Phase-transfer-catalyzed Michaelis-Becker synthesis of dialkyl methyl phosphonates

Article abstract of DOI:10.1080/10426500500263789

A liquid-liquid phase-transfer-catalyzed (PTC) Michaelis-Becker reaction was adopted in the preparation of dialkyl methyl phosphonate (R=Me, iPr; nBu, and iBu). This was performed by the reaction of an appropriate dialkyl hydrogen phosphonate with methyl iodide in the presence of benzyl triethyl ammonium chloride and sodium hydroxide as PTC and base, respectively. A liquid-liquid two-phase system (H₂O/CH₂Cl₂) introduced a suitable situation for the preparation of dialkyl methyl phosphonates with bulky alkyl groups (R=iPr, nBu, and iBu), but with R=Me, the hydrolysis of dimethyl hydrogen phosphonate (reagent) reduced the yield to 22%. In this case, a solid-liquid PTC-free system was successfully applied and yield of over 80% was obtained. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500263789

Phosphorus, Sulfur, and Silicon, 181:511–518, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500263789
Phase-Transfer-Catalyzed Michaelis-Becker Synthesis
of Dialkyl Methyl Phosphonates
Hossein Fakhraian
Akbar Mirzaei
Department of Chemistry, Imam Hossein University, Tehran, Iran
A liquid–liquid phase-transfer-catalyzed (PTC) Michaelis-Becker reaction was
adopted in the preparation of dialkyl methyl phosphonate (R = Me, iPr, nBu, and
iBu). This was performed by the reaction of an appropriate dialkyl hydrogen phos-
phonate with methyl iodide in the presence of benzyl triethyl ammonium chloride
and sodium hydroxide as PTC and base, respectively. A liquid–liquid two-phase
system (H O/CH Cl ) introduced a suitable situation for the preparation of di-
2
2
2
alkyl methyl phosphonates with bulky alkyl groups (R = iPr, nBu, and iBu), but
with R = Me, the hydrolysis of dimethyl hydrogen phosphonate (reagent) reduced
the yield to 22%. In this case, a solid–liquid PTC-free system was successfully ap-
plied and yield of over 80% was obtained.
Keywords Dialkyl methyl phosphonate; Michaelis-Becker reaction; phase-transfer-
catalyzed reaction
INTRODUCTION
Functionalized phosphonic acids and their derivatives have obvi-
ously interesting applications as insecticide (Dipterex), herbicide
1
,2
(
Glyphosate), and antibiotic (Phosphinothricine). Those are gener-
3
ally produced by the hydrolysis of their phosphonic ester homologues.
The Michaelis-Arbuzov (MA) and Michaelis-Becker (MB) reactions
are the most widely used methods for the preparation of phospho-
ꢀ
4
nic esters such as dialkyl alkyl phosphonates (DAAP:R P(O)(OR)2).
These two reactions occur following different mechanisms using tri-
alkyl phosphite (TAP:(P(OR)3) and dialkyl hydrogen phosphonate
ꢀ
(
DAHP:(RO)2P(O)H) as reagents and an alkyl halide (R X) as alkylat-
ing agent (Scheme 1). The cited reactions have their own advantages
5
,6
and disadvantages regarding the DAAP to be prepared.
Received February 24, 2005; accepted May 1, 2005.
Address correspondence to H. Fakhraian, Imam Hossein University, Department of
Chemistry, P.O. Box 16575-347, Tehran, Iran. E-mail: fakhraian@yahoo.com
511

5
12
H. Fakhraian and A. Mirzaei
SCHEME 1
ꢀ
With a bulky R X, the MA reaction requires forcing conditions to pro-
ꢀ
ꢀ
ceed and if R > R, a mixture of R P(O)(OR)2 and RP(O)(OR)2 is obtained
in which the latest (undesirable) is formed as the main product.
7
Upon warming TAP (with R = iPr and tBu), olefin elimination was
expected to occur readily. The same result was observed when methyl
8
iodide reacted above TAP in low temperature.
The above disadvantages of an MA reaction disappear in an MB
reaction, which requires milder conditions to occur and yields the main
ꢀ
product regardless of the size of R and R . The MB proceeds well with
ꢀ
a large R X where MA fails to act. The choice of TAP or DAHP as a
principal reagent—in MA and MB reactions, respectively—is resolved
in favor of the DAHP (when R > Me) due to their considerably lower
cost and more stability.
However, the general use of an MB reaction is limited by the re-
quirement of a strong anhydrous base (e.g., alkali metal or hydrides)
9
to form a conjugate base. It has been stated that because such bases
are reactive toward the alkylating agents, it is necessary to prepare
the organophosphorus alkali metal salts in stoichiometric quantities
prior exposing it to a alkylating agent. A stepwise procedure such as
this results in a high concentration of a strong nucleophile and leads to
undesirable side reactions.
Another threshold characteristic of the DAHP metal salt deriva-
tives is their limited solubility in inert organic solvents. A solid–liquid
Phase-Transfer Catalyzed (PTC)-free system has been extensively stud-
ied to prepare DAAP, but the limitation of the method is not explicitly
1
0−12
explained.
The PTC system, which is widely and successfully employed in
13
different branches of organic chemistry, was well suited to an MB
1
4−16
reaction
and substantially relieved the limitation previously de-
scribed. A PTC reaction can be proceed using a liquid–liquid or solid–
liquid system in which the mineral base (e.g., NaOH or K2CO3) abides
in a solid or liquid (aqueous) phase and DAHP with alkyl halide coexists
in an organic liquid phase.

PTC Michaelis-Becker Synthesis
513
A liquid–liquid (organic–aqueous) PTC system with sodium hydrox-
ide as a mineral base and a quaternary ammonium salt (such as methyl
tricaprylyl ammonium chloride) was successfully applied to the MB re-
action of DAHP with chloroacetamide.16 The preparation of DAMP has
not been deeply investigated by this method.
Despite many advantages, the PTC system has some limitations, one
of them being the hydrolytic activity of concentrated aqueous alkali. It
is generally known that DAHPs are hydrolyzed in aqueous environ-
ments, whether acidic or basic condition. So, attempts have been made
to accomplish an MB reaction in a solid–liquid system using quaternary
ammonium salt or crown ether as PTC.1
4,15
By this method, diethyl benzyl phosphonate was prepared with a 66%
yield using K2CO3 (as a base), C6H5CH2Cl (as an alkylating agent), and
◦
14
tetra-n-butyl ammonium bromide (as PTC) at 100 C after 3 h.
RESULTS AND DISCUSSION
We attempted to prepare Dialkyl Methyl Phosphonate (DAMP:
alkyl = Me, iPr, iBu, nBu) by a solid–liquid PTC-free, solid–liquid,
and liquid–liquid PTC MB reaction and compared the yield in three
procedures.
An MB reaction was carried-out by DAHP and methyl iodide ac-
cording to two-phase systems (solid–liquid and liquid–liquid) in the
presence or absence of PTC using sodium metal, sodium hydroxide, or
sodium carbonate as a basic agent. 31P NMR spectroscopy was utilized
to determine the conversion rate of DAHP.
DAHP was prepared by the McCombie method—recently
1
7
reconsidered —and an MB reaction was performed using DAHP
and methyl iodide by the three following two-phase systems:
1. a solid–liquid PTC-free system,
2. a solid–liquid PTC system, and
3. a liquid–liquid PTC system.
In our previous study, we showed that in the synthesis of dimethyl hy-
drogen phosphonate (DMHP) by esterification of phosphorus trichloride
with methanol, the hydrogen chloride cleavage of the formed product is
an undesirable side reaction and is difficult to control.
In the first experiment (Table I, entries 1–4), we intently tried to
perform the MB reaction according to the method 1 on the phospho-
rus trichloride-methanol reaction mixture in the worst unfavorable
conditions in which a large amount of HCl cleavage products were
formed (Scheme 2). So a dropwise addition of phosphorus trichloride

5
14
H. Fakhraian and A. Mirzaei
◦
to methanol at 25 C afforded the mixture of 1 (57%), 2 (35%), and 3
5%) (Table I, entry 1).
(
SCHEME 2
Succeeding the esterification of phosphorus trichloride with
methanol, a molar addition of sodium and methyl iodide did not vary
considerably the composition of the reaction mixture (Table I, entries 2
and 3), and a minor amount of 4 (6–10%) was obtained.
The second molar addition of sodium and methyl iodide caused the
presence of a considerable amount of 4 (79%) (Table I, entry 4). It can be
deduced that the sodium salts formation of 2,3—and their transforma-
tion to 1 by methyl iodide—appeared before the sodium salt formation
of 1 and the production of 4 (Scheme 2). So the formation of 2 and 3
by the hydrogen chloride cleavage of 1 increased the amount of sodium
and methyl iodide necessary to produce 4.
When the esterification process was conducted under optimized con-
ditions during which pure DMHP was synthesized, the sodium salt of
DMHP formed a very sticky viscous material that was very difficult to
a
TABLE I Proportional Composition (%) of the Phosphonic Acid
Derivatives After the Esterification of PCl
3
with methanol and MB
Reaction According to Solid-Liquid PTC-Free System (Method A)
PCl3
MeOH
Na
MeI
CHCl3 Time Temp
◦
Entry (mol, mL) (mol, mL) (mol, g) (mol, mL) (mL) (h)
( C)
1
2
3
4
Deriv.
1
2
3
4
0.05, 4.4 0.15, 5.5
—
0.05, 1.15
—
—
—
0.05, 3.1
10
10
—
—
0.5
25 57 35
5
2
1
—
6
10 29
3
22
—
—
—
—
—
—
40 reflux 35 35
15 reflux 42 18
10 reflux — — — 79 21
0.05, 1.15 0.05, 3.1
aBased on 31P NMR spectroscopy.

PTC Michaelis-Becker Synthesis
515
be mixed with methyl iodide. The same phenomenon was observed with
other DAHP.
For reducing the reaction time, we repeated the same reaction using
K2CO3 or NaOH as a mineral base and Benzyl Triethyl Ammonium
Chloride (BTEAC) as PTC (method b). So, the dropwise addition of the
DMHP solution (in CH2Cl2) to a suspension of a base (K2CO3 or NaOH)
in CH2Cl2 containing BTEAC (1 mol%) and methyl iodide prevented the
coagulation of the formed precipitate, but in these conditions, the con-
version of DMHP to dimethyl methyl phosphonate (DMMP) was not
◦
observed after several hours at a reflux temperature (40 C). In spite
of this, we obtained a very pure and stable DMHP, which was not fur-
ther subjected to the hydrogen chloride cleavage. We presume that in
such conditions, hydrogen chloride is neutralized and sodium salt of
2
((MeO)(NaO)P(O)H) and 3 ((NaO)2P(O)H) are transformed to 1 by
methyl iodide. This is perhaps the method for obtaining pure and sta-
ble HCl-free DMHP.
In order to overcome this anomaly in the MB reaction, we adopted
method c to facilitate the reagent mixing. In a liquid–liquid PTC system,
a high saturated sodium hydroxide aqueous solution (50%) served to
prepare the salt of DMHP, which was transferred to the organic phase
(
CH2Cl2) for further reaction with methyl iodide. These sequences of
reactions occurred readily at room temperature (RT) in 1 h (Table II).
Nevertheless, the yield was not more than 22% and a major part of the
reagent (DMHP) was hydrolyzed to 3 (Scheme 3).
SCHEME 3
Performing the same procedure for other DAHPs with more bulky
alkyl groups (R = iPr, iBu, and nBu), afforded a satisfactory yield (63–
95%) (Scheme 3). So there was a considerable reduction of reaction
TABLE II Reaction Time and Yield of DAMP
(
Alkyl = Me, iPr) in a Solid–Liquid PTC-Free (Method
A) and Liquid–Liquid PTC MB Reaction (Method C)
Solid-liquid PTC-free
time, yield
Liquid–liquid PTC
time, yield
DAMP
DMMP
DiPrMP
65 h, 84%
40 h, 33%
1 h, 22%
1 h, 63%

5
16
H. Fakhraian and A. Mirzaei
TABLE III 31P and H NMR Spectra of Dialkyl Methyl Phosphonate
1
DAMP (Alkyl = Me, iPr, nBu, iBu)
31P NMR
δ(ppm)
DAMP
1H NMR δ, J (ppm, Hz)
MeP(O)(OMe)2
MeP(O)(OiPr)2
MeP(O)(OiBu)2
34.1 (m)
29.5 (m)
31.7 (m)
1.4 (d, CH3P, 17.5), 3.75 (d, CH3O, 10)
1.09 (d, CH3, 7), 1.15 (d, CH3P, 7.5), 4.5 (m, CH)
0.91 (d, CH3P, 6.7), 0.95 (d, CH3, 6.7), 1.9 (m, CH),
3
.8 (m, CH2O)
0.91 (d, CH3P, 7.2), 0.94 (t, CH3 , 6.7), 1.4 (m, CH2),
.6 (m, CH2), 4.1 (m, CH2O)
MeP(O)(OnBu)2
30.7 (m)
1
time and a favorable yield in the preparation of DAMP with bulky
alkyl groups by the implementation of a liquid–liquid PTC system
(
Scheme 3 and Table II). The only disadvantage of this process was the
time-consuming phase-separation procedure. Effectively, the aqueous
phase was very viscous, making it difficult to separate from the organic
phase.
1
2
H NMR spectrum of the DMMP showed a large JH-P value (17.5
2
Hz), whereas the JH-P values in the other DAMP with more bulky
alkyl groups (R = iPr, iBu, and nBu) are ∼7 Hz (Table III).
CONCLUSIONS
A liquid–liquid PTC system was successfully applied to prepare a high
yield of pure DAMP with bulky alkyl groups (e.g., iPr, nBu, and iBu) in
a short time (1 h). This system was not adequate for the preparation of
DMMP, in which the reagent (DMHP) was hydrolyzed to (HO)2P(O)H.
According to the solid–liquid PTC-free system, a high yield of pure
DMMP were obtained by the use of an excess amount of sodium metal
and methyl iodide after 65 h at reflux temperature. An excess amount
of sodium metal and methyl iodide were consumed to convert the hydro-
gen chloride cleavage products of DMHP after the esterification process
(
i.e., (HO)2P(O)H and (MeO)(HO)P(O)H) to DMHP). So this can be ac-
counted for producing pure DMHP, which is free from the hydrogen
chloride cleavage.
EXPERIMENTAL
NMR spectra were recorded on a Bruker DPX-250 instrument (250 MHz
1
31
for H and 100 MHz for P). CDCl3 was used as a solvent; chemical
1
31
shifts were reported in δ (ppm) from TMS ( H) and 85%H3PO4 ( P),
with downfield shifts being positive.

PTC Michaelis-Becker Synthesis
517
Solid–Liquid Phase-Transfer-Catalyzed-Free
Michaelis-Becker Synthesis of DMMP
Small pieces of alkali metal sodium (1.15 g, 0.05 mol) and CHCl3 (10
mL) were placed in a 100-mL three-necked flask. Then DMHP was ob-
tained by the esterification of phosphorus trichloride (4.4 mL, 0.05 mol)
with MeOH (5.5 mL, 0.15 mol), diluted by 10 mL CHCl3, and added
dropwise to the flask. The reaction was continued at a reflux tempera-
ture for 40 h. Then methyl iodide (3.4 mL, 0.055 mol) was added and
the reaction was continued for another 15 h. An incomplete reaction
led us to add another equivalent amount of Na and methyl iodide and
to continue the reaction for another 10 h at a reflux temperature. The
product was centrifuged and a clear liquid was obtained. The evapo-
ration of the solvent left 5.2 g (0.042 mol, 84%) of DMMP with 80%
purity.
The previously mentioned procedure was repeated for the synthesis
of DiPrMP. So DiPrHP was obtained by the esterification of phospho-
rus trichloride (4.4 mL, 0.05 mol) with iPrOH (11.5 mL, 0.15 mol) was
diluted by 25 mL of heptane, and was added dropwise to a solution of
25 mL of heptane and 1.15 g of Na (cut to small pieces). The reaction
was continued at reflux temperature for 30 h. Then methyl iodide (6.2
mL, 0.1 mol) was added to the mixture and the reaction was continued
for another 10 h. After the evaporation of the solvent, 3 g (0.017 mol,
33%) of DiPrMP with 95% of purity was obtained.
Liquid-Liquid Phase-Transfer-Catalyzed Michaelis-Becker
Synthesis of DMMP
A solution of methyl iodide (12.4 mL, 0.2 mol), BTEAC (0.23 g), 50%
sodium hydroxide (25 g NaOH and 25 mL H2O), and 25 mL of CH2Cl2
was placed in a 200-mL three-necked flask immersed in an ice bath and
equipped with a stirring device and an inert gas fitting. Then a solution
of DMHP (11.2 g of 85% purity, 0.085 mol), BTEAC (0.23 g), and CH2Cl2
(
25 mL) was added dropwise (for 20 min) to the flask. Then the or-
ganic layer was separated and centrifuged and the solvent was vacuum
stripped. The pure product as a clear liquid weighed 2.3g (0.018 mol,
2
2%).
The previously mentioned procedure was repeated for the prepara-
1
31
tion of another DAMP (R = iPr, nBu, and iBu) ( H and P NMR char-
acteristics are in Table III).
The liquid–liquid PTC MB reaction in the solution of diisopropyl
hydrogen phosphonate (23.8 mL, 0.1 mol), methyl iodide (6.2 mL, 0.1
mol), and CH2Cl2 (50 mL) in the presence of BTEAC (0.23 g, 0.001 mol)

5
18
H. Fakhraian and A. Mirzaei
and 50% sodium hydroxide (25 g NaOH and 25 ml H2O) afforded 11.4
g (0.06 mole, 63%) of diisopropyl methyl phosphonate.
A liquid–liquid PTC MB reaction in the solution of di-n-butyl hydro-
gen phosphonate (18.3 mL, 0.094 mol), methyl iodide (6 mL, 0.094 mol)
and CH2Cl2 (50 mL) in the presence of BTEAC (0.23 g, 0.001 mol) and
5
0% sodium hydroxide (25 g NaOH and 25 ml H2O) afforded 18.6 g
(
0.09 mole, 95%) of di-n-butyl methyl phosphonate.
A liquid–liquid PTC MB reaction in the solution of diisobutyl hydro-
gen phosphonate (9.7 g, 0.05 mol), methyl iodide (3.1 mL, 0.05 mol) and
CH2Cl2 (50 mL) in the presence of BTEAC (0.23 g, 0.001 mol) and 50%
sodium hydroxide (25 g NaOH and 25 ml H2O) afforded 9.5 g (0.046
mole, 92%) of diisobutyl methyl phosphonate.
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