Transesterification of trialkyl phosphates from alkyl bromides

Article abstract of DOI:10.1016/j.tetlet.2005.03.065

The treatment of trialkyl phosphate with different alkyl bromides provides facile access to mixed phosphate esters. The presence of substoichiometric amounts of lithium bromide was found to be critical to this transesterification process, supporting a mechanism involving initial generation of phosphate anion, followed by its nucleophilic attack on alkyl bromide.

Full text of DOI:10.1016/j.tetlet.2005.03.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3565–3567
Transesterification of trialkyl phosphates from alkyl bromides
Christian Lherbet, Roselyne Castonguay and Jeffrey W. Keillor*
´ ´ ´ ´
Department of Chemistry, Universite de Montreal, C.P. 6128, Succ. Centre-ville, Montreal, Quebec, Canada H3C 3J7
Received 8 December 2004; revised 10 March 2005; accepted 11 March 2005
Available online 5 April 2005
Abstract—The treatment of trialkyl phosphate with different alkyl bromides provides facile access to mixed phosphate esters. The
presence of substoichiometric amounts of lithium bromide was found to be critical to this transesterification process, supporting a
mechanism involving initial generation of phosphate anion, followed by its nucleophilic attack on alkyl bromide.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Over the course of our synthesis of phosphonates and
phosphonamidates as potential enzyme inhibitors, we
observed from time to time the formation of small
amounts of dimethyl phosphate triesters in Arbusov
reactions involving the condensation of trimethyl phos-
phite with various alkyl bromide amino acid deriva-
tives.10 Intrigued by this side reaction, we investigated
further, presuming that the phosphorylating agent was
in fact trimethyl phosphate, present as an oxidative
impurity in the trimethyl phosphite. A rapid search of
the literature provided little precedence for the putative
transesterification reaction. The formation of mixed es-
ters upon the condensation of phosphate triesters has
been reported using harsh reaction conditions11 or with
highly activated alkylating agents,12 and the transesteri-
fication of dimethyl phosphonate esters using alkyl chlo-
rides is also known.13 Using these analogous results and
our serendipitous observations as a starting point, we
have established mild reaction conditions that permit
the rapid preparation of a variety of mixed phosphate
triesters and have briefly studied the mechanism of this
transformation.
The phosphate diester functional group forms the cova-
lent link between nucleotides in the structure of nucleic
acids, and many other biologically important molecules
can be enzymatically phosphorylated to form phosphate
monoesters in the course of the regulation of their phys-
iological roles.1 However, the bioactivity of biomimetic
phosphate mono- and diesters can be limited by their
cell permeability, owing to the negative charge carried
by their ionized non-alkylated oxygens. In phosphate
triesters this negative charge can be masked by enzymati-
cally labile alkyl groups, representing one recent strategy
that has been employed with success to increase cell
permeability of such biomimetic compounds.2
Trialkyl phosphate esters can thus serve as useful final
biomimetic targets or synthetic intermediates, and many
methods exist for their synthesis.3 Generally, alcohols
can be phosphorylated by reaction with P(III) species,4
followed by oxidation, or directly by reaction with acti-
vated P(V) species.5,6 However, these methods require
phosphorylating agents that are typically unstable,
are rarely commercially available and usually require
synthesis over several steps to prepare.7,8 The use of
phosphate diester anions as nucleophiles for the prepa-
ration of benzyl and allyl esters has also been reported,9
but these methods have not been broadly applied to the
general preparation of phosphate triesters through
transesterification.
Shown in Table 1 are the results from our exploration of
the use of bromides as mildly activated alkyl donors for
the transesterification of phosphate triesters, present in
large excess as reaction solvents, analogous to condi-
tions for the Arbusov reaction. In general, the unopt-
imized yields reported in Table 1 are good, and
demonstrate the broad utility of the transformation.
Some protected aminoalkyl bromide derivatives were
also studied in the interest of ultimately applying this
method to the synthesis of amino acid analogues.14 To
this end, a phosphate ester of homoserine was obtained
in good yield from the corresponding bromide that was
Keywords: Phosphate triester; Transesterification; Bromide.
*
Corresponding author. Tel.: +1 514 343 6219; fax: +1 514 343
7586; e-mail: jw.keillor@umontreal.ca
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.065

3566
C. Lherbet et al. / Tetrahedron Letters 46 (2005) 3565–3567
Table 1. Conversion of alkyl bromides to phosphates
Entry
Substrate (R–)
R1
Time (h)
Yield 1, %a
Yield 2, %a
1
2
3
PhtNCH2–
PhtNCH2–
PhtNCH2CH2–
Me
Et
12
15
16
76
85
24c
21
n/ob
n/o
Me
4
Me
15
n/o
n/o
5
6
PhC(O)CH2–
PhCO2CH2CH2–
Me
Me
11
16
60
89
40
10
7
Me
14
76
57
n/o
8
9
PhCH2–
Me
Me
16
14
n/o
ꢀ70% conversion
9:2 mixture of 1:2
a Unoptimized yields of isolated, purified product.
b n/o: product not observed.
c 43% with 1 equiv LiBr.
prepared according to a previously published proce-
dure.15 Furthermore, it is clear that while more electro-
philic activated alkyl bromides such as benzoylmethyl
bromide (entry 5) leads to a slightly increased propor-
tion of disubstituted phosphate triester (2), the mono-
substituted product (1) is always the major product.
This tendency is corroborated by the previously re-
ported exhaustive substitution observed with highly acti-
vated pivaloylmethyl chloride,7,13 and indicates that the
degree of transesterification may be attenuated by con-
trolling the electrophilicity of the alkylating agent.
anion as a reactive intermediate. Nucleophilic attack
by this intermediate on alkyl bromide would then lead
to rapid formation of the monosubstituted transesterifi-
cation product and regeneration of an equivalent of
bromide (Scheme 1).
In summary, the reaction of a variety of different alkyl
bromides with methyl and ethyl phosphate triesters
has been shown to provide the corresponding monosub-
stituted transesterification products in good yields. The
proposed mechanism is consistent with the mechanism
determined for similar reactions known in the liter-
ature.13,16,17 This simple reaction should provide easy
access to a broad range of mixed phosphate esters from
readily available and inexpensive starting materials.
The addition of LiBr, even at substoichiometric quanti-
ties, was found to be critical to conversion, demonstrat-
ing its importance in the operative mechanism of
transesterification of trimethyl or triethyl phosphates.
Adding 1.0equiv of LiBr, as opposed to 0.1 equiv in
the typical protocol, resulted in a marked increase in
the rate of conversion of 2-phthalimidoethyl bromide
(entry 3c), denoting its implication in the rate-limiting
step of the overall transformation.
Halide ions, from fluoride to iodide, have been shown
previously to be capable of generating phosphate anion
from methyl and ethyl phosphate esters. For example,
iodide is known to generate phosphate in the iodide-
mediated transesterification of trimethyl phosphate.13
Fluoride has also been shown to play this role in the
transesterification of electrophilic trichloroethyl phos-
phate esters.16,17 In consideration of this precedent,
our current results are consistent with the initial attack
of added bromide on the methyl or ethyl group of the
phosphate triester, displacing the phosphate diester
Scheme 1. Proposed mechanism for transesterification with alkyl
bromides studied herein.

C. Lherbet et al. / Tetrahedron Letters 46 (2005) 3565–3567
3567
2. Experimental
References and notes
1. The Enzymes; Boyer, P. D., Krebs, E. G., Eds.; Academic:
New York, 1986; Vol. 17A.
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2000, 20, 417–451.
2.1. Typical procedure for phosphate transesterification
from alkyl bromide
Trialkyl phosphate (10equiv) was added to a mixture of
alkyl bromide (1 equiv) and lithium bromide (0.1 equiv).
The solution was stirred at 110 °C for 30min up to
overnight, depending on the substrate.14 The mixture
was then cooled to room temperature and EtOAc
(5 mL) was added. The organic layer was washed four
times with 15 mL H2O, to remove traces of the residual
trialkyl phosphate, and then with 10mL brine. The
organic layer was then dried over MgSO4, filtered and
concentrated under reduced pressure to obtain an oil
that was purified by flash chromatography (100%
EtOAc) to give the desired product.
3. Oza, V. B.; Corcoran, R. C. J. Org. Chem. 1995, 60, 3680–
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Synthesis 1993, 968–972.
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dron Lett. 1997, 38, 1859–1862.
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14. Although most of the reactions represented in Table 1
were run overnight, when phthalimidomethyl bromide
(entry 1) was allowed to react for 30min, the conversion
and yields were essentially identical as those obtained
overnight. It is noteworthy that the optimal reaction time
may be much shorter for some substrates, which would
be advantageous if sensitive functional groups were
present.
Montreal, QC, 2004.
Acknowledgements
This work was supported by the Natural Sciences and
Engineering Research Council (NSERC) of Canada.
The authors also acknowledge financial support in the
form of scholarships from NSERC (R.C.) and the
´ ´
Universite de Montreal (C.L.).
Supplementary data
Spectral characterization data (1H, 13C, 31P NMR and
HRMS) of all products. These supplementary data are
available online with the paper in ScienceDirect and
can be found, in the online version at doi:10.1016/
j.tetlet.2005.03.065.
15. Logusch, E. W. Tetrahedron Lett. 1986, 27, 5935–5938.
16. McGuigan, C.; Jones, B. C. N. M.; Riley, P. A. Bioorg.
Med. Chem. Lett. 1991, 1, 607–610.
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D. W. J. Am. Chem. Soc. 1977, 99, 1277–1278.