Organophosphorus chemistry. Part 1: The synthesis of alkyl methylphosphonic acids

Article abstract of DOI:10.1039/b007077g

Several alkyl hydrogen methylphosphonates of structure RO(HO)P(O)Me were synthesised by a three-stage route [R =i-Pr, n-Bu, i-Bu, s-Bu, pinacolyl Me₃C-CH(Me)-, cyclopentyl and cyclohexyl]. Trimethyl phosphite was transesterified with alcohols in the presence of sodium catalyst to give the mixed phosphites (MeO)₂POR in 6-64% yield. Treatment of these with methyl iodide gave alkyl methyl methylphosphonates RO(MeO)P(O)Me in 66-95% yield. Selective demethylation of these compounds by bromotrimethylsilane, followed by methanolysis of the phosphorus silyl esters RO(Me₃SiO)P(O)Me, gave the hydrogen phosphonates in 60-97% yield.

Full text of DOI:10.1039/b007077g

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Organophosphorus chemistry. Part 1. The synthesis of alkyl
methylphosphonic acids
Christopher M. Timperley,* Michael Bird, Ian Holden and Robin M. Black
1
DERA, CBD Porton Down, Salisbury, Wiltshire, UK SP4 0JQ
Received (in Cambridge, UK) 31st August 2000, Accepted 10th November 2000
First published as an Advance Article on the web 11th December 2000
Several alkyl hydrogen methylphosphonates of structure RO(HO)P(O)Me were synthesised by a three-stage route
[R = i-Pr, n-Bu, i-Bu, s-Bu, pinacolyl Me3C-CH(Me)-,† cyclopentyl and cyclohexyl]. Trimethyl phosphite was
transesterified with alcohols in the presence of sodium catalyst to give the mixed phosphites (MeO)2POR in 6–64%
yield. Treatment of these with methyl iodide gave alkyl methyl methylphosphonates RO(MeO)P(O)Me in 66–95%
yield. Selective demethylation of these compounds by bromotrimethylsilane, followed by methanolysis of the
phosphorus silyl esters RO(Me3SiO)P(O)Me, gave the hydrogen phosphonates in 60–97% yield.
Introduction
The synthesis of pure alkyl hydrogen methylphosphonates of
structure RO(HO)P(O)Me is challenging. These compounds
are important in the verification of alleged use of chemical
warfare agents, since they are stable hydrolysis products of G
and V nerve agents.1,2 Most literature routes to alkyl hydrogen
methylphosphonates involve alkaline hydrolysis of symmetrical
or mixed phosphonates by treating them with an excess of
sodium hydroxide3,4 or barium hydroxide.5 Under these condi-
tions, dialkyl alkylphosphonates hydrolyse to the mono-ester
salts and the rates depend on the structure of the ester groups.6
The work-up of the reaction mixture is tedious, involving acid-
ification and extraction, and yields of isolated products are
often low. Another disadvantage is that the starting phos-
phonates are not readily available and have to be made in two
or three steps. An improved approach to alkyl hydrogen meth-
ylphosphonates involves controlled hydrolysis of methylphos-
phonic dichloride to give an anhydride that, on alcoholysis,
gives the desired products in moderate yields (Scheme 1).7,8
Clearly there is a need for improved syntheses of alkyl hydro-
gen methylphosphonates. In this paper we report a three-stage
synthesis starting from commercially-available trimethyl phos-
phite. Its partial transesterification, followed by an Arbusov
reaction with methyl iodide, gave alkyl methyl methylphos-
phonates in reasonable yields. Rapid reaction with bromo-
trimethylsilane, then methanolysis of the formed trimethylsilyl
esters, provided the desired acids without resort to aqueous
work-up (Scheme 2).
Scheme 1
Scheme 2
Results and discussion
Transesterification of trimethyl phosphite
A few mixed dialkyl alkyl phosphites of structure (RO)2PORЈ
have been prepared by reaction of alcohols with alkyl phos-
phorodichloridites in the presence of base (e.g. sodium methox-
ide or N,N-dimethylaniline)9–11 or by partial transesterification
of trialkyl phosphites.12–15 In this study, trimethyl phosphite was
transesterified with a number of alcohols. The reactions were
carried out at temperatures slightly below the boiling points of
the alcohols, with metallic sodium as catalyst, and in general
proceeded smoothly. After distillation, the mixed phosphites
1a–i were isolated in low to moderate yields (Scheme 3, Table 1).
These colourless liquids were stored under argon to prevent
Scheme 3
atmospheric oxidation to the corresponding phosphates and
were stable for many months in a refrigerator.
A limitation of the transesterification reaction as a prep-
arative method is that the outgoing alcohol must have a boiling
point that is not too close to that of the incoming alcohol;
otherwise, the reaction cannot be forced by distilling out the
originally esterified alcohol, and difficulty is encountered in the
separation of the product from the starting phosphite. An
example of this is the transesterification of trimethyl phosphite
with i-PrOH (bp 82 ЊC compared to 65 ЊC for MeOH) which
† The IUPAC name for pinacolyl is 3,3-dimethylbutan-2-yl.
26
J. Chem. Soc., Perkin Trans. 1, 2001, 26–30
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b007077g

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gave dimethyl isopropyl phosphite 1b in only 12% yield after
five distillations. The low yield of the mixed phosphite 1h from
cyclopentanol (6% after two distillations) was surprising given
the high yield of phosphite 1i from cyclohexanol (64% after
one distillation). The failure of the former reaction may have
been due to dehydration of the alcohol, with hydrolysis of the
trimethyl phosphite by the liberated water, or decomposition
of the mixed phosphite thermally to cyclopentene and dimethyl
phosphonate. An analogous explanation was used to account
for the failure to isolate a mixed phosphite from the attempted
transesterification of triethyl phosphite with tert-amyl alcohol
(2-methylbuten-2-ol).13
cmϪ1. The frequencies of the P–O–Me vibrations of the mixed
phosphites were 1026–1014 cmϪ1
.
The Arbusov rearrangement of dimethyl alkyl phosphites
In its simplest form, this reaction consists of heating a trialkyl
phosphite with the corresponding alkyl iodide. On distillation,
the alkyl iodide is recovered unchanged but the trialkyl phos-
phite is transformed almost quantitatively into the isomeric
dialkyl alkylphosphonate.17,18 The phosphorus atom increases
its valency from three to five and the product contains a direct
carbon–phosphorus bond. While Arbusov rearrangements of
trialkyl phosphites have been studied in vast detail, those of
mixed phosphites have received little attention. Heating
(MeO)2POEt and (EtO)2POMe with methyl iodide gave the
phosphonates MeO(EtO)P(O)Me and (EtO)2P(O)Me in 98%
and 60% yields respectively.9 We found by GC-MS analysis that
treatment of dimethyl propyl phosphites with methyl iodide
gave three products: methyl propyl methylphosphonates 2a–b,
dimethyl methylphosphonate 3 and methyl propyl propylphos-
phonates 4a–b (Scheme 4). The first two arise from breakdown
of the intermediate phosphonium salt and the third from com-
petition of the liberated propyl iodide for the starting phos-
phite. Therefore the reactivity of iodide ion to dealkylation of
the Arbusov intermediates decreases in the substituent order
OMe > OnPr > OiPr.18
The Arbusov rearrangement of alkyl dimethyl phosphites
was used to prepare alkyl methyl methylphosphonates 2b and
5a–f (Scheme 5). These stable colourless liquids were isolated in
high yield (Table 3). The reactions were conducted without
solvent using one molar equivalent of methyl iodide; less than
one percent of dimethyl methylphosphonate was produced.
A stoichiometric amount of methyl iodide is unnecessary as
it regenerates during the isomerisation. Comparative experi-
ments with dimethyl cyclohexyl phosphite showed that the
Spectroscopic data for compounds 1a–i are given in Table 2.
They have phosphorus chemical shifts between 140–135 ppm.
The frequencies of the P–O–C vibrations in the infrared spectra
of esters of trivalent phosphorus16 fall between 1030–1015
Table 1 Experimental data for dimethyl alkyl phosphites (MeO)2POR
Compound
R group
Yield (%)
Bp (ЊC/mmHg)
1a
1b
1c
1d
1e
1f
1g
1h
1i
n-Pra
21
12
40
44
24
16
58
6
46–49/10
37–38/8
i-Pr
n-Bub
61–62/10
53–55/10
54–56/10
47–48/10
69–70/10
80–81/10
92–94/7
i-Bu
s-Bu
t-Bu
Pinacolyl
Cyclopentyl
Cyclohexyl
64
a Previously made in 78% yield by transesterification of trimethyl phos-
phite, but no experimental details were given (lit.,12 bp 47–48 ЊC/14
mmHg). b Previously made by methanolysis of butyl phosphorodi-
chloridite BuOPCl2 in ether in the presence of N,N-dimethylaniline
(lit.,10 bp 65–66 ЊC/18 mmHg).
Table 2 Spectroscopic data for dimethyl alkyl phosphites (MeO)2POR (NMR data measured in CDCl3)
Compound
R
1H NMR δ, J/Hz
13C NMR δ, J/Hz
31P NMR δ IR ν/cmϪ1
1a
n-Pr
3.77 (2H, dt, J = 8.3, 6.7, OCH2), 3.52
(6H, d, J = 10.4, OCH3), 1.62 (2H, qt,
J = 6.5, CH2), 0.96 (3H, t, J = 7.4,
CH3)
48.7 (OCH3), 64.2 (OCH2), 24.4
(CH2), 10.3 (CH3)
139.4
1462, 1389, 1257, 1180,
1016 (P–OMe), 978
(P–OCH2), 818, 729
1b
1c
i-Pr
4.3 (1H, dsep, J = 6, 8.5, OCH), 3.48
(6H, d, J = 10.3, OCH3), 1.23 (6H, d,
J = 6.1, CH3)
3.8 (2H, m, OCH2), 3.52 (6H, d,
J = 10.4, OCH3), 1.61 (2H, m, CH2),
1.41 (2H, m, J = 7, CH2CH3), 0.94
(3H, t, J = 7.3, CH3)
66.6 (OCH), 49 (OCH3), 24.5
(CH3)
138.6
139.6
1373, 1263, 1178, 1020
(P–OMe), 974 (P–OCH),
741
1458, 1381, 1180, 1020
(P–OMe), 968 (P–OCH2),
881, 727
n-Bu
62 (OCH2), 48.7 (OCH3), 33.1
(CH2), 18.5 (CH2CH3), 13.5 (CH3)
1d
1e
i-Bu
s-Bu
3.6 (2H, dd, J = 7, 12, OCH2), 3.6
(6H, d, J = 10, OCH3), 1.88 (1H, m,
J = 7, CH), 0.87 (6H, d, J = 6.7, CH3)
4.12 (1H, m, OCH), 3.51 and 3.48
(6H, d, J = 10.3, OCH3), 1.5 (2H, m,
CH2), 1.25 (3H, d, J = 7.9, OCCH3),
0.94 (3H, t, J = 7.3, CH3)
68.9 (OCH2), 48.9 (OCH3), 29.7
(CH), 18.7 (CH3)
139.3
139.2
1469, 1392, 1367, 1180,
1018 (P–OMe), 951, 744
(P–OCH2)
1456, 1377, 1174, 1026
(P–OMe), 993 (P–OCH),
937, 727
71.5 (OCH), 48.3 and 48.2
(OCH3), 30.9 (CH2), 21.8
(OCCH3), 9.6 (CH3)
1f
t-Bu
3.48 (6H, d, J = 10.1, CH3), 1.45 (9H,
s, CCH3)
76.3 (OCCH3), 48.2 (OCH3), 31.1
(CH3)
135.2
140.1
1460, 1392, 1367, 1252,
1180, 1051, 1016
(P–OMe), 943 (P–OC),
812, 742
1479, 1375, 1180, 1082,
1043, 1018 (P–OMe),
1006, 945 (P–OCH), 930,
793, 744
1g
Pinacolyl 3.77 (1H, dq, J = 7, 10, OCH), 3.51
and 3.5 (6H, d, J = 10.1 and 10.4,
OCH3), 1.1 (3H, d, J = 6.4, OCCH3),
0.9 (9H, s, CH3)
77.4 (OCH), 48.7 and 48.5
(OCH3), 35.2 (OCH), 25.7 (CH3),
17.5 (OCCH3)
1h
1i
Cyclo-
pentyl
4.62 (1H, m, OCH), 3.5 (6H, d,
J = 11.2, OCH3), 1.8 (8H, m, ring CH2
groups)
4.04 (1H, m, J = 5.2, 9.5, OCH), 3.5
(6H, d, J = 10.4, OCH3), 2 and 1.45
(4H, m, C-2 and C-6 ring CH2), 1.75
and 1.26 (4H, m, C-3 and C-5 ring
CH2), 1.51 and 1.24 (2H, m, ring CH2)
75.2 (OCH), 48.4 (OCH3), 34.2
(C-2 and C-5 ring), 22.9 (C-3 and
C-4 ring)
71.9 (OCH), 48.4 (OCH3), 34.3
(C-2 and C-6 ring), 25.2 (C-3 and
C-5 ring), 23.8 (C-4 ring)
139.0
138.4
1365, 1267, 1173, 1014
(P–OMe), 978 (P–OCH),
879, 849, 741
1450, 1373, 1180, 1016
(P–OMe), 978 (P–OCH),
856, 808, 791, 744
Cyclo-
hexyl
J. Chem. Soc., Perkin Trans. 1, 2001, 26–30
27

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isomers was obtained. No attempt was made to separate these
diastereoisomers and NMR and IR spectra of the mixtures
were recorded.
Synthesis and cleavage of phosphorus silyl esters
Often phosphorus esters undergo facile transesterification reac-
tions with silyl halides to form the corresponding phosphorus
silyl esters and alkyl halides.19,20 The silyl esters are cleaved
by protic solvents under very mild conditions to yield the
phosphorus acids. Overall, the equivalent of hydrolysis of the
phosphorus ester is accomplished, but under conditions far
milder than could be used with the parent ester. For trans-
esterification, the reaction proceeds most rapidly with methyl
esters, and much slower with more highly-substituted alkyl
esters.21 The exceptional rapidity of the reaction of methyl
esters permitted selective silylation of the mixed phosphonates
with bromotrimethylsilane (Scheme 6). Methanol was used to
Scheme 4
Scheme 6
effect cleavage of the silyl ester link, generating phosphonic
acids 6a–g as viscous oils in high yields (Table 5).
The formation of the silyl ester depended on the nature of
the higher ester group in the starting mixed phosphonate.
With the bulky sec-butyl group on phosphorus, silylation was
incomplete and the corresponding acid 6d could be isolated
only in 90% purity due to co-distillation of the residual starting
phosphonate.
Spectroscopic data for phosphonic acids 6a–g are given in
Table 6. Their phosphorus chemical shifts are between 32–30
ppm. The phosphoryl vibration appears in the range 1213–1201
cmϪ1 in the infrared spectra. In the absence of moisture, the
phosphonic acids can be stored in a refrigerator for several
years without decomposition.
Scheme 5
Table 3 Experimental data for alkyl methyl methylphosphonates
RO(MeO)P(O)Me
Compound
R group
Yield (%)
Bp (ЊC/mmHg)a
2b
5a
5b
5c
5d
5e
5f
i-Pr
n-Bu
i-Bu
s-Bu
66
94
88
86
95
87
84
21–22/0.2
55/1
45/0.04
50/0.025
65/0.025
60/1
Pinacolylb
Cyclopentyl
Cyclohexylc
Conclusion
An improved route to alkyl hydrogen methylphosphonates has
been developed. The limiting step in the synthetic sequence
is the initial transesterification of trimethyl phosphite. The
Arbusov reaction of the resultant mixed phosphites is reliable
and high yielding. The silylation–desilylation procedure used in
the last step provided a mild method of dealkylation of alkyl
methyl methylphosphonates and resulted in selective methyl
ester cleavage. The three-stage synthesis is an improvement on
literature methods to alkyl hydrogen methylphosphonates that
involve alkaline hydrolysis of symmetrical or mixed phospho-
nates or alcoholysis of methylphosphonic anhydride.
45/0.2
a Approximate oven temperatures recorded during purification by
Kugelrohr distillation. b This compound has been prepared before
in 55% yield by treatment of methyl methylphosphonochloridate
Cl(MeO)P(O)Me with the sodium salt of pinacolyl alcohol (3,3-
dimethylbutan-2-ol) in ether (lit.,4 bp 100–102 ЊC/18 mmHg). c This
compound has been prepared similarly in 65% yield (lit.,4 bp 113 ЊC/10
mmHg).
reaction occurred to the same extent (i.e. quantitatively), but
much more slowly, when 0.05 molar equivalents of methyl
iodide were used.
Interaction of dimethyl tert-butyl phosphite with methyl
iodide did not give the desired phosphonate on distillation.
Instead an unidentified mixture of phosphorus products
formed that did not contain the tert-butyl group. The thermal
instability of butyl esters of methylphosphonic acid has been
noted before; elimination of but-1-ene from nBuO(HO)P(O)Me
occurred readily on heating.7
Spectroscopic data for methylphosphonates 2b and 5a–f are
given in Table 4. Their phosphorus chemical shifts are between
32–30 ppm. In the infrared spectra, the phosphoryl vibration
appears in the range 1246–1236 cmϪ1 and there are several
strong bands in the region 1090–1060 cmϪ1 characteristic of
different ester groups.4 During the synthesis of sec-butyl and
pinacolyl phosphonate derivatives a mixture of two diastereo-
Experimental
General details
All reagents were of commercial quality: trimethyl phosphite
obtained from Aldrich Ltd (Gillingham, UK) contained a small
amount of trimethyl phosphate, and was therefore distilled
prior to use. Anhydrous solvents were used for reactions. NMR
spectra were obtained on a JEOL Lambda 500 instrument
(operating at 500 MHz for 1H, 125 MHz for 13C, 470 MHz for
19F, and 202 MHz for 31P spectra) or a JEOL Lambda 300
instrument (operating at 300 MHz for 1H, 75 MHz for 13C, 282
MHz for 19F, and 121.5 MHz for 31P spectra) as solutions in
CDCl3, with internal reference SiMe4 for H and 13C, external
1
CFCl3 for 19F and external (MeO)3P (δ 140 ppm) for 31P spectra.
28
J. Chem. Soc., Perkin Trans. 1, 2001, 26–30

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Table 4 Spectroscopic data for alkyl methyl methylphosphonates RO(MeO)P(O)Me (NMR data measured in CDCl3)
Compound
R
1H NMR δ, J/Hz
13C NMR δ, J/Hz
31P NMR δ
IR ν/cmϪ1
1651, 1468, 1387, 1313,
2b
i-Pr
4.7 (1H, dsep, J = 6.2, 7.3, OCH),
3.71 (3H, d, J = 11.2, OCH3), 1.46
(3H, d, J = 17.1, P-CH3), 1.33 (6H,
d, J = 6.4, CH3)
4.04 (2H, dt, J = 9.2, 6.6, OCH2),
3.72 (3H, d, J = 11.1, OCH3), 1.65
(2H, m, J = 7, CH2), 1.45 (3H, d,
J = 17.6, P-CH3), 1.42 (2H, m,
J = 7, CH2CH3), 0.95 (3H, t,
J = 7.4, CH3)
3.8 (2H, m, OCH2), 3.7 (3H, d,
J = 11.1, OCH3), 1.94 (1H, tsep,
J = 7, CH), 1.49 (3H, d, J = 17.8, P-
CH3), 0.98 (6H, d, J = 6.8, CH3)
3.72/3.71 (3H, d, J = 11, OCH3),
4.48 (1H, m, OCH), 1.47 (3H, d,
J = 17.3, P-CH3), 1.33/1.32 (3H, d,
J = 6.3, OCCH3), 0.96/0.95 (3H, t,
J = 7.5, CH3)
4.26/4.23 (1H, dq, J = 6.4, 8.2,
OCH), 3.74/3.71 (3H, d, J = 11.3,
OCH3), 1.47 (3H, d, J = 18.4, P-
CH3), 1.29/1.28 (3H, d, J = 6.4,
OCCH3)
70.2 (OCH), 51.9 (OCH3), 24
(CH3), 11.6 (P-CH3)
29.7
1236 (P᎐O), 1180, 1107,
᎐
1051 (P–OMe), 977, 916,
811, 715
5a
n-Bu
65.4 (OCH2), 52.1 (OCH3), 32.5
(P-CH3), 18.7 (CH2), 13.6
(CH2CH3), 11.4 (CH3)
31.1
1649, 1466, 1313, 1244
(P᎐O), 1186, 1051
᎐
(P–OMe), 1028, 985,
920, 814
5b
5c
i-Bu
71.6 (OCH2), 52 (OCH3), 29.1
(CH), 18.7 (CH3), 9.65 (P-CH3)
31.6
1651, 1471, 1313, 1244
(P᎐O), 1184, 1057
᎐
(P–OMe), 1024, 918,
827, 808, 727
s-Bua
74.5/74.4 (OCH), 51.1/51.3
(OCH3), 30/20.9 (OCCH3),
11.5/9.5 (P-CH3), 9.1/8.5
29.5 and 29.8
1651, 1463, 1383, 1313,
1242 (P᎐O), 1176, 1053
᎐
(P–OMe), 1030, 999,
960, 910, 811, 756, 723
5d
5f
Pinacolyla
Cyclohexyl
81/80.7 (CCH3), 51.7/51.4
(OCH3), 25.5 (CH3), 16.9/16.6
(OCCH3), 11.5/10.5 (P-CH3)
29.5 and 30.3
29.6
1481, 1462, 1379, 1365,
1311, 1246 (P᎐O), 1080,
᎐
1057 (P–OMe), 1045,
1011, 976, 933, 910, 814,
737
4.4 (1H, m, OCH), 3.7 (3H, d,
J = 11.3, OCH3), 1.95/1.5 (4H, m,
C-2 and C-6 ring CH2), 1.75/1.35
(4H, m, C-3 and C-5 ring CH2),
1.47 (3H, d, J = 17.7, P-CH3), 1.23
(2H, m, C-4 ring CH2)
74.7 (OCH), 51.3 (OCH3), 33.3
(C-2 and C-6 ring), 24.6 (C-3
and C-5 ring), 23.1 (C-4 ring),
10.7 (P-CH3)
1647, 1452, 1311, 1242
(P᎐O), 1186, 1055
᎐
(P–OMe), 1034, 999,
920, 897, 806, 735
5e
5f
Cyclopentyl
Cyclohexyl
4.9 (1H, m, OCH), 3.72 (3H, d,
J = 11.9, OCH3), 1.46 (3H, d,
J = 17.4, P-CH3), 1.85–1.6 (8H, m,
ring CH2 groups)
4.4 (1H, m, OCH), 3.7 (3H, d,
J = 11.3, OCH3), 1.95/1.5 (4H, m,
C-2 and C-6 ring CH2), 1.75/1.35
(4H, m, C-3 and C-5 ring CH2),
1.47 (3H, d, J = 17.7, P-CH3), 1.23
(2H, m, C-4 ring CH2)
78.4 (OCH), 51.3 (OCH3), 33.6
(C-2 and C-5 ring), 21.2 (C-3
and C-4 ring), 10.6 (P-CH3)
29.7
29.6
1646, 1454, 1313, 1244
(P᎐O), 1186, 1051
᎐
(P–OMe), 999, 928, 901,
812
74.7 (OCH), 51.3 (OCH3), 33.3
(C-2 and C-6 ring), 24.6 (C-3
and C-5 ring), 23.1 (C-4 ring),
10.7 (P-CH3)
1647, 1452, 1311, 1242
(P᎐O), 1186, 1055
᎐
(P–OMe), 1034, 999,
920, 897, 806, 735
a Diastereoisomeric pair.
Table 5 Experimental data for alkyl hydrogen methylphosphonates
m = multiplet and sep = septet; br = broad), coupling constant
(J/Hz) and assignment. IR spectra were recorded as liquid films
on a Nicolet SP210 instrument using Omnic software. Reaction
mixtures were monitored by gas chromatography-mass spec-
trometry (GC-MS) using a Finnigan MAT GCQ instrument
with chemical ionisation (CI) using methane as reagent gas.
Molecular masses of pure phosphites and phosphonates were
confirmed with methane ϩve CI data. With the exception of
the sec-butyl derivative 6d which was 90% pure, the alkyl
hydrogen methylphosphonates were >95% pure by liquid
chromatography-mass spectrometry using atmospheric pres-
sure chemical ionisation. Their characterisation by tandem
mass spectroscopic techniques has been described elsewhere.1,2
RO(HO)P(O)Me
Compound
R group
Yield (%)
Bp (ЊC/mmHg)a
6a
6b
6c
6d
6e
6f
i-Prb
97
82
88
89
90
64
60
80/0.04
75/0.01
75/0.01
80/0.035
90/0.02
95/0.04
105/0.015
n-Buc
i-Bud
s-Bu
Pinacolyle
Cyclopentyl
Cyclohexylf
6g
a Approximate oven temperatures recorded during purification by
Kugelrohr distillation. b Previously made in 12% yield from alcoholysis
of methylphosphonic anhydride (lit.,8 bp 100–115 ЊC/3 mmHg) and in
60% and 41% yields respectively from hydrolysis of diisopropyl methyl-
phosphonate with aqueous sodium hydroxide in dioxane (lit.,4 bp
115 ЊC/0.5 mmHg) or with aqueous barium hydroxide (lit.,5 bp 97–
98 ЊC/0.08 mmHg). c Previously made in 76% yield from hydrolysis of
dibutyl methylphosphonate with aqueous sodium hydroxide in dioxane
(lit.,4 bp 132 ЊC/0.5 mmHg). d Previously made in 98% yield from
alcoholysis of methylphosphonic anhydride (lit.,7 bp 142–143 ЊC/0.5
mmHg). e Previously made in 88% yield from hydrolysis of methyl 3,3-
dimethylbutyl methylphosphonate with aqueous sodium hydroxide in
dioxane (bp not given)4 and in 18% yield from alcoholysis of methyl-
phosphonic anhydride (lit.,8 bp 135 ЊC/3 mmHg). f Previously made in
47% yield from alcoholysis of methylphosphonic anhydride (lit.,8 bp
150 ЊC/0.8 mmHg).
The synthesis of dialkyl alkyl phosphites
This general procedure is illustrated for the synthesis of di-
methyl pinacolyl phosphite. A 250 cm3 round-bottom flask was
equipped with a distillation rig, a pressure-equalising dropping
funnel and an argon bleed; the funnel and receiver were fitted
with calcium chloride guard tubes. Pinacolyl alcohol (23.5 g,
0.23 mol) was weighed into the dropping funnel and trimethyl
phosphite (49.6 g, 0.4 mol), a pea-sized piece of sodium metal,
and a magnetic flea were added to the flask. The flask was
heated to 100 ЊC and pinacolyl alcohol added dropwise with
stirring over 20 min. After evolution of methanol ceased (6.4 g
collected, theoretical yield 7.4 g), the residue was fractionated
under reduced pressure (10 mmHg). Three fractions were
collected (1) bp 22–27 ЊC, 18.92 g, (2) 27–68 ЊC, 2.4 g and (3)
68–72 ЊC, 28.14 g. The forerun was discarded. The second
Data in Tables 2, 4 and 6 are recorded as follows: chemical
shifts in ppm from reference on the δ scale, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
J. Chem. Soc., Perkin Trans. 1, 2001, 26–30
29

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Table 6 Spectroscopic data for alkyl hydrogen methylphosphonic acids RO(HO)P(O)Me (NMR data measured in CDCl3)
Compound
R
1H NMR δ, J/Hz
13C NMR δ, J/Hz
31P NMR δ
IR ν/cmϪ1
6a
i-Pr
11.02 (1H, br s, OH), 4.68 (1H, dsep,
J = 8.2, 6.1, OCH), 1.51 (3H, d,
J = 17.3, P-CH3), 1.33 (6H, d, J = 6.1,
CH3)
70.6 (OCH), 24 (CH3), 12.8
(P-CH3)
31.4
2981 (OH), 2306, 1693,
1377, 1315, 1178, 1143,
1202 (P᎐O), 1107
᎐
6b
n-Bu
11.94 (1H, br s, OH), 4.01 (2H, dt,
J = 9, 6.4, OCH2), 1.65 (2H, tt,
J = 6.6, 6.8, CH2), 1.49 (3H, d,
J = 16.9, P-CH3), 1.41 (2H, m, J = 7,
CH2CH3), 0.94 (3H, t, J = 7.3, CH3)
12.1 (1H, br s, OH), 3.77 (2H, dd,
J = 6.8, 7, OCH2), 1.95 (1H, m, J = 7,
CH), 1.5 (3H, d, J = 17.7, P-CH3), 0.9
(6H, d, J = 6.8, CH3)
11.3 (1H, br s, OH), 4.44 (1H, m,
J = 6, 7, OCH), 1.63/1.58 (2H, m,
J = 7.1, 9.5, 14.4, CH2), 1.48 (3H, d,
J = 17.7, P-CH3), 1.32 (3H, d, J = 6.3,
OCCH3), 0.94 (3H, t, J = 6.3, CH3)
11.6 (1H, br s, OH), 4.2 (1H, dq,
J = 9.5, 6.5, OCH), 1.48 (3H, d,
65.2 (OCH2), 32.3 (CH2), 18.6
(CH2CH3), 12.8 (CH3), 11.3
(P-CH3)
31.6
2960 (OH), 2297, 1678,
1466, 1313, 1205 (P᎐O),
᎐
1066, 1030, 997, 910, 804
6c
6d
i-Bu
s-Bu
71.1 (OCH2), 29 (CH), 18.7
(CH3), 11.5 (P-CH3)
32.1
31.4
2960 (OH), 2287, 1685,
1473, 1313, 1205 (P᎐O),
᎐
1038, 1003, 901
75.3 (OCH), 30.5 (CH2), 21.5
(OCCH3), 12.4 (P-CH3), 9.6
(CH3)
2973 (OH), 2306, 1689,
1459, 1383, 1313, 1209
(P᎐O), 1174, 1034, 1001,
᎐
899, 816
6e
Pinacolyl
80.9 (OCH), 34.8 (CCH3), 25.6
(CH3), 16.8 (OCCH3), 12.3
31.5
2962 (OH), 1481, 1381,
1365, 1311, 1207 (P᎐O),
᎐
J = 17.8, P-CH3), 1.28 (3H, d, J = 6.4, (P-CH3)
OCCH3), 0.92 (9H, s, CH3)
1078, 1014, 997, 933, 901
6f
Cyclopentyl
Cyclohexyl
10.9 (1H, br s, OH), 4.8 (1H, m,
OCH), 1.75–1.5 (ring CH2 groups),
1.38 (3H, d, J = 18, P-CH3)
11.82 (1H, br s, OH), 4.37 (1H, m,
J = 4, 8, OCH), 1.9–1.5 (8H, m, ring
CH2 groups), 1.3 (2H, m, C-4 ring
CH2), 1.5 (3H, d, J = 17.8, P-CH3)
78.7 (OCH), 34.2 (C-2 and C-5
ring), 23.1 (C-3 and C-4 ring),
12.4 (P-CH3)
75.1 (OCH), 33.6 (C-2 and C-6
ring), 25.1 (C-3 and C-4 ring),
23.6 (C-4 ring), 12.3 (P-CH3)
30.2
31.0
2960 (OH), 2289, 1678,
1452, 1313, 1213 (P᎐O),
᎐
997, 920, 814
6g
2937 (OH), 2312, 1682,
1452, 1311, 1201 (P᎐O),
᎐
1041, 1005, 908, 762
and third fractions contained 30% and 91% desired product
respectively. The third fraction was redistilled to give dimethyl
pinacolyl phosphite 1g as a colourless liquid (25.73 g, overall
58%); bp 69–70 ЊC/10 mmHg.
infrared spectra. The present work was funded by the Ministry
of Defence UK.
References
1 R. M. Black, R. J. Clarke, R. W. Read and M. T. J. Reid,
J. Chromatogr. A, 1994, 662, 301.
2 R. M. Black and R. W. Read, J. Chromatogr. A, 1997, 759,
79.
3 R. Rabinowitz, J. Am. Chem. Soc., 1960, 82, 4564.
4 H. Christol, M. Levy and C. Marty, J. Organomet. Chem., 1968, 12,
459.
5 E. Gryszkiewicz-Trochimowski, J. Quinchon and M. Bousquet,
Bull. Soc. Chim. Fr., 1962, 1645.
6 R. F. Hudson and L. Keay, J. Chem. Soc., 1956, 2463.
7 K. A. Petrov, R. A. Baksova, L. V. Korkhoyanu, L. P. Sinogeikina
and T. V. Skudina, J. Gen. Chem. (Engl. Transl.), 1965, 35, 723.
8 A. Pienaar, C. M. Erasmus, M. Wentzel and E. H. Cowley,
Phosphorus, Sulfur Relat. Elem., 1999, 148, 149.
9 S. R. Landauer and H. N. Rydon, J. Chem. Soc., 1953, 2224.
10 G. Kamai and F. M. Kharrasova, J. Gen. Chem. (Engl. Transl.),
1957, 27, 1034.
The synthesis of dialkyl alkylphosphonates
This general procedure is illustrated for the synthesis of methyl
pinacolyl methylphosphonate. Dimethyl pinacolyl phosphite
(9.7 g, 0.05 mol) and methyl iodide (7.1 g, 0.05 mol) were placed
into a 50 cm3 round-bottom flask equipped with a condenser
(fitted with a calcium chloride guard tube) and refluxed for 2 h.
A portion of the reaction mixture was analysed by GC-MS and
shown to comprise methyl pinacolyl methylphosphonate and a
trace of dimethyl methylphosphonate. The methyl iodide was
removed on a rotary evaporator. Bulb-to-bulb distillation of
the residue under reduced pressure gave pure methyl pinacolyl
methylphosphonate 5d as a colourless liquid (9.24 g, 94%); bp
65 ЊC/0.025 mmHg.
11 M. M. Sidky, F. M. Soliman and R. Shabana, Aust. J. Chem., 1978,
31, 139.
The synthesis of alkyl hydrogen alkylphosphonates
12 A. E. Arbusov and M. G. Imaev, Dokl. Chem. (Engl. Transl.), 1957,
112, 115.
13 F. W. Hoffmann, R. J. Ess and R. P. Usinger, J. Am. Chem. Soc.,
1956, 78, 5817.
14 F. W. Hoffmann and T. R. Moore, J. Am. Chem. Soc., 1958, 80,
1150.
15 M. M. Sidky, M. N. Aboudl-Enein and R. M. Taha, Egypt.
J. Chem., 1973, 43.
16 L. C. Thomas, The Identification of Functional Groups in
Organophosphorus Compounds, Academic Press, London, 1974.
17 A. H. Ford-Moore and J. H. Williams, J. Chem. Soc., 1947,
1465.
18 R. E. Engel, Synthesis of Carbon-Phosphorus Bonds, CRC
Press Inc., Florida, 1988, p. 35.
19 B. Borecka, J. Chojnowski, M. Cypryk, J. Michalski and
J. Zielinska, J. Organomet. Chem., 1979, 171, 17.
20 C. M. Timperley, I. J. Morton, M. J. Waters and J. L. Yarwood,
J. Fluorine Chem., 1999, 96, 95.
21 R. E. Engel, Handbook of Organophosphorus Chemistry, Marcel
Dekker Inc., New York, 1992, p. 178.
This general procedure is illustrated for the synthesis of pina-
colyl hydrogen methylphosphonate. Methyl pinacolyl meth-
ylphosphonate (0.97 g, 0.005 mol) was weighed into a 50 cm3
round-bottom flask to which chloroform (10 cm3) and a
magnetic flea were added. The flask was stoppered with a rub-
ber septum and purged with argon. The reaction mixture was
stirred and bromotrimethylsilane (0.66 cm3, 0.005 mol) was
added by syringe. After 12 h, the solvent was removed to leave a
colourless oil. Methanol (2 cm3) was added and then removed
on a rotary evaporator; this was repeated two more times. The
resultant viscous oil was distilled using a Kugelrohr apparatus
to give pinacolyl hydrogen methylphosphonate 6e as colourless
liquid (0.81 g, 90%); bp 90 ЊC/0.02 mmHg.
Acknowledgements
We thank Steve Marriott and Alison Bussey for providing the
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J. Chem. Soc., Perkin Trans. 1, 2001, 26–30