Published on the web May 3, 2013
583
Synthesis of Diverse Aromatic Oxophosphorus Compounds
by the Michaelis-Arbuzov-type Reaction of Arynes
Suguru Yoshida and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(Received February 14, 2013; CL-130116; E-mail: thosoya.cb@tmd.ac.jp)
Arynes, generated in situ from o-(trimethylsilyl)aryl triflates
by treatment with a fluoride, have been shown to react efficiently
with various alkoxyphosphines via a mechanism similar to the
Michaelis-Arbuzov reaction. Diverse aromatic oxophosphorus
compounds, including derivatives with an ortho-ester function,
have become easily available from a common aryne precursor by
this method.
benzyne generated by oxidative addition of o-bromofluoroben-
zene to magnesium was shown to react with alkoxyphosphines
to give aryloxophosphorus compounds but with low efficiency.7
We presumed that this reaction proceeded by the mechanism
akin to the Michaelis-Arbuzov reaction and could significantly
improve and expand the scopes. After extensive screening of the
reaction conditions, including aryne precursors, we succeeded in
developing an efficient fluoride-mediated C-P bond-forming
reaction of arynes with alkoxyphosphines (Table 1). Treating the
mixture of alkoxyphosphine 2a and o-(trimethylsilyl)phenyl
triflate (1a), one of the most widely-used benzyne precursors,8
with tetrabutylammonium fluoride trihydrate (TBAF¢3H2O) at
0 °C afforded phenylphosphonic diamide 3a in high yield
(Entry 1).9 Iodonium triflate 1b10 also worked as well or better
than 1a under similar conditions (Entry 2). On the other hand,
the use of benzyne generated from o-iodophenyl triflate (1c) by
the halogen-lithium exchanging method11 gave the product only
in low yield (Entry 3). This indicates that the presence of an
appropriate amount of water capable of quenching aryl anion
intermediate during the reaction is significant to achieve a
satisfactory result. In addition, an attempt to use anthranilic acid
(1d) as a benzyne precursor was unsuccessful (Entry 4).12 In
view of the ready availability of various aryne precursors,13 we
chose to use silylaryl triflates in subsequent studies on the basis
of optimal conditions.
Organophosphorus compounds play valuable roles in
various scientific fields, including organic and organometallic
chemistry, materials science, and agrochemical and pharmaceut-
ical science.1 In regard to bioactive organophosphorus com-
pounds, the structures vary in substituent patterns at the
phosphorus center such as phosphonic acids, phosphonates,
phosphonamidates, and phosphonic diamides.2 Despite the
growing importance of aromatic organophosphorus compounds
to facilitate drug discovery, the aromatic carbon-phosphorus
bond forming reaction has been still limited mostly to (i)
nucleophilic substitution3 or (ii) cross-coupling4 approaches
(Figure 1). From the viewpoint of preparing a wide variety of
aromatic organophosphorus compounds, a novel type of C-P
bond-forming reaction that is complementary with existing
methods has been awaited.5 Herein, we disclose that the reaction
of alkoxyphosphines with arynes just fit the purpose, providing
diverse aryloxophosphorus compounds efficiently under mild
conditions.
A broad substrate scope of arynes as well as highly
sterically controlled regiochemical outcomes of the products was
demonstrated using various silylaryl triflates (Table 2). All
tested methoxy-substituted benzynes reacted with 2a with a high
efficiency (Entries 1-3). In accordance with previous reports,14
The good chemistry between nucleophilic phosphorus and
electrophilic aryne in C-P bond formation has been known and
studied since more than half a century.6 In terms of aryl-
oxophosphorus synthesis, however, to the best of our knowl-
edge, only one exploratory research has been reported to date:
Table 1. Optimization of the reaction conditions
O
X
conditions
Nucleophilic substitution approach
OMe
P(Ni-Pr2)2
+
P(Ni-Pr2)2
O
P
O
P
Y
H
LG
1
2a
3a
(1.2 equiv)
Entry X
Y
1 Conditions
Yield/%a
Cross-coupling approach
O
P
1
2
3
SiMe3 OTf
1a TBAF¢3H2O (1.2 equiv),
89
O
cat. [Pd]
X
P
THF, 0 °C, 1 h
H
SiMe3 I(Ph)OTf 1b TBAF¢3H2O (1.2 equiv), quant.
CH2Cl2, rt, 1 h
I
Aryne approach: This work
OTf
1c n-BuLi (1.2 equiv),
THF, ¹78 °C to rt, 12 h
1d t-BuONO (2.0 equiv),
H2O (3.0 equiv),
18
O
P
A'
OR
P
A
A'
A
4b NH2 CO2H
c.m.c
E
E+
A, A' = O, N, C
CH3CN, 90 °C, 12 h
aIsolated yields. b1d (2.0 equiv) was used. cA complex
mixture.
Figure 1. Synthetic methods of aryloxophosphorus com-
pounds.
Chem. Lett. 2013, 42, 583-585
© 2013 The Chemical Society of Japan
Yoshida, Suguru
