for C7H13O2-
PF2S 230.2151, found 230.2134. Anal. Calcd for C7H13O2PF2S: C,
36.52; H, 5.69; S, 13.93. Found: C, 36.57; H, 5.73; S, 13.85.
Acknowledgment. The “Re´gion Haute-Normandie” is grate-
fully acknowledged for a grant to S.P. (PUNChOrga).
Supporting Information Available: Experimental procedure
for compound 11a; anatytical data for compounds 18a-18f, 19a-
19f, 21a-21b, 28-32, and 34-38; and 1H, 13C, 19F, and 31P NMR
spectra for compounds 18f, 31 and 37. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO051511C
J. Org. Chem, Vol. 71, No. 1, 2006 37