Phosphine-catalyzed α-P-addition on activated alkynes: A new route to P-C-P backbones

Article abstract of DOI:10.1021/ol061589v

(Chemical Equation Presented) n-Tributylphosphine was found to efficiently catalyze the α-P addition of H-phosphonates, H-phosphinates, and H-phosphine oxide pronucleophiles on alkynes bearing phosphane oxide activating moieties. The reaction leads to 2-a

Full text of DOI:10.1021/ol061589v

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4283-4285
Phosphine-Catalyzed
Activated Alkynes: A New Route to
P Backbones
r-P-Addition on
P−C−
Delphine Lecercle´, Marcin Sawicki, and Fre´de´ric Taran*
SerVice de Marquage Mole´culaire et de Chimie Bioorganique, Commissariat a`
l’Energie Atomique, Gif sur YVette, F-91191 France
frederic.taran@cea.fr
Received June 28, 2006
ABSTRACT
n-Tributylphosphine was found to efficiently catalyze the
r-P addition of H-phosphonates, H-phosphinates, and H-phosphine oxide pronucleophiles
on alkynes bearing phosphane oxide activating moieties. The reaction leads to 2-aryl-1-vinyl-1,1-diphosphane dioxide derivatives in good
yields affording a new route to P−C−P backbones. The products of this reaction are easily converted to biologically important 1,1-bis-
phosphonates analogues.
Catalysis employing tertiary phosphines has proven to be
useful for a series of transformations of electron-deficient
alkynes.1 In these reactions, the phosphine catalyst allows
redirection of the regioselectivity of the addition of nucleo-
philes to these Michael acceptors from the classical â-ad-
dition mode to an R or γ addition. Although phosphines-
catalyzed γ-addition reactions has been widely described,2
the R-addition has been explored only with nitrogen3 or
oxygen4 pronucleophiles. In connection with our efforts to
extend the R-addition reaction,5 we now report our investiga-
tions concerning the reaction of P-centered pronucleophiles
to alkynes activated by a phosphane oxide moiety. This
reaction should generate 1-vinyl-1,1-diphosphane dioxide
derivatives 3, whose preparation has only been sporadically
reported,6 and provide a new access to P-C-P backbones
(Scheme 1).
Scheme 1. Proposed Route to gem-Bis-phosphane Dioxide
Vinyl Derivatives 3
(1) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535-544.
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According to the postulated mechanism (Scheme 1), the
nucleophilic tertiary phosphine adds first to the triple bond
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(5) (a) Hanedanian, M.; Loreau, O.; Taran, F.; Mioskowski, C. Tetra-
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10.1021/ol061589v CCC: $33.50
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Published on Web 08/23/2006

of the electron-deficient alkyne 1, generating an active
phosphonium intermediate which then could undergo nu-
cleophilic R-P-addition of the H-phosphane oxide pronu-
cleophile 2 followed by elimination of the phosphine catalyst.
Several parameters including the nature of the phosphine
catalyst and the pKa of the pronucleophile 2 might therefore
influence the efficiency of the reaction.
Table 2. Phosphine-Catalyzed gem-Bis(phosphane oxide)vinyl
Derivative Synthesisa
As a model reaction, we investigated the R-P-addition of
diethyl phosphite 2a to alkynylphosphonate 1a using various
phosphines as catalysts. The results, summarized in Table
1, showed that the yield of the expected product 3a depends
Table 1. Optimization of the Reaction Conditionsa
entry
R3P
Ph3P
Ph2PMe
n-Bu3P
Et3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
solvent
yieldb (%)
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
dioxane
Et2O
EtOH
DMF
DMSO
5
10
42
65
34
20
98
18
2
a Reactions conducted in refluxing solvent (or 110 °C for DMF and
DMSO) under argon; the concentration of the substrates was 0.1 M. b Yields
of 3a were determined by HPLC.
on the nature of the phosphine and the solvent. As expected,
the requirement of a highly nucleophilic trialkylphosphine
is clearly illustrated by the reactivity order of the tested
phosphines (entries 1-4, Table 1). The use of ethanol as
solvent was also found essential to achieve complete conver-
sion of the substrate into the desired product (entry 7, Table
1). Previous findings showed that alcohols might act as
cocatalysts in phosphine-catalyzed isomerization of alkynoates.7
To explore the scope and limitation of the reaction, we
then carried out a series of R-P-additions using the optimized
conditions. Different P-pronucleophiles 2 were thus refluxed
in ethanol with arylalkynes 1 activated by a phosphonate,
phosphinate, or phosphine oxide group in the presence of
nBu3P. Whatever the combinations, the corresponding prod-
ucts were successfully obtained in moderate to high yields
(Table 2). The products bearing two different phosphane
oxide groups were isolated as a mixture of stereoisomers.
a Reaction conditions: alkyne 1 (0.5 mmol), P-pronucleophile 2 (0.55
mmol), n-Bu3P (0.1 mmol), EtOH reflux under Ar. b Isolated yields.
Compounds 3 are evident precursors of gem-bis-phospho-
nates analogues which are now recognized as an important
class of therapeutically active molecules for several human
pathologies, such as osteoporosis,8 rheumatoid arthritis,9 and
cancer.10 In this context, the presented method might be a
valuable new route for the synthesis as well as the labeling
of these important biologically active compounds. As an
example, the preparation of the heterocyclic bisphosphonate
4 was easily carried out in 4 steps (47% global yield) using
the presented reaction as a key step; the possibility of labeling
was also confirmed (Scheme 2). Compound 4 is an analogue
(7) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921-1923.
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Org. Lett., Vol. 8, No. 19, 2006

Scheme 2. Synthesis of Labeled Minodronate Analogue 4
Scheme 3. Formation of P-C-P-C-P Backbones
to minodronate (also known as YM529), a member of the
third-generation of biologically active bisphosphonates.11
Finally, we have undertaken the preparation of P-C-P-
C-P backbones using the n-Bu3P mediated R-P-addition
reaction. The reaction of H-phosphonylphosphonate 2d with
alkynyl phosphonates 1a and 1d proceeded smoothly to
afford, after chromatographic purification, the corresponding
vinylic triphosphane trioxides P(O)-C-P(O)-C-P(O) 3n
and 3o as pure Z isomers in good yields. Double R-P-addition
reaction of diethyl phosphite 2a was also achieved on bis-
alkynyl phosphine oxide 1i. The reaction conducted to the
expected product 3p as pure Z,Z isomer but required the use
of a less hindered phosphine (Et3P) and drastic conditions
which conducted to poor yield (Scheme 3).
of the nature of the two phosphane oxide groups, which
constitutes an undeniable advantage compared to classical
methods.12 An interesting possibility would be the synthesis
and biological evaluation of the phosphinates analogues of
the 1,1-bis-phosphonates currently used as therapeutic agents.
This structural modification should indeed decrease the
highly charged nature of these drugs and therefore increase
their uptake. From an organic synthesis point of view, the
present methodology offers a new route to compounds
bearing P(O)-C-P(O) moiety which are common precursors
of vinyl phosphane oxides13 and of ligands for catalysis.14
The presented reaction can also be successfully used for
the straightforward synthesis of compounds bearing P-C-
P-C-P backbones. Further investigations to prepare various
biochemically stable triphosphate analogues using this
methodology are currently underway.
In conclusion, we have developed a simple and practical
method for the preparation of 2-aryl-1-vinyl-1,1-diphosphane
dioxide derivatives. These products can be easily converted
into 1,1-bis-phosphonates which are important biologically
active drugs. The reported methodology allows the control
Acknowledgment. This work was supported by the
“Nuclear Toxicology” program of the CEA for which grateful
acknowledgment is made. We also thank E. Zekri and D.
Buisson (CEA) for experimental assistance with MS and LC/
MS measurements.
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Supporting Information Available: Experimental pro-
cedures for synthesis and full characterization for compounds;
1H NMR and 31P NMR spectra of products 3a-p and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061589V
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