Phosphonyl, Phosphonothioyl, Phosphonodithioyl, and Phosphonotrithioyl Radicals: Generation and Study of Their Addition onto Alkenes

Article abstract of DOI:10.1021/jo0348064

The treatment of benzyl dialkyl phosphites and dithiophosphites with benzeneselanyl chloride generates an Arbuzov-type transformation leading to the dialkyl selenophosphates 19a and 19b and to selenophosphorodithioates 21a and 21b. Interaction of these substrates with Lawesson's reagent yields the corresponding selenophosphorothioates 20a and 20b and the selenophosphorotrithioates 22a and 22b. When treated with a radical initiator in the presence of a hydrogen donor and an alkene, all eight phosphorus(V) precursors undergo homolytic cleavage of the P-Se bond to generate the phosphonyl, phosphonothioyl, phosphonodithioyl, or phosphonotrithioyl radicals. Most of these are shown to add onto electron-rich and electron-poor alkenes to deliver the expected adducts in fair to excellent yields. Cyclic precursor 19b displays peculiar behavior and, under the reaction conditions, produces only the corresponding cyclic phosphite. Application of this radical chain process is carried out on furanosyl 3-exo-methylene derivative 37 to diastereoselectively furnish five new 3-phosphonomethyl-, 3-phosphonothiomethyl-, and 3-phosphonodithiomethyl-3-deoxofuranoses 38a-c and 38f,g. The possibility of conducting tandem processes is also discussed through experiments involving (1R)-(+)-α-pinene (39) and diallylamine 41.

Full text of DOI:10.1021/jo0348064

P h osp h on yl, P h osp h on oth ioyl, P h osp h on od ith ioyl, a n d
P h osp h on otr ith ioyl Ra d ica ls: Gen er a tion a n d Stu d y of Th eir
Ad d ition on to Alk en es†
Chrystel Lopin,‡ Ge´raldine Gouhier, Arnaud Gautier, 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 J une 11, 2003
The treatment of benzyl dialkyl phosphites and dithiophosphites with benzeneselanyl chloride
generates an Arbuzov-type transformation leading to the dialkyl selenophosphates 19a and 19b
and to selenophosphorodithioates 21a and 21b. Interaction of these substrates with Lawesson’s
reagent yields the corresponding selenophosphorothioates 20a and 20b and the selenophospho-
rotrithioates 22a and 22b. When treated with a radical initiator in the presence of a hydrogen
donor and an alkene, all eight phosphorus(V) precursors undergo homolytic cleavage of the P-Se
bond to generate the phosphonyl, phosphonothioyl, phosphonodithioyl, or phosphonotrithioyl
radicals. Most of these are shown to add onto electron-rich and electron-poor alkenes to deliver the
expected adducts in fair to excellent yields. Cyclic precursor 19b displays peculiar behavior and,
under the reaction conditions, produces only the corresponding cyclic phosphite. Application of this
radical chain process is carried out on furanosyl 3-exo-methylene derivative 37 to diastereoselectively
furnish five new 3-phosphonomethyl-, 3-phosphonothiomethyl-, and 3-phosphonodithiomethyl-3-
deoxofuranoses 38a -c and 38f,g. The possibility of conducting tandem processes is also discussed
through experiments involving (1R)-(+)-R-pinene (39) and diallylamine 41.
In tr od u ction
Phosphonates 2 have attracted much attention during
the past decades because of their similarities with the
phosphate functional group 1 (Figure 1).1 The central role
played by the latter in numerous biological processes and
its position as a crucial constituent of many major
biomolecules have resulted in the development of various
synthetic methodologies designed at producing 2 as
mimics of the parent phosphate. The replacement of one
or more oxygen atom(s) in phosphonates by sulfur gener-
ates phosphonothioates, phosphonodithioates, or phospho-
notrithioates (3, 4, or 5, respectively).
F IGUR E 1. Structures of phosphates 1, phosphonates 2,
phosphonothioates 3, phosphonodithioates 4, and phospho-
notrithioates 5.
encompassing single or double phosphorus-sulfur bond-
(s). Thus, several reports have since then demonstrated
the efficiency of the method, when applied to O,O-
dialkylphophites 6 or O,O-dialkylthiophosphites 7; O,O-
dialkylphosphonates and phosphonothioates are gener-
ally obtained in good to excellent yields (Scheme 1).4
The large range of organophosphorus compounds con-
taining sulfur have found widespread use as pesticides,
in petroleum technology, and in metal ore extraction
techniques.2 The reported preparations of species 3-5
enter in two categories: the first ones rely on phosphorus-
carbon bond formation, while the others exploit modifica-
tions at phosphorus in phosphorus-carbon-bonded com-
pounds.3 The approach relying on the addition of
phosphorus-centered radicals onto alkenes was first
introduced in the early 1950s on substrates devoid of
sulfur and, more recently, was extended to substrates
(2) See, for instance: (a) Shell, D. C.; Hayward, E. C. U.S. Patent
4,024,049 (19770517), 1977. (b) Ukeles, S. D.; Ben-Yoseph, E.; Finkel-
stein, N. P. Eur. Patent 89-302,625 (19890316), 1989. (c) Kazama, H.;
Matsuoka, S. J pn. Patent 04,330,083 (92,330,383), 1992. (d) Kazama,
H.; Matsuoka, S. J pn. Patent 05,39,296 (93 39,296), 1993. (e) Nakan-
ishi, H.; Kuribayashi, T. J pn. Patent 05 09,490 (93 09,490), 1993. (f)
Tang, C. C.; Ma, F. P.; Zhang, K.; He, Z. J .; J in, Y. C. Heteroatom Chem.
1995, 6, 413-417. (g) Rodriguez, O. P.; Thompson, C. M. Phosphorus,
Sulfur Silicon Relat. Elem. 1996, 117, 101-110. (h) Kalir, A.; Kalir,
H. H. In The Chemistry of Organophosphorus Compounds; Hartley,
F. R., Ed.; Wiley: Chichester, New York, 1996; pp 767-780.
(3) Edmundson, R. S. In The Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; J ohn Wiley & Sons: Chichester, 1996;
Vol. 4, Chapter 5, pp 400-412.
† Taken from the Ph.D. Thesis of C.L.
‡ Present adress: Institut de Chimie Organique et Analytique, UMR
CNRS 6005, Universite´ d’Orle´ans-UFR de Sciences, Rue de Chartres-
BP 6759, F-45067 Orle´ans Cedex 2, France.
(1) Hartley, F. R., Ed. The Chemistry of Organophosphorus Com-
pounds, Vol. 4, Ter- and Quinque-valent Phosphorus Acids and Their
Derivatives; J ohn Wiley & Sons: Chichester, 1996.
10.1021/jo0348064 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003
9916
J . Org. Chem. 2003, 68, 9916-9923

Phosphonyl Radical Addition onto Alkenes
F IGURE 2. Phosphites 6, thiophosphites 7, dithiophosphites
8, and trithiophosphites 9, as well as radicals 10-13 generated
therefrom.
SCHEME 1. Ad d ition of P h osp h ites 6 a n d
Th iop h osp h ites 7 on to Alk en es 14
F IGURE 3. Structures of radical precursors 19-22, of radical
23, and of intermediates 24-26.
to a rapid disproportionation process.10 Hence, we elected
to rely on precursors encompassing a P-Se bond. Indeed,
O,O-diethylphenylselenophosphate (19a ) has been pre-
pared by Petragnani and used by Motherwell to generate
the corresponding phosphonyl radical 10a (Figure 3).11
Thus, radical 10a , when generated from 19a and a
radical initiator in the presence of a hydrogen donor, was
shown to add onto carbohydrate gem-difluoroenol ethers
to deliver the expected adducts in fair yields.
These literature data constitute the starting point of
this study. The corresponding diethylphenylselenophos-
phorothioate (20a), diethylphenylselenophosphorodithioate
(21a ), and diethylphenylselenophosphorotrithioate (22a ),
as well as the four related cyclic derivatives 19b-22b,
were considered as good precursors of radicals 10-13.
The choice of a selenoether group (rather than halogen
atoms) stemmed from the consideration that a competi-
tive addition process or a competitive homolytic cleavage
could arise under the reaction conditions with some of
these precursors.12 Thus, for instance, homolytic cleavage
of the P-Se bond in 22a would give rise to the desired
phosphonotrithioyl radical 13a while addition of the initia-
tor on the sulfur end of the PdS bond would generate
an undesired, stabilized phosphorus radical of the type
23.13
Our own studies on the radical chain addition of species
6 and 7 onto 1,1-difluoroalkenes showed the positive
effect of the sulfur atom in 11 on the course of the
reaction, when compared to the fully oxygenated ana-
logue (i.e., 10) (Figure 2).5 More recently, we described
the addition of S,S-dialkylphosphonodithioyl radicals 12
onto alkenes.6 In this paper, we report a more complete
and comparative study on the generation of radicals 10,
11, 12, and 13 as well as on their behavior toward
terminal alkenes.
The lower stability of the P-S bond (45-50 kcal/mol
versus 90-100 kcal/mol for the P-O bond) precluded us
from using S,S-dialkyl dithiophosphites and trithiophos-
phites (8 and 9, respectively) as precursors of radicals
12 and 13. Thus, for instance, dithiophosphites 8 are
notoriously difficult to prepare and handle and have been
reported to disproportionate and to be prone to decom-
position upon hydrolysis.7 In addition, the more stable,
cyclic 1,3,2-dithiaphosphinane 2-oxide (8b, R, R ) -CH2-
CH2CH2-) has been shown to easily form oligomers or
polymers.8,9 Analogously, attempts to prepare trithio-
phosphites have been reported to be unsuccessful, due
(4) (a) Stiles, A. R.; Vaughan, W. E.; Rust, F. F. J . Am. Chem. Soc.
1958, 80, 714-716. (b) Pudovik, A. N.; Konovalova, I. V. Zh. Obshch.
Khim. 1959, 29, 3338-3342; Chem. Abstr. 1960, 54, 15224b. (c) Kenny,
R. L.; Fisher, G. S. J . Org. Chem. 1974, 39, 682-686. (d) Battiste, D.
R.; Haseldine, D. L. Synth. Commun. 1984, 14, 993-1000. (e) Finke,
M.; Kleiner, H.-J . Liebigs Ann. Chem. 1974, 741-750. (f) Dingwall, J .
G.; Tuck, B. J . Chem. Soc., Perkin Trans. 1 1986, 2081-2090.
(5) Piettre, S. R. Tetrahedron Lett. 1996, 37, 2233-2236.
(6) Lopin, C.; Gautier, A.; Gouhier, G.; Piettre, S. R. Tetrahedron
Lett. 2000, 41, 10195-10200.
(7) (a) Hudson, R. F.; Keay, L. J . Chem. Soc. 1956, 3269-3271. (b)
Kardanov, N. A.; Provotorova, N. P.; Petrovskii, 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.
(8) (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.; Nifant’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. V. Zh. Obshch.
Khim. 1974, 44, 1694-1697.
(9) In our hands, compound 8b was formed in very poor yields
(<10%), and large amounts of insoluble, colorless material were
obtained.
(10) Nifant’ev, E. E.; Chechetkin, A. S.; Blagoveshchenskii, V. S.;
Sokurenko, A. M. Zh. Obsch. Khim. 1983, 53, 2695-2697.
(11) (a) Petragnani, N.; Toscano, V. G.; Moura Campos, M. Chem.
Ber. 1968, 101, 3070-3078. (b) Herpin, T. F.; Houlton, J . S.; Mother-
well, W. B.; Roberts, B. P.; Weibel, J .-M. J . Chem. Soc., Chem.
Commun. 1996, 613-614. (c) Herpin, T. F.; Motherwell, W. B.; Roberts,
B. P.; Roland, S.; Weibel, J .-M. Tetrahedron 1997, 53, 15085-15100.
(12) In particular, the dissociation energies of the analogous C-X
bonds (X ) Br: 68 kcal/mol; X ) S: 65 kcal/mol; X ) Se: 58 kcal/mol)
and literature data allow one to expect a cleaner and more selective
homolytic cleavage with selenophosphorodithioate 21 and selenophos-
phorotrithioate 22 than with the corresponding phosphorodithioyl
bromide i and phosphorotrithioyl bromide ii. The same can be said
for the phosphorotrithioate iii and phosphorotetrathioate iv.
J . Org. Chem, Vol. 68, No. 26, 2003 9917

Lopin et al.
TABLE 1. Op tim iza tion of th e Rea ction Con d ition s in th e Ca se of P r ecu r sor 19a a n d n -Oct-1-en e (27)
entry procedure n-octene 27 (equiv) 19a (equiv)
hydrogen donora (equiv)
AIBN (equiv) addition time (h) yieldsb (%)
1
2
3
4
A
B
C
D
1
1
1
3
2
3
1
n-Bu3SnH (4) or TTMSSH (4)
TTMSSH (3)
n-Bu3SnH (4)
0.5
0.25
0.5
8
2
0.2
8
60
59
50
20
10
n-Bu3SnH (1)
0.5
a
b
TTMSSH: tris(trimethylsilyl)silane. Isolated yields.
Resu lts a n d Discu ssion
precursor 19a and difluoroalkenes in the presence of a
radical initiator, Motherwell and his collaborators report
a procedure calling for the use of 0.5, 1, 3, and 4 equiv of
azobisisobutyronitrile (AIBN), alkene, 19a , and tri(n-
butyl)tin hydride (n-Bu3SnH), respectively, and an ad-
dition time of 8-10 h (Table 1, entry 1).11c In view of both
the probable higher reactivity of the unfluorinated al-
kenes considered in the present study and the purifica-
tion problems associated with the use of tin compounds,
a somewhat different procedure was worked out with 19a
and n-oct-1-ene (27). Replacement of tris(n-butyl)tin
hydride with tris(trimethylsilyl)silane (TTMSSH),20 and
decreasing the amount of AIBN to 0.25 equiv did not
induce any change in the course of the reaction. The
amount of precursor was also decreased, as was the
addition time of the TTMSSH/AIBN solution. Thus, it
was found that slow addition of 3 equiv of TTMSSH and
0.25 equiv of AIBN over a period of 2 h resulted in the
formation of the desired product in essentially the same
yield as with the original procedure (Table 1, entry 2).
Further diminishing the addition time resulted in a drop
of the yields (Table 1, entry 3). Conditions calling for a
large excess of alkene also produced a deleterious effect
on the course of the reaction (entry 4). Similar results
were obtained with precursors 20a , 21b, and 22b.
The eight precursors were then engaged in reactions
with n-oct-1-ene (27), methylenecyclohexane (28), phenyl
acrylate (29), and n-butyl vinyl ether (30). The results
are compiled in Table 2.
P r ep a r a tion of Ra d ica l P r ecu r sor s 19-22. In
analogy to the reported preparation of 19a , we used an
approach relying on an Arbuzov process on trialkyl
phosphites and O,S,S-trialkyl dithiophosphites. Thus,
triethyl phosphite was reacted with benzeneselanyl
chloride in toluene at 0 °C to afford precursor 19a (77%
yield).14 2-Chloro-1,3,2-phosphinane (24a )15 and 2-chloro-
1,3,2-dithiaphosphinane (24b)16 were quantitatively trans-
formed into the 2-benzyloxy derivatives 25a and 25b,
respectively, by interaction with benzyl alcohols in diethyl
ether, under basic conditions (procedures of Banwarth
and Holmes, respectively).17 To avoid any oxidation of the
phosphorus(III), these compounds were engaged without
further purification in the next step. Not unexpectedly,
benzeneselanyl chloride was found to selectively and
efficiently react on the benzyloxy unit to deliver seleno-
phosphate 19b and selenophosphorodithioate 21b in 76
and 70% isolated yields. Precursor 21a was generated
in a somewhat different manner. Phosphorus trichloride
was sequentially reacted with benzyl alcohol and ethaneth-
iol (2 equiv) under basic conditions. Direct treatment of
the thereby isolated and highly oxygen-sensitive O-
benzyl-S,S-diethyl dithiophophite (26) with benzenese-
lanyl chloride delivered 21a in 54% yield.18 The PdO
bond in all four precursors 19a , 19b, 21a , and 21b were
then converted into a PdS bond by reaction with 1 equiv
of Lawesson’s reagent in refluxing toluene (19a , 19b) or
refluxing CH2Cl2 (21a , 21b); isolated yields were found
to be 72, 58, 56, and 86%, respectively.19
In all cases but one, the selanylated precursors were
found to be totally consumed. Precursor 19b constantly
led to 60-65% consumption, thus demonstrating that the
homolytic cleavage is, in this particular case, a slower
process (see below). The facile homolytic cleavage of the
P-Se bond in the seven other precursors is in line with
the available literature data on the analogous C-Se
bond.21 The expected adducts, when formed, were easily
isolated by chomatography on silica in yields ranging
from 15 to 99%; complete regioselectivity was ob-
served in all cases. Byproducts included n-Bu3SnSePh
or (Me3Si)3SiSePh, and the corresponding phosphites 6
or thiophosphites 7 resulted from partial, competitive
hydrogen quenching of the phosphorus-centered radicals
Ad d ition s Rea ction s of Ra d ica ls 10-13 on to Al-
k en es. In his paper describing the interaction between
(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) Reference 11a reports the preparation of compound 19a from
triethyl phosphite and benzeneselanyl bromide. We satisfactorily used
the commercially available analogous chloride to achieve this trans-
formation; see the Experimental Section.
(15) Arbuzov, A. E.; Zoroastrova, V. H. Izv. Akad. Nauk. SSSR, Otd.
Khim. Nauk. 1952, 6, 770-778.
(16) This compound has been described in the past: (a) See refs 8b
and 14. (b) Martin, J .; Robert, J . B.; Taieb, C. J . Phys. Chem. 1976,
80, 2417-2421. However, we found these procedures nonreproducible
and yielding the desired compound in yields <35%. In the end,
dithiaphosphinane 24b was prepared in 45% yield by using the
conditions described for the corresponding phospholane: (c) Martin,
S. F.; Wagman, A. S. J . Org. Chem. 1996, 61, 8016-8023. See the
Experimental Section.
1
(10-100% in the H and 31P NMR spectra).22 The corre-
sponding dithiophosphites and trithiophosphites were not
observed, due to their propensity to disproportionate, to
dimerize and oligomerize, and to the low solubility of
these oligomers.8,10,23 The lower yields observed with
phenyl acrylate may more reflect a competitive polym-
(17) (a) Bannwarth, W.; Trzeciak, A. Helv. Chim. Acta 1987, 70,
175-186. (b) Swamy, K. C. K.; Holmes, J . M.; Day, R. O.; Holmes, R.
R. J . Am. Chem. Soc. 1990, 112, 6092-6094.
(18) Compound 26 was isolated by evaporation of the volatiles and
used without further purification. 1H and 31P NMR data indicated a
purity of 92-95%.
(19) (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.
(20) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese,
B.; Kopping, B. J . Org. Chem. 1991, 56, 678-683.
(21) Although this particular point is not discussed in ref 11b,c, one
can assume that the authors observed a total consumption of precursor
19a .
(22) After evaporation of the volatiles; at least 2 equiv of precursor
was used in each reaction; see the Experimental Section.
9918 J . Org. Chem., Vol. 68, No. 26, 2003

Phosphonyl Radical Addition onto Alkenes
TABLE 2. Yield s of P r od u cts Resu ltin g fr om th e Ad d ition Rea ction s of Ra d ica ls 10-13 on to Alk en es 27-30
a
b
See text. Isolated yields.
conformation A may be preferred over conformation B
due to the stabilizing overlap of the antibonding orbital
σ* of the P-Se bond with the lone pair of the Y atom(s)
(Figure 5).24-26 Obviously, such antiperiplanar arrange-
ments of the lone pairs of Y atoms and the P-Se bond in
precursors 19b-22b would result in different stabiliza-
tions, depending on the identity of atoms Y. The partial
transfer of electron density from a heteroatom (Y) to
another heteroatom (Se) would be expected to be en-
hanced when the former heteroatom is less electronega-
F IGURE 4. Structures of adducts 35 and 36.
erization process (and thus a competitive consumption
of the alkene) than a competitive reduction of the
phosphorus-centered radical by TTMSSH. It is notewor-
thy that phosphonodithioyl and phosphonotrithioyl radi-
cals (12 and 13) reacted sluggishly with n-butyl vinyl
ether (30).
Other alkenes also react in an analogous way. Thus
radical 12b was successfully added onto 2-methyl-
undec-1-ene and R-methylstyrene to deliver the corre-
sponding adducts 35 and 36 in 70 and 75% isolated
yields, respectively (Figure 4).
Several reasons may be invoked to explain the striking
differences observed in the behavior of both precursor
19b and radical 10b generated from it: in addition to
the uncomplete consumption of precursors 19b, no adduct
could be isolated, even in minor amounts, from the
addition reactions on alkenes 27-30 (Table 2, entry 5).
The first observation can be the translation of a stronger
P-Se bond in 19b than in the seven other precursors.
Conformational analysis of the chairlike cyclic precursors
19b, 20b, 21b, and 22b indicates that, in solution,
(24) For a discussion on stereoelectronic effects, see: (a) Deslong-
champs, P. Stereoelectronic Effects in Organic Chemistry; Pergamon
Press: Oxford, 1983. (b) Kirby, A. J . The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Springer-Verlag: Berlin, 1983.
(25) Stereoelectronic effects in cyclic phosphates have been exten-
sively studied, particularly in the context of hydrolysis. Thus, six-
membered monocyclic phosphates are in a chair conformation with an
axial ester bond, a reflection of the ground-state stereoelectronic effect
(nO f σ*P-O). See: (a) Lehn, J .-M.; Wipff, G. J . Chem. Soc., Chem.
Commun. 1975, 800-802. (b) Hall, C. R.; Inch, T. D. Tetrahedron 1980,
36, 2059-2095. (c) Gorenstein, D. G. Chem. Rev. 1987, 87, 1047-1077.
(26) Data from the literature also show that both phosphonotrithio-
ate v and phosphorotrithioate vi adopt a chairlike conformation, with
the tert-butyl group in v preferably equatorial. In the case of vi,
however, the exclusive conformation is the one in which the methoxy
group is in axial position (as depicted below), due to a stabilizing
overlap analogous to the one discussed hereabove, and, most probably,
weaker 1,3-diaxial interactions. See: Maryanoff, B. E.; MacPail, A.
T.; Hutchins, R. O. J . Am. Chem. Soc. 1981, 103, 4432-4445.
(23) For example, dithiophosphite dimers and oligomers are soluble
only in DMSO. See refs 8a and 10.
J . Org. Chem, Vol. 68, No. 26, 2003 9919

Lopin et al.
The data in Table 2 clearly show that radicals 11a and
11b, featuring two P-O bonds and one PdS bond, add
to a range of alkenes of different polarities to yield the
desired monoadducts in fair to excellent yields (entries
2 and 6). While phosphonyl radical 10a delivered the
expected adducts when generated in the presence of
neutral and electron-rich alkenes, no product was isolated
or detected with phenyl acrylate, an electron-poor sub-
strate (entry 1). Phosphonodithioyl radicals 12a and 12b
as well as phosphonotrithioyl radicals 13a and 13b,
however, were inert toward an electron-rich alkene such
as n-butyl vinyl ether, and reacted well with neutral and
electron-poor alkenes (entries 3, 4, 7, and 8). Polar factors
are known to greatly influence the rate of radical addi-
tions, and their importance may be seen in the results
obtained with n-butyl vinyl ether (30) (Table 2).33 Inas-
much as no kinetic data are available at this time, one
may cautiously argue against the electrophilic nature of
phosphonodithioyl radicals 12a and 12b, as well as of
phosphonotrithioyl radicals 13a and 13b (entries 3, 7, 4,
and 8, respectively).34 The data indicate that it is possible
to add a phosphorus-centered radical across a range of
formal reactivities from electrophilic to nucleophilic by
carefully choosing the precursor. Functional group ma-
nipulation allows for the interconversion of the different
groups and open access to virtually any of the four types
of products.35
The peculiar reactivity of cyclic phosphonyl radical 10b
reflects a higher rate for hydrogen abstraction than for
the addition process to the alkene, even though the latter
must be accumulating in the medium. Most carbon-
centered radicals are considered to be planar while
phosphorus-centered radicals adopt a pyramidal config-
uration. Electron spin resonance spectrometry studies
and theoretical evaluations have shown that more elec-
tronegative substituents on the phosphorus atom induce
a more pronounced pyramidal configuration of the radi-
cal; such would be the case of radicals 10a and 10b, when
compared to the others.36 Comparison of the data from
entries 1 and 5 suggests that the strain induced by the
cyclic structure of radical 10b would disfavor stabilization
and promote faster reduction than addition onto the
CdC bond of the alkenes, in accordance with the chain
mechanism depicted in Scheme 2. The replacement of one
or more oxygen atom(s) with sulfur changes this picture
dramatically by inducing a positive effect in the course
of the additions and is reminiscent of earlier observations
from this laboratory and others.5,11c
F IGURE 5. Conformations of precursors 19b-22b.
tive. Thus, a better overlap would occur with dithiaphos-
phinane oxide 21b than with dioxaphosphinane oxide
19b. In addition, the σ* orbital of the P-Se bond and
the n orbital of the singly bound heteroatoms Y are
expected to be of closer energetic levels when Y ) sulfur.
Other points concern both the longer P-S bond (when
compared to the P-O one) and the increasing atomic
radii (O < S < Se); these are expected to have a direct
impact on the 1,3-diaxial interactions and, therefore,
play a role in the adoption of the most favored conforma-
tion.27
An attempt to shed light on this issue included submit-
ting monocrystals of precursors 19b, 20b, 21b, and 22b
to X-ray diffraction analysis. Figure 6 depicts the com-
puter-generated ORTEP graphics for all four precursors
and unambiguously shows that 19b-22b actually all
adopt conformations of the type A, i.e., with the seleno-
ether group in axial position. Careful analysis of the data
indicates that a subtle difference exists between these
otherwise apparently similar conformations. Superim-
position of structures 19b and 22b points the finger at
the former structure in which the cycle undergoes a
distortion to place the selenoether group away from the
axial position (Figure 7). Measurement of the angles
formed between the P-Se bond and a straight line joining
C4 and the phosphorus atom, and comparison of the data
with the value obtained for cyclohexane shows differences
ranging from 3 to 9.6° (Table 3). Even though these
distortions may look modest, they might constitute a
basis to explain the observed behavior of 19b. Indeed, a
diminished overlap (nO f σ*P-Se) resulting from the
higher deviation of the selenoether group from the
dioxane axis would strengthened the P-Se bond and
slower the homolytic process.30-32
(27) Tedder has discussed the importance of polarity, bond strength,
and steric effects on the rate of free radical substitution. See: Tedder,
J . M. Tetrahedron 1982, 38, 313-329.
(28) All non-hydrogen atoms are represented by their displacement
ellipsoids drawn at the 50% probability level.
The reactions between all eight precursors 19-22 and
furanose derivative 37 were found to parallel the above-
(29) Hydrogen atoms are displayed with an arbitrary radius.
Hydrogen is depicted in blue, carbon in black, oxygen in red, phos-
phorus in purple, sulfur in orange, and selenium in green.
(30) In the case of precursor 19b, 35-40% of unconsumed 19b were
invariably recovered.
(31) In this context, data from the literature indicate that the lower
bond dissociation energy of the axial C-H bond in vii (when compared
to the equatorial one) is the result of an antiperiplanar orientation of
one of the lone pairs of the cyclic oxygens with respect to that bond.
See: (a) Belckwith, A. L. J .; Easton, C. J . J . Am. Chem. Soc. 1981,
103, 615-619. (b) Malatesta, V.; Ingold, K. U. J . Am. Chem. Soc. 1981,
103, 609-614. (c) Malatesta, V.; Scaiano, J . C. J . Org. Chem. 1982,
47, 1455-1459.
(32) Results reporting that radicals at C-2 form faster from thio-
acetals and oxathiocycloalkanes than from the corresponding acetals
are in line with our observations. See: (a) Batyrbaev, N. A.; Zorin, V.
V.; Moravskii, A. P.; Shuvalov, V. F.; Zlot-skii, S. S.; Rakhmankulov,
D. L. J . Gen. Chem. USSR 1983, 53, 364-369. (b) Lucken, E. A. C.;
Poncioni, B. J . Chem. Soc., J . Perkin Trans. 2 1974, 777-780.
(33) Tedder, J . M.; Walton, J . C. Tetrahedron 1980, 36, 701-707.
(34) Physicochemical studies will soon be initiated using Flash Laser
Photolysis and Electron Spin Resonance spectroscopy techniques, the
results of which will be reported in due course.
(35) (a) Edmunson, R. S. In The Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; Wiley: Chichester, New York, 1996;
pp 424-462. (b) Piettre, S. R. Tetrahedron Lett. 1996, 37, 4707-4710
and references therein.
(36) (a) Davies, A. G.; Griller, D.; Roberts, B. P. J . Am. Chem. Soc.
1972, 94, 1782-1783. (b) Roberts, B. P.; Singh, K. J . Organomet. Chem.
1978, 159, 31-35. (c) McLauchlan, K. A.; Simpson, N. J . K. J . Chem.
Soc., Perkin Trans. 2 1990, 1371-1377.
9920 J . Org. Chem., Vol. 68, No. 26, 2003

Phosphonyl Radical Addition onto Alkenes
F IGURE 6. ORTEP drawings of precursors 19b-22b with the adopted numbering scheme.28,29
SCHEME 2. Ra d ica l Ch a in P r ocess of th e
Ad d ition Rea ction of Ra d ica ls 10-13 on to Alk en esa
F IGURE 7. Side view and upper view of the superimposition
of precursors 19b and 22b.29
a
TTMSS ) ((CH3)3Si)3Si. bRadical initiator.
TABLE 3. An gle betw een th e Axia l C-H Bon d a n d th e
C1-C4 Axis in Cycloh exa n e a n d An gles betw een th e
P -Se Bon d a n d th e C1-C4 Axis in P r ecu r sor s 19b-22b
reaction conditions (procedure A) furnished the cyclic
allylphosphonothioate 40 (30% isolated yield), the result
of sequential radical addition, cyclobutane-ring fragmen-
tation, and hydrogen quenching of the thereby-produced
tertiary radical (Scheme 3).38,39 Precursor 20a was also
C6H12
100.0
19b
20b
21b
22b
angle (deg)
103.9
96.6
100.9
94.3
discussed data (Table 4). Here again, precursor 19b did
not undergo complete homolytic cleavage, and no adduct
was isolated in this case. This time, phosphonotrithioyl
radical 13a or 13b failed to add onto alkene 37, and this
might be the result of increased steric hindrance in the
furanosyl substrate. The reactions leading to products
38a -c,f,g displayed a very good diastereoselectivity, the
result of the known stereodirecting effect of the 2,3-
diisopropylidene acetal unit.6,37
(37) (a) Rees, R. D.; J ames, K.; Tatchell, A. R.; Williams, R. H. J .
Chem. Soc. C 1968, 2716-2721. (b) Sowa, W. Can. J . Chem. 1968, 46,
1586-1589. (c) Bourgeois, J . M. Helv. Chim. Acta 1975, 53, 363-372.
(d) Yoshimura, J . Adv. Carbohydr. Chem. Biochem. 1984, 42, 69-134.
(e) Giese, B.; Gonza`lez-Gomez, J . A.; Witzel, T. Angew. Chem., Int. Ed.
Engl. 1984, 23, 69-70. (f) Giese, B. Angew. Chem., Int. Ed. Engl. 1989,
28, 969-980. (g) Schmit, C. Synlett 1994, 241-242. (h) J ohnson, C.
R.; Bhumralkar, D. R.; De Clercq, E. Nucleosides Nucleotides 1995,
14, 185-194. (i) Lavaire, S.; Plantier-Royon, R.; Portella, C. J . Carbo-
hydr. Chem. 1996, 15, 361-370. (j) Lavaire, S.; Plantier-Royon, R.;
Portella, C. Tetrahedron: Asymmetry 1998, 9, 213-226. (k) Gautier,
A.; Garipova, G.; Dubert, O.; Oulyadi, H.; Piettre, S. R. Tetrahedron
Lett. 2001, 42, 5673-5676. (l) Dubert, O.; Gautier, A.; Condamine, E.;
Piettre, S. R. Org. Lett. 2002, 4, 359-362. (m) Lopin, C.; Gautier, A.;
Gouhier, G.; Piettre, S. R. J . Am. Chem. Soc. 2002, 124, 14668-14675.
The above phosphorus-centered radicals can also be
used in tandem cascade processes. Thus, interacting
precursor 20a and (1R)-(+)-R-pinene (39) under the same
J . Org. Chem, Vol. 68, No. 26, 2003 9921

Lopin et al.
TABLE 4. Str u ctu r es a n d Yield s of P r od u cts 38a -38h
TABLE 5. Ch em ica l Sh ifts of Com p ou n d s 19-22, 31-34,
a n d 38
radical precursor
yieldsb
(%)
entry
19-22
X
Y
R, R
producta
1
2
3
4
5
6
7
8
19a
20a
21a
22a
19b
20b
21b
22b
O
S
O
S
O
S
O
S
O
O
S
Et, Et
Et, Et
Et, Et
Et, Et
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
38a
38b
38c
38d
38e
38f
38g
38h
57
83
46
0
S
O
O
S
0
44
65
0
S
a
Diastereoselection in excess of 95% was observed in all cases.
Isolated yields.
b
SCHEME 3. Ad d ition Rea ction s of 20a to 39 a n d 41
reacted with N-tosylbisallylamine (41) to generate pyr-
rolidine 42 through a cascade radical addition (45%
isolated yield; a 7:3 mixture of cis and trans isomers,
respectively).40 Assignment of the diastereomeric ratio
was achieved with the help of 1-D and 2-D NMR
spectrometry (1H-1H COSY, 1H-13C COSY, 1H-31P
COSY, and NOESY experiments).41 Thus, for instance,
the spectra of the minor trans isomer displayed correla-
tions between the hydrogen on carbon 5 cis to the methyl
group, those of that methyl group, and the hydrogen on
carbon 3, indicative of a trans relationship between the
substituents; in the case of the cis isomer, however, the
lack of any correlation between the 5-hydrogen atom cis
to the methyl group and the 3-hydrogen atom demon-
strated the cis relationship of the two substituents on
carbon 3 and 4 of the pyrrolidinyl cycle.
a
Downfield from H3PO4.
cals addition to alkenes by extending the scope of the
reaction to phosphonodithioyl and phosphonotrithioyl
radicals 12 and 13. The synthesis of phosphonates and
phosphonothioates have been largely dominated by the
Michaelis-Arbusov and the Michaelis-Becker processes
involving the interaction between alkyl halides and
trialkyl phosphites or metalated dialkyl phosphites,
respectively.42 Other methods involving phosphoaldol and
Michael reactions have also been traditionally ex-
ploited to create carbon-phosphorus bonds (Abramov
and Pudovik reactions, respectively). These reactions
have been much less used for the preparation of phospho-
nodithioates and phosphonotrithioates due to the lability
of the P-S bond, as mentionned earlier. Classical Michae-
lis-Arbusov reaction between alkyl halides and trithio-
phosphites ((RS)3P) have been reported to be slow and
to require a large excess of alkyl halide.43 The efficient
approach developed in this paper thus successfully fills
The methodology described in this paper thus usefully
completes literature data on phosphorus-centered radi-
(38) For a related example of phosphorylation, see: Battiste, D. R.;
Haseldine, D. L. Synth. Commun. 1984, 14, 993-1000.
(39) An identical result was obtained from diethyl thiophosphite and
(1R)-(+)-R-pinene in the presence of Et3B/O2. See ref 37k. For the
opening of (1S)-(-)-â-pinene following a phosphorus-centered radical
addition, see: Mimeau, D.; Delacroix, O.; Gaumont, A.-C. Chem.
Commun. 2003, 2928-2929.
(40) Baldwin, J . E. Chem. Commun. 1976, 734-736. For a synthesis
of pyrrolidine by a 5-exo-trig radical cyclization, see: Berlin, S.;
Engman, L. Tetrahedron lett. 2000, 41, 3701-3704.
(41) (a) Bax, A.; Griffey, R. H.; Hawkins, B. L. J . Magn. Reson. 1983,
55, 301-315. (b) Bax, A.; Subramanian, S. J . Magn. Reson. 1986, 67,
565-569. (c) Marion, D.; Wuthrich, K. Biochem. Biophys. Res. Com-
mun. 1983, 113, 967-974.
(42) For a general discussion concerning these methods, see: Ed-
munson, R. S. In The Chemistry of Organophosphorus Compounds;
Hartley, F. R., Ed.; Wiley: Chichester, New York, 1996; Chapters 2-5,
pp 47-494.
(43) Al’fonsov, V. A.; Zamaletdinova, G. U.; Batyeva, E. S.; Pudovik,
A. N. J . Gen. Chem. USSR 1986, 56, 634-639.
9922 J . Org. Chem., Vol. 68, No. 26, 2003

Phosphonyl Radical Addition onto Alkenes
a gap in the synthesis of phosphonodithioates and
phosphonotrithioates via the direct formation of a P-C
bond.
carrying out tandem processes is demonstrated through
the use of substrates featuring two CdC bonds, i.e., (1R)-
(+)-R-pinene (39) and diallylamine 41. The approach thus
allows the clean production of phosphonates, phospho-
nothioates, phosphonodithioates, and phosphonotrithio-
ates and may find application in the field of nucleotide
analogues, as illustrated by the use of furanosyl deriva-
tive 37.
NMR Sp ectr om etr ic An a lysis. The 31P NMR data
for all precursors and the obtained adducts are compiled
in Table 5. Several points are worth noting. In a given
series, the known deshielding effect of a double-bonded
sulfur on the 31P NMR chemical shift is larger when two
oxygen atoms are single-bonded to the phosphorus (63-
67 ppm) than when two sulfur atoms are linked to the
phosphorus (5.5-22 ppm). Interestingly, the phosphorus
nucleus of the selenophosphorotrithioate 22b is strongly
shielded when compared to the acyclic analogue 22a
(entries 1 and 2, column 6; see below).
Exp er im en ta l Section
General procedures for all new compounds are given below.
Purifications and physical data are included in the Supporting
Information.
Syn t h esis of P r ecu r sor s 19b , 21a , a n d 21b . Gen er a l
P r oced u r e. A solution of the requisite substrate (25a , 25b,
or 26) (43.0 mmol) in toluene (25 mL) was added dropwise to
an ice-cold solution of phenylselanyl chloride (8.31 g, 43.0
mmol) in anhydrous toluene (25 mL) under argon. The
resultant mixture was stirred for 2 h at 0 °C, warmed to room
temperature, and evaporated under reduced pressure.
P r ep a r a tion of P r ecu r sor s 20a , 20b, 22a a n d 22b.
Gen er a l P r oced u r e. A solution of the requisite phosphorose-
lenoate (19a or 19b) or phosphoroselenodithioate (21a or 21b)
(7.63 mmol) and Lawesson’s reagent (3.10 g, 7.63 mmol) in
anhydrous CH2Cl2 (60 mL) was refluxed under argon for 2 h.
Ra d ica l Ad d ition of P r ecu r sor s 19a -22a a n d 19b-22b
on to Alk en es. Gen er a l P r oced u r e B. To a degassed reflux-
ing solution of the requisite precursor (2 equiv; 19a -22a and
19b-20b: 0.36 mol/L; 21b-22b: 0.42 mol/L) and alkene (1
equiv; 19a -22a and 19b-20b: 0.18 mol/L; 21b-22b: 0.14
mol/L) in anhydrous C6H6 was added a solution of TTMSSH
(3 equiv; 19a -22a and 19b-20b: 0.39 mol/L; 21b-22b: 1.0
mol/L) and AIBN (0.25 equiv; 19a -22a and 19b-20b: 0.032
mol/L; 21b-22b: 0.12 mol/L) in C6H6 over a period of time of
2 h (syringe-pump). After completion of the addition, the
resultant solution was refluxed for another hour, cooled to
room temperature, and evaporated under reduced pressure.
The crude material was chromatographed and eluted with the
solvents indicated in each case.
In the case of the adducts (entries 3-12), comparing
the acyclic series to the cyclic ones indicates a slight
deshielding effect in the phosphonothioate cases (∼-3
ppm; column 4), a shielding effect in the phosphon-
odithioate cases (∼+7 ppm; column 5) and a larger
shielding effect in the phosphonotrithioate cases (∼+17
ppm; column 6). Clearly, placing the sulfur atoms within
a six-membered cycle has a stronger impact on the
chemical shifts of the phosphorus nucleus in the case of
a PdS bond. The explanation of this interesting effect
lies, however, beyond the scope of the present study; the
issue will be addressed in a forthcoming paper.
Con clu sion
The new selenophosphate 19b, selenophosphorothio-
ates 20a and 20b, selenophosphorodithioates 21a and
21b, and selenophosphorotrithioates 22a and 22b are
easily generated in good overall yields from readily
available starting substrates and reagents, by a three-
or four-step sequence of reactions. These compounds show
good thermal stability and may be used as precursors of
the corresponding phosphorus-centered radicals by ho-
molytic cleavage of the P-Se bond. In particular, this
approach allows us to generate the hiterto unreported
phosphonotrithioyl radicals. When radicals 10a -13a and
10b-13b are produced in the presence of a range of
alkenes of different formal reactivities (from nucleophilic
to electrophilic), most of the expected adducts are formed
in good to excellent yields. Cyclic precursor 19b and
radical 10b feature unusual behavior, undergoing un-
complete homolytic cleavage and complete reduction,
respectively. Inspection of data gathered from X-ray
diffraction on monocrystals of the cyclic precursors
indicates a higher twisting of the six-membered ring in
19b and points at this feature as a possible reason for
this precursor behavior. Noteworthy is the fact that the
corresponding thioyl entities 20b and 11b produce the
expected adducts, thus pointing out the beneficial effect
of the double-bonded sulfur atom. The possibility of
Procedure A can similarly be carried out by using the
number of equivalents in Table 1.
Ack n ow led gm en t. C.L. is grateful to the MENRT
(France) for providing a grant. We thank Dr. S. Petit
for generating Figures 6 and 7, Dr H. Oulyadi for
carrying out 2 D-NMR experiments on 42 and for
helpful discussions concerning the assignment of dia-
stereomeric structures 42a and 42b, and Dr. L. Stella
for useful suggestions.
Su p p or tin g In for m a tion Ava ila ble: Purification proce-
1
dures and physical data for all new compounds as well as H,
13C, and 31P NMR spectra for compounds 20b, 22a , 31a -d ,
31f-h , 32b,d ,f,h , 33c,d ,f-h , 34b,c, 35, 36, 38a -c,f,g, 40, and
42; 2D H/H correlations for compounds 38g, 40, and 42; and
2D H/C correlation for compound 38g. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0348064
J . Org. Chem, Vol. 68, No. 26, 2003 9923