Organic Letters
Letter
discovery of organic molecules with high application promise.
In known reports, the synthesis of discrete phosphoryl nitriles
has been consequently achieved via the use of different Cu(I)
and Cu(II) catalysts independently by Lin,13 Liu and Zou,14
and Zhou and Zhang15 (Scheme 1B). In despite of these
important works in the synthesis of both racemic and chiral
phosphoryl nitriles, more efforts are still desirable in
developing new methods featuring unique advantages, such
as atom-economical transition-metal-free reactions16 as well as
regioselective reactions enabling both proximal and discrete
cyanophosphonation for the synthesis more diverse products
wherein the phosphoryl and cyano groups are located at
different sites. On the basis of the longstanding interest of our
group in exploring novel synthetic applications of enaminones,
we report herein a novel trifunctionalization protocol for
tertiary enaminones through the reaction of with diary-
lphosphine oxides and TMSCN under metal-free conditions.
More interestingly, regioselective discrete and proximal
cyanophosphonations have been realized via base catalysis
and acid promotion, respectively (Scheme 1C), significantly
expanding the molecular diversity of phosphoryl nitriles.
To start the work, the reaction of enaminone 1a,
diphenylphosphine oxide (2a), and TMSCN (3) was selected
for the optimization of the reaction parameters. The typical
Scheme 2. Scope of the Discrete Cyanophosphonation
a
Table 1. Typical Optimization Data for the Discrete
Cyanophosphonation
Yield from a 1 mmol scale reaction.
a
of alkyl-ketone-derived enaminones (e.g., 4u; Scheme 2). We
were more delighted to find that the postsynthetic elaboration
of the natural product progesterone was also realized to afford
product 4v in fair yield. On the other hand, diarylphosphine
oxides containing different electron-withdrawing and -donating
groups in the phenyl ring were also smoothly employed in the
title synthesis (4aa−af; Scheme 2). Dimethyl- and dieth-
ylphosphine oxide, however, were not successfully transformed.
Amazingly, the interesting and unprecedented proximal
cyanophosphonation was achieved with identical starting
materials simply by switching the reaction conditions. The
systematic investigation of the reaction conditions proved that
acidic conditions promoted the selective formation of the gem-
phosphoryl nitrile product. The independent comparison of
acid species, medium, temperature, acid loading, and reaction
time proved that heating the substrate in CHCl3 at 90 °C in a
sealed tube in the presence of AcOH (2 equiv) with stirring for
18 h gave the optimal yield of product 5a (see Table S2 for
optimization data).
b
entry
variation
yield (%)
1
2
3
4
5
6
none
78
0
43
72
30
81
heptane as the solvent
water as the solvent
with 0.15 mmol of TBAH
no base catalyst
with 1 mL of MeCN
a
General conditions: 1a (0.3 mmol), 2a (0.4 mmol), 3 (0.6 mmol),
b
MeCN (2 mL), stirred for 12 h. Isolated yields based on 1a.
data) showed that using MeCN as the solvent was favorable
(entries 1−3). In addition, TBAH as the base additive was also
crucial for the efficient generation of 4a (entries 4 and 5).
Interestingly, modifying the concentration of the reaction
system further improved the reaction result (entry 6). Notably,
1H NMR analysis of the crude product 4a given by this
reaction under the optimized conditions proved that the
possible byproduct 5a (see Scheme 3 and the Supporting
In subsequent study, the scope of the discrete cyanophos-
phonation reaction was investigated. First, phosphine oxide 2a
was fixed to react with TMSCN and different enaminones. The
results demonstrated highly broad tolerance of the reaction
toward the enaminone component. The enaminones featuring
a phenyl group containing substituents at the para (4a−i),
meta (4j−l), and ortho (4m) sites, enaminones functionalized
with two substituents (4o−q), and fused aryl- and heteroaryl-
based enaminones (4r−t) were all practically used for the
synthesis of the target products (Scheme 2). Moreover, the
method also displayed satisfactory application in the reactions
Under the optimized parameters, the scope of the selective
proximal cyanophosphonation was also examined. Analo-
gously, broad substrate tolerance was also identified. The
reactions of 2a with a broad array of enaminones derived from
aryl methyl ketones (5a−q), heteroaryl methyl ketones (5r,
5s), and the natural product 16-dehydropregnenolone (5t)
were run to provide diverse products resulting from the
proximal cyanophosphonation (Scheme 3). Furthermore,
variation of the phosphine oxide component led to the
synthesis of different diarylphosphorylated products in
moderate to excellent yields (5aa−af; Scheme 3). The
structures of the vicinal and proximal products 4 and 5 were
clearly assigned by analysis of the single-crystal structures of 4a
1
and 5a. Again, H NMR analysis of the crude product 5a
proved the excellent selectivity of this reaction since no
5050
Org. Lett. 2021, 23, 5049−5053