Phosphorylation of alcohols with N-phosphoryl oxazolidinones employing copper(II) triflate catalysis

Article abstract of DOI:10.1021/ol051104n

(Chemical Equation Presented) Phosphoryl transfer from N-phosphoryl 5,5-diphenyl oxazolidinone is efficiently catalyzed by copper(II) triflate. The utility of this method has been demonstrated in the phosphorylation of representative primary, secondary, tertiary, phenolic, and allylic alcohols. These reaction conditions are significantly milder than employing alkoxides and allow the phosphorylation of biologically relevant molecules.

Full text of DOI:10.1021/ol051104n

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3271-3274
Phosphorylation of Alcohols with
N-Phosphoryl Oxazolidinones Employing
Copper(II) Triflate Catalysis
Simon Jones* and Chaiwat Smanmoo
Department of Chemistry, UniVersity of Sheffield, Dainton Building, Brook Hill,
Sheffield S3 7HF, UK
simon.jones@sheffield.ac.uk
Received May 12, 2005
ABSTRACT
Phosphoryl transfer from N-phosphoryl 5,5-diphenyl oxazolidinone is efficiently catalyzed by copper(II) triflate. The utility of this method has
been demonstrated in the phosphorylation of representative primary, secondary, tertiary, phenolic, and allylic alcohols. These reaction conditions
are significantly milder than employing alkoxides and allow the phosphorylation of biologically relevant molecules.
Phosphate esters have been recognized in a variety of
biological molecules as diverse as nucleic acids, proteins,
carbohydrates, lipids, coenzymes, and steroids.1 Given the
ever blurring distinctions between molecular biology and
synthetic chemistry, development of new and efficient
methods for the installation of these functional groups is an
important goal in organic chemistry. The methods that
currently exist for the introduction of a phosphate group into
a substrate molecule largely depend on the substrate itself,
since functional group tolerance is the key to facilitating
efficient phosphorylation.2 For example, one of the most
widely used methods for preparing oligonucleotides is
through the use of a phosphoramidite reagent to form the
phosphite triester, followed by oxidation to the phosphate
triester.3 Here, care must be taken with the stability of the
phosphorus(III) intermediates and sensitivity of other func-
tional groups to the oxidation protocol. Methods also exist
employing phosphorus(V) reagents, usually by reaction of
the substrate with a chlorophosphate, either through the
formation of an alkoxide4 or by using proton scavengers such
as triethylamine.5 Although widely used, these reaction
conditions are not always compatible with the base-sensitive
functional groups present in the substrate and are sometimes
limited by the stability of the chlorophosphate.
We have previously reported alternative strategies to
achieve the phosphoryl transfer employing TiCl4 and titanium
esters as catalysts and a chlorophosphate as the phosphate
source.6 We have also shown that N-phosphoryl oxazolidi-
nones can be used as an effective phosphate source in the
(1) Corbridge, D. E. C. Phosphorus 2000. Chemistry, Biochemistry &
Technology; Elsevier: Oxford, 2000; Chapters 10 and 11.
(3) (a) Perich, J. W.; Johns, R. B. Tetrahedron Lett. 1987, 28, 101-
102. (b) Beaucage, S. L.; Iyer, R. P. Tetrahedron 1993, 49, 1925-1963.
(4) (a) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J. Am. Chem.
Soc. 1972, 94, 5098-5100. (b) Granata, A.; Perlin, A. S. Carbohydr. Res.
1981, 94, 165-171.
(5) Hwang, Y.; Cole, P. A. Org. Lett. 2004, 6, 1555-1556.
(6) (a) Jones, S.; Selitsianos, D. Org. Lett. 2002, 4, 3671-3673. (b) Jones,
S.; Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003, 68,
5211-5216.
(2) (a) Slotin, L. A. Synthesis 1977, 737-752. (b) Oza, V. B.; Corcoran,
R. C. J. Org. Chem. 1995, 60, 3680-3584. (c) Uchiyama, M.; Aso, Y.;
Noyori, Y.; Hayakawa, Y. J. Org. Chem. 1993, 58, 373-379. (d) Chouinard,
P. M.; Bartlett, P. A. J. Org. Chem. 1986, 51, 75-78. (e) Marugg, J. E.;
McLaughlin, L. W.; Piel, N.; Tromp, M.; van der Marel, G. A.; van Boom,
J. H. Tetrahedron Lett. 1983, 24, 3989-3992. (f) Khwaja, T. A.; Reese, C.
B.; Stewart, J. C. M. J. Chem. Soc. 1970, 2092-2100. (g) Evans, D. A.;
Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453.
10.1021/ol051104n CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

presence of lithium and magnesium alkoxides.7 These
reagents are attractive since they are easily prepared, have
long shelf lives, and are easy to handle. However, given the
need to generate highly basic alkoxides, reactions were
limited to substrates with base-tolerant functional groups that
could be selectively deprotonated by reactive organo-lithium
and magnesium reagents. In this work, we describe progress
in the development of milder reaction conditions to facilitate
this process by an amalgamation of the use of Lewis acid
catalysis and N-phosphoryl oxazolidinones.
Initially, we attempted phosphoryl transfer from 5,5-
diphenyl oxazolidinone to benzyl alcohol in the presence of
TiCl4 according to the procedure that we developed with
phosphoryl chlorides.6a However, no conversion of starting
material was observed. Thus, the catalytic activity of a
number of other Lewis acids was evaluated (Scheme 1, Table
the best catalyst being Cu(OTf)2. It is interesting to note that
with the exception of titanium esters, the three most active
catalysts in this study were identical to those previously
observed in the reaction of alcohols with chlorophosphates.6a
Having identified a suitable catalyst system, optimization
studies were then carried out using benzyl alcohol as the
test substrate (Scheme 1, Table 2).
Table 2. Optimization of Reaction Conditions for the
Cu(OTf)2-Catalyzed Reaction as Described in Scheme 1a
equiv of
Cu(OTf)2
and ligand
entry
ligand
base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
none
2,6-lutidine
DBU
DABCO
product (%)b
1
2
none
1
0.2
0.05
0.1
0.2
0.3
0.5
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
25
50
70
80
90
95
10
15
20
40
55
0
3
1
4
1
Scheme 1. Reagents Used for Initial Optimization
5
1
6
1
7
1
8
2
9
3
10
11
12
13
14
15
16
4
5
6
1
1
1
1
0
10
50
1). All reactions were carried out in the presence of 1 equiv
of Et3N and the oxazolidinone with 0.2 equiv of catalyst
under a nitrogen atmosphere at room temperature for 48 h.
a Reactions performed with 1 equiv of BnOH, 1 equiv of base, 1 equiv
of N-phosphoryl 5,5-diphenyl oxazolidinone, 0.2 of equiv Cu(OTf)2, and
ligand in CH2Cl2 under a nitrogen atmosphere at 20 °C for 48 h. b Calculated
from the ratio of the integrals corresponding to representative signals in
1
the H NMR spectrum.
Table 1. Screening of Catalytic Activity for Phosphoryl
Transfer as Described in Scheme 1a
Variation of the catalyst loading indicated a linear increase
in the amount of Cu(OTf)2 to the apparent reaction rate
(Scheme 1, Table 2, entries 1-7). For further work, 0.2 equiv
was chosen as the optimal catalyst loading, which provided
sufficient catalytic activity with the lowest acceptable load-
ing. In an attempt to enhance the catalytic activity further, a
catalyst M(OTf)n
product (%)b
none
0
50
34
60
10
30
20
70
Mg(OTf)2
Gd(OTf)3
Y(OTf)3
Sc(OTf)3
Eu(OTf)3
La(OTf)3
Cu(OTf)2
a Reactions performed with 1 equiv of BnOH, 1 equiv of Et3N, 1 equiv
of N-phosphoryl 5,5-diphenyl oxazolidinone, 0.2 of equiv M(OTf)n, and
0.2 equiv of BEN in CH2Cl2 under a nitrogen atmosphere at 20 °C for 48
h. b Calculated from the ratio of the integrals corresponding to representative
1
signals in the H NMR spectrum.
Seven Lewis acids [Cu(OTf)2, Sc(OTf)3, La(OTf)3, Eu(OTf)3,
Y(OTf)3, Gd(OTf)2 and Mg(OTf)2] were screened; however,
no product was obtained in any case. The reaction was then
repeated in the presence of 0.2 equiv of N,N′-ethylenebis-
(benzaldimine) (BEN) under otherwise identical conditions.
The results indicated the necessity of ligand-assisted catalysis,
Figure 1. Ligands used in optimization of reaction conditions
(Table 2).
number of different chelating ligands8 were also screened,
again using the same oxazolidinone and benzyl alcohol
(7) Jones, S.; Smanmoo, C. Tetrahedron Lett. 2004, 45, 1585-1588.
3272
Org. Lett., Vol. 7, No. 15, 2005

these additives, BEN 1 proved to be the optimal ligand. Use
of the correct base in these reactions was also crucial to their
success (entries 4 and 13-16). Triethylamine gave the
optimum result (entry 4), with other bases being inferior,
and no reaction occurring at all without added base (entry
13).
Table 3. Phosphorylation of Representative Alcohols as
Described in Scheme 2
These optimized reaction conditions were then applied to
the phosphorylation of a range of representative primary,
secondary, tertiary, and phenolic alcohols that had previously
been evaluated with the same diethyl and diphenyl N-
phosphoryl oxazolidinones using n-BuLi (Scheme 2, Table
Scheme 2. General Method for Phosphorylation
3).7 Pleasingly these followed the same trend in reactivity
that had been reported previously. Primary and secondary
alcohols (entries 1-6) led to good yields of the desired
phosphate products, and even tertiary alcohols (entries 7 and
8) gave moderate yields. However, phenolic substrates
(entries 9-11) once again gave moderate to low yields. In
each case, the isolated yields of the diethyl phosphates were
a Based on isolated product.
(Scheme 1, Table 2, entries 4 and 8-12). Although all led
to rate acceleration compared to reactions conducted without
Table 4. Comparison of the Phosphorylation of Biologically Relevant Molecules with Copper Triflate and n-BuLi Using
N-(5,5-Diphenyl oxazolidinyl) Diphenyl Phosphate
a Reactions perfomed by pretreatment of the alcohol with 1.0 equiv of n-BuLi in THF at -78 °C under a nitrogen atmosphere, followed by addition of
1 equiv of N-phosphoryl 5,5-diphenyl oxazolidinone and stirring for 12 h. b Reactions performed with 1 equiv of alcohol, 1 equiv of Et3N, 1 equiv of
N-phosphoryl 5,5-diphenyl oxazolidinone, 0.2 equiv of Cu(OTf)2, and 0.2 equiv of BEN in CH2Cl2 under a nitrogen atmosphere at 20 °C for 48 h.
Org. Lett., Vol. 7, No. 15, 2005
3273

less than those obtained using the n-BuLi protocol, while
the yields of diphenyl phosphates were higher.7 Thus, this
method for phosphoryl transfer is more applicable to the
synthesis of diphenyl phosphates than diethyl.
similarly gave the desired phosphate triester only when
treated with the Cu(OTf)2 catalyst (entry 4).
The reaction presumably proceeds through a coordinated
species analogous to reactions catalyzed by Cu(II) bound
bis-oxazoline complexes.9 The ligand-bound Cu(II) activates
the PdO bond, making it susceptible to nucleophilic attack
by the alcohol, and the oxazolidinone then acts as a leaving
group.
In summary, we have established a catalytic route for the
phosphorylation of a range of alcohols using N-phosphoryl
oxazolidinones that is comparable to that employing alkoxide
substrates. However, the strength of this new method lies in
its applicability to phosphorylation of sensitive substrates.
Having established reaction conditions that appeared
general for a wide range of substrates, a direct comparison
of the two procedures was made by considering substrates
that appeared to be sensitive to the harsh reaction conditions
of the alkoxide reaction. In all cases studied (Table 4), only
minor quantities of material were obtained using the n-BuLi
protocol. However, the Cu(OTf)2 reaction conditions repeat-
edly gave good yields of the desired phosphate triesters.
Geraniol gave the phosphate triester in exceptional yield
(entry 1), and more importantly, adenosine and guanosine
appeared to be phosphorylated with good chemo and
regioselectivity at the 5′ hydroxyl group (entries 2 and 3),
leading to phosphate diesters. These were formed by hy-
drolysis during purification on silica gel, eluting with a
methanol/water mixture. The sterol used in this study
Acknowledgment. We thank the Thai Government for a
Royal Thai Scholarship (C.S.) and the University of Sheffield
for support.
Supporting Information Available: Experimental details
1
and data and copies of H NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051104N
(8) All ligands were either purchased or prepared by literature methods.
See Supporting Information for more details.
(9) Johnson, J. S.; Evans. D. A. Acc. Chem. Res. 2000, 33, 325-335.
3274
Org. Lett., Vol. 7, No. 15, 2005