Dealkylation of phosphonate esters with chlorotrimethylsilane

Article abstract of DOI:10.1081/NCN-100002541

Chlorotrimethylsilane completely dealkylates phosphonate esters at elevated temperature in a sealed reaction vessel. These conditions are tolerated by a variety of functional groups and lead to high conversions of dimethyl, diethyl and diisopropyl phosphonates to their corresponding phosphonic acids.

Full text of DOI:10.1081/NCN-100002541

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DEALKYLATION OF PHOSPHONATE ESTERS WITH
CHLOROTRIMETHYLSILANE
A. J. Gutierrez a , E. J. Prisbe a & J. C. Rohloff a
a Department of Chemical Development, Gilead Sciences, Inc., 333 Lakeside Dr., Foster
City, California, 94404, U.S.A.
Version of record first published: 07 Feb 2007.
To cite this article: A. J. Gutierrez , E. J. Prisbe & J. C. Rohloff (2001): DEALKYLATION OF PHOSPHONATE ESTERS WITH
CHLOROTRIMETHYLSILANE, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1299-1302
To link to this article: http://dx.doi.org/10.1081/NCN-100002541
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1299–1302 (2001)
DEALKYLATION OF PHOSPHONATE ESTERS
WITH CHLOROTRIMETHYLSILANE
A. J. Gutierrez,∗ E. J. Prisbe, and J. C. Rohloff
Department of Chemical Development, Gilead Sciences, Inc.,
333 Lakeside Dr., Foster City, California 94404
ABSTRACT
Chlorotrimethylsilane completely dealkylates phosphonate esters at elevated
temperature in a sealed reaction vessel. These conditions are tolerated by a
variety of functional groups and lead to high conversions of dimethyl, diethyl
and diisopropyl phosphonates to their corresponding phosphonic acids.
Phosphonic acids are generated from their dialkyl esters by reaction with
conc. HCl or HBr, however the conditions are too harsh for many functional groups
(1,2). Bromotrimethylsilane (TMSBr) selectively cleaves PO dialkyl esters yield-
ing bis(trimethylsilyl) esters which are easily hydrolyzed with water under neutral
conditions (3). In contrast, chlorotrimethylsilane (TMSCl) has been used mainly
for deprotection of the more labile dimethyl phosphonates (4). For diethyl phospho-
nates, the low reactivity of TMSCl results in long reaction times and unsatisfactory
yields (5). The rate of diester cleavage is accelerated by addition of sodium or
lithium iodide (6). Here we report a procedure using TMSCl to completely dealky-
late diethyl and diisopropyl phosphonates in high yield. The procedure is amenable
to laboratory and industrial scale preparations.
To assess the ability of TMSCl to cleave dialkyl phosphonates, 1.0 M so-
lutions of 1 in chlorobenzene were mixed with TMSCl in sealed glass pressure
tubes and heated at temperatures ranging from 130–140◦C (Fig. 1). As substi-
tution to 2 progressed, modest increases in the internal pressure of the reaction
vessels were observed due to the formation of volatile alkyl chloride. The pressure
∗ Corresponding author.
1299
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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GUTIERREZ, PRISBE, AND ROHLOFF
Figure 1. Cleavage of phosphonate diesters to phosphonic acids using TMSCl.
reached a maximum at reaction completion, then returned to atmospheric pressure
on cooling back to room temperature. The conversions to phosphonic acids 3 were
monitored by evaporating an aliquot of the reaction mixture, adding D2O and ob-
1
serving the resulting formation of phosphonic acids 3 by H and 31P NMR (3)
(Table 1).
Dialkyl phosphonates (1a–g) containing several functional groups were evalu-
ated for ease of diester cleavage and compatibilty to the reaction conditions. Heating
1a–g with TMSCl in chlorobenzene at 130–140◦C, followed by hydrolysis, lead
to complete conversions to phosphonic acids 3a–g (Table 1). In most cases these
deprotections went to completion in 8 to 12 hours. The high percent conversions
to 3a–g show that a variety of functional groups including carboxylic esters, ethers
and alkenes are compatible with these conditions. Among the compounds eval-
uated, the more labile dimethyl phosphonate 1a was the most easily deprotected
by TMSCl in chlorobenzene. However, diethyl phosphonates 1b, 1d–g were also
completely cleaved after slightly longer heating times and even the more hindered
isopropyl ester groups of 1c were removed if a greater excess of TMSCl was used.
These rates of cleavage are consistent with their rates of cleavage by TMSBr (3).
The heating time required for diester cleavage of diethyl phosphonates 1e and 1f
with TMSCl in chlorobenzene was 10 h. By comparison, heating 1e and 1f with
TMSCl, in the absence of solvent, afforded their phosphonic acids 3e and 3f after 4
Table 1. Cleavage of Dialkyl Phosphonates 1a with Chlorotrimethylsilane in Chlorobenzene
Phosphonate
1
TMSCl
(equiv.)
Temp.
(◦C)
Time
(h)
% Conv.b
R
Rꢁ
CH3
C2H5
(CH3)2CH
C2H5
C2H5
C2H5
C2H5
3
1a
1b
1c
1d
1e
1f
CH3OOCCH2
C2H5OOCCH2
C2H5OOCCH2
C6H5OCCH2
C6H5CH2
3
4
6
4
4
4
4
130
140
140
140
140
140
140
8
18
36
12
10
10
8
98
98
98
98
99
CH2=CH
98
>99
c
1g
CH3OCH2CH2OCH2
aFor descriptions of R and Rꢁ, see Figure 1.
bPercent conversions of 1 to 3 were estimated by measuring their 1H and 31P NMR absorbances in
D2O.
cFor preparation of this phosphonate see [7].

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DEALKYLATION OF PHOSPHONATE ESTERS
1301
Figure 2. Preparation of PMEA and PMPA from their diethylesters using TMSCl.
and 5 days respectively (4). The deprotections with TMSCl also work well in DMF,
acetonitrile, and dichloroethane. However the latter two solvents produce higher
reaction vessel pressures.
The deprotection of dialkyl phosphonates using TMSCl is potentially very
useful in the large scale synthesis of phosphonic acid derivatives as a replacement
for TMSBr which is considerably more expensive and more difficult to handle.
For instance, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) 6 and (R)-9-[2-
(phosphonomethoxy)propyl]adenine (PMPA) 7 continue to attract widespread at-
tention as broad spectrum antivirals including potent and selective activity against
human immunodefficiency virus (8).
One reported synthesis of 6 and 7 utilizes TMSBr for cleavage to the phospho-
nic acids from the diethyl esters 4 and 5 (9). By comparison, the same deprotections
were performed with TMSCl (10,11). (Fig. 2) affording 6 and 7 in equivalent yields
and purities as those obtained with TMSBr. The process is amenable to large scale
synthesis. Equivalent results were obtained for preparing 6 and 7 when the process
was scaled to 5 kg in a 30 gal glass-lined Pfaudler reactor. The ease in which 4 and
5 are deprotected with TMSCl in chlorobenzene is in striking contrast to depro-
tection by heating with TMSCl in the absence of solvent, which is not effective in
deprotecting adenosine diethyl phosphonates (12).
In summary, TMSCl in chlorobenzene readily cleaves dialkyl phosphonates in
high yield in the presence of a wide variety of functional groups. These conditions
also efficiently cleave the ethyl ester groups of adenine containing diethylphos-
phonates. TMSCl should be a useful and economical reagent for laboratory and
industrial scale preparation of phosphonic acid derivatives.
REFERENCES
1. Kosolopoff, G. M. in “Organophosphorus Compounds”, John Wiley and Sons, Inc.,
New York, 1950.
2. For the deprotection of diethyl PMPA 5 with conc. HCl, we observe 10–16% acid
catalyzed deamination of adenine to hypoxanthine. Data not shown.

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GUTIERREZ, PRISBE, AND ROHLOFF
3. a) McKenna, C. E.; Schmidhauser, J. J. C. S. Chem. Commun. 1979, 739. b) McKenna,
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33, 1207–1213. d) Bronson, J. J.; Kim, C. U.; Ghazzouli, I.; Hitchcock, M. J. M.;
Kern, E.; Martin, J. C. Nucleosides and Antiviral Agents; Martin, J. C., Ed.; American
Chemical Society, Washington, DC, 1989, 72–87. e) Starret, J. E. Jr.; Tortolani, D. R.;
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10. General procedure for cleavage of dialkyl phosphonates – preparation of 6: Diethyl
PMEA 4 (9) (41.1 g, 0.125 mol) and chlorobenzene (0.125 L) were charged to a 1 L
ACETM glass pressure reactor containing a thermowell and a pressure gauge. The
contents were stirred while TMSCl (56 mL, 0.44 mol) was added slowly. The reaction
vessel was purged with N2, sealed, and heated to 125◦C. The internal reactor pressure
increased incrementally to a maximum of 30 psi after 9 h. The contents were cooled
to r.t. at which time the pressure returned to ambient pressure and water (160 mL) was
added with vigorous stirring. The layers were separated and the lower aqueous layer
containing the product was collected. The aqueous layer was adjusted to pH = 3.2
with 25% NaOH (∼36 g), the resulting slurry cooled to 0◦C and the solid collected by
vacuum filtration. Water (40 mL) was added to the wet cake, the resulting slurry was
heated to 70◦C for 1 h, and then cooled to 0◦C. The solid product was collected by vac-
uum filtration and dried under vacuum (50◦C/28 mmHg) affording 33.0 g (0.120 mol,
96%) PMEA 6. NMR data for PMEA 6 was consistent with literature values. Holy,
A.; Rosenberg, I. Collect. Czech. Chem. Commun. 1987, 52, 2801–2809.
11. In the same manner as above 48.3 g (0.140 mol) diethyl PMPA 5 (9) were depro-
tected with 4.5 equiv. TMSCl and yielded 30.3 g (0.105 mol, 75%) of PMPA 7 (99%
pure by quantitative HPLC assay versus an external standard). 1H NMR (300 MHz,
D2O, δ): 8.31 (s, 2H, Adenine–2H, –8H), 4.39 (dd, J = 14, 3 Hz, 1H, –CH2N), 4.20
(dd, J = 14, 7 Hz, 1H, –CH2N), 3.89 (m, 1H, –CH–), 3.58 (dd, J = 13, 9 Hz, 1H,
–OCH2P), 3.38 (dd, J = 13, 9 Hz, 1H, –OCH2P), 1.07 (d, J = 6 Hz, 3H, –CH3) 31
NMR (121 MHz, D2O, δ): 15.79.
P
12. Hampton, A.; Sasaki, T.; Paul, B. J. Am. Chem. Soc. 1973, 95, 4404–4414.

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