ChemComm
Cite this: Chem. Commun., 2011, 47, 6156–6158
COMMUNICATION
Synthesis of thiophosphoramidates in water: Click chemistry for
phosphatesw
ˇ
Milena Trmcic and David R. W. Hodgson*
´
Received 18th March 2011, Accepted 8th April 2011
DOI: 10.1039/c1cc11586c
An aqueous method for the preparation of N,S-dialkyl
thiophosphoramidates is reported. Thiophosphorylation of
alkylamines was performed using SPCl3 in aqueous reaction
media, and the resulting thiophosphoramidate-S-anions were
S-alkylated with soft electrophiles. Ranges of amines and
electrophiles were explored.
Our approach hinges on exploiting the greater intrinsic
nucleophilicities of amines in comparison to water. Thus,
through control of amine concentrations and other experi-
mental parameters, we hoped to be able to induce selective
N-thiophosphorylation of amines versus hydrolysis of the
thiophosphorylating agent. Similar approaches have been used
for the preparation of carboxylic amides and sulfonamides,5 but,
surprisingly, this approach has not been exploited significantly
with (thio)phosphoric amide systems.
Phosphate esters and their structural analogues represent a
major class of biomolecules that plays central roles in genetic
transmission, membrane formation, signalling and metabolism.
The synthesis of phosphate esters and their analogues has been
revolutionized by the phosphoramidite method.1 However, the
preparation of phosphoramidites is often time-consuming,
requiring global protection and anhydrous conditions.
Thereafter, the formation of phosphate esters requires
anhydrous conditions and a range of reagents that are highly
effective in automated oligonucleotide synthesizers, but
cumbersome in general laboratory usage.
We first explored conditions for thiophosphorylation of the
model amines ethanolamine and benzylamine with SPCl3
(Scheme 2 and Table 1).
Scheme 2 Optimisation of aqueous N-thiophosphorylation.
We sought to overcome these limitations by developing
aqueous ‘‘click’’ methods that employ off-the-shelf reagents
for the preparation of N,S-dialkyl thiophosphoramidates that
represent simple mimics of phosphate diesters. Building on the
use of phosphoryl chloride (OPCl3) for the preparation of
N-phosphorylated amines,2–4 we began to investigate the use
of thiophosphoryl chloride (SPCl3) for the preparation of
N-thiophosphorylated amines, which could then be elaborated,
through S-alkylation, to give N,S-dialkyl thiophosphoramidates
(Scheme 1). A key aim was to ensure clean conversions, where
the requirement for time-consuming ion exchange or HPLC
purifications that can often hamper the preparation of
phosphate esters was significantly reduced or removed.
We used THF as a co-solvent given that SPCl3 appears to
display very limited solubility in water. In all cases, satisfactory
conversions (mostly 490%) to thiophosphoramidate 2 were
obtained. Varying the numbers of equivalents of SPCl3, aiming
to enhance conversions in the case of ethanolamine, afforded
no improvements (entries 2–4). We also explored the number
of equivalents of NaOH employed, but we found that 5 equiv.
represented the optimum number (data not shown). The only
Table 1 Screening thiophosphorylation conditionsa
Entry
Substrate 1
Eq. of SPCl3
2 (%)
1
2
3
1
98b, 94c
96b, 93c
92b, 86c
1.1
1.2
Scheme 1 Retrosynthetic strategy for the preparation of N,S-dialkyl
thiophosphoramidates in aqueous solvent mixtures.
4
5
a
1.3
1.0
91b, 94c
Department of Chemistry, Science Laboratories, Durham University,
South Road, Durham, DH1 3LE, UK.
E-mail: d.r.w.hodgson@durham.ac.uk
w Electronic supplementary information (ESI) available: General
experimental procedures and 1H and 31P NMR spectra of reaction
products. See DOI: 10.1039/c1cc11586c
97b, 499c
See ESIw for details. Determined by 31P NMR spectroscopy.
b
c
Determined by 1H NMR spectroscopy.
c
6156 Chem. Commun., 2011, 47, 6156–6158
This journal is The Royal Society of Chemistry 2011
Trmic, Milena
