N-Phosphoryl oxazolidinones as effective phosphorylating agents

Article abstract of DOI:10.1016/j.tetlet.2004.01.003

A number of N-phosphoryl oxazolidinones have been prepared and evaluated, the best being 5,5-diphenyl oxazolidinones, the utility of which was demonstrated in the phosphorylation of a number of representative primary, secondary, tertiary, and phenolic alcohols.

Full text of DOI:10.1016/j.tetlet.2004.01.003

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1585–1588
N-Phosphoryl oxazolidinones as effective phosphorylating agents
Simon Jones* and Chaiwat Smanmoo
Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, UK
Received 20 November 2003; revised 15 December 2003; accepted 5 January 2004
Abstract—A number of N-phosphoryl oxazolidinones have been prepared and evaluated, the best being 5,5-diphenyl oxazolid-
inones, the utility of which was demonstrated in the phosphorylation of a number of representative primary, secondary, tertiary, and
phenolic alcohols.
Ó 2004 Elsevier Ltd. All rights reserved.
The physical properties and chemical reactivity of
phosphate esters interlinks many areas in biology and
chemistry. Introduction of a phosphate monoester into a
molecule such as a drug candidate enhances the water
solubility, hence altering its bioavailability. There are
many methods for the introduction of phosphate esters,
including direct coupling to phosphate salts,1 formation
of phosphite esters through reaction with a phosphor-
amidite followed by oxidation2 and by reaction with a
chlorophosphate.3 The latter route offers considerable
advantages, since a suitably protected, organic soluble,
phosphate triester is formed. Many methods have been
developed to achieve this transformation in an effective
manner, including reaction with alkoxides,4 use of
nucleophilic catalysis,5 and employing Lewis acid
catalysis.6;7 However all of these methods rely upon the
commercial availability and stability of chlorophos-
phates. Additionally the susceptibility of some activated
phosphate triester products to subsequent displacement
by the nucleophilic chloride counter-ion often leads to
problems in the use of these reagents in synthesis. In
order to circumvent these issues, we sought to develop
phosphoryl chloride equivalents that functioned just as
effectively but had improved stability and contained a
non-nucleophilic counter-ion. Herein we describe the
synthesis and evaluation of N-phosphoryl oxazolid-
inones as alternatives to phosphoryl chlorides.
best yield of phosphorylated alcohol, in addition to
being the most easiest and cost effective to prepare. Both
diethyl and diphenyl phosphoryl chlorides were used
throughout. Unsubstituted oxazolidinones 1a,b were
prepared using commercially available 2-oxazolidinone
(Scheme 1).
5,5-Dimethyl and 5,5-diphenyl oxazolidinones were
prepared using chemistry developed by Bull et al.8
Treatment of Boc–glycine methyl ester 2 with 4 equiv of
the respective Grignard reagent gave the tertiary alco-
hols 3a,b in good yield (Scheme 2). Cyclization with
t-BuOK in THF gave oxazolidinones 4a,b that were
converted to their diethyl 5a,c and diphenyl 5b,d phos-
phates in good yield.
4,4-Disubstituted oxazolidinones were prepared as out-
lined in Scheme 3. The 4,4-dimethyl analogues were
prepared starting from commercially available amino-
alcohol 7a, while the 4,4-diphenyl oxazolidinones were
accessed via LiAlH4 reduction of diphenylglycine. Each
amino alcohol was condensed with dimethyl carbonate
to give oxazolidinones 8a and 8b followed by conversion
to their corresponding diethyl and diphenyl N-oxazo-
lidinone phosphates 9a–d.
With the desired range of N-phosphoryl oxazolidinones
in hand the reactivity was evaluated with respect to an
alcohol substrate. Chlorophosphates are known to react
A number of N-phosphoryl oxazolidinones were first
prepared as outlined below. The aim was to evaluate
which of the oxazolidinone frameworks gave the
O
O
O
P
(i)
OR
OR
1a R = Et (85%)
1b R = Ph (87%)
O
NH
O
N
Keywords: Oxazolidinone; Phosphorylation.
* Corresponding author. Tel.: +44-114-222-9483; fax: +44-114-222-
9346; e-mail: simon.jones@sheffield.ac.uk
Scheme 1. Reagents: (i) n-BuLi, THF, then (RO)2P(O)Cl.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.003

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S. Jones, C. Smanmoo / Tetrahedron Letters 45 (2004) 1585–1588
O
O
O
P
O
O
(iii)
OR2
OR2
(ii)
(i)
HO
R1 R1
MeO
O
N
O
NH
N
H
Ot-Bu
N
H
Ot-Bu
R1
R1
O
R1
R1
2
3a R1 = Me (70%)
3b R1 = Ph (89%)
4a R1 = Me (85%)
5a R1 = Me, R2 = Et (70%)
5b R1 = Me, R2 = Ph (85%)
5c R1 = Ph, R2 = Et (85%)
5d R1 = Ph, R2 = Ph (80%)
4b R1 = Ph (77%)
Scheme 2. Reagents: (i) 4 equiv R1MgBr, THF; (ii) t-BuOK, THF; (iii) n-BuLi, THF, then (R2O)2P(O)Cl.
O
O
O
P
R1 R1
Ph Ph
OR2
OR2
(iii)
(ii)
(i)
HO
O
N
HO
O
NH
R1
NH2
NH2
R1
O
R1
R1
8a R1 = Me (70%)
8b R1 = Ph (70%)
9a R1 = Me, R2 = Et (63%)
9b R1 = Me, R2 = Ph (70%)
9c R1 = Ph, R2 = Et (80%)
9d R1 = Ph, R2 = Ph (88%)
6
7a R1 = Me
7b R1 = Ph (80%)
Scheme 3. Reagents: (i) LiAlH4, THF; (ii) (MeO)2C(O), K2CO3; (iii) n-BuLi, THF, then (R2O)2P(O)Cl.
with alcohols using triethylamine as a proton scavenger.
However, given that the leaving group ability of the
oxazolidinone was considerably worse than that of
chloride [pKa (HCl) )7; pKa (oxazolidinone) 10] the
nucleophilicity of the alcohol was increased by forma-
tion of the alkoxide. In this study, lithium and magne-
sium chloroalkoxides were compared in their reactivity
(Scheme 4).
Encouraged by this result, the diethyl phosphoryl oxa-
zolidinones 1a, 5a,c, and 9a,c were evaluated to deter-
mine which of the oxazolidinone frameworks was the
optimum for further development. Once again, benzyl
alcohol 10 was employed as substrate, the reactions this
time being left overnight (14 h) under otherwise identical
conditions (Scheme 5).
The results summarized in Table 1 indicate that substi-
tution is essential for reactivity, the unsubstituted oxa-
zolidinone giving no product (entry 1). Interestingly,
poor mass recovery was also observed here suggesting
that reaction of the alkoxide occurs at the carbonyl
group, resulting in cleavage of the oxazolidinone ring, a
phenomenon that has been observed with N-acyl oxa-
zolidinones.9 5,5-Substituted oxazolidinones appeared
to be essential for reactivity (entries 2 and 3), while the
4,4-substituted examples appeared significantly less
reactive (entries 4 and 5).
Treatment of benzyl alcohol 10 with 1 equiv of either
n-butyllithium or methyl magnesium chloride in ether
generated the alkoxide, which was then solubilized by
subsequent addition of dichloromethane. N-Phosphoryl
oxazolidinone 5a was added and the reaction left to stir
for 8 h followed by aqueous work-up. The benzyl diethyl
phosphate 11 was indeed formed and the lithium alk-
oxide was found to be superior to the magnesium
chloroalkoxide and thus used in all further studies.
(i)
OH
OM
(i)
OH
OM
10
10
O
O
P
O
O
P
OEt
OEt
O
N
OEt
OEt
O
N
R1
R2
5a
R1 R2
1a
5a,c
9a,c
O
O
P
OEt
OEt
O
O
P
O
NH
O
OEt
OEt
O
NH
R2
O
11 (M = Li, 70%)
R1
R1 R2
(M = MgCl, 40%)
11
Scheme 4. Reagents: (i) n-BuLi or MeMgCl, Et2O, then CH2Cl2.
Scheme 5. Reagents: (i) n-BuLi, Et2O, then CH2Cl2.

S. Jones, C. Smanmoo / Tetrahedron Letters 45 (2004) 1585–1588
Table 1. Reactivity of 4,4 and 5,5 substituted oxazolidinones
1587
Li
O
O
P
Entry
Compound R1
R2
Yield (%)a
OBn
OEt
OEt
O
N
1
2
3
4
5
1a
5a
5c
9a
9c
H
H
0
70
70
35
20
Me
Ph
H
H
H
Steric interaction
Me
Ph
H
Figure 2.
a Refers to isolated yield.
(Fig. 2). The steric compression is even more pro-
nounced with the 4,4 diphenyl analogue 9c leading to
the lowest yield of all the substituted oxazolidinones
evaluated. Of course, one may also consider a mecha-
nism involving adjacent attack, followed by pseudoro-
tation of the intermediate formed. This process would
also be prone to reduced reaction rates resulting from
increased steric effects at the 4 position. Further exper-
iments are currently underway to accrue more infor-
mation on these mechanistic pathways.
The results can be rationalized by considering the
mechanism for the reaction. It is highly likely that the
reaction proceeds via an associative SN2(P) process
whereby the nucleophile attacks along a trajectory
directly opposite the leaving group.10 This places the
benzyl alcohol nucleophile and the oxazolidinone leav-
ing group in the axial positions of the trigonal bipyr-
amidal intermediate 12 (Scheme 6).
The intermediate 12 is stabilized via co-ordination of the
lithium ion to the carbonyl group of the oxazolidinone,
which was confirmed by molecular modeling of this
species (Fig. 1).11
The oxazolidinone deemed to be the most appropriate
phosphorylation agent was 5,5-diphenyl oxazolidinone
5c since this gave the best yield of product phosphate
and was prepared in the highest yield as a solid that
could be purified by recrystallization.
This clearly shows the trigonal bipyramidal structure
with the alkoxy and both ethoxy groups occupying the
equatorial positions. Reduced yields were obtained with
reagent 9a since the 4,4 dimethyl groups experience
severe steric interactions with the ethoxy groups in going
from a tetrahedral structure to the trigonal bipyramidal
intermediate, thus destabilizing this intermediate
With a suitable oxazolidinone framework optimized,
diethyl 5c and diphenyl oxazolidinones 5d were evalu-
ated against a variety of primary, secondary, tertiary,
and phenolic substrates (Scheme 7). The results are
summarized in Table 2.
Unsurprisingly the diethyl oxazolidinone 5c gave
slightly higher yields since there is less steric compres-
sion in the intermediate formed with this reagent com-
pared to the diphenyl analogue 5d. Primary alcohols all
reacted in good to excellent yields (entries 1–3), while
secondary alcohols appeared to react better with diethyl
phosphate 5c than reagent 5d (entries 4–6). It is inter-
esting to note that even tertiary alcohols gave reasonable
yields of the desired phosphate esters (entries 7 and 8).
Phenolic substrates also gave reasonable yields (entries
9–11) although steric compression may well again be
responsible for the low yield observed with m-meth-
oxyphenol and diphenyl reagent 5d.
Li
O
O
P
O
O
P
LiOBn
OEt
OEt
O
N
OBn
O
N
OEt
OEt
Ph
Ph
Ph
Ph
12
O
O
P
EtO
EtO
O
NLi
OBn
Ph
Ph
Scheme 6. Mechanism of reaction of the oxazolidinone.
In summary we have developed N-phosphoryl oxazol-
idinones as alternative phosphorylating agents suitable
for a variety of alcohol substrates. Of the reagents pre-
pared, 5,5-diphenyl oxazolidinones were determined to
be the best framework for such reagents.
O
(i)
OR1
OR1
R
P
ROH
ROLi
O
O
O
N
O
P
O
OR1
OR1
O
NH
5c R1 = Et
5d R1 = Ph
Ph
Ph
Ph
Ph
Figure 1. Minimized structure of intermediate 12.
Scheme 7. Reagents: (i) n-BuLi, Et2O, then CH2Cl2.

1588
S. Jones, C. Smanmoo / Tetrahedron Letters 45 (2004) 1585–1588
Table 2. Evaluation of N-phosphoryl oxazolidinones 5c and 5d with
alcohol substrates (from Scheme 7)
Acknowledgements
Yield (%)a
We thank the Thai Government for a Royal Thai
scholarship (C.S.).
Entry
Alcohol (ROH)
Oxazolidi-
none
5c
5d
5c
5d
97
79
95
86
1
2
Ph
OH
OH
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5c
5d
94
83
3
4
OH
5c
5d
93
43
OH
5c
5d
92
67
OH
5
6
5c
5d
88
62
OH
OH
5c
5d
63
47
7
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11. Modeling performed using Quantum CAChe, Version
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5c
5d
59
42
OH
8
5c
5d
62
51
9
Br
OH
5c
5d
58
48
10
O2N
OH
OH
11
5c
5d
44
38
OCH3
a Refers to isolated yield.