Organic Letters
Letter
date, there has been no reported methodology tolerant of a
variety of functional groups, for a high yielding and operationally
simple synthesis of acyl phosphoramidates. Such a method
would be advantageous for research on acyl phosphoramidates
as more stable acyl phosphate mimetics (Scheme 1).
The Staudinger reaction has long been known as an efficient
method for the construction of a phosphorus nitrogen bond in
the form of an iminophosphorane. The iminophosphorane is
highly reactive toward oxygen nucleophiles such as water or
carbonyl compounds, yielding the phosphine oxide and amine
or imine, respectively. More recently, a modification reported by
Bertozzi et al. provides an alternative reaction pathway in which
the iminophosphorane undergoes intramolecular rearrange-
ment to give an amide adduct.3 Herein, we report on a
modification of the Staudinger reaction in which the
iminophosphorane intermediate undergoes rearrangement to
yield an acyl phosphoramidate adduct (Scheme 2).
We next screened reaction conditions and activating agents to
demonstrate the dependence on the stoichiometric quantity of
TMS-Cl. Accordingly, the reaction did not proceed in the
absence of TMS-Cl, while 0.5 equiv of TMS-Cl gave incomplete
conversion after 48 h (Table 1, entries 1 and 2). BSTFA gave
comparable results to TMS-Cl; however, LCMS analysis
indicated the increased formation of byproducts. Lewis acids,
BF3·Et2O, ScOTf3, and CeCl3, were also investigated as
activators; however, by LCMS they afforded complex mixtures
of byproducts and trace amounts of the desired product (Table
1, entries 4−7). Following these results, 1.2 equiv of TMS-Cl
was chosen as the preferred H-phosphonate activation agent.
Initial exploration of the substrate scope focused on the nature
of the P(III) reaction partner while benzoyl azide was chosen as
the reactant (Scheme 3). In each case, the desired product was
a
Scheme 3. Reaction Scope Using H-Phosphonates
Scheme 2. Synthetic Route To Access Phosphonamidates
H-Phosphonates (dialkyl phosphites) are known as versatile
intermediates in the synthesis of phosphorus containing
compounds.4 H-Phosphonates are reactive P(III) nucleophiles
and act through a tautomeric phosphite structure; however, this
reactivity is limited by the thermodynamic equilibrium strongly
favoring the non-nucleophilic H-phosphonate. This is consistent
with H-phosphonates being unreactive in the Staudinger
reaction. One method of activating H-phosphonates involves
the chemoselective O-functionalization using an oxophilic
reagent such as TMS-Cl. Using this protocol, it was envisioned
that the resulting intermediate putatively undergoes a 1,3-
migration and subsequent desilylation on aqueous workup to
give the desired acyl phosphoramidate (Scheme 2). Similar 1,3-
migrations of silyl5a and acyl5b groups have been reported
previously and are analogous to the Abramov reaction using O-
silyl phosphites.5c To this end, TMS-Cl was added to a mixture
of dibenzyl H-phosphonate 2a and benzoyl azide 1a in the
presence of triethylamine. After chromatographic purification
phosphoramidate 3a was isolated in 88% yield (Table 1, entry
3).
a
Isolated yields using Procedure A.
isolated in high yield (90−96%). The reaction rate by LCMS
was found to be dependent on P-substituents and is consistent
with the reactivity trend for P(III) nucleophiles in the Arbuzov
reaction.6 Of note, the highly labile methyl and tert-butyl
phosphites gave the desired products in 85% and 89% yield,
respectively, with no detectable formation of the corresponding
phosphoramidic acid. This result highlights the mildness of the
reaction conditions used for this methodology.
The methodology was further extended to the reaction of H-
phosphonates with commercially available DPPA, giving access
to a range of imidodiphosphates. A related methodology has
recently been reported, but the reaction conditions required
high temperature with a limited substrate scope due to the
omission of any activator such as TMS-Cl.7a The imidodiphos-
phate moiety is a biologically relevant pyrophosphate mimetic
with greater stability, as demonstrated by the known nucleoside
imidodiphosphates7b in addition to ATP7c and GTP7d
analogues. Employing the previously optimized reaction
conditions (Table 1, entry 3), the corresponding imidodiphos-
phate derivatives 5a−f were isolated in high yield (84−92%)
(Scheme 4). The workup procedure for the synthesis of
imidodiphosphates 5a−f was modified to include an additional
aqueous acid wash since the products formed a stable complex
with triethylamine which complicated chromatographic purifi-
cation.
Table 1. Optimization of the Reaction Conditions
a
b
entry
activator
equiv
solvent
time (h)
conversion
1
2
3
4
5
6
7
TMS-Cl
TMS-Cl
TMS-Cl
BSTFA
BF3·Et2O
Sc(OTf)3
CeCl3
0
DCM
DCM
DCM
DCM
DCM
DMF
DMF
18
48
18
18
18
18
18
0
0.5
1.2
1.2
1.2
1.2
1.2
50%
88%
79%
trace
trace
trace
To explore further the substrate scope, a range of acyl azides
were prepared and subjected to procedure conditions (Scheme
5). Dibenzyl H-phosphonate 2a was used as a model reactant
since the relatively low reactivity would allow the limits of the
methodology to be tested. All functional groups and hetero-
a
b
1.5 equiv of Et3N used in all entries. Determined by LCMS.
465
Org. Lett. 2021, 23, 464−468