Synthesis of dialkyl-hydroxymethylphosphonates in heterogeneous conditions

Article abstract of DOI:10.1080/10426500211718

This article describes the synthesis of a series of dialkyl-hydroxymethylphosphonates bearing various alkyl ester groups by the Pudovik reaction. The employed method uses anhydrous potassium carbonate as a catalyst in heterogeneous (solid/liquid) or mixed (solid/liquid and homogenous) conditions. All these syntheses are performed without any phase transfer agent and involve an anionic intermediate in a low polar or apolar solvent. These different products, obtained with high yields, have been characterised by ¹H and ³¹P NMR and also by mass spectrometry. A study of fragmentation in the FAB ionisation process is given.

Full text of DOI:10.1080/10426500211718

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Dialkyl-Hydroxymethylphosphonates in
Heterogeneous Conditions
Thomas Jeanmaire a , Yves Hervaud a & Bernard Boutevin a
a Ecole Nationale Supérieure de Chimie de Montpellier , Montpellier, France
Published online: 27 Oct 2010.
To cite this article: Thomas Jeanmaire , Yves Hervaud & Bernard Boutevin (2002) Synthesis of Dialkyl-
Hydroxymethylphosphonates in Heterogeneous Conditions, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:5,
1137-1145, DOI: 10.1080/10426500211718
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Phosphorus, Sulfur and Silicon, 2002, 177:1137–1145
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Copyright 2002 Taylor & Francis
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DOI: 10.1080/10426500290092415
SYNTHESIS OF
DIALKYL-HYDROXYMETHYLPHOSPHONATES
IN HETEROGENEOUS CONDITIONS
Thomas Jeanmaire, Yves Hervaud, and Bernard Boutevin
Ecole Nationale Supe´rieure de Chimie de Montpellier,
Montpellier, France
(Received December 4, 2001)
This article describes the synthesis of
a series of dialkyl-
hydroxymethylphosphonates bearing various alkyl ester groups by
the Pudovik reaction. The employed method uses anhydrous potas-
sium carbonate as a catalyst in heterogeneous (solid/liquid) or mixed
(solid/liquid and homogenous) conditions. All these syntheses are per-
formed without any phase transfer agent and involve an anionic in-
termediate in a low polar or apolar solvent. These different products,
obtained with high yields, have been characterised by 1H and 31P NMR
and also by mass spectrometry. A study of fragmentation in the FAB
ionisation process is given.
Keywords: 1H and 31P NMR; hydroxymethylphosphonates; mass
spectrometry
INTRODUCTION
Dialkyl -hydroxyalkylphosphonates exhibit the following general
structure (Scheme 1):
SCHEME 1 General structure of dialkyl -hydroxyalkylphosphonates.
They are obtained mainly through hydrophosphonylation of
carbonyl compounds such as aldehydes or ketones by dialkyl hydro-
genphosphonates. This reaction, usually base-catalysed, is well known
Address correspondence to Y. Hervaud, Ecole Nationale Supe´rieure de Chimie, 8, rue
de Ecole Normale, F-34296 Montpellier Cedex 5, France.
1137

1138
T. Jeanmaire et al.
3
in phosphorus organic chemistry as the Pudovik reaction.1
Scheme 2.)
(see
SCHEME 2 Pudovik reaction.
The literature indicates that aldehydic substrates are more reactive
than ketones.4
R1, R2 = H, H > H, CH3 > CH3, CH3.
However, the nucleophilic behaviour of the phosphonate is ambigu-
ous. Actually, there is a tautomeric equilibrium5 (Scheme 3) between
the dialkylhydrogenphosphonate with pentavalent phosphorus (V) and
the corresponding dialkylphosphite trivalent form(III).
SCHEME 3 Tautomeric equilibrium of dialkylhydrogenphosphonates.
In the case of phosphorus ethylic esters, the equilibrium constant K
equals 10 7 in water at 25 C. Moreover, although the tricoordinate form
is the more acidic,5 7 we observe only P-alkylation and no O-alkylation
at all.
The active form is supposed to be tricoordinated(III) and the equilib-
rium can be described in Scheme 4.
SCHEME 4 Reactivity of dialkylhydrogenphosphonates toward carbonyl
groups.

Hydroxymethylphosphonates
1139
In the present work, we will only describe the synthesis of dialkyl
hydroxymethylphosphonates HOCH2P(O)(OR)2 with R = Me, Et, and
iPr according to the Pudovik method.
During the last few years, many organic syntheses involving anions
(carbanions, oxanions. . .) have been perfomed in phase transfer cataly-
sis conditions.8 This technique allows to perform base catalyzed reac-
tions with alkaline hydrolysis sensible reagents.9
The formaldehyde reagent is available either in solid polymeric
paraformaldehyde –(H2CO)n-, or in aqueous formol form. With
paraformaldehyde, the reaction can be carried out in solution or in bulk
in the presence of basic catalysts such as alkaline metal alcoxide,10
solid mineral bases like fluoride,11 alumina,12 and especially tertiary
14
amines.13
Nitrogenous catalysts are restricted to tertiary amines
in order to avoid the Kabachnik-Fields reaction15
amino compound.
which gives the
16
Uzlova et al.17 used aqueous formol in liquid–liquid phase transfer
catalysis (LL PTC ) using the couple water/dichloromethane at room
temperature, with sodium hydroxide as a catalyst and (nBu)4NHSO4
as phase transfer agent. Yields increase from 24% with R = Me to 53%
with R = Et.
The two types of reaction are summarized in Scheme 5. In all cases,
we note that the reactions are less and less exothermic in the order
R = CH3 < C2H5 < iC3H7. Thus the reaction in bulk of dimethylhydro-
genphosphonate with formol is very exothermic and undergoes the for-
mation of by-products.
SCHEME 5 General methods of synthesis of dialkyl hydroxymethylphos-
phonates.
Zimmerer18 and Pelchowicz19 showed, without giving rates, that
sodio-derivatives of dialkylhydrogenphosphonate (RO)2P(O)Na iso-
merize, on heating, in dialkylalkylphosphonates R P(O)(OR)2 and
monoalkylhydrogenphosphonates HP(O)(OR)(ONa). Particularly with
methyl esters, isomerizations are complex and give various re-
arrangement products.
Rosenberg et al.20 described the same synthesis in mild condi-
tions, at room temperature, in methanol, with sodium methoxide as a
catalyst, with a yield of 85%. Diisopropylhydrogenphosphonate is a

1140
T. Jeanmaire et al.
sterically hindered reagent and needs thermal activation21 or the use of
strong and not nucleophilic nitrogenous bases such as 1,8 diazabicyclo
[5,4,0]undec-7-ene (DBU).22
Makosza and Wojciechowski23 showed that anhydrous potassium
carbonate is a strong enough base to deprotonate dialkylhydro-
genphosphonate (pKa 15) in heterogeneous solid-liquid conditions
with small amounts of phase transfer agent (crown ether or qua-
ternary ammonium). The advantage of this method is the direct
applicability of dialkyl hydrogenphosphonate instead of their metal
salts.
The authors have performed several Michael addition reactions with
dialkylhydrogenphosphonate and electrophilic alkenes and also nucle-
ophilic substitutions with good yields.
Furthermore, Bodarenko et al.24 carried out alkylation of di-
alkylphosphonate with methyliodide and anhydrous potassium carbon-
ate as a catalyst without any phase transfer agent. Also the separation
difficulties of the crude product are avoided.
In this work, we have studied the reaction of various dialkylhydro-
genphosphonates with paraformaldehyde, in heterogeneous or mixed
conditions, with anhydrous potassium carbonate and without any phase
transfer agent.
RESULTS AND DISCUSSION
We synthesized various dialkyl hydroxymethylphosphonates in solu-
tion with paraformaldehyde and anhydrous potassium carbonate as a
catalyst. Carbonates are commonly used in heterogeneous phase as a
non-nucleophilic solid “soft” base because they are easy to handle and
to eliminate by filtration at the end of the reaction.20
Syntheses, made without any phase transfer agent, at room temper-
ature, can be schematised as follows in Scheme 6.
SCHEME 6 Pudovik reaction in heterogeneous conditions.
Scheme 7 represents the suggested mechanism of pudovic reaction
in heterogeneous conditions.
The rate of conversion of dialkylhydrogenposphonate is followed by
capillary GC. All the experimental data are gathered in Table I.

Hydroxymethylphosphonates
1141
SCHEME 7 Proposed mechanism of Pudovik reaction in heterogeneous
conditions.
Characteristics of these solvents are high calorific capacity (Cp) and
medium to low dielectric constant (ε) as it is reported in Table II.
The solvents used have a various nature in term of acidity and polar-
ity. Light alcohols such as methanol and ethanol, which are fairly polar
and protic, are used. In these light alcohols, the catalyst is more soluble
but the mixture remains heterogeneous. Isopropanol and cyclohexane
have quite the same low polarity and only differ by their acidity.
In such conditions, the catalyst remains little or not soluble in the
chosen solvents and by thus, the heterogeneity of the reaction is kept.
High calorific capacities (Cp) allow to limit exothermicity during the
reaction especially with dimethylhydrogenphosphonate.
It is necessary to use the alcohol corresponding to the phosphorus
ester in order to avoid transesterification reactions.25,26 These reations
prove the existence of potassium alcoxide in the medium, generated
by reaction of the catalyst with the solvent (it can be avoided in
TABLE I Experimental Conditions and Yields for the Addition
of Dialkylhydrogenphosphonates to Paraformaldehyde in
Various Solvents
R
Solvent
Time (h)
Yield GC
CH3
C6H12
CH3OH
C6H12
1
1
1
100
100
13
C2H5
C6H12
C2H5OH
C6H12
15
5
1
100
100
1
CH(CH3)2
C6H12
15
3
1
100
0
100
(CH3)2CHOH
(CH3)2CHOHa
aReaction performed at 60 C.

1142
T. Jeanmaire et al.
TABLE II Calorific Capacities and
Solvents Dielectric Constants
Solvent
Cp at 25 C (J/mol K)
ε
CH3OH
81.1
112.3
156.5
154.9
33.0
25.3
2.64
2.02
C2H5OH
(CH3)2CHOH
C6H12
using cyclohexane for example). Besides this alcoxide may also act as
catalyst.
Whatever the nature of the solvent, we notice that the speed of
the reaction increases in the following order HP(O)(OiPr)2 < HP(O)
(OEt)2 < HP(O)(OMe)2. Actually the reaction with dimethylhydrogen-
phosphonate is fast and exothermic while we observe a slow-down
with the other phosphonates. This phenomenon can be explained on
one hand by the increase of the steric hindrance which decreases the
phosphonate nucleophilicity and on the other hand by the tautomeric
equilibrium. Actually, the more the phosphonate bears a donor ester
group, the more the equilibrium (Scheme 3) between the phosphonate
pentavalent form Pv(V) and the phosphite trivalent form PIII(III) is
shifted to the P(V) form to the detriment of the active P(III) form. In the
case of diisopropyl esters, a soft thermical activation permits to reduce
significantly the reaction time without undergoing the formation of
by-products.
The various dialkyl -hydroxymethylphosphonates have been stud-
ied in mass spectrometry (FAB+ ionisation) and all the molecular ions
(M + H)+ are observed with good intensities. All fragments are given
as follows m/z and (abundance in percent). The fragmentation mecha-
nisms of dimethyl hydroxymethylphosphonate are complex and we will
only study the ethyl and isopropyl species.
The different fragments are described in Scheme 8. We note the suc-
cessive loss of ester by olefin elimination (ethylene and propylene re-
spectively) leading to a common ion in the two products.
We notice that the loss of ester is preferential to the loss of the neutral
formol molecule, actually no ions at m/z = 139 and 167 are detected. The
olefin elimination needs the presence of hydrogen linked to the carbon
to the oxygen (Scheme 9). It implies that the abundance in the isopropyl
series is higher than in ethyl one.
After the total loss of ester groups, we obtain a common ion fragment
at m/z 113. It looses a neutral formol fragment to give a positive ion at
m/z 83 which corresponds to the protonated phosphonic acid (H4PO+).
3
By dehydration of the previous fragment, we obtain a new ion at m/z 65.

Hydroxymethylphosphonates
1143
SCHEME 8 Detailed mass spectrometry of dialkylhydroxymethylphos-
phonates.
SCHEME 9 Mechanism of loss of phosphonate ester in mass spectrometry.
CONCLUSION
We have synthesised, in very high yields, a range of dialkyl hydroxy-
methylphosphonates bearing various ester groups, by the reaction in-
volving dialkylhydrogenphosphonate and paraformaldehyde according
to the Pudovik reaction. The method we used employed anhydrous

1144
T. Jeanmaire et al.
potassium carbonate as a catalyst in heterogeneous or mixed catalysis
conditions. This reaction, taking place in solvents of various nature,
shows that it is possible to generate anionic phosphonyl intermediates
in heterogeneous conditions and without any phase transfer agent.
This method, cheap and easy to perform, permits to obtain simply
functionalised phosphonated products and may be useful for various
base-catalyzed reactions involving dialkylhydrogenphosphonates.
EXPERIMENTAL PART
Into a two-necked round-bottomed flask, equipped with a condenser
and a magnetic stirrer, was introduced dialkylhydrogenphosphonate
HP(O)(OR)2, paraformaldehyde, solvent and 5% (molar) of powdered
anhydrous potassium carbonate K2CO3. The heterogeneous solution is
vigorously stirred during various times. At the end of the reaction, the
solution is filtered through 0.45 m porosity filter and the solvent is re-
moved under vacuum. The products are obtained with yields near 98%.
For example, we introduce 16.61 g (0.1 mmol) of diisopropyl hydro-
genphosphonate, 3.6 g (0.12 mmol) of paraformaldehyde, 35 ml of iso-
propanol and 0.69 g (0.005 mmol) of anhydrous K2CO3. The solution is
stirred vigorously during 1 h at 60 C, then treated as described before.
Dimethyl Hydroxymethylphosphonate
2
1H NMR (CDCl3) : 5.4 (s, 1H, OH); 3.7 (d, 2H, CH2 P, JHP = 6 Hz);
3.6 (d, 6H, POCH3, 3JHP = 10.5 Hz).
31P NMR (CDCl3) : 28.3 (s).
2
Bp = 92 C under 4 10 mbar.
FABMS (3-NOBA); m/z (%): 141 (100); 123 (8); 111 (7); 93 (16); 79 (25).
Diethyl Hydroxymethylphosphonate
1H NMR (CDCl3) : 5.2 (s, 1H, OH); 4.0 (m, 4H, O CH2CH3); 3.7
(d, 2H, PCH2, 2JHP = 6 Hz); 1.2 (t, 6H, O CH2CH3, 3JHH = 7.3 Hz).
31P NMR (CDCl3) : 25.92 (s).
Bp = 95 C under 5 10 2mbar.
FABMS (3-NOBA); m/z (%): 169 (100); 141 (10); 113 (25); 83 (5); 65 (8).
Diisopropyl Hydroxymethylphosphonate
1H NMR (CDCl3) : 5.1 (s, 1H, OH); 4.6 (m, 2H, O CH); 3.7 (d, 2H,
CH2P, 2 JHP = 6 Hz); 1.2 (d, 12H, C(CH3)2).
31P NMR (CDCl3) : 24.08 (s).

Hydroxymethylphosphonates
1145
Bp = 92 C under 2.5 10 2mbar.
FABMS (3-NOBA); m/z (%): 197 (100); 155 (52); 113 (100); 83 (4);
65 (4).
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