Facile synthesis of simple mono-alkyl phosphates from phosphoric acid and alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.06.083

Simple aliphatic alcohols can be selectively converted into mono-alkyl phosphate esters at the laboratory scale using the acetic anhydride-mediated activation of inorganic phosphate.

Full text of DOI:10.1016/j.tetlet.2008.06.083

Tetrahedron Letters 49 (2008) 5300–5301
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of simple mono-alkyl phosphates from phosphoric
acid and alcohols
*
Cyril Dueymes, Céline Pirat, Robert Pascal
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS—Université Montpellier 1 et Université Montpellier 2 CC 1706, Université Montpellier 2,
Place E. Bataillon, 34095 Montpellier cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple aliphatic alcohols can be selectively converted into mono-alkyl phosphate esters at the laboratory
scale using the acetic anhydride-mediated activation of inorganic phosphate.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 9 June 2008
Revised 17 June 2008
Accepted 18 June 2008
Available online 22 June 2008
Keywords:
Phosphorylation
Mono-alkyl phosphate
Acetic anhydride
Phosphate monoesters constitute simple models of membrane
constituents or biological intermediates involved in many cell sig-
naling and regulation pathways. For chemical purposes, phosphate
or phosphoric acid can be introduced in the synthesis of phospho-
diesters or other related species as a monoprotected phosphoric
acid. Unfortunately, most monosubstituted phosphate esters de-
rived from simple alcohols are not commercially available, which
is probably in relation with their instability linked to a specific
mechanism of degradation. Indeed, they can undergo a dissociative
breakdown in acidic or neutral media through a resonance stabi-
lized transition state related to metaphosphate ion.1 There is a
need for laboratory-scale syntheses of simple alkyl phosphate es-
ters or phosphate derivatives carrying selectively removable
groups. Together with well established procedures,2–5 the ongoing
publication of new reports6,7 on this subject illustrates the need for
laboratory scale methods for their preparation. Methods starting
from phosphorus oxychloride, generally in the presence of pyri-
dine, followed by hydrolysis suffer from a lack of selectivity, yield-
ing mixtures of mono-, di-, and even tri-substituted derivatives.5
The difficulty in their synthesis is to selectively stop the reaction
at the stage of the monosubstituted derivative. A possibility is to
start from activated phosphodiesters8 and then to remove protect-
ing groups. Alternatively, methods involving activated phosphates
are likely to selectively induce monophosphorylation of alcohols
through dissociative mechanisms resulting in the transfer of the
equivalent of a metaphosphate ion ðPOꢀ3 Þ, whatever this species
could be a reaction intermediate or not.1 Polymetaphosphate has
been used in this way,2 but other methods involving monomeric
metaphosphate9 or the trichloroacetonitrile-promoted activation3
of phoshoric acid have also been proposed. Alternatively, the for-
mation of phosphate esters by azeotropic dehydration in the pres-
7
ence of catalyst has been performed.
Here, we report on a
practical and efficient protocol for the conversion of simple alco-
hols into the corresponding monophosphate esters using acetic
anhydride activation of inorganic phosphate.
This method of activation (see Scheme 1) involves the forma-
tion of acetyl phosphate a high energy biochemical intermediate
capable of phosphorylating alcohols or other nucleophiles.10
A
one-pot procedure was carried out without inconvenient, starting
from less acidic aliphatic alcohols (Table 1). But alcohols with a
more pronounced acidic character were shown to lead to lower
yields probably due to the inactivation of acetic anhydride through
ester formation.
In those cases, the fact of performing the formation of acetyl
phosphate mixed anhydride in an independent step in a non-react-
ing solvent (acetonitrile) before the introduction of the alcohol of
O
1) pyridine, NEt3
H3PO4 + Ac2O
Ac O P O
O
O
R O P O
O
2) ROH
* Corresponding author. Tel.: +33 467 14 4229; fax: +33 467 63 1046.
E-mail address: robert.pascal@univ-montp2.fr (R. Pascal).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.083

C. Dueymes et al. / Tetrahedron Letters 49 (2008) 5300–5301
5301
Table 1
amine or tetra-alkylammonium salt. This can be made readily on
a cation exchange resin column (H+ form) even in the case of
acid-sensitive t-Bu-phosphate.12
Synthesis of phosphate monoestersa
Entry
R
Yieldb (%)
In conclusion, a series of phosphate esters, including protecting
groups removable through a variety of procedures, has been pre-
pared through a simple procedure in convenient yields.
1
2
3
4
5
6
7
8
9
Methyl
Ethyl
t-Butyl
Dodecyl
Benzyl
2-Hydroxyethyl
Allyl
2-Cyanoethyl
2,2,2-Trichloroethyl
51
56
63
56c
38
56
72
56
38d
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.083.
a
Prepared via method (a) unless otherwise mentioned (see Ref. 11 for experi-
mental procedure).
References and notes
b
As recrystallized cyclohexylamine salts.
c
Method (b).
Method (c).
1. Williams, N. H. Biochim. Biophys. Acta 2004, 1697, 279–287.
d
2. (a) Cherbuliez, E.; Rabinowitz, J. Helv. Chim. Acta 1956, 39, 1455–1461; (b)
Cherbuliez, E.; Rabinowitz, J. Helv. Chim. Acta 1956, 39, 1461–1467; (c)
Cherbuliez, E.; Rabinowitz, J. Helv. Chim. Acta 1958, 41, 1168–1175.
3. Cramer, F.; Rittersdorf, W.; Bohm, W. Liebigs Ann. Chem. 1962, 654, 180–188.
4. Khwaja, T. A.; Reese, C. B.; Stewart, J. C. M. J. Chem. Soc. (C) 1970, 2092–2100.
5. Slotin, L. A. Synthesis 1976, 737–752.
6. Weber, P.; Fonvielle, M.; Therisod, M. Tetrahedron Lett. 2003, 44, 9047–9049.
7. (a) Sakakura, A.; Katsukawa, M.; Ishihara, K. Org. Lett. 2005, 7, 1999–2002; (b)
Sakakura, A.; Katsukawa, M.; Ishihara, K. Angew. Chem., Int. Ed. 2007, 46, 1423–
1426; (c) Sakakura, A.; Katsukawa, M.; Hayashi, T.; Ishihara, K. Green Chem.
2007, 9, 1166–1169.
8. Jones, S.; Smanmoo, C. Tetrahedron Lett. 2004, 45, 1585–1588.
9. (a) Ramirez, F.; Marecek, J. F.; Yemul, S. S. J. Org. Chem. 1983, 48, 1417–1420; (b)
Iwamoto, N.; Okamoto, Y.; Takamuku, S. Bull. Chem. Soc. Jpn. 1986, 59, 1505–
1508.
10. (a) Lipmann, F. Adv. Enzymol. Relat. Areas Mol. Biol. 1946, 6, 231–267; (b) Di
Sabato, G.; Jencks, W. P. J. Am. Chem. Soc. 1961, 83, 4393–4400; (c) Herschlag,
D.; Jencks, W. P. J. Am. Chem. Soc. 1986, 108, 7938–7946.
11. Typical experimental procedure: Method (a). To a stirred mixture of crystalline
phosphoric acid (1.0 g, 10.2 mmol) and pyridine (4.15 mL, 51 mmol), the
alcohol (102 mmol) and then triethylamine (2.8 mL, 20.4 mmol) were added
via a dropping funnel. After complete dissolution, acetic anhydride (1.93 mL,
20.4 mmol) was added dropwise. The reaction mixture was stirred for 2 h at
90 °C, and then cooled to room temperature. After addition of water (5 mL), the
reaction mixture was stirred at 90 °C for 1 h and cooled to room temperature.
The solution was diluted with water (12 mL). The aqueous phase was washed
three times with diethyl ether (25 mL) and concentrated. The oily liquid was
dissolved in acetone/water (9:1). Then cyclohexylamine (2.1 mL, 30.6 mmol)
was added. The mixture was cooled at 4 °C and allowed to crystallize for 12 h,
and the white solid formed was collected by filtration and dried. The solid was
heated in ethanol, the insoluble residue was filtered off, and the filtrate was
cooled for 12 h at 4 °C. The white solid was filtered, washed with ethanol, and
dried under vacuum. Method (b) as method (a) except that the workup was
modified as follows. The phosphate ester was extracted from the aqueous
phase as a triethylamine salt with CH2Cl2; the organic layer was concentrated
and precipitated as previously. Method (c). The reaction was carried by
performing the activation of phosphate in an independent stage: a mixture of
crystalline phosphoric acid, pyridine, and triethylamine was stirred until
complete dissolution in acetonitrile (10 mL). Acetic anhydride was added
dropwise to the solution. Then the alcohol was added and the reaction mixture
was stirred at 90 °C for 12 h. The workup was then carried out as mentioned in
method (a).
interest was shown to improve the overall yield. Another side-
reaction identified in the course of this study consisted in pyro-
phosphate formation,10b,c which is inevitable even in the presence
of large excess of the alcohol, but phosphodiester formation was
not observed in our experiments. Though they must be much lesser
nucleophiles than phosphate dianion, aliphatic alcohols compete
favorably when using them in high excess, which can be accounted
for by the dissociative character of the phosphoryl transfer reac-
tion. As a result, the influence of the nucleophilic power of the
attacking group is moderate since bond formation is limited at
the ꢀtransition state, which is resembling metaphosphate ion
ðPO3 Þ.1
O
AcO
P
Nu
O O
In most cases, the monoester can be separated from unreacted
phosphate, pyrophosphate, and other side-products by crystalliza-
tion as a divalent cyclohexylamine salt. The stability of the base-la-
bile 2-cyanoethyl ester to this purification method is noteworthy,
and was attributed to the electrostatic effect of phosphate dianion
likely to destabilize a negatively charged transition state. In subse-
quent synthetic transformations, the monophosphate esters pre-
pared in this way can be reacted to give phosphodiesters or
mixed anhydrides,12 for instance by activation with dicyclohexyl-
carbodiimide. But any coupling step requires the conversion of
the cyclohexylamine salt into the salt of a non-reactive tertiary
12. Biron, J. P.; Pascal, R. J. Am. Chem. Soc. 2004, 126, 9198–9199.