Copper-mediated selective cross-coupling of 1,1-dibromo-1-alkenes and heteronucleophiles: Development of general routes to heterosubstituted alkynes and alkenes

Article abstract of DOI:10.1021/om3005614

Efficient and general procedures for the cross-coupling of 1,1-dibromoalkenes and N-, O-, and P-nucleophiles are reported. Fine-tuning of the reaction conditions allows for either site-selective, double, or alkynylative cross-coupling, therefore providing

Full text of DOI:10.1021/om3005614

Article
pubs.acs.org/Organometallics
Copper-Mediated Selective Cross-Coupling of 1,1-Dibromo-1-alkenes
and Heteronucleophiles: Development of General Routes to
Heterosubstituted Alkynes and Alkenes
Kevin Jouvin,† Alexis Coste,† Alexandre Bayle,† Frederic Legrand,† Ganesan Karthikeyan,†
́
́
́
Krishnaji Tadiparthi,† and Gwilherm Evano*,‡
†Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
78035 Versailles Cedex, France
́
de Versailles Saint-Quentin en Yvelines, 45 Avenue des Etats-Unis,
‡Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
Libre de Bruxelles, Avenue F. D.
S
* Supporting Information
ABSTRACT: Efficient and general procedures for the cross-coupling of 1,1-dibromoalkenes and N-, O-, and P-nucleophiles are
reported. Fine-tuning of the reaction conditions allows for either site-selective, double, or alkynylative cross-coupling, therefore
providing divergent and straightforward entries to numerous building blocks such as bromoenamides, ynamides, ketene N,N-
acetals, bromoenol ethers, ynol ethers, ketene O,O-acetals, or vinylphosphonates and further expanding the copper catalysis
toolbox with useful and versatile processes.
compounds, ranging from the simplest building blocks to
complex natural and/or biologically relevant compounds.1 An
overview of most representative Ullmann/Goldberg-like copper-
mediated cross-coupling available to date is shown in Figure 1. A
simple glance at this gross picture and extreme simplification
reveals that there is one key partner missing in this scheme: gem-
dibromoalkenes.
Those reagents are easily and conveniently prepared from the
corresponding aldehydes using the Ramirez dibromoolefination6
or the more practical Lautens modification.7 They serve as
important starting materials or intermediates in an impressive
number of chemical transformations, the most famous one
probably being the Corey−Fuchs alkyne synthesis, where an
aldehyde is converted to the dibromide, which, upon treatment
with a strong base and reaction with an electrophile, gives the
corresponding substituted alkyne.8 More recently, they have
been shown to be especially useful and versatile building blocks
INTRODUCTION
■
Over the last 10 years or so, the use of copper-based catalytic
systems has enabled the design of efficient and general reactions,
especially for the formation of carbon−heteroatom bonds.1 The
introduction of simple, readily available, and inexpensive
chelating ligands, the most common ones being diamines2 or
amino acids,3 has allowed the dramatic softening of the reaction
conditions compared to the classical Ullmann4 and Goldberg5
ones and the broadening of the scope of these cross-coupling
reactions as well. Indeed, most heteronucleophiles can now
participate in these reactions, provided that the right
combination of ligand, base, and solvent is used, and the nature
of the halide coupling partner has also been extensively studied.
While the first developments mostly focused on the use of aryl
halides, the catalytic systems designed for these coupling partners
were then quickly adapted for vinyl and alkynyl halides, therefore
greatly expanding the scope of copper-mediated cross-coupling
reactions and solving some long-standing problems at the same
time. They also provided the chemical community with highly
efficient tools that have found numerous academic and industrial
applications for the preparation of an impressive array of
Special Issue: Copper Organometallic Chemistry
Received: June 20, 2012
© XXXX American Chemical Society
A
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Figure 1. Overview of copper-catalyzed reactions for the formation of carbon−heteroatom bonds.
in transition-metal-mediated reactions, mostly with palladium-
based catalytic systems.9 The great advantage inherent to the
nature of these reagents 1 is that they are typically more reactive
than the corresponding monobromides, therefore rendering the
cross-coupling quite facile, and their reactivity can be finely tuned
depending on the reaction partner and conditions. Indeed, they
can participate in site-selective cross-coupling reactions,10 where
only the sterically less hindered trans C−Br bond is involved in
the transformation (Scheme 1),11 yielding with excellent
strategy that has been especially successful and reliable for the
preparation of stereodefined olefins, even on complex substrates.
Slight modifications of the reaction conditions and/or the
stoichiometry of the reactions usually allow driving the reaction
to the formation of products 3, resulting from a double cross-
coupling, where the two halogen atoms are formally substituted.
In addition, gem-dibromoalkenes have also proven to be
especially suitable precursors of alkynyl−transition metal
complexes or synthetic equivalents of electrophilic alkynyl
residues, yielding substituted alkynes 4 after cross-coupling. In
all of these transformations, all reaction partners typically
involved in palladium-catalyzed cross-coupling reactions have
been used with vinyl dibromides for the formation of carbon−
carbon bonds (Grignard or organozinc reagents, stannanes,
boronic acids, terminal alkynes, etc.), which clearly demonstrated
the versatility of these reagents in palladium-catalyzed processes.
In sharp contrast, and apart from Hayes'12 and Bisseret's13
reports on the palladium-catalyzed intermolecular cross-coupling
with dialkylphosphites yielding alkynylphosphonates and intra-
molecular cross-coupling from the Lautens group14 and
others,13,15 the use of gem-dibromoalkenes in carbon−heter-
oatom bond-forming reactions has been less studied, despite the
enormous potential of these reactions. They would indeed
potentially provide efficient entries to a wide range of
heteroatom-substituted alkenes and alkynes, highly valuable
building blocks in organic synthesis, depending on the coupling
mode and the nature of the heteronucleophile used in the
process. On the basis of our experience in copper-catalyzed
reactions,16 we felt that the use of copper catalysis might provide
Scheme 1. 1,1-Dibromo-1-alkenes in Metal-Catalyzed Cross-
Coupling Reactions
stereoselectivity vinyl bromides 2, in which the remaining
bromine atom can be involved in a second cross-coupling, a
Scheme 2. Envisioned Copper-Mediated Cross-Coupling between 1,1-Dibromo-1-alkenes and Heteronucleophiles
B
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efficient systems to perform either site-selective, double, or
alkynylative cross-coupling with various heteronucleophiles
(Scheme 2). They indeed provided efficient routes to nitro-
gen-,17 oxygen-,18 and phosphorus19-substituted alkenes and
alkynes of general structures 6, 7, and 8. We report here a full
account of the development of these reactions as well as
extensions of our studies that broaden the scope of these
procedures as well as insights into the mechanism of these
reactions.
the removal of both the heterogeneous base and the catalyst. A
brief survey of the scope of this transformation showed that it can
successfully be applied to aryl- and alkyl-substituted dibromides
1, with more or less efficiency however, and that lactams and
oxazolidinones perform equally well, yielding the corresponding
1-bromoenamides with similar efficiency. It does therefore
provide a straightforward and practical entry to these useful
building blocks, in which the remaining bromide atom could
serve as an anchor for further functionalization, and nicely
complements the most efficient synthesis of these compounds
reported to date relying on the hydrobromination of the
corresponding ynamides using magnesium dibromide in wet
dichloromethane, a process in which the E-bromoenamides are
predominantly formed.20
RESULTS AND DISCUSSION
■
Selective Cross-Coupling with Nitrogen Nucleophiles:
Divergent Synthesis of 1-Bromoenamides, Ketene N,N-
Acetals, and Ynamides. We initiated our studies with the
cross-coupling between 1,1-dibromo-1-alkenes and nitrogen
nucleophiles, a reaction that could provide straightforward
entries to 1-bromoenamides, ketene N,N-acetals, or ynamides
depending on the coupling mode and provided that high levels of
selectivity between all reaction pathways could be achieved.
The selective monocoupling was actually one of the most
difficult one to optimize, mostly because of the fast elimination of
hydrobromic acid from Z-1-bromoenamides 10 in the presence
of a base and the ease of the second cross-coupling yielding
competitive formation of ketene N,N-acetals. However, using an
excess of vinyl dibromides 1 in the presence of catalytic amounts
of copper(I) iodide and N,N′-dimethylethylenediamine and 2
equivalents of potassium phosphate in 1,4-dioxane at 80 °C
cleanly promoted the formation of 10, which could be obtained
in reasonable yields as 2:1 mixtures of stereoisomers (Chart 1),
After demonstrating that gem-dibromides can participate in
selective mono-cross-coupling with N-nucleophiles, we next
moved to their use in alkynylative cross-coupling, which might
provide an original and efficient entry to ynamides, building
blocks whose chemistry has considerably expanded over the past
five years21 due to the development of new and efficient copper-
mediated methods for their synthesis. Among all methods
available for their preparation, the most efficient ones rely on the
use of bromoalkynes,22 terminal alkynes,23 potassium alkynyl
trifluoroborates,16g propiolic acids,24 and copper acetylides25 as
alkynylating agents, and the use of 1,1-dibromo-1-alkenes would
therefore provide an interesting and practical alternative to these
procedures. Due to the easy elimination from 1-bromoenamides
10, the optimization of this alkynylative cross-coupling with
sulfonamides as test substrates was relatively simple, and
changing the base to cesium carbonate together with increasing
the number of equivalents of this base from two to four smoothly
allowed for the production of the desired ynamides 12, which
were virtually formed as the sole products of the reactions (Chart
2).17 The choice of the base/solvent couple turned out to be a
critical parameter for this cross-coupling since the use of
potassium phosphate in toluene in place of cesium carbonate in
1,4-dioxane completely modified the outcome of the reaction,
ketene N,N-acetals resulting from a second cross-coupling being
isolated as the major products in this case (see below). Due to the
growing potential of ynamides in organic synthesis, the scope of
this cross-coupling was extensively studied with a wide range of
dibromides 1 and sulfonamides 11 possessing representative
substitution patterns. While the nature of the substituents on the
starting sulfonamide 11 had virtually no effect on the outcome of
the reaction, the substitution patterns of the dibromides had a
marked influence on the yields due to a slower elimination step
with gem-dibromoolefins substituted with an alkyl group, a
shortcoming that could be easily overcome by running the
reaction in DMF at 70 °C instead of in 1,4-dioxane at 60 °C with
these substrates. Using these optimized conditions, all N-
sulfonyl-ynamines 12 could be obtained in yields ranging from
64% to 97%, except in the case of methyl-substituted ynamide
12j, the low yield (25%) obtained with this substrate being
certainly due to its high sensitivity to basic conditions and its
extremely fast rate of hydrolysis. A wide range of substituents are
tolerated on both reaction partners since the reaction conditions
were shown to be compatible with bulky alkyl groups, electron-
donating as well as -withdrawing substituents, or heteroar-
omatics. Notably, the presence of an aromatic chloride was also
shown to be compatible since no competitive amination or
reduction was observed.
Chart 1. Site-Selective Cross-Coupling with N-Nucleophiles
to 1-Bromoenamides
the Z-olefin being the major one in all cases, as demonstrated by
NOE experiments. Besides the need for an excess of 1 to ensure
the selective formation of 1-bromoenamides 10, the number of
equivalents of potassium phosphate was found to be the key
parameter in this selective mono-cross-coupling: while the use of
a single equivalent of the base resulted in low conversion,
increasing this number to three dramatically favored the
elimination since only traces of 10 could be detected in crude
reaction mixtures. A major practical advantage of this procedure
is that no workup is required since a simple filtration allows for
To further test the efficiency of this alkynylation of
sulfonamides, the synthesis of a bis-ynamide from bis-
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Chart 2. Alkynylative Cross-Coupling with Sulfonamides to
N-Sulfonyl-ynamines
Chart 3. Alkynylative Cross-Coupling with Pyrrolidinone,
Carbamates, and Oxazolidinones
sulfonamide 14 was evaluated. Under our standard conditions
and using 3 equivalents of (2,2-dibromovinyl)benzene 13, the
desired product 15 resulting from a double alkynylation could be
isolated in 86% yield after 48 h at 60 °C in 1,4-dioxane (Scheme
3).
The synthesis of ynamides from other representative N-
nucleophiles commonly used in the chemistry of ynamides was
next envisioned. The reactivity of pyrrolidinone, carbamates, and
oxazolidinones 16 was therefore assayed with various dibromides
1 possessing representative substituents: the alkynylation was
found to be a little less efficient with these N-nucleophiles
compared to the one involving sulfonamides, which is mostly due
to the lower acidity of these substrates (pKa values in DMSO of
24 and 20−21 for pyrrolidinone and oxazolidinones, respec-
tively, vs 16−18 for sulfonamides), but still gave the
corresponding ynamides 17 in good to excellent yields (Chart
3). Importantly, the presence of bulky substituents around the
nitrogen, which can dramatically lower the yields with other
procedures, had no detrimental effect on the cross-coupling,
therefore enabling the alkynylation of a wide range of chiral
ynamides. Here again, the reaction from alkyl-substituted 1,1-
dibromo-1-alkenes was best performed in DMF at 70 °C rather
than in 1,4-dioxane at 60 °C to avoid the formation of 1-
bromoenamides, which are extremely difficult to separate from
the corresponding ynamides, and facilitate the elimination step.
Finally, the alkynylation of π-excessive nitrogen nucleophiles
18 with vinyl dibromides 1 was examined. Compared to the
synthesis of other classes of ynamides, their preparation, mostly
relying on the copper-catalyzed cross-coupling with bromoal-
kynes, is typically more difficult due to competing direct
nucleophilic addition of the nitrogen nucleophile to the alkynyl
bromide, yielding heterocyclic 2-bromoenamines.22c,26 The use
of 1,1-dibromo-1-alkenes 1 might therefore be a good alternative
since the formation of these byproducts is not possible with these
reagents.
Benzimidazole was first chosen as a model substrate to initiate
those studies: if the reaction turned out to be a bit more sluggish
Scheme 3. Double Alkynylation of a Bis-sulfonamide Using a Vinyl Dibromide
D
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compared to the one involving standard N-nucleophiles such as
sulfonamides, oxazolidinones, or secondary amides, a simple
increase of the reaction temperature to 80 °C allowed for a
smooth alkynylation. The reaction was found to be compatible
with a variety of aromatic groups, and the presence of electron-
withdrawing or -donating substituents had virtually no effect on
the reaction (Chart 4). Cinnamaldehyde-derived dibromide was
nucleophiles and extensively studying the scope and potential of
these transformations, we focused our attention on the
optimization of the third and last possible coupling mode with
these reagents: the double cross-coupling. Provided that a
combination of the proper catalytic system, base, solvent, and
temperature could allow for a selective double cross-coupling
and suppress the competitive mono-cross-coupling and elimi-
nation pathways, this could provide an interesting entry to
stabilized ketene N,N-acetals 20, useful intermediates in organic
synthesis that combine two enamines in one functional group
and exhibit significant nucleophilicity at C-2 due to the
delocalization of the lone pairs of both nitrogen atoms into the
double bond. Due to the lack of general methods for their
preparation,29 this might bring a practical procedure for their
synthesis as well as provide additional insights into the reactivity
of vinyl dibromides in copper catalysis.
Chart 4. Alkynylative Cross-Coupling with Conjugated N-
Heterocycles
On the basis of results obtained during the optimization of the
alkynylative cross-coupling, where we had noticed that
considerable amounts of products resulting from a double
cross-coupling 20 were formed when potassium phosphate was
used instead of cesium carbonate, regardless of the reaction
stoichiometry used (1.5 equivalents of the dibromide 1
compared to the nitrogen nucleophile 16 in order to try to
avoid the second cross-coupling), the optimized conditions were
relatively easy to obtain, and we found that toluene was slightly
more efficient than 1,4-dioxane for this transformation, which
was best performed using 2.5 equivalents of the nitrogen
nucleophile with respect to the gem-dibromoolefin 1. The scope
and limitations of the ketene aminal synthesis was briefly
evaluated using our optimized conditions, and the reaction was
found to be best performed with lactams, which gave the
corresponding products in reasonable to good yields, the
reaction being again more efficient with aryl- or alkenyl-
substituted dibromoalkenes 1 (Chart 5).17b In this case, the
Chart 5. Double Cross-Coupling with Lactams to Ketene N,N-
Acetals
also found to be an excellent reaction partner, providing the
corresponding styryl-substituted alkynylbenzimidazole 19b in
excellent yield. The slower alkynylation with alkyl-substituted
dibromoalkenes turned out to be more pronounced with
benzimidadoles, and the corresponding products, such as 19a,
could be isolated only in low yields, while the cross-coupling
involving substituted benzimidazoles was found to be equally
efficient. Extending this chemistry to include indazoles as
substrates proved to be quite successful, which is particularly
noteworthy since the corresponding stable alkynylated products
might provide excellent platforms for molecular diversity and
drug discovery. A number of N-alkynylindazoles can be readily
prepared using our reaction conditions with excellent
regioselectivity for the N1 alkynylation product, and, as with
benzimidazoles, a variety of functional groups are tolerated.17d
This procedure was later extended by other groups to the use of
indazoles using TMEDA as the ligand,27 which seems to be
superior to DMEDA in some cases, and to the alkynylation of
imidazoles and pyrazoles using a preformed soluble copper
catalyst, [Cu(Phen)(PPh3)Br].28
use of other N-nucleophiles such as sulfonamides or conjugated
N-heterocycles did not give the corresponding ketene acetals,
and the alkynylative cross-coupling was preferred with these
reagents, which might be due to a faster elimination from these
substrates and to an unfavorable second cross-coupling due to
the steric bulk associated with these nucleophiles. As a note, the
use of carbamate-protected 1,2-diamines did not yield the
formation of the expected cyclic ketene N,N-acetals but
tetrahydropyrazine derivatives resulting from an alkynylative
After demonstrating that 1,1-dibromo-1-alkenes can partic-
ipate in site-selective and alkynylative cross-coupling with N-
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cross-coupling followed by a 6-endo-dig cyclization, which is in
accordance with similar results from the Urabe group.30
Chart 6. Site-Selective Cross-Coupling with Phenols to 1-
Bromoenol Ethers
We have therefore been able to demonstrate that 1,1-dibromo-
1-alkenes can participate in copper-catalyzed cross-coupling
reactions with a variety of nitrogen nucleophiles and that all
possible coupling mode are possible with these reagents,
provided that the right stoichiometry is used. A fine-tuning of
the reaction conditions and the nature of the base and the
solvent, which are key parameters in these coupling reactions, as
well as the nature of the nitrogen-nucleophile, therefore allows
for divergent preparations of 1-bromoenamides, ynamides, or
ketene N,N-acetals, useful reagents in organic synthesis that are
now readily available from simple starting materials and
inexpensive copper-based catalytic systems. A logical extension
of this work was the application of these procedures to other
nucleophiles commonly used in copper catalysis, alcohols being
especially attractive coupling partners due to the high potential of
the products that might arise from their selective cross-coupling
with vinyl dibromides. The development of the corresponding
procedures is described in the following section.
Selective Cross-Coupling with Oxygen Nucleophiles:
Straightforward Synthesis of 1-Bromoenol Ethers,
Ketene Acetals, and Ynol Ethers. Phenols were chosen as
substrates for these studies since they would provide products
resulting either from a site-selective, alkynylative, or double
cross-coupling that would be much more stable than the one
obtained with aliphatic alcohols, the corresponding ynol ethers
and ketene acetals being well known for their instability. As with
N-nucleophiles, we initiated our studies with the site-selective
cross-coupling using a slight excess of 1. While the nature of the
base was found to be the key parameter with N-nucleophiles, the
ligand appeared to be of crucial importance in this case. As
expected, the cross-coupling was much more sluggish and the
suppression of the competing dimerization of the starting
dibromides to the corresponding diynes31 turned out to be quite
challenging. The use of aromatic N,N-bidentate ligands such as
1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline,
or 2,2′-bipyridine however allowed for a clean site-selective
cross-coupling, and the optimized conditions relied on the use of
15 mol % copper(I) iodide, 30 mol % 2,2′-bipyridine, and 4.5
equivalents of potassium phosphate in toluene at 110 °C.
With the optimized conditions in hand, we examined the
reactivity of various 1,1-dibromo-1-alkenes 1 and phenols 21
possessing representative substituents and substitution patterns
(Chart 6).18 Para-, meta-, and ortho-substituted phenols were all
readily transformed to the corresponding bromoenol ethers 22,
although the cross-coupling was slowed down in the last case.
The presence of electron-withdrawing or -donating groups had
virtually no effect on the outcome of the reaction, and even the
challenging 4-bromophenol could be smoothly transformed to
the corresponding enol-ether 22g, without competing cross-
coupling or reduction. In this case, the nature of the substituent
on the starting dibromides 1 was found to have little influence on
the reaction time and yields, and the corresponding alkyl- (22a-
s), alkenyl- (22t), and aryl- (22u-v) substituted bromoenol
ethers were obtained in comparable yields and efficiency. In all
cases, a site-selective cross-coupling favoring the formation of the
Z-isomers occurred with synthetically useful levels of stereo-
selectivity, which nicely complements the synthesis of their E-
isomers by hydrobromination of the corresponding ynol ethers
with bromotrimethylsilane in methanol, a reaction that we found
to be nonselective in the case of phenol-derived ynol ethers.32
Compared to the analogous coupling involving N-nucleophiles,
higher levels of selectivity were obtained in all cases with phenols
(typically 9:1 with phenols compared with 7:3 with lactams and
oxazolidinones), which might be due to the slower cross-
coupling with phenols, that would imply a better differentiation
of the two C−Br bonds and ensure a greater selectivity for the
least hindered trans C−Br bond. Due to the very different nature
of the ligands used for the site-selective cross-coupling involving
N- and O-nucleophiles, distinct reaction mechanisms might also
be operating and could account for the nucleophile-dependent
selectivities. Indeed, on the basis of computational studies by
Buchwald and Houk33 and by Fu,34 the use of N- and O-
nucleophiles as well as the use of different chelating ligands might
result in either a different activation mode of the 1,1-
dibromoalkene (oxidative addition, atom transfer, or single-
electron transfer) or a shift in the rate-limiting step depending on
the coordination of the nucleophile before or after the oxidative
addition.
The alkynylative cross-coupling was next envisioned with the
hope of providing a useful alternative to the existing routes to O-
substituted alkynes relying on either the use of lengthy stepwise
sequences35 or alkynylation with alkynyl hypervalent iodonium
salts,36 which has strongly hampered the development of these
most useful building blocks. With this goal in mind, we spent a
considerable amount of time trying to optimize all reaction
parameters in order to find a system that would allow direct
alkynylative cross-coupling, and most of the possible combina-
tions of ligands, bases, solvents, and temperatures were
evaluated. We were, however, unfortunately unable to cleanly
isolate the expected ynol ethers 23 in decent yields, mostly
because of the much slower elimination step from the
intermediate bromoenol ethers 22 compared to their nitrogen
analogues. We therefore decided to slightly modify our strategy
and found that exposure of the crude reaction mixtures obtained
after the site-selective cross-coupling described above to
potassium tert-butoxide after dilution with 1,4-dioxane triggered
a rapid and clean β-elimination and allowed for the isolation of
the long-sought-after ynol ethers 23 in a one-pot, two-step
process and in good yields.18 The elimination being an especially
clean process, the scope of our ynol ether synthesis is basically
the same as that of the site-selective cross-coupling, and ynol
ethers 23 with representative substitution patterns could be
obtained with high efficiency (Chart 7), which nicely comple-
F
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ments their classical synthesis involving the procedures cited
above.
While the use of aliphatic alcohols as partners in copper-
catalyzed cross-coupling with gem-dibromoolefins mostly results
in dimerization of the latter and would anyway generate products
that would not be compatible with the reaction conditions, we
thought that trifluoroethanol 25, whose pKa is relatively close to
that of phenols, might participate in site-selective or double
cross-couplings and therefore broaden the scope of these
reactions. We were actually able to demonstrate that this was
indeed the case, and a brief study summarized in Scheme 4 shows
that trifluoroethanol-derived bromoenol ethers 26 and ketene
acetal 28 can be readily obtained using our standard conditions
with synthetically useful yields and, in the first case, reasonable
levels of selectivity in favor of the Z-isomers, which were
predominantly formed, as in the case of phenol derivatives.
In view of these results, oxygen nucleophiles can therefore
participate in site-selective and double cross-coupling reactions,
providing efficient entries to mono- and bis-oxygenated alkenes,
and can also be alkynylated to ynol ethers with gem-
dibromoolefins using a one-pot, two-step process. To complete
these studies, we moved to the use of another class of
nucleophiles commonly used in copper-catalyzed carbon−
heteroatom bond-forming reactions: phosphorus nucleophiles.
Results obtained with these substrates are described in the
following paragraphs.
Chart 7. Synthesis of Ynol Ethers by Site-Selective Coupling/
Elimination
Cross-Coupling with Dialkylphosphites: New Entry to
Vinylphosphonates. Copper-catalyzed reactions involving P-
nucleophiles such as dialkyl/diaryl phosphines, diarylphosphine
oxides, dialkylphosphites, and H-phosphinates have recently
emerged as useful and efficient alternatives to the corresponding
palladium-catalyzed transformations. Compared to other
nucleophiles, this area has been however much less studied,
despite recent progress that unambiguously demonstrated the
efficiency and high potential of these reactions.
A reoptimization of the reaction conditions was finally
performed in order to selectively promote a double cross-
coupling, and this time, problems associated with the high
sensitivity of the ketene acetals 24 toward hydrolysis or during
their purification considerably complicated the optimization.
The desired ketene acetals 24 arising from a clean double copper-
catalyzed phenoxylation could however be obtained in virtually
pure form by performing the reaction with excess phenol (4
equivalents) in 1,4-dioxane at 110 °C under the catalysis of
copper(I) iodide (10 mol %) and 2,2′-bipyridine (20 mol %)
followed by simple removal of the catalyst and base by filtration
over paper filter, concentration of the crude mixture, and
elimination of excess phenol by extraction of the apolar product
24 with pentane. Using this optimized procedure, a set of ketene
acetals 24, previously unknown and possessing representative
substitution patterns on both the phenol and the double bond,
could be obtained in good yields, as shown from the structures
collected in Chart 8.
To initiate our studies on the cross-coupling between 1,1-
dibromo-1-alkenes and P-nucleophiles, we initially focused on
the use of diphenylphosphine as a model nucleophile. However,
we were not able to promote any kind of cross-coupling with this
substrate, and even after considerable experimentation on the
nature of the copper source, ligand, base, solvent, and
temperature, we could not suppress the dimerization of the
dibromoalkenes,31 the corresponding diynes being isolated as the
major products in couple trials, or the catalyst poisoning
observed in most cases. The replacement of diphenylphosphine
with the corresponding phosphine borane was not more
successful, and limited success was also met with diphenylphos-
phine oxide. To our delight, the use of diisopropylphosphite was
found to be much more efficient. Indeed, upon reaction with
copper iodide, N,N′-dimethylethylenediamine, and potassium
phosphate in toluene at 120 °C for a day and provided that 2.5
equivalents of the phosphite were used (the use of less than 2
equivalents yielded the formation of complex and especially
messy mixtures of products), a single product was formed, which
turned out to be, quite unexpectedly, a vinylphosphonate. These
compounds are especially useful small organic molecules used in
polymer science as copolymers, additives, or flame-retardants, in
medicinal chemistry, and as building blocks for the introduction
of remote phosphonate functional groups or to prepare
biologically active molecules.37 Their preparation being still far
from a trivial task,38 we decided to study the scope of our
transformation that might provide an interesting alternative to
the preparation of these building blocks.
Chart 8. Double Cross-Coupling with Phenols to Ketene O,O-
Acetals
Using our optimized conditions, which required a rather high
loading of both copper(I) iodide and ligand, which is in sharp
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Scheme 4. Site-Selective and Double Cross-Coupling with 2,2,2-Trifluoroethanol
contrast with results obtained with N- and O-nucleophiles, the
cross-coupling between a set of vinyl dibromides 1 and a series of
dialkylphosphites 29 was examined: results from these studies are
shown in Chart 9.19 As evidenced with these results, the reaction
to be insensitive to the presence of electron-withdrawing or
-donating groups when starting from aryl-substituted dibromides
1. We also briefly studied the cross-coupling involving the more
challenging disubstituted, benzophenone- and acetophenone-
derived 1,1-dibromoalkenes. Again, the reaction was found to be
quite efficient since the corresponding synthesis of trisubstituted
1-alkenylphophonates 30r and 30s could be isolated in 58% and
78% yield. In the last case, the E-isomer was formed
predominantly, with a selectivity similar to that observed when
starting from monosubstituted gem-dibromoalkenes.
Chart 9. Cross-Coupling with Dialkylphosphites to
Vinylphosphonates
To further test this procedure, a double cross-coupling was
finally envisioned by reacting bis-dibromoalkene 31 with 5
equivalents of diisopropylphosphite 32 under our standard
conditions. To our delight, the corresponding bis-1-alkenyl-
phosphonate 33 could be isolated in an excellent 83% yield and
with reasonable selectivity in favor of the E,E-isomer (Scheme 5).
As demonstrated with these results, phosphorus-based
nucleophiles behave in a dramatically different way compared
to their nitrogen or oxygen analogues: while most of them
completely inhibit the catalyst, the use of dialkylphosphites gives
a completely different reaction in which both bromine atoms are
formally substituted, with phosphorus and hydrogen atoms,
respectively. The mechanism that might be involved in this
reaction will be discussed in the last section of this article.
Heteronucleophiles not Participating in Copper-
Catalyzed Cross-Coupling Reactions with 1,1-Dibromo-
1-alkenes. Besides all heteronucleophiles described in the
previous paragraphs, whose use in combinations with gem-
dibromoalkenes and copper-based catalytic systems was found to
provide new routes to a wide range of heterosubstituted alkenes
and alkynes, the reactivity of a certain number of other
heteronucleophiles was also evaluated. While sulfonamides,
cyclic secondary amides, carbamates, oxazolidinones, conjugated
N-heterocycles, phenols, trifluoroethanol, and dialkylphosphites
were in most cases readily coupled with all kinds of vinyl
was found to be quite general, and 1-alkenylphosphonates 30
could be obtained in all cases with reasonable to good yields and
with useful selectivities in favor of the E-isomer. A variety of
substituents can be successfully introduced on both the
phosphonate and alkene moieties, and the reaction was found
Scheme 5. Copper-Catalyzed Synthesis of a Bis-1-alkenylphosphonate from a Bis-dibromoalkene
H
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Chart 10. Nonparticipating Heteronucleophiles in Copper-Catalyzed Cross-Coupling Reactions with 1,1-Dibromo-1-alkenes
dibromides, the use of other substrates shown in Chart 10 was
found to be more problematic. Indeed, acyclic secondary amides,
Boc-protected amines, hydrazine or hydroxylamine derivatives,
diphenylamine, ureas, pyrazole, pyrrole, and indole were
reluctant to participate in either site-selective, alkynylative, or
double cross-coupling, mostly due to either their lower basicity
or their increased steric bulk, and dimerization of the starting 1,1-
dibromoalkenes was observed with these substrates, as well as in
the case of aliphatic alcohols, silanols, dialkylphosphates, or
sulfinates. In contrast, no reaction at all occurred when starting
from thiophenol, diphenylphosphine, or its oxide, which might
be due to catalyst poisoning with these substrates.
compounds are perfectly stable and can be stored for months
without noticeable degradation.
Copper-Catalyzed Cross-Coupling Reactions with 1,1-
Dibromo-1-alkenes on Complex Substrates. One last point
that we had to address to ensure the generality of our procedures
was to test them with complex substrates. Although many
chemical transformations do perform well when applied to
relatively simple or commercially available molecules, it is of
great importance to test them in “real life” situations, in which
they are clearly challenged and pushed way beyond their limits, to
ensure their robustness, compatibility, and selectivity. To this
aim, a series of site-selective, alkynylative, and double cross-
coupling reactions between structurally complex 1,1-dibromo-1-
alkenes and nucleophiles were next envisioned, and representa-
tive examples are collected in Scheme 6. As shown by these
results, the presence of various functional groups and the use of
more demanding substrates did not affect the cross-coupling
reactions, even if the yields were found to be lower in some cases,
which are therefore suitable for the preparation of structurally
complex 1-bromoenamides, ynamides, 1-bromoenol ethers, ynol
ethers, and vinylphosphonates. For example, citronellal-derived
dibromides 34 and 51 were readily transformed to the
corresponding 1-bromoenamide 36, 1-bromoenol ether 45,
ynol ether 48, or vinylphosphonate 52 in reasonable to good
yields, affording the corresponding monocoupled products in
which the stereocenter from the starting citronellal was readily
incorporated. Dibromide 37, another readily available complex
gem-dibromoolefin obtained by a Ramirez dibromoolefination
from the corresponding prolinal derivative, was also smoothly
transformed to the corresponding ynamide 39 or vinyl-
phosphonate 50 in good yields and without epimerization,
showing that structurally complex dibromoalkenes perform well
in selective copper-mediated cross-coupling reactions with
representative heteronucleophiles. The complexity can also
arise from the use of more complex heteronucleophiles, as shown
with the alkynylation of azetidinyl-sulfonamide 40, chaetomi-
nine-derived sulfonamide 42, O17-methylestradiol 46, and
menthol-derived phosphite 54 or with the synthesis of
bromoenol ether 47.
Gram-Scale Copper-Catalyzed Cross-Coupling Reac-
tions with 1,1-Dibromo-1-alkenes. To fully assess the
efficiency of our procedures and to further demonstrate the
efficiency and versatility of 1,1-dibromo-1-alkenes in copper-
catalyzed cross-coupling with heteronucleophiles, we decided to
make sure all our procedures are not limited to the scale used
during our systematic studies, i.e., 0.67 to 2.0 mmol. To this end,
a series of site-selective, alkynylative, and double cross-coupling
reactions were assayed on gram/multigram scales with
representative N-, O-, and P-nucleophiles. Results from those
studies are shown in Chart 11 and demonstrate that ynamides,
ketene N,N-acetals, 1-bromoenol ethers, ynol ethers, ketene
O,O-acetals, and vinylphosphonates can easily be obtained on a
gram scale without noticeable change in yields. A major
advantage of these procedures that is especially appreciable on
a big scale is that they do not require workups after the cross-
coupling reactions since simple filtrations of crude reaction
mixtures over a short plug of silica allows for the elimination of
the base and catalyst. The low cost of both copper source (the
cost of copper iodide is typically $160 USD for a kilogram) and
ligand (N,N′-dimethylethylenediamine typically costs $160 USD
for 25 g) is also a real advantage of these copper-based processes,
which can therefore easily be performed on large scales at
reasonable costs. As a note, the purity of copper(I) iodide has
virtually no influence since 99.999% purity, which we used for
our studies to avoid possible cocatalysis by contaminants and
ensure the reproducibility of our results, and 98% purity gave
exactly the same results. All together, the development of copper-
catalyzed cross-coupling between heteronucleophiles and 1,1-
dibromo-1-alkenes allows for an easy and divergent synthesis of a
wide range of heterosubstituted alkenes and alkynes that can, in
most cases, hardly be obtained using other methods. Our
syntheses are easily amenable on a gram scale, which should
contribute to the development of these useful building blocks.
Apart from ketene O,O-acetals and alkyl-substituted, tosyl-
protected ynamines, which are quite prone to hydrolysis (they
are readily hydrolyzed overnight in chloroform), all other
After carefully studying the scope of all possible modes of
cross-coupling between 1,1-dibromo-1-alkenes and various
heteronucleophiles using copper catalysis as well as their scale-
up and the use of the optimized procedures with complex
substrates, we decided to try to obtain some insights into the
reaction mechanisms involved in the formation of products
resulting from formal site-selective, alkynylative, or double cross-
coupling reactions as well as in the synthesis of vinyl-
phosphonates, various reaction pathways being possible to
explain the formation of these products.
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Chart 11. Gram-Scale Cross-Coupling with 1,1-Dibromo-1-alkenes
Insights into the Reaction Mechanism. First, non-
catalyzed processes involving formation of bromoalkynes and
addition of heteronucleophiles yielding heterosubstituted
alkenes possessing a bromide in the 2-position39 and their
subsequent and low-yielding transformation to the correspond-
ing heterosubstituted alkynes or ketene acetals under harsh
conditions and/or with poor substrate scope39a,40 have been
rigorously discarded in all our cases by performing careful control
experiments in the absence of the copper salt and ligand. Besides
these noncatalytic processes, various reaction pathways involving
at least one copper-catalyzed step can account for the formation
of products resulting from formal site-selective, alkynylative, or
double cross-coupling reactions in the case of N- and O-
nucleophiles. Indeed, while the formation of products resulting
from a mono-cross-coupling from 6 can only arise by activation
of one bromide atom from the starting dibromides 1, the
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Scheme 6. Copper-Catalyzed Cross-Coupling Reactions with 1,1-Dibromo-1-alkenes on Complex Substrates
selective cross-coupling involving the sterically less hindered
trans C−Br accounting for the preferential formation of the Z-
isomer, the formation of heterosubstituted alkynes 7 can involve
either an elimination step from bromoalkenes 6 or a cross-
coupling from intermediate bromoalkynes 56 and the formation
of bis-heterosubstituted alkenes 8 can arise from hydro-
amination/hydroalkoxylation of the corresponding alkynes 7
or a second copper-catalyzed cross-coupling from 6 (Scheme 7).
K
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Scheme 7. Possible Pathways Involved in the Copper-Catalyzed Cross-Coupling of 1,1-Dibromo-1-alkenes with
Heteronucleophiles
The intermediacy of bromoalkynes 56 in the formation of
ynamides is highly unlikely since control experiments have
demonstrated that the latter are formed in really poor yields
when bromoalkynes 56 are reacted with N-nucleophiles under
our optimized conditions shown in Charts 2 and 3. Moreover,
lowering the reaction temperature for the cross-coupling
performed with alkyl-substituted dibromides 1 allowed for the
isolation of significant amounts of 1-bromoenamides 6, which
were shown to be readily converted to the corresponding
ynamides when treated with cesium carbonate at 70 °C in DMF.
A unified mechanism involving site-selective cross-coupling
followed by elimination therefore accounts for the formation of
heterosubstituted alkynes 7 upon cross-coupling between
dibromides 1 and heteronucleophiles 5.
Concerning the formation of ketene acetals 8, hints
concerning the reaction mechanism were found in their isolation
upon copper-catalyzed reactions between heteronucleophiles 5
and heterosubstituted bromoalkenes 6, under the reaction
conditions shown in Charts 5 and 8, and in the presence of
bromoalkenes 6 before completion of the reaction yielding
ketene acetals 8. To unambiguously demonstrate the mechanism
involved in their formation, deuterated (13D and 57D) and
nondeuterated (13 and 57) dibromoalkenes were respectively
reacted with deuterated and nondeuterated pyrrolidinone and
phenols under our coupling conditions optimized for the site-
selective cross-coupling (Scheme 8). Results from these
experiments unambiguously demonstrate that the vinylic
hydrogen atom of the starting dibromides is fully retained
during the reaction, clearly indicating that β-elimination followed
by hydroamination or hydroalkoxylation is not a competitive
pathway and that ketene acetals 8 are formed by two consecutive
copper-mediated cross-coupling reactions.
Finally, and because of the high polarization of the triple bonds
of ynamides and ynol ethers, which renders these compounds
highly sensitive to nucleophilic addition, even with weak
nucleophiles, the formation of bromoenamides and bromoenol
ethers might result from hydrobromination of these highly
electrophilic alkynes, which is however rather unlikely under
basic conditions. To make sure this was however not the case,
especially when mixtures of isomers were obtained where one of
them could be formed through a different, non-copper-catalyzed
mechanism, additional experiments with deuterated and non-
deuterated vinyl dibromides 27 and 27D were performed with
deuterated and nondeuterated pyrrolidinone and phenols,
respectively. Here again, the vinylic hydrogen atom of the
starting dibromides is fully retained during the reaction, therefore
allowing us to discard a competitive hydrobromination reaction
in the formation of 6.
A different mechanism is involved in the formation of
vinylphosphonates upon cross-coupling between dibromides 1
and dialkylphosphites 29, where the latter serve as both coupling
partners and reducing agents. Starting from these reagents, a
Hirao reduction involving phosphite conjugate addition/
protonation/halophilic elimination would yield an intermediate
vinyl bromide whose cross-coupling would then account for the
formation of 30.41 Alternatively, a site-selective cross-coupling
might occur first and would generate an α-bromovinylphosph-
onate, an intermediate in which the electron-withdrawing group
would facilitate the conjugate addition involved in the Hirao-like
reduction. Based on the greater reactivity of vinyl dibromides
than that of bromoalkenes toward copper-mediated cross-
coupling reactions and on the easier reduction of α-
bromovinylphosphonates than vinyl dibromides with dialkyl-
phosphites, the first hypothesis, which would first involve a Hirao
reduction that typically proceeds under harsher conditions and
with more polar solvents, seems highly unlikely. Indeed, a simple
control experiment consisting of the reaction between excess
diisopropylphosphite and (2,2-dibromovinyl)benzene in toluene
at 120 °C with or without potassium phosphate showed that the
Hirao reduction does not proceed under the conditions used for
the copper-catalyzed cross-coupling, indicating that the cross-
coupling is most certainly the first step of the process that would
proceed through the intermediacy of α-bromovinylphospho-
nates resulting from a site-selective cross-coupling and whose
reduction with a second equivalent of phosphite would yield the
corresponding vinylphosphonates.
CONCLUSION
■
As stated in the Introduction, copper catalysis has undergone
nothing short of a renaissance over the past decade and has
enabled the design of efficient and general reactions for the
formation of carbon−heteroatom bonds, which are now
commonly used for the preparation of simple building blocks
and complex molecules as well. These developments provided
the chemical community with highly efficient tools that have
found numerous academic and industrial applications and clearly
had a deep impact on organic synthesis.
Further developments in copper catalysis will mostly follow
two main directions, the first one being the design of new
catalytic systems with improved efficiencies that will allow
overcoming the existing limitations, such as the catalyst loading,
the need for thermal activation, or the limited efficiency of cross-
L
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Scheme 8. Mono- and Double-Cross-Coupling with Deuterated Substrates
coupling involving aryl chlorides, and the second one being the
development of new reactions and the use of novel coupling
partners for copper catalysis. In this area, we have demonstrated
that vinyl dibromides can be successfully coupled with a wide
range of heteronucleophiles and therefore provide efficient and
straightforward entries to numerous building blocks such as 1-
bromoenamides, ynamides, ketene N,N-acetals, 1-bromoenol
ethers, ynol ethers, ketene O,O-acetals, and vinylphosphonates.
M
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(16) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003. (c) Toumi, M.; Couty, F.; Evano, G. Synlett 2008, 29. (d) Coste,
We envision great acceptance of these new processes, which,
combined with the high versatility of 1,1-dibromoalkenes and
their availability, should break new ground in copper catalysis.
́
A.; Toumi, M.; Wright, K.; Razafimahaleo, V.; Couty, F.; Marrot, J.;
Evano, G. Org. Lett. 2008, 10, 3841. (e) Toumi, M.; Couty, F.; Marrot, J.;
Evano, G. Org. Lett. 2008, 10, 5027. (f) Evano, G.; Toumi, M.; Coste, A.
Chem. Commun. 2009, 4166. (g) Jouvin, K.; Couty, F.; Evano, G. Org.
Lett. 2010, 12, 3272. (h) Laouiti, A.; Rammah, M. M.; Rammah, M. B.;
Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6.
(17) (a) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem.,
Int. Ed. 2009, 48, 4381. (b) Coste, A.; Couty, F.; Evano, G. Org. Lett.
2009, 11, 4454. (c) Coste, A.; Couty, F.; Evano, G. Org. Synth. 2010, 87,
231. (d) Jouvin, K.; Evano, G. Chim. Oggi 2011, 29, 31.
(18) Jouvin, K.; Bayle, A.; Legrand, F.; Evano, G. Org. Lett. 2012, 14,
1652.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures, characterization, and copies
of 1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: gevano@ulb.ac.be.
Notes
■
(19) Evano, G.; Tadiparthi, K.; Couty, F. Chem. Commun. 2011, 47,
179.
The authors declare no competing financial interest.
(20) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(21) For reviews, see: (a) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(22) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 2368. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera,
E. L. Org. Lett. 2004, 6, 1151.
ACKNOWLEDGMENTS
■
The authors thank the CNRS, the University of Versailles, the
University of Brussels, and the ANR (projects ProteInh ANR-07-
JCJC-0025-01, DYNAMITE ANR-2010-BLAN-704, and VIN-
FLUSUP ANR-11-JS07-003-01) for financial support. K.J. and
̀
A.C. respectively acknowledge the Ministere de la Recherche and
the National Cancer Institute for graduate fellowships. G.K. and
K.T. acknowledge the University of Versailles for postdoctoral
fellowships.
(23) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
(24) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000.
(25) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756.
(26) (a) Laroche, C.; Li, J.; Freyer, M. W.; Kerwin, S. M. J. Org. Chem.
2008, 73, 6462. (b) Burley, G. A.; Davies, D. L.; Griffith, G. A.; Lee, M.;
Singh, K. J. Org. Chem. 2010, 75, 980. (c) Das, B.; Reddy, G. C.;
Balasubramanyam, P.; Salvanna, N. Synthesis 2011, 816.
(27) Wang, M.-G.; Wu, J.; Shang, Z.-C. Synlett 2012, 23, 589.
(28) Das, B.; Salvanna, N.; Reddy, G. C.; Balasubramanyam, P.
Tetrahedron Lett. 2011, 52, 6497.
(29) Ketene N,N-acetals related to 20 have been prepared by acylation
of acetamidines. See: (a) Miescher, K.; Marxer, A.; Urech, E. Helv. Chim.
Acta 1951, 34, 16. (b) Ono, M.; Tanaka, H.; Hayakawa, K.; Tamura, S.
Chem. Pharm. Bull. 1983, 31, 3534.
(30) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc.
2008, 130, 1820.
(31) Coste, A.; Couty, F.; Evano, G. Synthesis 2010, 1500.
(32) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840.
(33) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 6205.
REFERENCES
■
(1) For reviews, see: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2009, 48, 6954. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054.
(2) For a perspective article, see: Surry, D. S.; Buchwald, S. L. Chem.
Sci. 2010, 1, 13.
(3) For an account, see: Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(4) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Ullmann,
F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211.
(5) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(6) Ramirez, F.; Desal, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84,
1745.
(7) (a) Fang, Y.-Q.; Lifchits, O.; Lautens, M. Synlett 2008, 413.
(b) Bryan, C.; Aurregi, V.; Lautens, M. Org. Synth. 2009, 86, 36.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(9) For reviews, see: (a) Legrand, F.; Jouvin, K.; Evano, G. Isr. J. Chem.
2010, 50, 588. (b) Chelucci, G. Chem. Rev. 2012, 112, 1344.
(10) For a review on site-selective cross-coupling of polyhalogenated
compounds, see: Wang, J.-R.; Manabe, K. Synlett 2009, 1405.
(11) (a) Zapata, A. J.; Ruiz, J. J. Organomet. Chem. 1994, 479, C6.
(b) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. (c) Shen, W.;
Thomas, S. A. Org. Lett. 2000, 2, 2857.
(12) Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873.
(13) Thiegles, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron
Lett. 2004, 45, 907.
(14) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Fang, Y.-
Q.; Lautens, M. J. Org. Chem. 2008, 73, 538. (c) Nagamochi, M.; Fang,
Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955. (d) Fayol, A.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 4203. (e) Bryan, C. S.; Lautens, M. Org.
Lett. 2008, 10, 4633. (f) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem.
2007, 72, 5152. (g) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens,
M. Chem. Commun. 2009, 5236. (h) Yuen, J.; Fang, Y.-Q.; Lautens, M.
Org. Lett. 2006, 8, 653. (i) Bryan, C. S.; Braunger, J. A.; Lautens, M.
Angew. Chem., Int. Ed. 2009, 48, 7064. (j) Newman, S. G.; Lautens, M. J.
Am. Chem. Soc. 2010, 132, 11416.
(15) (a) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett.
2008, 10, 4899. (b) Arthuis, M.; Pontikis, R.; Florent, J.-C. Org. Lett.
2009, 11, 4608. (c) Wang, Z.-J.; Yang, J.-G.; Yang, F.; Bao, W. Org. Lett.
2010, 12, 3034. (d) Xia, Z.; Wang, K.; Zheng, J.; Ma, Z.; Jiang, Z.; Wang,
X.; Lv, X. Org. Biomol. Chem. 2012, 10, 1602.
(34) Yu, H.-Z.; Jiang, Y.-Y.; Fu, Y.; Liu, L. J. Am. Chem. Soc. 2010, 132,
18078.
́
(35) For a general reference, see: Witulski, B.; Alayrac, C. In Science of
Synthesis: Houben-Weyl Methods of Molecular Transformations; de
Meijere, A., Ed.; Thieme: Stuttgart, 2005; Vol. 24, pp 933−956.
(36) (a) Stang, P. J.; Surber, B. W. J. Am. Chem. Soc. 1985, 107, 1452.
(b) Stang, P. J.; Surber, B. W.; Chen, Z.-C.; Roberts, K. A.; Anderson, A.
G. J. Am. Chem. Soc. 1987, 109, 228. (c) Tuncay, A.; Anaclerio, B. M.;
Zolodz, M. Tetrahedron Lett. 1999, 40, 599. (d) Stang, P. J.; Boehshar,
M.; Lin, J. J. Am. Chem. Soc. 1986, 108, 7832. (e) Stang, P. J.; Kitamura,
T.; Boehshar, M.; Wingert, H. J. Am. Chem. Soc. 1989, 111, 2225.
(37) For reviews, see: (a) Dembitsky, V. M.; Al Quntar, A. A. A.; Haj-
Yehia, A.; Srebnik, M. Mini-Rev. Org. Chem. 2005, 5, 91. (b) Gaumont, A.
C.; Gulea, M. In Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; Molander, G. A., Ed.; Thieme: Stuttgart, 2006; Vol. 33,
pp 665−694.
(38) For a Wadsworth−Horner−Emmons approach, see: (a) Teulade,
́
M.-P.; Savignac, P.; Aboujaoude, E. E.; Lietge, S.; Collignon, N. J.
Organomet. Chem. 1986, 304, 283. (b) Inoue, H.; Tsubouchi, H.;
Nagaoka, Y.; Tomioka, K. Tetrahedron 2002, 58, 83. For a review on
transition-metal-catalyzed preparation of vinylphosphonates, see:
Maffei, M. Curr. Org. Synth. 2004, 1, 355.
N
dx.doi.org/10.1021/om3005614 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(39) (a) Xu, H.; Gu, S.; Chen, W.; Li, D.; Dou, J. J. Org. Chem. 2011, 76,
2448. (b) Yamagishi, M.; Okazaki, J.; Nishigai, K.; Hata, T.; Urabe, H.
Org. Lett. 2012, 14, 34.
(40) (a) Jin, H.; Yang, Y.; Kuang, C.; Yang, Q. Synlett 2011, 2886.
(b) Ni, Z.; Wang, S.; Mao, H.; Pan, Y. Tetrahedron Lett. 2012, 53, 3907.
(41) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. J. Org. Chem.
1981, 46, 3745. (b) Abbas, S.; Hayes, C. J.; Worden, S. Tetrahedron Lett.
2000, 41, 3215. (c) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron
2002, 58, 1491.
O
dx.doi.org/10.1021/om3005614 | Organometallics XXXX, XXX, XXX−XXX