Organic Letters
Letter
to be the common side product (vide infra). Detailed reaction
conditions, including structures of the starting materials, are
Scheme 2. Substrate Scope of P(O)−H Compounds and
a
Amine Nucleophiles
We next explored the potential of diselenide 1g to catalyze
coupling of a diverse set of H-phosphonates. Dialkyl
phosphites provided good to excellent yields of the
corresponding phosphoramidate products (4a−4k and 4n),
while the hydrolytically prone diphenylphosphites afforded a
lower yield of product 4l. No product (4m) formation was
observed with dibenzylphosphite; we hypothesize that the
selenoate undergoes nucleophilic substitution reaction at the
benzylic position of the phosphite, thereby deactivating the
catalyst.
We also evaluated the potential of diselenide 1g to
functionalize H-phosphinates18 and secondary phosphine
oxides19 with amines to form phosphonamidates and
phosphinamides, respectively (Scheme 2b,c and Table S1).
Reaction of alkyl phenylphosphinates and diarylphosphine
oxides with primary amines led to high yields of products 4o−
p and 4r−s, respectively. 9,10-Dihydro-9-oxy-10-phosphaphe-
nanthrene-10-oxide, which contains aryloxy group, provided
low yield of the product 4q likely because of the susceptibility
of this phosphine oxide to hydrolysis. Low reaction yield (4t)
was also observed with dibutylphosphine oxide, presumably
because of its propensity to oxidize and disproportionate.20
Reactions of amino alcohols with H-phosphonates (see
products 4h and 4i) suggest that alcohols are poor nucleophile
partners. Indeed, attempts at condensing n-butanol with
diethylphosphite led to unreacted starting materials, as
monitored by 31P NMR. Addition of DMAP as a base and
cocatalyst to the reaction mixture marginally enhanced the
yield (9%) of the desired product 6a; however, these
conditions also led to the conversion of the diethylphosphite
starting material into TEPP (6b) from reaction with water
produced during the catalytic cycle.9b,21
Reactions with nucleophiles weaker than water, i.e., aniline
and aliphatic alcohols, will potentially be accompanied by
formation of pyrophosphate. In accordance with this
hypothesis, we found that treatment of diethylphosphite with
5 mol % 1g and 5 mol % DMAP in anhydrous acetonitrile at
60 °C afforded TEPP (6b) in 86% yield. Conversely, phenols
reacted efficiently with diethylphosphite in the presence of 5
mol % 1g and 5 mol % DMAP to provide their corresponding
phosphate esters 6c−g as major products (Scheme 3 and Table
S2). Formation of TEPP can be compensated for in these cases
by addition of excess (1.5 equiv) phosphite. High yield of
product 6c was obtained from reaction between diethylphos-
phite and phenol at room temperature. We also explored the
reactivity of various substituted phenols. Reaction with 1-
naphthol, 2-nitrophenol, 4-methoxyphenol, and 2-amino-5-
nitrophenol resulted in high yields of the corresponding
products (6d−6g), demonstrating that variability in electronic
properties and position of substituents are reasonably
tolerated. Thiophenol also reacted to form phosphorothioate
6h in near quantitative yield.
a
Reaction conditions: P(O)−H compound (0.50 mmol), amine (0.55
mmol), and diselenide 1g (5 mol %) were stirred in MeCN (2.5 mL)
at 60 °C for the indicated time period in the presence of ambient air;
see Table S1 for detailed conditions of each reaction. Only 1 mol %
b
c
of 1g was used. Reaction was conducted in THF (2.5 mL) instead.
d
HCl salt of the corresponding amine was converted in situ into its
e
free form by addition of equimolar triethylamine (0.55 mol). MS and
31P NMR indicated the formation of tetraethyl pyrophosphate instead.
f
g
Catalyst deactivated. The corresponding starting material has
diastereomeric ratio (Rp/Sp) of 98:2.
We probed the mechanistic underpinnings of the catalyzed
reaction by analyzing the stereochemistry of the phosphorus
center. We prepared diastereomerically enriched (Rp)−
menthyl phenylphosphinate (2p, 98:2 dr) and treated it with
benzylamine (Figure 3a). Evaluation of the resulting product
4p by chiral HPLC showed that the reaction proceeded in
stereospecific fashion (97:3 dr). The same reaction with less
enriched 2p (58:42 dr) led to a similar outcome. X-ray
Catalyst 1g can tolerate amines bearing a diversity of functional
groups, including esters (to yield the corresponding product 4f,
4g, and 4i), amide (4f), alkyne (4k), and unprotected purine
base (4n). In the presence of unprotected alcohol, the more
nucleophilic amine was preferentially phosphorylated (see
products 4h and 4i). Unsurprisingly, aromatic amines (4j)
proved to be poor nucleophilic partners. In cases with less
reactive partners, tetraethylpyrophosphate (TEPP) was found
C
Org. Lett. XXXX, XXX, XXX−XXX