Triethylphosphate/phosphorus pentoxide as an efficient reagent for the phosphorylation of phenols

Article abstract of DOI:10.1080/10426507.2011.639822

A simple, efficient, and novel method has been developed for the phosphorylation of phenols. Treatment of phenols with a mixture of triethylphosphate/phosphorus pentoxide gives the corresponding phosphate derivatives in good yields. This method is easy, rapid, and offers good yields for the phosphorylation of phenols. The reaction of triethylphosphate with phosphorus pentoxide was also studied by variable-temperature ³¹P-NMR spectroscopy. Copyright

Full text of DOI:10.1080/10426507.2011.639822

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Phosphorus, Sulfur, and Silicon and the
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Triethylphosphate/Phosphorus Pentoxide
as an Efficient Reagent for the
Phosphorylation of Phenols
Babak Kaboudin a & Ramin Mostafalu a
a Department of Chemistry , Institute for Advanced Studies in Basic
Sciences , Gava Zang , Zanjan , Iran
Accepted author version posted online: 12 Jan 2012.Published
online: 05 Apr 2012.
To cite this article: Babak Kaboudin & Ramin Mostafalu (2012) Triethylphosphate/Phosphorus
Pentoxide as an Efficient Reagent for the Phosphorylation of Phenols, Phosphorus, Sulfur, and Silicon
and the Related Elements, 187:6, 776-780, DOI: 10.1080/10426507.2011.639822
To link to this article: http://dx.doi.org/10.1080/10426507.2011.639822
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Phosphorus, Sulfur, and Silicon, 187:776–780, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.639822
TRIETHYLPHOSPHATE/PHOSPHORUS PENTOXIDE AS
AN EFFICIENT REAGENT FOR THE PHOSPHORYLATION
OF PHENOLS
Babak Kaboudin and Ramin Mostafalu
Department of Chemistry, Institute for Advanced Studies in Basic Sciences,
Gava Zang, Zanjan, Iran
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and novel method has been developed for the phosphorylation
of phenols. Treatment of phenols with a mixture of triethylphosphate/phosphorus pentoxide
gives the corresponding phosphate derivatives in good yields. This method is easy, rapid, and
offers good yields for the phosphorylation of phenols. The reaction of triethylphosphate with
phosphorus pentoxide was also studied by variable-temperature 31P-NMR spectroscopy.
Keywords Phosphorylation; phenols; phosphorus pentoxide; triethylphosphate
INTRODUCTION
The organic chemistry of phosphorus compounds has became increasingly useful and
important in organic synthesis. Phosphate esters are valuable intermediates for the prepa-
ration of medicinal compounds and synthetic intermediates.1 The synthesis of phosphate
esters is an important objective in organic synthesis, because their wide use in the prepa-
ration of biologically active molecules as diverse as nucleic acids, proteins, carbohydrates,
lipids, coenzymes, and steroids as well as in the reduction of phenols to aromatic hydro-
carbons.2 Many effective methods have been developed for the preparation of phosphates.3
These methods involve: (1) the reaction of a dialkyl phosphite with phenol in the pres-
ence of triethylamine in carbon tetrachloride,4 (2) phosphorylation of phenols with diethyl
cyanophosphonate in the presence of triethylamine,5 (3) phosphorylation of phenols via the
activation of trialkyl phosphate with molecular iodine,6 and (4) the use of a phosphoramidite
Received 5 October 2011; accepted 6 November 2011.
The authors gratefully acknowledge support by the Institute for Advanced Studies in Basic Sciences (IASBS)
Research Council under Grant no. G2010IASBS120.
Address correspondence to Babak Kaboudin, Department of Chemistry, Institute for Advanced Studies in
Basic Sciences, Gava Zang, Zanjan 45137-66731, Iran. E-mail: kaboudin@iasbs.ac.ir
776

PHOSPHORYLATION OF PHENOLS
777
reagent to form the phosphate triester, followed by oxidation to the phosphate ester.7 How-
ever, these methods have problems, including the use of chlorinated solvents and strong
bases, low yields, and side-reactions. In addition, some of the starting materials have to be
synthesized, and cleavage of a Et-O-P bond of the phosphorylating agent occurred in the
phosphorylation of phenols using of diethyl chlorophosphate.8 Recently, phosphorylation
of alcohols and phenols with N-phosphoryl 5,5ꢁ-diphenyl oxazolidinones in the presence
of copper (II) triflate and N,N-ethylene bis(benzaldimine) as a ligand has been reported.9
We have previously reported alternative strategies to achieve the phosphoryl transfer
employing a chlorophosphate as the phosphate source in solvent-free condition in the
presence of magnesia and alumina.10 The development of simple and general synthetic
routes for widely used organic compounds from readily available reagents is one of the major
challenges in organic synthesis. As part of our efforts for the synthesis of organophosphorus
compounds,11 we now report a new and efficient method for the synthesis of phosphate
esters from the reaction of a mixture of triethyl phosphate and phosphorus pentoxide with
phenols producing good yields of phosphate esters.
RESULTS AND DISCUSSION
The phosphorylation of phenol (1a), chosen as a model compound, was studied in the
presence of triethyl phosphate (Scheme 1). The progress of the reaction was monitored by
(thin layer chromatography) TLC, and the experimental data for the screening conditions
are listed in Table 1. Treatment 1a with triethyl phosphate failed to give the corresponding
phosphate adduct 2a after 24 h at 50–120 ◦C (Entries 1–4). When the reaction was carried
out at 70 ◦C in the presence of a mixture of triethyl phosphate and phosphorus pentoxide
(4:1 w/w), compound 2a was obtained in 36% isolated yield after 24 h (Entry 5). The
phosphorylation of 1a with a mixture of triethyl phosphate and phosphorus pentoxide
proceeded smoothly at 120 ◦C for 24 h and gave 2a in 78% isolated yield (Entry 6).
Scheme 1
Under the above optimized conditions, phenols were employed in the phosphorylation
reactions (Scheme 1). The obtained results are summarized in Table 1. The phosphorylation
of different substituted phenols gave the corresponding adducts in 46–81% isolated yields
(Entries 7–14). The phosphorylation of benzyl alcohol also gave the corresponding adduct
in a lower yield (41%), which was possibly due to low acidity (Entry 15). It was also possible
to carry out this reaction for 1-naphthol and gave the corresponding phosphorylated adduct
in a lower yield (42%), which was possibly due to the steric effect (Entry 16). Thus, the
conditions reported herein tolerate a phosphorylation reaction of a wide variety of phenols.
We were interested to study the role of phosphorus pentoxide by the reaction of tri-
ethyl phosphate with phosphorus pentoxide by variable-temperature 31P-NMR spectroscopy
◦
(Scheme 2). The 31P-NMR spectrum of the mixture at 70 C shows two completely re-
solved peaks at δ −10.23 (triethyl phosphate) and −22.33 ppm in a ratio of 1:0.7 respectively

778
B. KABOUDIN AND R. MOSTAFALU
Scheme 2
(Figure 1a). The peak at −22.33 is due to the tetraethyl pyrophosphate (TEPP).12 The ratio of
the TEPP to triethyl phosphate increases with increasing temperature to 120 ◦C (Scheme 2
and Figure 1b).
We also examined the reaction of thiophenol in the presence of a mixture of triethyl
phosphate and phosphorus pentoxide. The reaction failed to give phosphorylated product
and no other product was detected after 48 h at 120 ◦C.
In summary, we have developed a simple and practical method for the phosphoryla-
tion alcohols. Phosphorylation of phenols using very inexpensive and air stable reagents,
can be synthesized in moderate to good yields. In addition, the other advantages of this
environmentally benign and safe protocol include a simple reaction setup, not requiring
specialized equipment, and gives moderate to good yields of products.
EXPERIMENTAL
All chemicals were commercial products and was distilled or recrystallized before
use. NMR spectra were taken with a 400 Brucker Avance instrument with the chemical shifts
being reported as δ ppm and couplings expressed in Hertz. The chemical shift data for each
signal in 1H NMR are given in units of δ relative to CHCl3 (δ = 7.26) for CDCl3 solution.
For 13C NMR spectra, the chemical shifts in CDCl3 and DMSO are recorded relative to the
CDCl3 resonance (δ = 77.0). The chemical shifts of 31P are recorded relative to external
1
85% H3PO4 (δ = 0) with broadband H decoupling. Silica gel column chromatography
Table 1 Phosphorylation of phenols with a mixture of phosphorus pentoxide in triethyl phosphate at 120 ◦C
Entry
R
Reaction temperature ( ◦C)
Time (h)
Yield%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
o-MeC6H4-
m-MeC6H4-
m-FC6H4-
m-ClC6H4-
m-BrC6H4-
m-NO2C6H4-
p-MeC6H4-
3,4-di-Me-C6H3-
PhCH2-
50a
70a
24
24
24
24
24
24
48
24
48
48
48
48
24
24
48
36
24
–
–
–
–
90a
120a
70
36
78
75
81
48
63
65
46
78
78
41
42
54
120
120
120
120
120
120
120
120
120
100
120
120
α-Naphthyl
β-Naphthyl
aReaction carried out without addition of phosphorus pentoxide.

PHOSPHORYLATION OF PHENOLS
779
Figure 1 31P-NMR spectrum of the reaction of triethyl phosphate with phosphorus pentoxide (a) 70 ◦C and
(b) 120 ◦C.
was carried out with Silica gel 100 (Merck no. 10184). Merck Silica-gel 60 F254 plates
(no. 5744) were used for the preparative TLC.
General Procedure for the Phosphorylation of Phenols (2)
The phenol (5 mmol) was added to a mixture of triethyl phosphate (4 g) and phospho-
rus pentoxide (1 g) at 120 ◦C. The reaction mixture was stirred for the time reported in Table
1. The reaction mixture was poured into water, extracted with diethyl ether (3 × 25 mL),
washed with brine (2 × 25 mL), and evaporated. The crude product was purified by simple
filtration chromatography through a short plug of silica gel, eluting with EtOAc/n-hexane
(2:8), and evaporation of the solvent under reduced pressure gave pure products in 41–81%
yields. All products gave satisfactory spectral data in accord with the assigned structures
and literature reports.5–7,10
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2. Nifantiev, E. E.; Grachev, M. K.; Burmistruv, S. Y. Chem Rev. 2000, 100, 3755-3799.

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