Copper-mediated cross-coupling of 1,1-dibromo-1-alkenes with dialkyl phosphites: A convenient synthesis of 1-alkenylphosphonates

Article abstract of DOI:10.1039/c0cc01617a

An efficient and stereoselective procedure for the preparation of E-1-alkenylphosphonates by copper-mediated cross-coupling between 1,1-dibromo-1-alkenes and dialkyl phosphites is reported. The reaction allows for formal substitution of both bromine atoms

Full text of DOI:10.1039/c0cc01617a

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Copper-mediated cross-coupling of 1,1-dibromo-1-alkenes with dialkyl
phosphites: a convenient synthesis of 1-alkenylphosphonateswz
Gwilherm Evano,* Krishnaji Tadiparthi and Franc¸ ois Couty
Received 27th May 2010, Accepted 18th June 2010
DOI: 10.1039/c0cc01617a
An efficient and stereoselective procedure for the preparation of
E-1-alkenylphosphonates by copper-mediated cross-coupling
between 1,1-dibromo-1-alkenes and dialkyl phosphites is reported.
The reaction allows for formal substitution of both bromine atoms,
respectively, by an hydrogen and a dialkoxyphosphoryl.
Scheme
1 1-Alkenylphosphonates by copper-mediated cross-
1-Alkenylphosphonates are especially useful small organic
molecules.1 In addition to their extensive use in polymer
science as copolymers, additives or flame-retardants,1,2 they
are routinely used as building blocks for the introduction
of remote phosphonate functional groups or to prepare
biologically active molecules.1 Quite recently, the alkenyl-
phosphonate scaffold itself has been used as a promising
pharmacophore.3 They have also been shown over the years
to be key starting materials for an impressive range of
chemical transformations such as, for example, asymmetric
hydrogenation,4 enantioselective organocatalytic condensation
with aldehydes,5 enantioselective intramolecular Stetter
reaction,6 or dipolar 1,3-cycloaddition.7
coupling of 1,1-dibromo-1-alkenes with dialkyl phosphites.
should be able to act as both a selective reducing agent23 and
cross-coupling partner to give E-1-alkenylphosphonates 4.24 If
successful, this procedure would be especially convenient for
the preparation of these useful building blocks and would
also avoid a preliminary stereoselective synthesis of the
cross-coupling partner 3, which would now be generated
in situ. Herein, we describe the successful development of such
a one pot sequence that allows a straightforward preparation
of a wide range of 1-alkenylphosphonates.
To test our hypothesis, b,b-dibromostyrene 5 was reacted
with excess (2.5 equiv.) diisopropylphosphite 6 in the presence
of various copper-based catalytic systems. After quite some
experimentation, we eventually found that the reaction was
best performed using potassium phosphate as base, copper
iodide as a source of copper(I) and N,N0-dimethylethylenediamine
as a ligand in toluene at 120 1C for a day (Scheme 2).25 Using
these conditions, 1-alkenylphosphonate 7 could be obtained in
60% yield with useful levels of stereoselectivity (E/Z: 90/10)
and with minor amounts of side products resulting from
the dimerization of starting dibromide 5.20c The exclusive
formation of 7 is in sharp contrast with results from the
Hayes group who showed that alkynylphosphonates were
predominantly formed upon reaction of alkenyl-dibromides
and dialkyl phosphites with palladium acetate, dppf and
propylene oxide in DMF at 80 1C.26 The present method
therefore offers a complementary catalytic system that allows
the selective formation of alkenylphosphonates.
In addition to
a number of traditionally employed
approaches that often lack generality and selectivity,1,8 several
transition-metal mediated methods for the synthesis of
1-alkenylphosphonates have recently emerged.9 They include
the cross metathesis reaction with ethenylphosphonate,10
hydrophosphonylation of alkynes,11 Heck cross-coupling
strategies,12 addition of zirconocene to alkynylphosphonates
followed by reaction with electrophiles,13 and palladium-14 or
copper-15 catalyzed coupling of dialkyl phosphites with vinyl
halides, vinyl boronates16 and hypervalent alkenyl iodonium
salts.17 Despite their efficiency, preparation of 1-alkenyl-
phosphonates is far from being a trivial task and there is
still a strong need for alternative methods that would allow
the synthesis of alkenylphosphonates from readily available
starting materials.
Drawing inspiration from our experience in copper
catalysis18,19 and from recent studies of our group on the
behaviour of vinyl dibromides with copper(I) salts,20,21 we
thought that an attractive alternative for the preparation of
1-alkenylphosphonates 4 would rely on the cross-coupling of
readily available 1,1-dibromo-1-alkenes 122 with dialkyl
phosphites 2 (Scheme 1). By using an excess of the latter, it
Surprisingly, our initial fears that the Hirao reduction,
which is typically performed in highly polar solvents (DMF,
ethanol or triethylamine),23 might not be compatible with the
use of a non polar solvent turned out to be unfounded, even if
this reaction was found to be slower in toluene.
The coupling of diisopropylphosphite
6 with various
gem-dibromoalkenes was next investigated using the optimized
Institut Lavoisier de Versailles, UMR CNRS 8180,
´
Universite de Versailles Saint-Quentin en Yvelines, 45,
avenue des Etats-Unis, 78035 Versailles Cedex, France.
E-mail: evano@chimie.uvsq.fr; Fax: +33 1 39 25 44 52;
Tel: +33 1 39 25 44 11
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization, copies of 1H and 13C NMR spectra for
all new compounds. See DOI: 10.1039/c0cc01617a
Scheme 2 Optimized reaction conditions.
ꢀc
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Chem. Commun., 2011, 47, 179–181 | 179

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Table 1 Scope and limitationsa
conditions: illustrative examples are shown in Table 1. The
reaction was found to be rather general, and 1-alkenyl-
phosphonates could be obtained in all cases with reasonable
to good yields and with useful selectivities in favor of the
E-isomer. The reaction was found to be compatible with a
variety of aromatic groups (Table 1, entries 1–10), and the
presence of electron withdrawing or donating groups
had virtually no effect. Vinyl- and alkyl-substituted gem-
dibromoalkenes were also found to be suitable reaction
partners (Table 1, entries 11–15), even in the presence
of a bulky substituent (Table 1, entry 14). In the case of a
benzyl-substituted dibromide, migration of the double bond
was, however, observed (Table 1, entry 16).
Yieldb
(%)
E/Z
Entry 1,1-Dibromo-1-alkene l-Alkenylphosphonate
1
2
90/10 60 (60c)
92/8
58
3
4
5
89/11 67
89/11 56
87/13 52
The reaction is not limited to the small scale used for the
coupling reactions described above (i.e., 1 mmol) since it could
be conveniently performed on a gram scale with comparable
yield (Table 1, entry 1).
The scope of the reaction was next investigated with respect
to the dialkyl phosphite reaction partner (Scheme 3). Other
dialkyl phosphites such as diethyl- or dibutyl-phosphite were
found to perform well for the reduction/cross-coupling
sequence, the former being a little superior in terms of yield
and selectivity. Only diphenylphosphite did not participate in
the reaction since no reduced or coupled product could be
detected in the crude reaction mixture.
6
88/12 84
7
8
9
83/17 52
80/20 67
92/8
95/5
60
48
Scheme
3 Reduction/cross-coupling using various dialkyl
10
11
phosphites.
We next briefly turned our attention to the more challenging
synthesis of trisubstituted 1-alkenylphophonates starting from
benzophenone and acetophenone-derived 1,1-dibromoalkenes
10 and 12 (Scheme 4). Again, the reaction was found to be
quite efficient since the corresponding phosphonates 11 and 13
could be isolated in 58 and 78% yield. In the last case, the
E-isomer27 was formed predominantly, with a selectivity similar
to the one observed with disubstituted 1-alkenylphosphonates.
88/12 71
81/19 45
12
13
14
92/8
59
495/5 48
15
93/7
54
16
495/5 62
a
Conditions: Diisopropylphosphite (2.5 equiv.), CuI (40 mol%),
N,N0-dimethylethylenediamine (80 mol%), K3PO4 (6 equiv.), toluene
(0.3 mol Lꢁ1), 120 1C, 20–24 h. Yield of pure, isolated product.
Reaction performed on a gram scale.
b
c
Scheme 4 Synthesis of trisubstituted 1-alkenylphosphonates.
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Scheme
5 Synthesis of 1-alkenylphosphonates from complex
substrates.
Finally, the formation of 1-alkenylphosphonates from
complex substrates was evaluated to test our procedure further
(Scheme 5). Proline- and citronellal-derived dibromides 14 and
16 were converted to enantiopure 1-alkenylphosphonates 15
and 17 while (ꢁ)-menthol-derived phosphite 1928 was
smoothly coupled with gem-dibromoalkene 18 to give
phosphonate 20, the chirality now being introduced on the
phosphonate group. Finally, double coupling performed on
bis-dibromide 21 provided bis-1-alkenylphosphonate 22 in an
excellent 83% yield.
In conclusion, an efficient stereoselective synthesis of
1-alkenylphosphonates has been described. This reaction has
been shown to be general and provides a straightforward entry
to 1-alkenylphosphonates that is complementary to previously
reported synthetic routes. This method has the advantageous
feature that it starts from readily available 1,1-dibromo-
1-alkenes which act as attractive synthetic equivalents of
E-alkenyl bromides. Further studies on the applications of
this method, on the use of other nucleophiles and on the
reaction mechanism, which is still unclear and is undoubtedly
more complicated than a simple Hirao reduction/cross-
coupling sequence, will be reported in due course.
The authors thank the CNRS for financial support.
K. T. acknowledges the University of Versailles for a post-
doctoral fellowship. We are indebted to Dr Elyane Kizilian
(Lavoisier Institute) for her help with mass spectrometry
analyses.
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ꢀc
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Chem. Commun., 2011, 47, 179–181 | 181