ods,1,8,13 Hirao and co-workers introduced a Pd-catalyzed
cross-coupling reaction of H-phosphonates with aryl and
vinyl halides.14-16 After further development and modifica-
tions, this method constitutes the current state of the art in
the synthesis of C(sp2)-P bonds.17
In recent years, application of microwaves to synthetic
organic chemistry has become increasingly popular and
attracted considerable practical18,19 and theoretical atten-
tion.20 Among various chemical transformations investi-
gated,19 the palladium-catalyzed cross-coupling reactions
have been recognized as an exceptionally successful area of
application of this controllable thermal source for conducting
organic reactions. Both the C-C bond forming cross-
coupling reactions, as well as those for the C-N and C-O
bond formation using the Buchwald-Hartwig chemistry,21
were efficiently carried out under microwave irradiation
conditions.19,22
synthesis of aryl- and vinylphosphonates under microwave
conditions, using this one-component Pd(0) catalyst.
For the purpose of optimization of the experimental
conditions, we chose as a model reaction coupling between
bromobenzene and diethyl H-phosphonate. All experiments
were performed in standard, sealed microwave vessels, under
an inert gas atmosphere.
First, screening of various common solvents was carried
out by comparing a degree of conversion into diethyl
phenylphosphonate during 3 min at 120 °C, using 31P NMR
spectroscopy (Table 1).
Table 1. Solvent Screeninga
In contrast, the use of microwaves to facilitate cross-
coupling reactions involving phosphorus nucleophiles still
remains largely unexplored. Only recently, a single report
on a Pd-catalyzed microwave-assisted coupling of H-
phosphonate and H-phosphinate derivatives with aryl triflate
(yields ca. 19-52%), during synthesis of progesterone
antagonists, has appeared.9
Due to the synthetic and practical importance of aryl- and
vinylphosphonate derivatives, we describe herein our sys-
tematic investigations on the reaction conditions for the
microwave-assisted palladium-catalyzed C-P bond forma-
tion. Although a plethora of ligands for the cross-coupling
reactions involving palladium have been developed, and
some of them were successfully applied in the reactions with
H-phosphonate nucleophiles,23 a catalyst of choice for this
kind of chemistry remains Pd(PPh3)4.17 In line with these,
we set out to develop a general-purpose protocol for the
entry
solvent
conversionb (%)
1
2
3
4
5
6
7
THF
39
65c
29
30
38
51c
28
DMSO
acetone
dioxane
DMF
NMP
toluene
a Reaction conditions: 0.1 M (EtO)2P(O)H, 1.1 equiv of Ph-Br; after
initial heating, the reaction temperature was maintained for 3 min at 120 °C.
b Determined by 31P NMR spectroscopy. c At concentrations higher than
0.1 M, starting material decomposition was observed.
As is apparent from Table 1, the reaction proceeded
reasonably well in all solvents tested. Although the best
results were obtained for DMSO and NMP (Table 1, entries
2 and 6), severe side reactions occurred when the concentra-
tion of the reactants was increased to 0.25 M (a concentration
range convenient for preparative syntheses). In DMSO, the
starting H-phosphonate was oxidized to a P(V) species,
probably via a Swern-type oxidation (formation of Me2S),
while in NMP, a partial cleavage of one of the ethyl groups
from (EtO)2P(O)H was observed. Therefore, as a solvent for
the further studies, THF was selected (Table 1, entry 1), due
to its good efficiency in the coupling reaction and easy
handling during the workup procedure.
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Engels, J. W.; Parsch, J. In Molecular Biology in Medicinal Chemistry;
Dingermann, T., Steinhilber, D., Folkers, G., Eds.; Wiley-VCH Verlag
GmbH & Co.: Chichester, 2005. Harnden, M. R.; Parkin, A.; Parratt, M. J.;
Perkins, R. M. J. Med. Chem. 1993, 36, 1343–1355. Lazrek, H. B.; Rochdi,
A.; Khaider, H.; Barascut, J.-L.; Imbach, J.-L.; Balzarini, J.; Witvrouw,
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Stawinski, J.; Nawrot, B. New J. Chem. 2003, 27, 1698–1705
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(15) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis 1981,
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were examined for their ability to promote the cross-coupling
of the model substrates (Table 2). The best results were
56–57
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(17) Prim, D.; Campagne, J. M.; Joseph, D.; Rioletti, B. Tetrahedron
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24
4). These bases secured ca. 40% conversion into phenylphos-
phonate 1 within 3 min at 120 °C, while the other carbonates
investigated, as well as K3PO4 and propylene oxide, were
by far less efficient.
Attempted increasing of the coupling rate, by applying
temperatures higher than 120 °C, failed due to progressing
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