Solid-phase synthesis of some alkyl hydrogen methylphosphonates

Article abstract of DOI:10.1080/713744564

Eleven alkyl hydrogen methylphosphonates of structure RO(HO) P(O)Me were made by phosphoramidite chemistry on hydroxymethyl polystyrene resin; R = Me, Et, n-Pr, i-Pr, n-Bu, n-hexyl, n-octyl, cyclohexyl, cycloheptyl, cyclooctyl, and 3,3-dimethylbutan-2-yl

Full text of DOI:10.1080/713744564

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Phosphorus, Sulfur, and Silicon and the Related
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Solid-Phase Synthesis of Some Alkyl Hydrogen
Methylphosphonates
a
a
a
a
a
Hubert Barucki , Robin M. Black , Kenneth I. Kinnear , Ian Holden , Robert W. Read
&
a
Christopher M. Timperley
a
Defence Science and Technology Laboratory , Wiltshire, United Kingdom
Published online: 27 Oct 2010.
To cite this article: Hubert Barucki , Robin M. Black , Kenneth I. Kinnear , Ian Holden , Robert W. Read & Christopher M.
Timperley (2003) Solid-Phase Synthesis of Some Alkyl Hydrogen Methylphosphonates, Phosphorus, Sulfur, and Silicon and the
Related Elements, 178:10, 2279-2286, DOI: 10.1080/713744564
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Phosphorus, Sulfur, and Silicon, 178:2279–2286, 2003
Copyright ꢀC Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390234885
SOLID-PHASE SYNTHESIS OF SOME ALKYL
HYDROGEN METHYLPHOSPHONATES
Hubert Barucki, Robin M. Black, Kenneth I. Kinnear,
Ian Holden, Robert W. Read, and Christopher M. Timperley
Defence Science and Technology Laboratory, Wiltshire,
United Kingdom
(Received May 15, 2003)
Eleven alkyl hydrogen methylphosphonates of structure RO(HO)
P(O)Me were made by phosphoramidite chemistry on hydroxymethyl
polystyrene resin; R = Me, Et, n-Pr, i-Pr, n-Bu, n-hexyl, n-octyl, cyclo-
hexyl, cycloheptyl, cyclooctyl, and 3,3-dimethylbutan-2-yl ie. pinacolyl
or Me C CH(Me) .
3
Keywords: Alkyl hydrogen methylphosphonates; alkyl methyl-
phosphonic acids; chemical warfare agent; solid-phase chemistry;
trivalent phosphorus
Verification of compliance is an important component of the Chemical
1
Weapons Convention. Alkyl hydrogen methylphosphonates of struc-
ture RO(HO)P(O)Me are the primary hydrolysis products of G and
V-type nerve agents.2 They do not occur naturally in the environ-
ment or in biological systems and are therefore important indicators
of production or use of nerve agents. For example, isopropyl hydrogen
methylphosphonate was identified in biomedical samples from casual-
ties following the release of sarin, i-PrO(Me)P(O)F, by terrorists in the
3
Tokyo subway and in bomb craters found near a Kurdish community in
4
Iraq. Laboratories engaged in verification analysis require a range of
alkyl hydrogen methylphosphonates, covering the nerve agents of pos-
sible concern. Recently we prepared a homologous series of these com-
5
pounds in three-steps using solution chemistry. We now describe their
synthesis on a polymer support. The range of solid-phase reactions that
6
can be performed has expanded considerably. However, phosphorus
Address correspondence to Christopher M. Timperley, Dstl Chemical and Biological
Sciences, Porton Down, Salisbury, Wiltshire, SP4 0JQ, England. E-mail: cmtimperley@
dstl.gov.uk
2
279

2
280
H. Barucki et al.
chemistry has not been featured to any great extent except in the long
established use of versatile phosphoramidite reagents in the automated
synthesis of oligonucleotides. Outside the oligonucleotide field, multi-
step transformations of small phosphorus species on solid-support are
7
little known. The chemistry described represents the first steps to-
ward the goal of establishing a combinatorial library of alkyl hydrogen
alkylphosphonates.
RESULTS AND DISCUSSION
We focused initially on the synthesis of model dialkyl hydrogen
ꢁ
ꢁ
phosphates from 2-cyanoethyl N,N,N ,N -tetraisopropylphosphorodia-
midite 1 using a coupling strategy similar to one developed for con-
8
structing internucleotide linkages. Reagent 1 was attached to hydrox-
ymethylpolystyrene resin using tetrazole as an activator (Scheme 1).
Displacement of the diisopropylamino group by ethanol or isopropanol
in the presence of tetrazole took place rapidly and, after oxidation with
t-butyl hydroperoxide in toluene, gave phosphates 3a–b. Selective
N(i-Pr)2
N(i-Pr)2
N(i-Pr)2
O
i
NC(CH ) O-P
NC(CH ) O-P
2
2
2 2
1
2
ii
RO
O
P
iii
RO
P
O
O
NC(CH ) O OH
NC(CH ) O
2
2
2 2
R = Et 4a δ P -0.8
i-Pr 4b δ P -2.0
3a δ P -1.6
3b δ P -2.3
SCHEME 1 Reagents and conditions: i, hydroxymethyl polystyrene, tetrazole,
◦
CH
2
Cl
2
; ii, ROH, tetrazole, MeCN, 25 C, 5 min, then 1M t-BuOOH, toluene,
◦
◦
25 C, 5 min; iii, CF
3
CO
2
H, 25 C, 60 min.

Alkyl Hydrogen Methylphosphonates
2281
cleavage from the resin was effected by trifluoroacetic acid and gave
target compounds 4a–b in 90+% purity by multinuclear NMR analysis
(
Table I).
Alkyl hydrogen methylphosphonates derived from the G nerve
agents were prepared next (Scheme 2). Hydroxymethyl polystyrene
9
was derived with chloro(N,N-diisopropylamino)methylphosphine 5 us-
ing a molar equivalent of triethylamine in dichloromethane. Treatment
of the product 6 with a range of alcohols, followed by oxidation, gave
the polymer-bound alkyl methylphosphonates 7a–k which, on acidic
cleavage from the resin, yielded the desired methylphosphonates 8a–k.
Their phosphorus NMR shifts agreed with literature values and struc-
tures were confirmed by LC-MS analyses (Table II). Overall yields were
no greater than 30% but purities were high. The low yields reflected
N(i-Pr)2
Cl
N(i-Pr)2
O
i
Me-P
Me-P
5
6
ii
RO
O
iii RO
Me
O
O
P
P
Me OH
a-k
8
7a-k
R = Me a, Et b, n-Pr c, i-Pr d, n-Bu e,
n-hexyl f, n-octyl g, cyclohexyl h,
cycloheptyl i, cyclooctyl j, pinacolyl k
SCHEME 2 Reagents and conditions: i, hydroxymethyl polystyrene, Et
3
N,
◦
CH
2
Cl
2
; ii, ROH, tetrazole, MeCN, 25 C, 15 min, then 1M t-BuOOH, toluene,
◦
◦
2
5 C, 5 min; iii, CF
3
CO
2
H, 25 C, 60 min.

2
282
H. Barucki et al.
6
i
EtO
Me
O
O
(i-Pr) N
O
O
2
P
P
Me
7b
9
ii
ii
EtO
O
HO
O
P
P
Me OH
Me OH
8b
10
15% δ P 32.5
85% δ P 26.9
◦
SCHEME 3 Reagents and conditions: i, EtOH, tetrazole, MeCN, 25 C, 5 min
◦
◦
3 2 2 2
then 1M t-BuOOH, toluene, 25 C, 5 min; ii, CF CO H, CH Cl , 25 C, 60 min.
difficulty in release of product, a fact established by NMR analysis of
the resin.
The same transformations were achieved using Wang resin
4-benzyloxybenzyl alcohol) instead of hydroxymethyl polystyrene. Re-
(
gardless of the support, success of the route depended on the time
allowed for alcoholysis of phosphoramidite 6. The optimal time was
15 min. Lesser times resulted in incomplete reaction and complicated
the outcome: when ethanolysis was stopped after 5 min, and the syn-
thetic sequence continued, two phosphorus acids formed (Scheme 3).
Displacement of the diisopropylamino group and oxidation gave the
required phosphonate 7b that, after treatment with acid, gave ethyl hy-
drogen methylphosphonate 8b. Unreacted starting material also under-
went oxidation to give phosphoramidate 9. Trifluoroacetic acid caused
P N and benzylic P O bond cleavage, yielding unwanted methylphos-
phonic acid 10.11 This side process, detrimental to making alkyl hy-
drogen methylphosphonates, could be applied to the synthesis of other
alkylphosphonic acids of structure RP(O)(OH)2, where R is Et, n- or i-Pr.

Alkyl Hydrogen Methylphosphonates
2283
TABLE I NMR Data for Alkyl 2-Cyanoethyl Hydrogen Phosphates
4a–b of Structure RO(CNCH
2
CH
2
O)
2
P(O)OH Measured in CDCl
3
R
1H NMR δ, J/Hz
13C NMR δ, J/Hz
Et
4a
10.38 (1H, br s, OH), 4.3–4.06
4H, m, OCH2), 2.75 (2H, t,
116.7 (CN), 64.6 (OCH2),
61.8 (OCH2), 19.7 (CH2CN),
16.3 (CH3)
(
J = 6.2, CH2CN), 1.36 (3H, t,
J = 6.2, CH3)
i-Pr 4b 11.32 (1H, br s, OH), 4.62 (1H,
sep, J = 6.2, OCH), 4.26–4.12
116.6 (CN), 73.1 (OCH),
61.2 (OCH2), 23.4 (CH3),
19.4 (CH2CN)
(
2H, m, OCH2), 2.75 (2H, t,
J = 6.2 Hz, CH2CN), 1.4–1.3
(
6H, m, CH3)
These compounds also may be environmental indicators of nerve agent
use and could be made similarly from phosphoramidites RP[N(i-Pr)2]2
with omission of the alcoholysis step.
For the chemistry to allow access to a diverse range of pentavalent
phosphorus species, several cleavage reagents should ideally be avail-
able. Trifluoroacetic acid, poorly effective in dilute solution, worked ef-
ficiently and cleanly in the minimum volume of dichloromethane. Bet-
ter results were obtained with hydroxymethyl polystyrene rather than
Wang resin. However, trifluoroacetic acid cannot be used when the de-
rived resin contains acid-sensitive groups required in the end product.
TABLE II Phosphorus NMR Data for Resin-Bound Intermediates 7a–k and
the Alkyl Hydrogen Methylphosphonates 8a–k (Measured in CDCl ) and
3
LC-MS Data for the Latter
31P (δ, ppm)
31P (δ, ppm)
31P lit.
data for 8
LC-MS data for
8 MH (m/z)
+
Compound
R
7
8
a
b
c
d
e
f
g
h
i
Me
Et
n-Pr
i-Pr
n-Bu
n-hexyl
n-octyl
cyclohexyl
cycloheptyl
cyclooctyl
pinacolyla
34.0
32.4
32.4
32.7
32.5
32.8
32.3
32.4
32.4
34.6
32.5
32.8
33.8
33.9
36.9
33.2
34.9
35.2
37.2
34.2/37
—
34.1
111
125
139
139
153
181
209
179
193
207
181
b
—
b
c
33.4 , 31.4
31.6 c
—
—
b
c
33.2 , 31
—
j
k
32.6
32.5/35.8
—
b
c
33.4 , 31.5
a
Pair of diastereoisomers.
b
c
10
From Pienaar et al.
5
From Timperley et al.

2
284
H. Barucki et al.
In this case, the design of milder reagents is essential for success and
presents a significant challenge: Classical chemistry that works well in
solution is not necessarily suited to the solid-phase. For example, treat-
ment of phosphonate 7b in dichloromethane with hydrogen in the pres-
ence of 5% palladium on charcoal or with 30% hydrobromic acid, gave
no reaction after 24 h (both methods deprotect alkyl benzyl methylphos-
phonates in solution). Failure is due presumably to the heterogeneity
of the first system and insufficient reactivity of the second. Clearly a
better understanding of the steric and electronic effects of the resin
is required before the solid-phase methodology can be extended to the
synthesis of more complex organophosphorus compounds.
In conclusion, we have made two dialkyl hydrogen phosphates and
eleven alkyl hydrogen methylphosphonates on solid support. Overall
yields were not high and reflected difficulties in releasing the products
from the hydroxymethyl polystyrene resin A phosphonamidate strat-
egy using an aminated polystyrene, and acid release in the last step,
may overcome this limitation. The methodology described here com-
plements the solution phase route to alkyl hydrogen methylphospho-
5
nates that we developed earlier but does not surpass it in terms of
efficiency.
EXPERIMENTAL
Materials
Reagents were commercial quality. Re-distilled triethylamine was
ꢁ
ꢁ
stored over calcium hydride. 2-Cyanoethyl N,N,N ,N -tetraisopropyl-
phosphorodiamidite 1, hydroxymethyl polystyrene (70–90 mesh), and
4-benzyloxybenzyl alcohol (70–90 mesh) were purchased from Aldrich,
Ltd., UK. Anhydrous solvents and argon atmospheres were used in all
experiments. NMR data were measured in CDCl3 using previously de-
scribed instrumentation.5
NMR Method
3
1
1
P{ H} NMR spectra of derived resins were obtained by placing the
resin in a conventional 5 mm tube to a depth of ca. 0.5 cm and care-
fully adding CDCl3 until one-half of the coil volume was occupied
by the swollen resin and the other half by CDCl3. The sample was
shimmed and the spectra recorded in non-spinning mode (1000 pulses).
The spectra were transformed using an exponential line broadening of
20 Hz.

Alkyl Hydrogen Methylphosphonates
2285
LC-MS Method
Compounds were analyzed as 10 mg/mL solutions in water. LC-MS was
performed using a published method.12 Brief details are as follows: A
Hewlett-Packard LC system consisting of a model 1050 pump plus sol-
vent conditioner was used. The system was fitted with a 150 × 2 mm
internal diameter Columbus C18 column (Phenomenex). The mobile
phase comprised 0.02 M ammonium formate in H2O (solvent A) and
0
.02 M ammonium formate in MeOH (solvent B). The elution gradient
was 5% B (0–5 min) to 90% B (15–20 min) at a flow rate of 0.2 mL/min.
Injections (10 mL) were made using a Rheodyne 9125 injector fitted
with a 20 mL PEEK loop. The effluent was introduced into a Finnigan
TSQ700 mass spectrometer operated in atmospheric pressure chemi-
cal ionisation mode. Source conditions: corona current 2 mA, vaporiser
◦
◦
temperature 400 C, capillary temperature 150 C, sheath gas (nitrogen)
0 psi and auxiliary gas (nitrogen) flow meter reading 20. The source
6
octapole (Q0) was operated at an offset of −5 V. Compounds gave a sin-
gle major peak in the total ion chromatogram (Table II). All produced
+
+
protonated molecular ions (MH ) and the ammoniated ion (M + NH ).
4
Resin-Bound (N,N-Diisopropylamino)methylphosphine 6
Hydroxymethyl polystyrene (2 g, 0.67 mmol/g substitution) was sus-
3
pended in dichloromethane (20 cm ) and stirred for 15 min at room tem-
3
perature. Triethylamine (0.18 cm , 1.34 mmol) was added, followed by
chloro(N,N-diisopropylamino)methylphosphine 5 (0.24 g, 1.34 mmol).
The mixture was stirred at room temperature for 2 h, filtered, and the
3
resin washed successively with dichloromethane (125 cm ) and ace-
3
tonitrile (125 cm ). It was dried with a stream of argon (1.98 g, 99 %).
δp 121.3 ppm (broad singlet).
General Procedure for Resin-Bound Alkyl
Methylphosphonates 7a–k
Intermediate 6 (1.98 g, 0.67 mmol/g) in a reactor column connected
to an Applied Biosystems 392 DNA/RNA synthesizer was subjected to
this sequence: addition of acetonitrile to column (300 s), flush to waste
(
(
30 s), block flush (30 s), reverse flush (30 s), addition of 1-H tetrazole
0.5M in acetonitrile) and isopropanol (1.5 cm ) in acetonitrile (6 cm )
3
3
to column (30 s delivery then 15 min), flush to waste (30 s), block flush
30 s), reverse flush (30 s), addition of acetonitrile to column (300 s),
(
flush to waste (30 s), block flush (30 s), reverse flush (30 s), addition of
t-BuOOH (1M solution in toluene) to column (30 s delivery with 5 min

2
286
H. Barucki et al.
waiting time), flush to waste (30 s), block flush (30 s), reverse flush (30
s), addition of acetonitrile to column (300 s), flush to waste (30 s), block
flush (30 s), reverse flush (900 s). The resin was dried under argon to
give 7d (1.98 g). δp 32.7 ppm (broad singlet). Other derivatives were
prepared similarly from different alcohols.
Preparation of Isopropyl Methylphosphonic Acid 8d
Intermediate 7d (1.98 g, 0.67 mmol/g) was suspended in dichloro-
3
methane (2 cm ) in a Wheaton vial and stirred for 30 min at room
3
temperature. Trifluoroacetic acid (0.2 cm ) was added and stirring con-
tinued for a further 3 h. The mixture was filtered and the resin washed
3
3
with dichloromethane (3 × 5 cm ) and acetonitrile (3 × 5 cm ). The fil-
trate was concentrated to yield 8d as a colorless liquid (δp 33.8 ppm).
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[
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at the Millennium: Fascinated by Fluorine (Elsevier, Oxford, UK, 2000), chap. 29,
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[
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