Study of the Stability of O,O -Dialkyl- O -Arylthiophosphate: Evidence of the Formation of O,S -Dialkyl- O -Arylphosphate

Article abstract of DOI:10.1080/10426507.2014.974751

During the synthesis of cationic lipids that included thiophosphoramidate moiety or pincer ligands based on O,O-diethyl-thiophosphonate as coordination group, the rearrangement of O,O-diethyl-thiophosphoryl in O,S-diethylthiophosphoryl group was observed. This rearrangement, which does not occur by a simple heating at 130°C, is catalyzed by nucleophilic amine like N,N-dimethylaminopyridine. However, at some occasion, dealkylation of the O,S-diethylthiophosphoryl compound is observed.

Full text of DOI:10.1080/10426507.2014.974751

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Study of the Stability of O,O-Dialkyl-O-
Arylthiophosphate: Evidence of the Formation of
O,S-Dialkyl-O-Arylphosphate
Stéphanie S. Le Corre, Aurore Fraix, Mathieu Berchel & Paul-Alain Jaffrès
To cite this article: Stéphanie S. Le Corre, Aurore Fraix, Mathieu Berchel & Paul-Alain Jaffrès
(2015) Study of the Stability of O,O-Dialkyl-O-Arylthiophosphate: Evidence of the Formation
of O,S-Dialkyl-O-Arylphosphate, Phosphorus, Sulfur, and Silicon and the Related Elements,
190:5-6, 747-750, DOI: 10.1080/10426507.2014.974751
To link to this article: http://dx.doi.org/10.1080/10426507.2014.974751
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Date: 15 March 2016, At: 06:25

Phosphorus, Sulfur, and Silicon, 190:747–750, 2015
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.974751
STUDY OF THE STABILITY OF
O,O-DIALKYL-O-ARYLTHIOPHOSPHATE: EVIDENCE OF
THE FORMATION OF O,S-DIALKYL-O-ARYLPHOSPHATE
Ste´phanie S. Le Corre, Aurore Fraix, Mathieu Berchel,
and Paul-Alain Jaffre`s
Universite´ de Brest, UEB, CEMCA, Brest, France
GRAPHICAL ABSTRACT
Abstract During the synthesis of cationic lipids that included thiophosphoramidate moiety or
pincer ligands based on O,O-diethyl-thiophosphonate as coordination group, the rearrange-
ment of O,O-diethyl-thiophosphoryl in O,S-diethylthiophosphoryl group was observed. This
rearrangement, which does not occur by a simple heating at 130◦C, is catalyzed by nucle-
ophilic amine like N,N-dimethylaminopyridine. However, at some occasion, dealkylation of the
O,S-diethylthiophosphoryl compound is observed.
Keywords Rearrangement; thiophosphonate; organocatalysis
In previous works, we have shown that O,O-diethylthiophosphoryl moiety was adapted
to produce N,S-monoanionic bidentate ligand or1 S,N,S-monoanionic pincer ligand.2 This
functional group was used as coordination site to produce stable palladium and silver com-
plexes. It is worth noting that O,O-dialkylthiophosphoryl moiety is not altered in presence of
water or oxygen, thus, greatly facilitating the handling of such compounds. In other works,
we have incorporated the O,O-dialkylthiophosphoryl moiety3 in place of the of phospho-
ramidate moiety4,5 in the structure of cationic lipids to produce vectors for gene delivery.
Recently, we have reported an original method to prepare O,O-diethylthiophosphonate by
making use of a [1,3]6 or [1,4]7 base-assisted rearrangement also identified as phospho-Fries
rearrangement. This original method uses only air nonsensitive precursors constituting an
advantage when compared to the methods previously reported. With the aim to prepare
Received 21 July 2014; accepted 5 October 2014.
Address correspondence to Paul-Alain Jaffre`s, Universite´ de Brest, UEB, CEMCA, UMR CNRS
6521, 6 Avenue Le Gorgeu, 29238 Brest, France. E-mail: pjaffres@univ-brest.fr; http://www-tmp.univ-
brest.fr/phosvec/home
747

748
S. S. LE CORRE ET AL.
Figure 1 Preliminary results that unexpectedly produced compound 2.
O-aryl-O,O-diethylthiophosphonate at a multigram scale, we have investigated the pu-
rification of its direct synthetic precursor O-(2-bromophenyl)-O,O-diethyl-thiophosphate
1 (scheme 1) by distillation under vacuum (Kugelroch). In this experiment, compound
1 was synthesized in tetrahydrofuran by reaction of diethylchlorothiophosphate with 2-
bromophenol in presence of triethylamine and 4-dimethylaminopyridine (DMAP) as pre-
viously reported.6 At the end of the reaction, most of the amine hydrochloride salts formed
were removed by filtration before Kugelroch distillation (140◦C, 2.10−2 mbar). In the course
of this distillation, we observed by 31P NMR the presence of a new compound (10%) that
was actually the most abundant product. After separation and characterization, compound
2 was unambiguously identified as O-(2-bromophenyl)-O,S-diethyl thiophosphate 2. One
CH2-O at 4.02 ppm and one CH2-S at 3.05 ppm were observed by 1H NMR analyses. 31
P
NMR resonance at 25.8 ppm for 2 was in agreement with the presence of a P O double bond
and 13C NMR and 2D experiments (HMBC, HMQC) were consistent with the structure of
compound 2. This result indicates that a rearrangement, characterized by the migration of an
alkyl group from one oxygen atom to the sulfur atom, occurred. This type of rearrangement
has some common features with the Pistschimuka reaction8 (reaction of thiophosphoryl-
based compounds with iodomethane) and it was also reported by Zhankai et al.9 but in
that case the author exclusively used O,O-diallylthiophosphate as substrate. From their
studies they concluded that the allylic system was needed to allow a [3,3]-sigmatropic
type rearrangement. On the contrary, our initial finding reported above indicates that even
alkyl derivatives can produce the same type of rearrangement. This preliminary result en-
couraged us to study further this type of rearrangement which represent an easy access
to O,S-dialkylphosphono derivatives present in some pesticides (e.g., Methamidophos),
but also to identify the parameters that influence this type of rearrangement that can ex-
plain the formation of O,S-dialkylphosphono side products when this rearrangement is not
desired.
First of all, compound 1 was synthesized and purified by column chromatography on
silica gel to study the rearrangement on a pure substrate. After heating this compound at
138◦C for 15 h in p-xylene, only the 31P signal of the substrate 1 was detected thus attesting
of the absence of rearrangement in such a condition. Then different nucleophilic bases (N-
methylimidazole, N,N-dimethylaminopyridine, triethylamine, and spermine) were added
(20 mol%) to the reaction media and the mixture was heated for the same period of time
at 138◦C. In all these experiments, the rearranged product 2 was detected. The best results
were obtained with DMAP. However, even with DMAP only a partial conversion was
obtained (65%). Accordingly, the quantities of DMAP were increased to 40 and 60 mol%.

STUDY OF THE STABILITY OF O,O-DIALKYL-O-ARYLTHIOPHOSPHATE
749
Figure 2 Suggested mechanism for the P S to P O rearrangement of compound 1 and the subsequent dealky-
lation to produce the salt 3.
In the last condition, a full conversion was obtained but even at 40 mol% of DMAP another
product that exhibited a 31P NMR signal at 13.9 ppm was detected. This side product was
present in large quantities (73%) when 60 mol% of DMAP was employed. MALDI TOF
1
spectrometry indicate the presence of N,N-dimethyl-N’-ethylpyridinium salt and the H
NMR spectrum was consistent with the presence of a salt that would likely result from the
dealkylation of the rearranged product 2 by N,N-dimethylaminopyridine at the CH2 group
bonded to the oxygen atom. This dealkylation at this position of the O,S-diethylphosphoryl
moiety is confirmed by 1H that exhibit the P-S-CH2-R moiety at 2.8 ppm. On the basis of
these results, the suggested mechanism that would explain the formation of the salt 3 is
shown on Figure 2.
EXPERIMENTAL
To a solution of O-(2-bromophenyl)-O,O-diethylthiophosphate (1.22 mmol; 400 mg)
in xylene (para isomer; 10 mL) was added N,N-dimethylaminopyridine DMAP (0.24 mmol;
20 mol%:30 mg). The reaction mixture was stirred at room temperature for 10 min. Then,
the mixture was stirred and heated at 138◦C (reflux of p-xylene) for 15 h. After cooling
to room temperature, diethyl ether was added and the mixture was washed with water and
dried over MgSO4. Filtration and evaporation of the solvents produced an oil which was
purified by chromatography on silica gel (petroleum ether/ethyl acetate 9/1; rf = 0.12) to
give O-(2-bromophenyl)-O,S-diethyl thiophosphate 2 in 21% yield (83 mg).
3
1H-NMR (400.08 MHz, CDCl3): 1.32 (t, JHH = 8 Hz, 3H, S-CH2-CH3); 1.40 (t,
3JHH = 8 Hz, 3H, O-CH2-CH3); 2.93 (m, 2H, S-CH2-CH3); 4.32 (m, 2H, O-CH2-CH3);
3
3
7.03 (t, JHH = 8 Hz, 1H, C4-H); 7.24 (t, JHH = 8 Hz, 1H, C5-H); 7.54 (m, 2H, C3-H,
C6-H).
31P-NMR (161.97 MHz, CDCl3): 25.8

750
S. S. LE CORRE ET AL.
13C-NMR (125.80 MHz, CDCl3): 15.92 (S-CH2-CH3); 16.20 (O-CH2-CH3); 25.86
(S-CH2-CH3); 64.61 (O-CH2-CH3); 114.57 (C2); 121.68 (C3); 126.23 (C4); 128.46 (C5);
133.56 (C6); 147.50 (C1).
ACKNOWLEDGMENT
The authors are thankful to Prof. D. Villemin for fruitful discussions.
FUNDING
This work was supported by CNRS.
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