Direct α-chlorination of O,O-dialkyl chalcogenophosphonates with phosphorus oxychloride

Article abstract of DOI:10.1016/S0040-4039(01)01382-X

α-Chlorination of phosphonates, and O,O-dialkyl thio- and selenophosphonates involving the direct reaction of their lithiated anion with phosphorus oxychloride is described. The reaction gives good results where previously known methods fail. The role of the chalcogen atom, and the influence of the nature of the alkyl chain with respect to the reactivity are discussed.

Full text of DOI:10.1016/S0040-4039(01)01382-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7547–7549
Direct a-chlorination of O,O-dialkyl chalcogenophosphonates
with phosphorus oxychloride
Ste´phane Mons, Nicolas Sabourault, Emmanuel Klein, Charles Mioskowski* and Luc Lebeau*
Universite´ Louis Pasteur de Strasbourg-Laboratoire de Synthe`se Bioorganique associe´ au CNRS Faculte´ de Pharmacie-74,
route du Rhin-BP 24-67401 Illkirch, France
Received 20 July 2001; revised 25 July 2001; accepted 27 July 2001
Abstract—a-Chlorination of phosphonates, and O,O-dialkyl thio- and selenophosphonates involving the direct reaction of their
lithiated anion with phosphorus oxychloride is described. The reaction gives good results where previously known methods fail.
The role of the chalcogen atom, and the influence of the nature of the alkyl chain with respect to the reactivity are discussed.
© 2001 Elsevier Science Ltd. All rights reserved.
a-Halogenation of phosphonates, and their thio- and
seleno-derivatives, is an important way to selectively
activate the phosphonate alkyl chain in order to intro-
duce a substituent a to the phosphonyl moiety. Only a
few methods are described in the literature; they usually
involve the substitution of an existing a-hydroxyl
group,1–6 the reaction of the carbanion of the phospho-
nate with a halogen donor,7–18 or a radical19–21 or
electrochemical22,23 halogenation. Most of the time, the
a-position is activated by a substituent, which proved
necessary in some cases for the reaction to take place,
or to ensure better yields. Finally, no a-halogenation of
O,O-dialkyl thio- or selenophosphonate is described in
the literature.
chlorinating reagents (N-chlorosuccinimide, tetra-
ethylammonium trichloride,24 sulfuryl chloride) left the
selenophosphonates unreacted. Herein, we present the
scope of this new halogenation reaction.
We investigated the title reaction with a series of phos-
phonates, seleno-, and thiophosphonates varying the
nature of the phosphorus substituents (Scheme 1).
Results are listed in Table 1.
Typical procedure
Dibenzyl methaneselenophosphonate 1a26 (335 mg,
0.988 mmol) in 5 ml anhydrous THF at −78°C was
treated with 1.6 M n-butyllithium in hexane (650 ml,
1.05 equiv.) for 3 min.27 Then freshly distilled phospho-
rus oxychloride (100 ml, 1.07 mmol) was rapidly added
and the reaction mixture allowed to warm up to room
temperature. The solution was hydrolyzed with satu-
rated aqueous ammonium chloride and extracted with
ether. The organic layer was dried over magnesium
sulfate, and the solvent removed in vacuo. The crude
In the course of our work on the synthesis of non-
hydrolyzable analogs of polyphosphates, we investi-
gated the reaction between lithiated anions of
O,O-dialkyl selenophosphonates and phosphorus oxy-
chloride. We discovered that a-chlorination of the start-
ing material takes place instead of the expected
phosphonylation reaction. The use of other potentially
.Ch
P
1) n-BuLi
2) POCl3
.Ch
R2
P
R2
R3
R1O
R1O
R1O
R1O
R3
1a-j
Cl
2a-j
Ch = O, S, Se
Scheme 1.
Keywords: chlorination; phosphonate; selenophosphonate; phosphorus oxychloride.
* Corresponding authors. Fax: +333 90 24 43 06; e-mail: mioskowski@bioorga.u-strasbg.fr; lebeau@aspirine.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01382-X

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S. Mons et al. / Tetrahedron Letters 42 (2001) 7547–7549
Table 1. a-Chlorination of O,O-dialkyl chalcogenophosphonates
Entry
Substratea
Ch
R1
R2
R3
Product
Yield (%)b
n-BuLi, POCl3
n-BuLi, CCl4
NCS, (BzO)2
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Se
Se
Se
Se
Se
Se
Se
S
Bn
Bu
Et
Et
Et
H
H
H
Pr
Me
Ph
Bn
H
H
H
H
H
Me
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
50 [21]
52 [19]
51 [12]
8 [46]
0 [22]
0 [9]
0 [0]
0 [0]
0 [0]
0 [0]
0 [0]
0 [0]
0 [0]
Nd
0 [17]
6 [61]
2 [83]c
37 [18]
Nd
0 [18]
0 [29]
62 [18]
3 [21]c
69 [0]
Et
Bu
Bu
Bn
Bu
25 [60]
21 [53]
13 [67]
23 [43]
9
10
O
O
H
Ph
Nd
Nd
1j
2j
a Methaneselenophosphonates 1a and 1b and methanethiophosphonate 1h were prepared using a ‘one-pot’ procedure. Dichloromethylphosphine
was reacted with 2 equiv. of an alcohol in the presence of triethylamine, immediately followed by the oxidation of the resulting phosphonite by
selenium or sulphur powder. Selenophosphonate 1c–f were prepared in 85–96% yield by reacting the adequate alkylmagnesium bromide with
triethyl phosphite, followed by oxidation with selenium powder. a-Benzylation of 1b afforded compound 1g in excellent yield. Phosphonates 1i
and 1j were prepared as described in the literature.25
b Recovered starting material is indicated in brackets.
c Yield determined by 31P NMR. nd: not determined.
residue was purified by chromatography over silica gel
(hexane/ether 98:2 to 95:5) to afford the dibenzyl
chloromethaneselenophosphonate 2a28 (184 mg, 50%)
along with some unreacted starting material 1a (70 mg,
21%).
In conclusion, we describe herein the first direct a-chlo-
rination of O,O-dialkyl seleno- and thiophosphonates
using a novel reaction involving phosphorus oxychlo-
ride as a halogen donor. The procedure we developed
proved to be efficient to perform a-chlorination of
methanechalcogenophosphonates whereas other exist-
ing methods require the activation of the a-position by
substituents. Furthermore, selenophosphonates can be
conveniently and quantitatively converted into the cor-
responding phosphonate with oxone31 or m-chloroper-
benzoic acid,32 providing an indirect way to
a-halogenated phosphonates. Also, it is noteworthy
that direct reaction of the lithiated anions of phospho-
nates and, to our own experience, of selenophospho-
nates with iodine hardly affords the a-iodo derivatives,
whereas substitution of an existing chlorine atom using
sodium iodide gives excellent results.33 a-Chloro-
selenophosphonates may then serve as precursors for
their a-iodo analogs, as well as for selenophosphonic
analogs of a-amino acids.20 Optimization and further
studies of this new halogenation reaction are in
progress.
Chlorination of methaneselenophosphonates 1a, 1b,
and 1c with phosphorus oxychloride proceeded
smoothly to afford the a-chlorinated products 2a, 2b,
and 2c in almost identical yields, which suggests that
the nature of the O-alkyl groups is not crucial. By
contrast, an increase in the steric hindrance of the
P-alkyl subsituent of selenophosphonates led to low
yields (entries 4 and 5), except when electronic effects
may stabilize the intermediate anion (entries 6 and 7).
In the phosphonate and thiophosphonate series (entries
8–10), both yields and completions are lower and
decrease in the order Se>S>O. It is likely that complex-
ation of the lithium cation by the chalcogen plays an
important role here.29,30
For comparison purposes, a-halogenations using n-
butyllithium/carbon
tetrachloride12,13
and
N-
Acknowledgements
chlorosuccinimide20,21 were investigated. As already
described by Savignac et al.,27a a-chlorination of phos-
phonates with n-butyllithium/carbon tetrachloride does
not take place with methanephosphonates such as 1i
(entry 9), but it does for 1j (entry 10) because of the
greater stability of the intermediate anion. For the same
reasons, a-chlorination of the thio- and selenophospho-
nates described here could not be achieved satisfactorily
when using this method (entries 1–5 and 8) unless the
corresponding anion is stabilized (entries 6 and 7).
Also, radical conditions do not seem to be compatible
with O,O-dialkyl selenophosphonates which are fully
decomposed within minutes with release of a red sele-
nium precipitate.
This work was supported by ARC (Association pour la
Recherche sur le Cancer, France) and MENRT (Minis-
te`re de l’Education Nationale, de la Recherche et de la
Technologie, France).
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