U.S. patent application number 12/450940 was filed with the patent office on 2010-05-13 for method for the preparation of phosphine butadiene ligands, complexes thereof with copper and use thereof in catalysis.
This patent application is currently assigned to Centre National De La Recherche Scientifique (C.N.R.S.). Invention is credited to Hamid Kaddouri, Armelle Ouali, Fouad Ouazzani, Marc Taillefer.
Application Number | 20100121076 12/450940 |
Document ID | / |
Family ID | 38695561 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100121076 |
Kind Code |
A1 |
Taillefer; Marc ; et
al. |
May 13, 2010 |
METHOD FOR THE PREPARATION OF PHOSPHINE BUTADIENE LIGANDS,
COMPLEXES THEREOF WITH COPPER AND USE THEREOF IN CATALYSIS
Abstract
The present invention relates to a method for preparing
phosphine butadiene-type ligands, and their use, particularly as
catalytic metal ligands used in the reactions leading to the
formation of carbon-carbon and carbon-heteroatom bonds.
Inventors: |
Taillefer; Marc;
(Vailhauques, FR) ; Kaddouri; Hamid; (Montpellier,
FR) ; Ouazzani; Fouad; (Fes, MA) ; Ouali;
Armelle; (Toulouse, FR) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 320850
ALEXANDRIA
VA
22320-4850
US
|
Assignee: |
Centre National De La Recherche
Scientifique (C.N.R.S.)
Paris
FR
Ecole Nationale Superieure De Chimie De Montpellier
Montpellier
FR
Universite Sidi Mohammed Ben Abdellah
Fes
MA
|
Family ID: |
38695561 |
Appl. No.: |
12/450940 |
Filed: |
April 21, 2008 |
PCT Filed: |
April 21, 2008 |
PCT NO: |
PCT/IB2008/000984 |
371 Date: |
October 19, 2009 |
Current U.S.
Class: |
548/377.1 ;
556/23; 568/17; 568/635 |
Current CPC
Class: |
C07F 9/5045 20130101;
C07F 9/5022 20130101 |
Class at
Publication: |
548/377.1 ;
556/23; 568/17; 568/635 |
International
Class: |
C07D 231/12 20060101
C07D231/12; C07F 1/08 20060101 C07F001/08; C07F 9/06 20060101
C07F009/06; C07C 41/14 20060101 C07C041/14 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 20, 2007 |
FR |
07 02878 |
Claims
1. A process for the preparation of a butadienylphosphine of
formula (1): ##STR00054## in which: R.sup.a and R.sup.b, which are
identical or different, each represent a radical chosen
independently from alkyl, aryl, heteroaryl, monoalkylamino,
dialkylamino, alkoxy, aryloxy and heteroaryloxy; R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5, which are identical or different, are
chosen independently from hydrogen, a hydrocarbon radical, an aryl
radical and a heteroaryl radical; said process comprising the
stages of: a) bringing a phosphonium halide of formula (2) into
contact with a strong base in a polar aprotic solvent at low
temperature, to result in the phosphonium diylide (3): ##STR00055##
where R.sup.1 is as defined above, Z and Z' have definitions
identical to those of R.sup.a and R.sup.b defined above and X
represents a halogen atom chosen from fluorine, chlorine, bromine
and iodine; b) which diylide (3) is reacted, in the polar aprotic
solvent medium, at a temperature generally of between -70.degree.
C. and +10.degree. C., with a halophosphine (4): ##STR00056## where
R.sup.a and R.sup.b are as defined above and X' represents a
halogen atom chosen from fluorine, chlorine, bromine and iodine; to
result in the phosphonium ylide (5a), which undergoes a prototropic
rearrangement to give the phosphonium ylide (5b): ##STR00057##
where R.sup.a, R.sup.b, R.sup.1, Z and Z' are as defined above; c)
the ylide (5b) then being brought together with an
.alpha.,.beta.-unsaturated carbonyl derivative of formula (6):
##STR00058## in which R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
defined above, to result, after removal of the solvent and optional
purification, in the butadienylphosphine (1).
2. The process as claimed in claim 1, in which the R.sup.a and
R.sup.b substituents of the butadienylphosphine of formula (1) are
identical and each represent a radical chosen independently from
alkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy,
aryloxy and heteroaryloxy.
3. The process as claimed in claim 1, in which the R.sup.4 and/or
R.sup.5 substituents can be connected so as to form, with the
carbon atom which carries them, a carbocyclic or heterocyclic group
having from 3 to 20 carbon atoms which is saturated, unsaturated,
monocyclic or polycyclic, in the latter case comprising two or
three rings, it being possible for the adjacent rings to be
aromatic in nature.
4. The process as claimed in claim 1, in which the strong base is
butyllithium.
5. The process as claimed in claim 1, in which the polar aprotic
solvent is tetrahydrofuran.
6. The process as claimed in claim 1, in which the
butadienylphosphine of formula (1) obtained is of Z configuration
or of E configuration or is in the form of a mixture in all
proportions of the Z and E configurations.
7. The process as claimed in claim 1, in which the
butadienylphosphine of formula (1) obtained exhibits the following
characteristics: R.sup.a and R.sup.b are identical and each
represent a radical chosen from methyl, ethyl, propyl, butyl,
phenyl, naphthyl, pyridyl or quinolyl; R.sup.1 represents hydrogen,
methyl, ethyl or propyl; R.sup.2, R.sup.3 and R.sup.4, which are
identical or different, are chosen independently from hydrogen,
methyl, ethyl and propyl; R.sup.5 is chosen from hydrogen, methyl,
ethyl, propyl, butyl, pentyl, phenyl, naphthyl, pyridyl and
quinolyl.
8. The process according to claim 1, in which the
butadienylphosphine of formula (1) obtained exhibits the following
characteristics: R.sup.a and R.sup.b each represent phenyl; R.sup.1
represents hydrogen; R.sup.2, R.sup.3 and R.sup.4, which are
identical or different, are chosen independently from hydrogen,
methyl, ethyl and propyl; R.sup.5 is chosen from methyl, ethyl,
propyl, phenyl, naphthyl, pyridyl and quinolyl.
9. The process as claimed in claim 1, in which the
butadienylphosphine obtained is (Z)-Ph(C.sub.4H.sub.4)PPh.sub.2,
(E)-Ph(C.sub.4H.sub.4)PPh.sub.2,
(Z)--CH.sub.3(C.sub.4H.sub.4)PPh.sub.2 or
(E)-CH.sub.3Ph(C.sub.4H.sub.4)PPh.sub.2, where Ph represents
phenyl.
10. A complex comprising copper and at least one
butadienylphosphine of formula (1): ##STR00059## in which: R.sup.a
and R.sup.b, which are identical or different, each represent a
radical chosen independently from alkyl, aryl, heteroaryl,
monoalkylamino, dialkylamino, alkoxy, aryloxy and heteroaryloxy;
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which are identical
or different, are chosen independently from hydrogen, a hydrocarbon
radical, an aryl radical and a heteroaryl radical.
11. The complex as claimed in claim 10, in which the R.sup.a and
R.sup.b substituents of the butadienylphosphine of formula (1) are
identical and each represent a radical chosen independently from
alkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy,
aryloxy and heteroaryloxy.
12. The complex as claimed in claim 10, in which the
butadienylphosphine of formula (1) is of Z configuration or of E
configuration or is in the form of a mixture in all proportions of
the Z and E configurations.
13. The complex as claimed in claim 10, in which the
butadienylphosphine of formula (1) exhibits the following
characteristics: R.sup.a and R.sup.b are identical and each
represent a radical chosen from methyl, ethyl, propyl, butyl,
phenyl, naphthyl, pyridyl or quinolyl; R.sup.1 represents hydrogen,
methyl, ethyl or propyl; R.sup.2, R.sup.3 and R.sup.4, which are
identical or different, are chosen independently from hydrogen,
methyl, ethyl and propyl; R.sup.5 is chosen from hydrogen, methyl,
ethyl, propyl, butyl, pentyl, phenyl, naphthyl, pyridyl and
quinolyl.
14. The complex as claimed in claim 10, in which the
butadienylphosphine of formula (1) exhibits the following
characteristics: R.sup.a and R.sup.b each represent phenyl; R.sup.1
represents hydrogen; R.sup.2, R.sup.3 and R.sup.4, which are
identical or different, are chosen independently from hydrogen,
methyl, ethyl and propyl; R.sup.5 is chosen from methyl, ethyl,
propyl, phenyl, naphthyl, pyridyl and quinolyl.
15. The complex as claimed in claim 10, in which the
butadienylphosphine of formula (1) is
(Z)-Ph(C.sub.4H.sub.4)PPh.sub.2, (E)-Ph(C.sub.4H.sub.4)PPh.sub.2,
(Z)--CH.sub.3(C.sub.4H.sub.4)PPh.sub.2 or
(E)-CH.sub.3Ph(C.sub.4H.sub.4)PPh.sub.2, where Ph represents
phenyl.
16. The complex as claimed in claim 10, which is the
phenylbutadienyldiphenylphosphine/copper iodide monomer complex
[Ph-CH.dbd.CH--CH.dbd.CH--PPh.sub.2].sub.2CuI
(iododi{.eta.-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper
complex), where Ph represents the phenyl radical.
17. The complex as claimed in claim 10, which is the
methylbutadienyldiphenylphosphine/copper iodide monomer complex
[CH.sub.3--CH.dbd.CH--CH.dbd.CH--PPh.sub.2].sub.2CuI
(iododi{.eta.-[(4-methyl-1,3-butadienyl)diphenylphosphine]}copper
complex), where Ph represents the phenyl radical.
18. A process for the creation of a carbon-carbon (C--C) bond or of
a carbon-heteroatom (C-HE) bond by reacting a compound carrying a
leaving group with a nucleophilic compound carrying a carbon atom
or a heteroatom (HE) capable of replacing the leaving group, thus
creating a C--C or C-HE bond, in which process the reaction is
carried out in the presence of an effective amount of a catalytic
system comprising at least one copper/butadienylphosphine
complex.
19. The process as claimed in claim 18, in which the
copper/butadienylphosphine is a complex of the formula (1):
##STR00060## in which: R.sup.a and R.sup.b, which are identical or
different, each represent a radical chosen independently from
alkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy,
aryloxy and heteroaryloxy; R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5, which are identical or different, are chosen independently
from hydrogen, a hydrocarbon radical, an aryl radical and a
heteroaryl radical.
20. The process as claimed in claim 19, in which the compound
carrying a leaving group is a compound comprising a double bond or
a triple bond in the .alpha. position with respect to said leaving
group or an aromatic compound.
21. The process as claimed in claim 19, in which the nucleophilic
compound is an acyclic, cyclic or polycyclic hydrocarbon organic
compound comprising at least one atom carrying a free doublet,
which may or may not comprise a charge, and or comprise a carbon
atom which can donate its electron pair.
22. The process as claimed in claim 19, in which the ratio between
the number of moles of the compound carrying the leaving group to
the number of moles of the nucleophilic compound generally varies
between 0.1 and 2.0.
23. The process as claimed in claim 19, in which the total amount
of copper/butadienylphosphine complex catalyst, expressed by the
molar ratio of the number of moles of complex, expressed as copper,
to the number of moles of compound carrying a leaving group,
generally varies between 0.001 and 0.5.
24. The process as claimed in claim 19, in which a base having a
pKa of between 4 and 30 is involved.
25. The process as claimed in claim 19, in which a base chosen from
carbonates, hydrogencarbonates, phosphates or hydroxides of alkali
metals or of alkaline earth metals, alkali metal hydrides, alkali
metal alkoxides and tertiary amines is involved.
26. The process as claimed in claim 19, which is carried out in the
presence of a polar organic solvent.
27. The process as claimed in claim 19, in which the nucleophilic
compound and/or the compound carrying the leaving group is (are)
used as solvent(s) for the reaction.
28. The process as claimed in claim 19, in which the
copper/butadienylphosphine complex is prepared in situ.
Description
[0001] The present invention relates to a process for the
preparation of phosphorus-comprising ligands of butadienylphosphine
type and to their applications, in particular as ligands for
catalytic metals used in reactions for the formation of
carbon-carbon and carbon-heteroatom bonds.
[0002] Butadienyl phosphorus-comprising derivatives have been known
since the 1960s and are of interest in organic synthesis as a
result of their electrophilic nature and their biological activity,
in particular antiviral activity.
[0003] With the development of asymmetric synthesis, butadienyl
phosphorus-comprising derivatives today form the subject of
intensive research for their great importance in coordination
chemistry by the presence, in these derivatives, of two ligands
much employed in coordination chemistry: the phosphine ligand and
the butadiene ligand.
[0004] Processes for the synthesis of derivatives of
butadienylphosphine type are currently few in number. They
generally employ sophisticated starting compounds and/or numerous
synthetic stages, thus resulting in mediocre overall yields.
[0005] Thus, for example, M. D. Fryzuk et al. (J. Org. Chem.,
(1988), 53, 4425-4426) disclose a process for the preparation of
butadienylphosphines in two stages, the first stage consisting of a
hydrozirconation of a conjugated enyne, thus rendering the process
relatively complex to carry out.
[0006] Z. Xi et al. (Tetrahedron Lett., (2004), 45, 2427-2429) also
bring in an alkyne as starting compound, which alkyne is reacted
with a zirconium complex.
[0007] M. P. Teulade and P. Savignac (Tetrahedron Lett., (1989),
30(46), 6327-6330) provide a general synthesis of
butadienylphosphines based on a Wittig-Horner reaction starting
from cyclic phosphonates, and J. L. Cabioch and J. M. Denis (J.
Organomet. Chem., (1989), 377(2-3), 227-233) provide, for their
part, an example of the synthesis of an unsubstituted primary
butadienylphosphine starting from the corresponding phosphonate in
the presence of an aluminum salt.
[0008] Yet other syntheses have been described; however, all
comprise a large number of stages, require starting materials which
are expensive or difficult to employ or to prepare, result in the
desired products only with low yields or else do not make possible
access to a great variety of butadienylphosphines.
[0009] Consequently, a first objective of the present invention
consists in providing a synthetic route suited to the preparation
of varied butadienylphosphines, with acceptable yields, which is
easy to use, advantageously with a minimum of stages, starting from
starting compounds which are relatively common or easy to
prepare.
[0010] It has now been discovered that this first objective, and
also others which will become apparent during the description of
the invention which follows, is achieved in all or at least in part
by virtue of the process for the preparation of
butadienylphosphines set out below.
[0011] A subject matter of the present invention is first of all
the process for the preparation of a butadienylphosphine of formula
(1):
##STR00001##
in which formula: [0012] R.sup.a and R.sup.b, which are identical
or different, preferably identical, each represent a radical chosen
independently from alkyl, aryl, heteroaryl, monoalkylamino,
dialkylamino, alkoxy, aryloxy and heteroaryloxy; [0013] R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which are identical or
different, are chosen independently from hydrogen, a hydrocarbon
radical, an aryl radical and a heteroaryl radical; said process
comprising the stages of:
[0014] a) bringing a phosphonium halide of formula (2) into contact
with a strong base, in a polar aprotic solvent, for example
tetrahydrofuran, at low temperature, generally between -70.degree.
C. and 0.degree. C., for example -50.degree. C., to result in the
phosphonium diylide (3):
##STR00002##
where R.sup.1 is as defined above, Z and Z' have definitions
identical to those of R.sup.a and R.sup.b defined above and X
represents a halogen atom chosen from fluorine, chlorine, bromine
and iodine;
[0015] b) which diylide (3) is reacted, in a polar aprotic solvent
medium, for example tetrahydrofuran, at a temperature generally of
between -70.degree. C. and +10.degree. C., for example -10.degree.
C., with a halophosphine (4):
##STR00003##
where R.sup.a and R.sup.b are as defined above and X' represents a
halogen atom chosen from fluorine, chlorine, bromine and iodine; to
result in the phosphonium ylide (5a), which undergoes a prototropic
rearrangement to give the phosphonium ylide (5b):
##STR00004##
where R.sup.a, R.sup.b, Z and Z' are as defined above;
[0016] c) the ylide (5b) then being brought together, generally at
a temperature of between 0.degree. C. and 50.degree. C., for
example at ambient temperature, in a polar aprotic solvent, such as
tetrahydrofuran, with an .alpha.,.beta.-unsaturated carbonyl
derivative of formula (6):
##STR00005##
in which R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
above, to result, after removal of the solvent and optional
purification, in the butadienylphosphine (1).
[0017] In one embodiment, R.sup.4 and/or R.sup.5 can be connected
so as to form, with the carbon atom which carries them, a
carbocyclic or heterocyclic group having from 3 to 20 carbon atoms
which is saturated, unsaturated, monocyclic or polycyclic, in the
latter case comprising two or three rings, it being possible for
the adjacent rings to be aromatic in nature.
[0018] The process described above can advantageously be carried
out in just one reactor (one pot), that is to say without it being
necessary to isolate all or some of the intermediates. However, of
course and if desired, it is possible to isolate one or more of the
intermediates, advantageously when they are stable.
[0019] The strong base used for the preparation of the phosphonium
diylide (3) described above is generally a metal base, that is to
say a strong base comprising one or more metals advantageously
chosen from alkali metals and alkaline earth metals, in particular
from lithium, sodium, potassium, magnesium, calcium and barium.
Strong lithium bases are preferred, in particular butyllithium. In
this case, the counterion of the phosphonium diylide (3) is the
lithium cation.
[0020] In the present invention, the following terms have the
meanings below, unless otherwise indicated: [0021] "alkyl"
represents a saturated linear or branched hydrocarbon radical
comprising from 1 to 10 carbon atoms, preferably from 1 to 6 carbon
atoms, in particular the methyl radical, the ethyl radical, the
propyl radicals, the butyl radicals, the pentyl radicals, the hexyl
radicals, the heptyl radicals, the octyl radicals, the nonyl
radicals and the decyl radicals; [0022] "aryl" represents a mono-
or polycyclic aromatic hydrocarbon radical, for example the phenyl
radical and the naphthyl radical; [0023] "heteroaryl" represents a
mono- or polycyclic aromatic hydrocarbon radical additionally
comprising one or more identical or different heteroatoms chosen
from nitrogen, oxygen or sulfur, each of the rings comprising 5 or
6 members; examples of heteroaryl radicals are the pyridyl
radicals, the quinolyl radicals, the imidazolyl radicals and the
tetrazolyl radicals, without this list constituting any limitation;
[0024] "hydrocarbon radical" as indicated for the R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 radicals represents a linear, branched
or cyclic (mono- or polycyclic) hydrocarbon radical comprising from
1 to 20 carbon atoms and being able to comprise one or more
unsaturations in the form of double and/or triple bond(s), for
example, and without implied limitation, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl,
benzyl, phenyl, vinyl, allyl and others; [0025] in the terms
"alkoxy", "aryloxy", "heteroaryloxy", "monoalkylamino" and
"dialkylamino", the definitions of the terms alkyl-, aryl- and
heteroaryl- correspond to the generic terms defined above.
[0026] All the radicals having the definitions appearing above can
optionally be substituted by one or more halogen atoms,
advantageously chosen from fluorine, chlorine, bromine and iodine,
by one or more linear or branched alkyl, alkenyl and/or alkynyl
radicals comprising from 1 to 10 carbon atoms, or by one or more
hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryl, heteroaryl, amino,
alkylamino, dialkylamino, carboxy, carbonyl, carbonylamino,
carbonylalkylamino, carbonyldialkylamino radicals, it being
possible for the substituents to be identical or different.
[0027] In the expanded formula of the compound of formula (1) shown
above, the bonds in "wavy" lines indicate that the two double bonds
can occur in the cis or trans configuration, that is to say that
the butadienylphosphine of formula (1) can be of E or Z
configuration.
[0028] The butadienylphosphines obtained according to the process
of the invention can be specifically of Z configuration (formula
(1Z)) or of E configuration (formula (1E)) or in the form of a
mixture in all proportions:
##STR00006##
[0029] The E and Z isomers of the phosphines obtained according to
the process of the present invention can be separated, if
necessary, according to conventional methods or processes known to
a person skilled in the art.
[0030] Depending on the applications envisaged, preference is given
to the butadienylphosphines of Z configuration or to the
butadienylphosphines of E configuration or else to the mixtures of
the E and Z butadienylphosphines in all proportions.
[0031] The process of the invention is particularly well suited to
the preparation of the butadienylphosphines of formula (1), of Z or
E configuration, in which: [0032] R.sup.a and R.sup.b, which are
identical or different, each represent a radical chosen
independently from alkyl, in particular methyl, ethyl, propyl or
butyl; aryl, in particular phenyl or naphthyl; heteroaryl, in
particular pyridyl or quinolyl; and, preferably, R.sup.a and
R.sup.b are identical and each represent phenyl; [0033] R.sup.1
represents hydrogen or alkyl, in particular methyl, ethyl or
propyl; preferably, R.sup.1 represents hydrogen; [0034] R.sup.2,
R.sup.3 and R.sup.4, which are identical or different, are chosen
independently from hydrogen, an alkyl radical, an aryl radical and
a heteroaryl radical, in particular from hydrogen and an alkyl
radical, especially methyl, ethyl or propyl; [0035] R.sup.5 is
chosen from hydrogen, an alkyl radical, an aryl radical and a
heteroaryl radical; preferably, R.sup.5 represents alkyl, in
particular methyl, ethyl, propyl, butyl or pentyl, or also
represents phenyl, naphthyl, pyridyl or quinolyl.
[0036] The process of the invention makes it possible in particular
to obtain the butadienylphosphines (Z)-Ph(C.sub.4H.sub.4)PPh.sub.2,
(E)-Ph(C.sub.4H.sub.4)PPh.sub.2, (Z)--CH.sub.3
(C.sub.4H.sub.4)PPh.sub.2 and
(E)-CH.sub.3Ph(C.sub.4H.sub.4)PPh.sub.2, where Ph represents
phenyl.
[0037] The process described above makes it possible to obtain the
butadienylphosphines of formula (1) from compounds which are
readily available commercially or are easily prepared from
procedures known from the literature. In addition, the low number
of stages of the process makes it easy to operate.
[0038] As indicated above, the process can advantageously be
carried out in just one operation (one pot), that is to say without
it being necessary to isolate and/or to purify the synthetic
intermediates. However, it is possible to isolate and/or purify the
intermediates, for example for the purpose of studying the
satisfactory progression of the reaction or its kinetics, of
analyzing the intermediates formed, and others.
[0039] The butadienylphosphines of formula (1), the process of
preparation of which represents a first subject matter of the
present invention, can entirely advantageously be used as ligands
for copper in order to form complexes.
[0040] This is because butadienylphosphines are of great interest
in coordination chemistry and in catalysis due to the fact that
they combine two ligands of great importance in organometallic
chemistry: conjugated dienes and phosphines.
[0041] Such complexes of copper with at least one
butadienylphosphine of formula (1) as defined supra constitute
another subject matter of the present invention.
[0042] The complexes according to the invention can be represented
schematically under the form Pho-Bu/Cu, where Pho-Bu represents a
butadienylphosphine of formula (1) defined above and Cu represents
a copper atom. This schematic representation does not in any way
indicate the number of moles of butadienylphosphine present, with
respect to the number of copper atoms present.
[0043] The term "monomer complex" is used to describe a Pho-Bu/Cu
complex which comprises one copper atom, the term "dimer complex"
is used to describe a Pho-Bu/Cu complex which comprises two copper
atoms, the term "trimer complex" is used to describe a Pho-Bu/Cu
complex which comprises three copper atoms, and the like.
[0044] The invention also relates to phenyl- or
methyl-butadienyldiphenylphosphine/copper iodide monomer complexes
[Ph-CH.dbd.CH--CH.dbd.CH--PPh.sub.2].sub.2CuI
(iododi{.eta.-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper
complex) and [CH.sub.3--CH.dbd.CH--CH.dbd.CH--PPh.sub.2].sub.2CuI
(iododi{.eta.-[(4-methyl-1,3-butadienyl)diphenylphosphine]}copper
complex), where Ph represents the phenyl radical.
[0045] The Pho-Bu/Cu complexes defined above can be prepared
according to conventional techniques known to a person skilled in
the art. For example, the Pho-Bu/Cu complexes can be prepared by
bringing at least one butadienylphosphine, in particular of formula
(1) defined supra, into contact with metallic copper or a copper
(copper(I) or copper(II)) derivative, for example a copper halide,
such as cupric or cuprous iodide, bromide or chloride, or other
derivatives, in particular organocopper compounds, for example
copper acetylacetonate.
[0046] The reaction is generally carried out under an inert
atmosphere, for example under nitrogen or argon, in an organic
solvent medium, preferably a polar aprotic solvent, for example
acetonitrile. The complexing reaction is usually carried out at a
temperature of between 0.degree. C. and 80.degree. C., depending on
the nature of the compounds present, and the reaction temperature
is generally ambient temperature.
[0047] The complex is generally obtained in the form of a
precipitate which is isolated from the reaction medium according to
techniques known per se, for example by filtration, and optionally
recrystallization from a solvent, advantageously identical to that
used for the complexing reaction.
[0048] According to an alternative form, the Pho-Bu/Cu complex can
advantageously be prepared in situ in the reaction medium for the
reaction catalyzed by the Pho-Bu/Cu complex. Such an alternative
form is illustrated in the arylation examples (examples C) which
follow.
[0049] Because of their very great advantage in catalysis,
copper/butadienylphosphine complexes, in particular those of Z
configuration, are applied entirely appropriately as catalytic
system for reactions for the creation of carbon-carbon (C--C) or
carbon-heteroatom (C-HE) bonds according to the "Ullmann process"
(F. Ullmann and H. Kipper, Ber. Dtsch. Chem. Ges., 1095, 38,
2120-2126).
[0050] The copper-catalyzed Ullmann reaction is one of the most
widely used methods industrially due to the attractive cost of
copper, in comparison with the costs of other noble metals, such as
palladium, ruthenium and others.
[0051] Recently, Buchwald et al. (J. Am. Chem. Soc., 2001, 123,
7727-7729) have provided for the use of conventional copper ligands
in carrying out this copper-catalyzed reaction. International
patent application WO-A-03/101966 describes copper ligands which
make possible a reaction of Ullmann type under mild conditions,
with catalytic amounts of copper. These ligands are mainly ligands
of oxime type which require a specific synthesis and consequently
result in relatively expensive reaction products.
[0052] Thus, another objective of the invention is to provide
copper ligands which are easier to prepare and which result in
lower reaction costs than those generated to date for coupling
reactions of Ullmann type. As other objective, the present
invention is targeted at obtaining synthetic yields which are
further improved, in comparison with the yields obtained with the
processes known in the field.
[0053] According to another aspect, the present invention relates
to a process for the creation of a carbon-carbon (C--C) bond or of
a carbon-heteroatom (C-HE) bond by reacting a compound carrying a
leaving group with a nucleophilic compound carrying a carbon atom
or a heteroatom (HE) capable of replacing the leaving group, thus
creating a C--C or C-HE bond, in which process the reaction is
carried out in the presence of an effective amount of a catalytic
system comprising at least one copper/butadienylphosphine
complex.
[0054] The inventors have now discovered that catalytic systems
based on copper complexed with a butadienylphosphine make it
possible to bring about the creation of a carbon-carbon (C--C) bond
or of a carbon-heteroatom (C-HE) bond by reacting a compound
carrying a leaving group with a nucleophilic compound carrying a
carbon atom or a heteroatom (HE) capable of replacing the leaving
group, thus creating a C--C or C-HE bond.
[0055] The general scheme of the process according to the present
invention can be illustrated as follows:
##STR00007##
in which: [0056] Y--R.sup.0 represents a compound carrying a
leaving group Y; and [0057] R-Q: represents a nucleophilic
compound, R being the residue of said nucleophilic compound and Q
being a carbon atom or a heteroatom (HE) which can replace said
leaving group Y.
[0058] According to a first alternative form of the process of the
present invention, an arylation reaction is carried out by reacting
an aromatic compound carrying a leaving group with a nucleophilic
compound.
[0059] According to another alternative form of the process of the
invention, a vinylation or alkynylation reaction is carried out by
respectively reacting, with a nucleophilic compound, a compound
comprising a double bond or a triple bond in the .alpha. position
with respect to a leaving group.
[0060] In the account which follows of the present invention, the
term "arylation" is used in its broad sense, since the use is
envisaged of an unsaturated compound carrying a leaving group which
is either of unsaturated aliphatic type or of carbocyclic or
heterocyclic aromatic type.
[0061] "Nucleophilic compound" is understood to mean a hydrocarbon
organic compound, both acyclic and cyclic or polycyclic, the
characteristic of which is to comprise at least one atom carrying a
free doublet, which may or may not comprise a charge, and
preferably a nitrogen, oxygen, sulfur, boron or phosphorus atom, or
comprises a carbon atom which can donate its electron pair.
[0062] As mentioned above, the nucleophilic compound comprises at
least one atom carrying a free doublet which can be contributed by
a functional group and/or a carbanion.
[0063] Mention may in particular be made, as functional groups
and/or carbanions comprising said at least one atom, of the
following atoms and groups:
##STR00008##
[0064] According to another alternative form of the invention, the
nucleophilic compound comprises at least one nitrogen atom carrying
a free doublet included in a saturated, unsaturated or aromatic
ring; the ring generally comprises from 3 to 8 atoms.
[0065] It should be noted that, when the nucleophilic compound
comprises a functional group, examples of which are given above,
which carries one or more negative charges, said compound then
occurs in a salified form. The counterion is generally a metal
cation, such as an alkali metal, preferably lithium, sodium or
potassium, or an alkaline earth metal, preferably calcium, or the
residue of an organometallic compound, such as, in particular, an
organomagnesium or organozinc compound.
[0066] A first advantage of the process of the invention is to
carry out the reaction at moderate temperature.
[0067] Another advantage is to be able to use a broad range of
agents for the coupling, in particular of agents for the arylation,
of nucleophiles, not only iodides but also bromides, chlorides or
triflates, in particular aryl iodides, aryl bromides, aryl
chlorides or aryl triflates.
[0068] Another advantage of the process of the invention is to
resort to catalysis via copper rather than palladium or nickel,
that is to say a catalyst which is less toxic and which is
additionally advantageous from the economic viewpoint.
[0069] The process of the invention concerns a large number of
nucleophilic compounds and examples are given below, by way of
illustration, without any limiting nature.
[0070] A first category of substrates (nucleophilic compounds) to
which the process of the invention applies comprises nitrogenous
organic derivatives and more particularly primary or secondary
amines; hydrazine or hydrazone derivatives; amides; sulfonamides;
urea derivatives; or heterocyclic derivatives, preferably
nitrogen-comprising and/or sulfur-comprising heterocyclic
derivatives.
[0071] More specifically, the primary or secondary amines can be
represented by the general formula (Ia):
##STR00009##
in which formula (Ia): R.sup.11 and R.sup.12, which are identical
or different, are chosen from hydrogen, a hydrocarbon radical (1 to
20 carbon atoms, as defined above), an aryl radical or a heteroaryl
radical and from any sequence of two or more of the abovementioned
groups, it being understood that at most one of the R.sup.11 and
R.sup.12 groups represents a hydrogen atom.
[0072] The amines preferably employed correspond to the formula
(Ia) in which R.sup.11 and R.sup.12, which are identical or
different, represent a C.sub.1 to C.sub.15, preferably C.sub.1 to
C.sub.10, alkyl group, a C.sub.3 to C.sub.8, preferably C.sub.5 or
C.sub.6, cycloalkyl group, or a C.sub.6 to C.sub.12 aryl or
arylalkyl group.
[0073] Mention may be made, as more particular examples of R.sup.11
and R.sup.12 groups, of C.sub.1 to C.sub.4 alkyl, phenyl, naphthyl
or benzyl groups.
[0074] Mention may be made, as more specific examples of amines of
formula (Ia), of aniline, N-methylaniline, diphenylamine,
benzylamine and dibenzylamine.
[0075] The present invention does not exclude the presence of one
or more unsaturations in the hydrocarbon chain(s), such as one or
more double and/or triple bonds, which may be conjugated or
nonconjugated.
[0076] The hydrocarbon chain(s) can also be interrupted by one or
more heteroatoms (for example, oxygen, sulfur, nitrogen or
phosphorus) and/or by a nonreactive functional group, such as, for
example, --CO--.
[0077] It should be noted that the amino group can be in the form
of anions. The counterion is then a metal cation, preferably an
alkali metal cation and more preferably sodium or potassium.
Mention may be made, as examples of such compounds, of sodium amide
or potassium amide.
[0078] The hydrocarbon chain can optionally carry one or more
substituents, as indicated above, in particular atoms, groups or
radicals chosen from halogen, ester, amino, alkylphosphine and/or
arylphosphine, insofar as they do not interfere.
[0079] The saturated or unsaturated, linear or branched acyclic
aliphatic groups can optionally carry a cyclic substituent. The
term "ring" denotes a saturated, unsaturated or aromatic carbocylic
or heterocyclic ring.
[0080] The acyclic aliphatic group can be connected to the ring via
a valence bond, a heteroatom or a functional group, such as oxy,
carbonyl, carboxyl, sulfonyl, and the like.
[0081] It is possible to envisage, as examples of cyclic
substituents, cycloaliphatic, aromatic or heterocyclic
substituents, in particular cycloaliphatic substituents comprising
6 carbon atoms in the ring or benzene substituents, these cyclic
substituents themselves optionally carrying any substituent,
insofar as they do not interfere with the reactions occurring in
the process of the invention. Mention may in particular be made of
the alkyl or alkoxy groups comprising from 1 to 4 carbon atoms.
[0082] Among the aliphatic groups carrying a cyclic substituent,
cycloalkylalkyl groups, for example cyclohexylalkyl groups, or
arylalkyl groups, preferably C.sub.7 to C.sub.12 arylalkyl groups,
in particular benzyl or phenylethyl groups, are more particularly
targeted.
[0083] In the general formula (Ia), the R.sup.11 and R.sup.12
groups can also represent, independently of one another, a
saturated carbocyclic group or a carbocyclic group comprising one
or two unsaturations in the ring, generally a C.sub.3 to C.sub.8
ring, preferably comprising 6 carbon atoms in the ring; it being
possible for said ring to be substituted. Mention may be made, as
preferred examples of groups of this type, of cyclohexyl groups
which are optionally substituted, in particular by linear or
branched alkyl groups having from 1 to 4 carbon atoms.
[0084] The R.sup.11 and R.sup.12 groups can represent,
independently of one another, an aromatic hydrocarbon group and in
particular a benzene hydrocarbon group corresponding to the general
formula (F.sub.1):
##STR00010##
in which: [0085] t represents 0, 1, 2, 3, 4 or 5; and [0086] W
represents a group chosen from linear or branched C.sub.1-C.sub.6
alkyl, linear or branched C.sub.1-C.sub.6 alkoxy, linear or
branched C.sub.1-C.sub.6 alkylthio, --NO.sub.2, --CN, halogen and
CF.sub.3.
[0087] The aromatic hydrocarbon group can thus be substituted. W
illustrates some types of preferred substituents but the list is
not limiting.
[0088] R.sup.11 and R.sup.12 can also represent, independently of
one another, a polycyclic aromatic hydrocarbon group with the rings
being able to form, with one another, ortho-fused or ortho- and
peri-fused systems. Mention may more particularly be made of a
naphthyl group, it being possible for said ring to be
substituted.
[0089] R.sup.11 and R.sup.12 can also represent, independently of
one another, a polycyclic hydrocarbon group composed of at least
two saturated and/or unsaturated carbocycles or of at least two
carbocycles, only one of which is aromatic, which form, with one
another, ortho- or ortho- and peri-fused systems. Generally, the
rings are C.sub.3 to C.sub.8 rings, preferably C.sub.6 rings.
Mention may be made, as more specific examples, of the bornyl group
or the tetrahydronaphthyl group.
[0090] R.sup.11 and R.sup.12 can also represent, independently of
one another, a saturated, unsaturated or aromatic heterocyclic
group comprising in particular 5 or 6 atoms in the ring, including
one or two heteroatoms, such as nitrogen atoms (unsubstituted by a
hydrogen atom), sulfur atoms and oxygen atoms; it being possible
for the carbon atoms of this heterocycle also to be
substituted.
[0091] R.sup.11 and R.sup.12 can also represent a polycyclic
heterocyclic group defined as being either a group composed of at
least two aromatic or nonaromatic heterocycles comprising at least
one heteroatom in each ring and forming, with one another, ortho-
or ortho- and peri-fused systems or a group composed of at least
one aromatic or nonaromatic hydrocarbon ring and at least one
aromatic or nonaromatic heterocycle forming, with one another,
ortho- or ortho- and peri-fused systems, it being possible for the
carbon atoms of said rings optionally to be substituted.
[0092] Mention may be made, as examples of R.sup.11 and R.sup.12
groups of heterocyclic type, inter alia, of the furyl, thienyl,
isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyranyl or phosphino groups and the quinolyl,
naphthyridinyl, benzopyranyl or benzofuranyl groups.
[0093] The number of substituents present in each ring depends on
the carbon fusion of the ring and on the presence or absence of
unsaturation in the ring. The maximum number of substituents
capable of being carried by a ring is easily determined by a person
skilled in the art.
[0094] Other nucleophilic compounds capable of being employed in
the process of the invention are, for example, the hydrazine
derivatives corresponding to the formula (Ib):
##STR00011##
in which: [0095] R.sup.13 and R.sup.14, which are identical or
different, have the meanings given for R.sup.11 and R.sup.12 in the
formula (Ia) and at most one of the R.sup.3 and R.sup.4 groups
represents a hydrogen atom.
[0096] The R.sup.13 and R.sup.14 groups more particularly represent
a C.sub.1 to C.sub.15, preferably C.sub.1 to C.sub.10, alkyl group,
a C.sub.3 to C.sub.8, preferably C.sub.5 or C.sub.6, cycloalkyl
group, or a C.sub.6 to C.sub.12 aryl or arylalkyl group. More
preferably, R.sup.13 and R.sup.14 represent a C.sub.1 to C.sub.4
alkyl, phenyl, benzyl or naphthyl group.
[0097] Mention may be made, as other nucleophiles, of oximes and
hydroxylamines, which can be represented by the general formulae
(Ic) and (Id) respectively:
##STR00012##
in which formulae: [0098] R.sup.15 and R.sup.16, which are
identical or different, have the definitions given for R.sup.11 and
R.sup.12 in the formula (Ia) and at most one of the R.sup.15 and
R.sup.16 groups represents a hydrogen atom; [0099] R.sup.17 has the
definitions given for R.sup.11 or R.sup.12 in the formula (Ia),
with the exception of the hydrogen atom; and [0100] R.sup.18 is
chosen from the hydrogen atom, a saturated or unsaturated, linear
or branched acyclic aliphatic group and a saturated or unsaturated
monocyclic or polycyclic carbocyclic group, and from any sequence
of two or more of said groups.
[0101] Preferred examples of oximes or hydroxylamines of formulae
(Ic) and (Id) respectively are those for which R.sup.15, R.sup.16
and R.sup.17 represent C.sub.1 to C.sub.15, preferably C.sub.1 to
C.sub.10, alkyl, C.sub.3 to C.sub.8, preferably C.sub.5 or C.sub.6,
cycloalkyl or C.sub.6 to C.sub.12 aryl or arylalkyl.
[0102] Mention may be made, as more particular examples of
R.sup.15, R.sup.16 and R.sup.17 groups, of C.sub.1 to C.sub.4
alkyl, phenyl, naphthyl or benzyl groups. With regard to R.sup.18,
it preferably represents C.sub.1 to C.sub.4 alkyl or benzyl.
[0103] According to another aspect, the present invention employs
nucleophilic compounds of hydrazine type which can be represented
by the following formula (Ie):
##STR00013##
in which: [0104] R.sup.19, R.sup.20 and R.sup.21, which are
identical or different, have the definitions given for R.sup.11 and
R.sup.12 in the formula (Ia); [0105] R.sup.21 represents a hydrogen
atom or a protective group G; and [0106] at least one of the
R.sup.19, R.sup.20 and R.sup.21 groups does not represent a
hydrogen atom; [0107] or else R.sup.19 and R.sup.20 can together
form, with the nitrogen atom which carries them, a saturated,
unsaturated or aromatic monocyclic or polycyclic C.sub.3-C.sub.20
heterocyclic group.
[0108] Preferred hydrazines of formula (Ie) above are those in
which R.sup.19 and R.sup.20, which are identical or different,
represent C.sub.1-C.sub.15, preferably C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.8, preferably C.sub.5 or C.sub.6, cycloalkyl or
C.sub.6-C.sub.12 aryl or arylalkyl. More preferably, the hydrazines
are those of formula (Ie) in which R.sup.19 and R.sup.20, which are
identical or different, represent C.sub.1 to C.sub.4 alkyl, phenyl,
benzyl or naphthyl.
[0109] R.sup.19 and R.sup.20 can be connected together, so as to
form, with the nitrogen atom which carries them, a saturated,
unsaturated or aromatic monocyclic or polycyclic C.sub.3-C.sub.20
heterocyclic group comprising two or three ortho-fused rings, that
is to say at least two rings which have two carbon atoms in
common.
[0110] For the polycyclic compounds, the number of atoms of each
ring can preferably vary between 3 and 6. According to a preferred
embodiment, R.sup.19 and R.sup.20 together form a cyclohexane or
fluorenone ring.
[0111] In the above formula (Ie), R.sup.21 preferably represents a
hydrogen atom, alkyl (preferably C.sub.1-C.sub.12), alkenyl or
alkynyl (preferably C.sub.2-C.sub.12), cycloalkyl (preferably
C.sub.3-C.sub.12), or aryl or arylalkyl (preferably
C.sub.6-C.sub.12). More preferably, R.sup.21 represents a hydrogen
atom or a C.sub.1-C.sub.4 alkyl group.
[0112] It should be noted that, when the nucleophilic compound
comprises an NH.sub.2 group, both hydrogen atoms can react. In such
a case, and in order to increase the selectivity of the reaction,
one or both hydrogen atoms can advantageously be masked by the use
of a protective group. Such protective groups are well known in the
field and mention may be made of the protective groups commonly
used, such as, for example, acyl (acetyl, benzoyl), BOC
(butoxycarbonyl), CBZ (carbobenzoxy), FMOC
(trifluoromethyloxycarbonyl) or MSOC
(2-(methane-sulfenyl)ethoxycarbonyl) groups. Reference may be made,
on this subject, for example, to the work by T. W. Greene et al.,
Protective Groups in Organic Synthesis, 2.sup.nd edition, John
Wiley & Sons Inc., as regards the reactions for protecting and
deprotecting amino groups.
[0113] Other nucleophilic compounds which can be employed in the
process of the present invention are the compounds of hydrazone
type, which can be represented by the formula (If):
##STR00014##
in which: [0114] R.sup.22, R.sup.23 and R.sup.24, which are
identical or different, have the definitions given for R.sup.11 and
R.sup.12 in the formula (Ia); [0115] at most one of the R.sup.22
and R.sup.23 groups represents the hydrogen atom; [0116] or else
R.sup.22 and R.sup.23 can together form, with the nitrogen atom
which carries them, a saturated, unsaturated or aromatic monocyclic
or polycyclic C.sub.3-C.sub.20 carbocyclic or heterocyclic
group.
[0117] Preferred examples of hydrazones of above formula (If) are
those in which R.sup.22 and R.sup.23, which are identical or
different, represent C.sub.1-C.sub.15, preferably C.sub.1-C.sub.10,
alkyl, C.sub.3-C.sub.8, preferably C.sub.5 or C.sub.6, cycloalkyl,
or C.sub.6-C.sub.12 aryl or arylalkyl. More preferably, examples of
hydrazones of formula (If) are those in which R.sup.22 and
R.sup.23, which are identical or different, represent C.sub.1 to
C.sub.4 alkyl, phenyl, benzyl or naphthyl.
[0118] R.sup.22 and R.sup.23 can together form, with the nitrogen
atom which carries them, a saturated, unsaturated or aromatic
monocyclic or polycyclic C.sub.3-C.sub.20 carbocyclic or
heterocyclic group comprising two or three ortho-fused rings.
[0119] For the polycyclic compounds, the number of atoms of each
ring can preferably vary between 3 and 6. According to a preferred
embodiment, R.sup.22 and R.sup.23 together form a cyclohexane or
fluorenone ring.
[0120] In the above formula (If), R.sup.24 preferably represents a
hydrogen atom or an alkyl (preferably C.sub.1-C.sub.12), alkenyl or
alkynyl (preferably C.sub.2-C.sub.12), cycloalkyl (preferably
C.sub.3-C.sub.12), or aryl or arylalkyl (preferably
C.sub.6-C.sub.12) group. More preferably, R.sup.24 represents a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group.
[0121] The invention is also targeted at the compounds of amide
type corresponding more particularly to the formula (Ig):
R.sup.25--NH--CO--R.sup.26 (Ig)
in which R.sup.25 and R.sup.26 have the meanings given for R.sup.11
and R.sup.12 in the formula (Ia).
[0122] Mention may be made, as examples of compounds of formula
(Ig), of oxazolidin-2-one, benzamide and acetamide.
[0123] The invention also applies to compounds of sulfonamide type
which can, for example, correspond to the formula (Ih):
R.sup.27--SO.sub.2--NH--R.sup.28 (Ih)
in which R.sup.27 and R.sup.28 have the meanings given for R.sup.11
and R.sup.12 in the formula (Ia).
[0124] Mention may be made, as example of compounds of formula
(Ih), of tosylhydrazide.
[0125] Mention may be made, as other types of nucleophilic
substrates, of urea derivatives, such as guanidines, which can be
represented by the formula (Ii):
##STR00015##
in said formula (Ii), the R.sup.29 groups, which are identical or
different, have the meanings given for R.sup.11 and R.sup.12 in the
formula (Ia).
[0126] Mention may be made, as example of compounds of formula
(Ii), of N,N,N',N'-tetramethylguanidine.
[0127] Yet other examples of nucleophilic compounds which can be
used in the process of the present invention comprise amino acids
and their derivatives, for example those corresponding to the
following formula (Ij):
##STR00016##
in which: [0128] R.sub.AA represents a hydrogen atom or the residue
of an amino acid, preferably a hydrogen atom; a linear or branched
C.sub.1-C.sub.12 alkyl optionally carrying a functional group; a
C.sub.6-C.sub.12 aryl or arylalkyl; or a functional group,
preferably a hydroxyl group; [0129] R.sup.30 and R.sup.31 have the
definitions given for R.sup.11 and R.sup.12 in the formula (Ia);
[0130] R.sub.h represents a hydrogen atom, a metal cation,
preferably an alkali metal cation, or a C.sub.1-C.sub.12
hydrocarbon group, preferably a C.sub.1-C.sub.12 alkyl group.
[0131] According to a preferred embodiment, R.sub.AA in the above
formula (Ij) represents alkyl, optionally comprising a functional
group, for example --OH, --NH.sub.2, --CO--NH.sub.2, --NH--CNH--,
--HN--C(O)--NH.sub.2, --COOH, --SH or --S--CH.sub.3, or an
imidazole, pyrrole or pyrazole group.
[0132] Examples of such amino acids comprise glycine, cysteine,
aspartic acid, glutamic acid or histidine.
[0133] Nucleophilic substrates entirely well suited to the use of
the process of the invention are the heterocyclic derivatives
comprising at least one nucleophilic atom, such as a nitrogen,
sulfur or phosphorus atom.
[0134] More specifically, such compounds correspond to the general
formula (Ik):
##STR00017##
in said formula (Ik): [0135] A symbolizes the residue of a ring
forming all or part of an aromatic or nonaromatic, monocyclic or
polycyclic heterocyclic system, one of the carbon atoms of which is
replaced by at least one nucleophilic atom, such as a nitrogen,
sulfur or phosphorus atom; [0136] R.sup.32, which are identical or
different, represent(s) the substituent(s) of the ring; [0137] n
represents the number of substituents on the ring.
[0138] The invention applies in particular to the monocyclic
heterocyclic compounds corresponding to the formula (Ik) in which A
symbolizes a saturated, unsaturated or aromatic heterocycle
comprising in particular 5 or 6 atoms in the ring which can
comprise from 1 or 3 heteroatoms, such as nitrogen, sulfur and
oxygen atoms, at least one of which from among them is a
nucleophilic atom, such as NH or S.
[0139] A can also represent a polycyclic heterocyclic compound
defined as being composed of at least two aromatic or nonaromatic
heterocycles comprising at least one heteroatom in each ring and
forming, with one another, ortho- or ortho- and peri-fused systems
or composed of at least one aromatic or nonaromatic carbocycle and
at least one aromatic or nonaromatic heterocycle forming, with one
another, ortho- or ortho- and peri-fused systems.
[0140] It is also possible to start from a substrate resulting from
the linking of a saturated, unsaturated or aromatic heterocycle,
such as mentioned above, and of a saturated, unsaturated or
aromatic carbocycle. Carbocycle is preferably understood to mean a
ring of cycloaliphatic or aromatic type having from 3 to 8 carbon
atoms, preferably 6 carbon atoms.
[0141] It should be noted that the carbon atoms of the heterocycle
can optionally be substituted, in their entirety or for a portion
of them only, by R.sup.32 groups.
[0142] The number of substituents present on the ring depends on
the number of atoms in the ring and on the presence or absence of
unsaturations in the ring. The maximum number of substituents
capable of being carried by a ring is easily determined by a person
skilled in the art.
[0143] In the formula (Ik), n is preferably 0, 1, 2, 3 or 4; more
preferably, n is equal to 0 or 1.
[0144] Examples of substituents are given below but this list does
not exhibit a limiting nature.
[0145] The R.sup.32 group or groups, which are identical or
different, preferably represent one of the following groups: [0146]
a linear or branched C.sub.1 to C.sub.6, preferably C.sub.1 to
C.sub.4, alkyl group, such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl or tert-butyl; [0147] a linear or
branched C.sub.2 to C.sub.6, preferably C.sub.2 to C.sub.4, alkenyl
or alkynyl group, such as vinyl or allyl; [0148] a linear or
branched C.sub.1 to C.sub.6, preferably C.sub.1 to C.sub.4, alkoxy
or thioether group, such as the methoxy, ethoxy, propoxy,
isopropoxy or butoxy groups, an alkenyloxy group, preferably an
allyloxy group, or a phenoxy group; [0149] a cyclohexyl, phenyl or
benzyl group; [0150] a group or a functional group, such as
hydroxyl, thiol, carboxyl, ester, amide, formyl, acyl, aroyl,
amide, urea, isocyanate, thioisocyanate, nitrile, azide, nitro,
sulfone, sulfonic, halogen, pseudohalogen or trifluoromethyl.
[0151] The present invention applies very particularly to the
compounds corresponding to the formula (Ik) in which the R.sup.32
group or groups more particularly represent an alkyl or alkoxy
group.
[0152] More particularly, the optionally substituted residue A
represents one of the following rings: [0153] a monocyclic
heterocycle comprising one or more heteroatoms:
[0153] ##STR00018## [0154] a bicycle comprising a carbocycle and a
heterocycle comprising one or more heteroatoms:
[0154] ##STR00019## [0155] a tricycle comprising at least one
carbocycle or one heterocycle comprising one or more
heteroatoms:
##STR00020##
[0156] As examples of heterocyclic compounds, it is preferable to
use those which correspond to the formula (Ik) in which A
represents a ring such as imidazole, pyrazole, triazole, pyrazine,
oxadiazole, oxazole, tetrazole, indole, pyrrole, phthalazine,
pyridazine or oxazolidine.
[0157] As regards the nucleophilic compounds capable of also being
employed in the process of the invention, mention may also be made
of the compounds of alcohol type or of thiol type which can be
represented by the following formula (Im):
R.sup.33--Z (Im)
in which formula (Im): [0158] R.sup.33 represents a hydrocarbon
group having from 1 to 20 atoms and has the meanings given for
R.sup.11 or R.sup.12 in the formula (Ia); and [0159] Z represents a
group of OM.sup.1 or SM.sup.1 type, in which M.sup.1 represents a
hydrogen atom or a metal cation, preferably an alkali metal
cation.
[0160] The preferred compounds correspond to the formula (Im) in
which R.sup.33 represents a hydrocarbon group having from 1 to 20
carbon atoms which can be a saturated or unsaturated, linear or
branched acyclic aliphatic group, a saturated, unsaturated or
aromatic, monocyclic or polycyclic carbocyclic or heterocyclic
group, or any sequence of two or more of the abovementioned
groups.
[0161] More specifically, R.sup.33 preferably represents a
saturated, linear or branched, acyclic aliphatic group preferably
having from 1 to 12 carbon atoms and more preferably from 1 to 4
carbon atoms.
[0162] The invention does not exclude the presence of an
unsaturation in the hydrocarbon chain, such as one or more double
and/or triple bonds, which can be conjugated or nonconjugated.
[0163] As mentioned for R.sup.11 defined in the formula (Ia), the
hydrocarbon chain can optionally be interrupted by a heteroatom or
a functional group or carry one or more substituents.
[0164] In the formula (Im), R.sup.33 can also represent a saturated
or unsaturated carbocyclic group preferably having 5 or 6 carbon
atoms in the ring, a saturated or unsaturated heterocyclic group
comprising in particular 5 or 6 atoms in the ring, including 1 or 2
heteroatoms, such as nitrogen, sulfur, oxygen or phosphorus atoms,
a monocyclic aromatic carbocyclic or heterocyclic group, preferably
phenyl, pyridyl, furyl, pyranyl, thiophenyl, thienyl, phospholyl,
pyrazolyl, imidazolyl or pyrrolyl, or a fused or nonfused
polycyclic aromatic carbocyclic or heterocyclic group, preferably
naphtyl.
[0165] Provided that R.sup.33 comprises a ring, the latter can also
be substituted. The substituent can have any nature insofar as it
does not interfere with the main reaction. The number of
substituents is generally at most 4 per ring but is most often
equal to 1 or 2. Reference may be made to the definition of
R.sup.32 in the formula (Ik).
[0166] The invention is also targeted at the case where R.sup.33
comprises a sequence of aliphatic and/or cyclic, carbocyclic and/or
heterocyclic groups.
[0167] An acyclic aliphatic group can be connected to a ring via a
valence bond, a heteroatom or a functional group, such as oxy,
carbonyl, carboxy, sulfonyl, and the like.
[0168] A more particular target is cycloalkylalkyl, for example
cyclohexylalkyl, groups or aralkyl groups having from 7 to 12
carbon atoms, in particular benzyl or phenylethyl groups.
[0169] The invention is also targeted at a sequence of carbocyclic
and/or heterocyclic groups and more particularly a sequence of
phenyl groups separated by a valence bond or an atom or functional
group, such as oxygen, sulfur, sulfo, sulfonyl, carbonyl,
carbonyloxy, imino, carbonylimino, hydrazo, or (C.sub.1-C.sub.10,
preferably C.sub.1-C.sub.6)alkylenediimino.
[0170] The saturated or unsaturated, linear or branched acyclic
aliphatic group can optionally carry a cyclic substituent. "Ring"
is understood to mean a saturated, unsaturated or aromatic
carbocyclic or heterocyclic ring.
[0171] The preferred compounds of formula (Im) correspond more
particularly to the general formula (Im.sub.1):
##STR00021##
in which: [0172] D symbolizes the residue of a monocyclic or
polycyclic aromatic carbocyclic group or a divalent group composed
of any sequence of two or more monocyclic aromatic carbocyclic
groups; [0173] R.sup.34 represents one or more identical or
different substituents; [0174] Z represents a group of OM.sup.1 or
SM.sup.1 type in which M.sup.1 represents a hydrogen atom or a
metal cation, preferably an alkali metal cation; and [0175] n'
represents 0, 1, 2, 3, 4 or 5.
[0176] Reference may be made, as examples of R.sup.34 substituents,
to those identified under R.sup.32 defined in the formula (Ik).
[0177] Use is more particularly made, among the compounds of
formula (Im.sub.1), of those for which the (D) residue represents:
[0178] a monocyclic or polycyclic aromatic carbocyclic group with
rings which can form, with one another, an ortho-fused system
corresponding to the formula (F.sub.11):
[0178] ##STR00022## [0179] in said formula (F.sub.11), m represents
a number equal to 0, 1 or 2, the R.sup.34 and n' symbols, which are
identical or different, having the meanings given above; [0180] a
group composed of a sequence of two or more monocyclic aromatic
carbocyclic groups corresponding to the formula (F.sub.12):
[0180] ##STR00023## [0181] in said formula (F.sub.12), the R.sup.34
and n' symbols, which are identical or different, have the meanings
given above, p is a number equal to 0, 1, 2 or 3 and W represents a
valence bond, a C.sub.1 to C.sub.4 alkylene or alkylidene group,
preferably a methylene or isopropylidene group, or a functional
group, such as oxy, carbonyl, carboxy, sulfonyl and others.
[0182] The compounds of formula (Im) employed preferably correspond
to the formulae (F.sub.11) and (F.sub.12), in which: [0183]
R.sup.34 represents a hydrogen atom, a hydroxyl group, a --CHO
group, an --NO.sub.2 group or a linear or branched alkyl or alkoxy
group having from 1 to 6 carbon atoms, preferably from 1 to 4
carbon atoms, more preferably methyl, ethyl, methoxy or ethoxy;
[0184] W symbolizes a valence bond, an alkylene or alkylidene group
having from 1 to 4 carbon atoms, or an oxygen atom; [0185] m is
equal to 0 or 1; [0186] n' is equal to 0, 1 or 2; and [0187] p is
equal to 0 or 1.
[0188] Mention may more particularly be made, by way of
illustration of compounds corresponding to the formula (Im), of:
[0189] those in which the D residue corresponds to the formula
(F.sub.11) in which m and n' are equal to 0, such as phenol or
thiophenol; [0190] those in which the D residue corresponds to the
formula (F.sub.11) in which m is equal to 0 and n' is equal to 1,
such as hydroquinone, pyrocatechol, resorcinol, alkylphenols,
alkylthiophenols, alkoxyphenols, salicyl aldehyde,
para-hydroxy-benzaldehyde, methyl salicylate, the methyl ester of
para-hydroxybenzoic acid, chlorophenols, nitrophenols or
para-acetamidophenol; [0191] those in which the D residue
corresponds to the formula (F.sub.11) in which m is equal to 0 and
n' is equal to 2, such as dialkylphenols, vanillin, isovanillin,
2-hydroxy-5-acetamidobenzaldehyde,
2-hydroxy-5-propionamidobenzaldehyde, 4-allyloxy-benzaldehyde,
dichlorophenols, methylhydroquinone or chlorohydroquinone; [0192]
those in which the D residue corresponds to the formula (F.sub.11)
in which m is equal to 0 and n' is equal to 3, such as
4-bromovanillin, 4-hydroxy-vanillin, trialkylphenols,
2,4,6-trinitrophenol, 2,6-dichloro-4-nitrophenol, trichlorophenols,
dichlorohydroquinones or 3,5-dimethoxy-4-hydroxy-benzaldehyde;
[0193] those in which the D residue corresponds to the formula
(F.sub.11) in which m is equal to 1 and n' is greater than or equal
to 1, such as dihydroxy-naphthalene, 4-methoxynaphth-1-ol or
6-bromo-naphth-2-ol; [0194] those in which the D residue
corresponds to the formula (F.sub.12) in which p is equal to 1 and
n' is greater than or equal to 1, such as 2-phenoxy-phenol,
3-phenoxyphenol, phenylhydroquinone, 4,4'-dihydroxybiphenyl,
4,4'-isopropylidenediphenol (bisphenol A),
bis(4-hydroxyphenyl)methane, bis(4-hydroxyphenyl) sulfone,
bis(4-hydroxyphenyl) sulfoxide or tetrabromobisphenol A.
[0195] Mention may be made, among the other nucleophilic compounds
belonging to completely different families which are capable of
being employed in the process of the invention, of the compounds
comprising phosphorus and the compounds comprising phosphorus and
nitrogen, preferably those corresponding to the following
formulae:
phosphides of formula (R.sup.35).sub.2--P.sup.- (In);
phosphines of formula (R.sup.35).sub.3--P (Io);
phosphonium azayldiides of formula
(R.sup.35).sub.3--P.sup.+--N.sup.2- (Ip);
phosphonium azaylides of formula
(R.sup.35).sub.3--P.sup.+--NR.sup.36 (Iq);
in which formulae (In) to (Iq), the R.sup.35 groups, which are
identical or different, and the R.sup.36 group represent: [0196]
C.sub.1-C.sub.12 alkyl; [0197] C.sub.5-C.sub.6 cycloalkyl; [0198]
C.sub.5-C.sub.6 cycloalkyl substituted by one or more
C.sub.1-C.sub.4 alkyl groups or C.sub.1-C.sub.4 alkoxy groups;
[0199] phenylalkyl, the aliphatic part of which has from 1 to 6
carbon atoms; [0200] phenyl; or [0201] phenyl substituted by one or
more C.sub.1-C.sub.4 alkyl groups or C.sub.1-C.sub.4 alkoxy groups
or by one or more halogen atom(s).
[0202] Mention may be made, as particularly preferred
phosphorus-comprising compounds, of tricyclohexyl-phosphine,
trimethylphosphine, triethylphosphine, tri(n-butyl)phosphine,
tri(isobutyl)phosphine, tri(tert-butyl)phosphine,
tribenzylphosphine, dicyclohexylphenylphosphine,
triphenylphosphine, dimethylphenylphosphine, diethylphenylphosphine
or di(tert-butyl)phenylphosphine.
[0203] Other compounds capable of being used in the process of the
invention are the hydrocarbon derivatives comprising a nucleophilic
carbon.
[0204] Mention may more particularly be made of the anions of
malonate type comprising a --OOC--HC.sup.---COO-- group.
[0205] Mention may be made of the anions of alkyl malonate type of
formula (Ir):
R.sup.37--OOC--HC.sup.-(R.sup.38)--COO--R'.sup.37 (Ir)
in which: [0206] R.sup.37 and R'.sup.37, which are identical or
different, represent an alkyl group comprising from 1 to 12 atoms,
preferably from 1 to 4 atoms; [0207] R.sup.38 is chosen from a
hydrogen atom; C.sub.1-C.sub.12 alkyl; C.sub.5-C.sub.6 cycloalkyl;
C.sub.5-C.sub.6 cycloalkyl substituted by one or more
C.sub.1-C.sub.4 alkyls or C.sub.1-C.sub.4 alkoxys; phenyl; phenyl
substituted by one or more C.sub.1-C.sub.4 alkyls or
C.sub.1-C.sub.4 alkoxys or by one or more halogen atoms; or
phenylalkyl, the aliphatic part of which comprises from 1 to 6
carbon atoms.
[0208] Mention may also be made of the anions of malononitrile and
malonodinitrile type comprising an
R.sup.37--OOC--HC.sup.-(R.sup.38)--CN or NC--HC.sup.---CN group
respectively, in which R.sup.37 and R.sup.38 have the meanings
given above.
[0209] The compounds of nitrile type comprising an R'.sup.28--CN
group, in which R'.sup.28 has any nature and has the meanings given
for R.sup.11 in the formula (Ia) and also represents a metal
cation, preferably an alkali metal cation, more preferably still
lithium, sodium or potassium, are also suitable.
[0210] Mention may be made, as examples of nitriles, of
acetonitrile, cyanobenzene, optionally carrying one or more
substituents on the benzene ring, or ethanal cyanohydrin
CH.sub.3CH(OH)CN.
[0211] Also capable of being employed in the process of the
invention are the compounds of acetylenide type, which can be
represented schematically by the formula (Is):
R.sup.39--C.ident.C.sup.- (Is)
in said formula, R.sup.39 has any nature and has in particular the
meanings given for R.sup.11 in the formula (Ia) and the counterion
is a metal cation, preferably sodium or potassium.
[0212] Mention may be made, as more specific examples, of sodium
acetylide, potassium acetylide, sodium diacetylide or potassium
diacetylide.
[0213] Mention may be made, as other categories of nucleophilic
compounds which can be employed in the process of the invention, of
the compounds of profen type and their derivatives, which can be
represented by the following formula (It):
R.sup.40--HC.sup.---COO--R.sup.41 (It)
in which formula: [0214] R.sup.40 has the meanings given for
R.sup.11 in the formula (Ia); and [0215] R.sup.41 represents an
alkyl group having from 1 to 12 carbon atoms, preferably from 1 to
4 atoms.
[0216] The preferred compounds are those which correspond to the
formula (It) in which R.sup.40 represents an alkyl group having
from 1 to 12 carbon atoms, a cycloalkyl group having 5 or 6 carbon
atoms and an aryl group having 6 or 12 carbon atoms, or a
nitrogenous heterocycle having 5 or 6 atoms.
[0217] Mention may also be made, as nucleophilic compounds, of
those comprising a carbanion and for which the counterion is a
metal, corresponding to the following formulae:
##STR00024##
in which: [0218] the R.sup.42 group represents: [0219] an alkyl
group having from 1 to 12 carbon atoms; [0220] a cycloalkyl group
having 5 or 6 carbon atoms; [0221] a cycloalkyl group having 5 or 6
carbon atoms substituted by one or more alkyl radicals having 1 to
carbon atoms and/or one or more alkoxy radicals having from 1 or 4
carbon atoms; [0222] a phenylalkyl group, the aliphatic part of
which comprises from 1 to 6 carbon atoms; [0223] a phenyl group;
[0224] a phenyl group substituted by one or more alkyl radicals
having from 1 to 4 carbon atoms or one or more alkoxy radicals
having from 1 to 4 carbon atoms or by one or more halogen atoms; or
[0225] a saturated, unsaturated or aromatic heterocyclic group
preferably comprising 5 or 6 atoms and comprising, as
heteroatom(s), sulfur, oxygen or nitrogen; [0226] the R'.sup.42 and
R''.sup.42 groups represent a hydrogen atom or a group such as
R.sup.42; [0227] two of the R.sup.42, R'.sup.42 and R''.sup.42
groups can be connected together to form a saturated, unsaturated
or aromatic carbocycle or heterocycle preferably having 5 or 6
carbon atoms; [0228] M.sub.2 represents a metal element from Group
Ia of the Periodic Table of the Elements; [0229] M.sub.3 represents
a metal element from Groups IIa and IIb of the Periodic Table of
the Elements; [0230] X.sub.1 represents a chlorine or bromine atom;
[0231] v is the valency of the metal M.sub.3; and [0232] w is equal
to 0 or 1.
[0233] In the present text, reference is made, above and in the
continuation, to the Periodic Table of the Elements published in
the Bulletin de la Societe Chimique de France, No. 1 (1966).
[0234] Among the compounds of formulae (Iu.sub.1) to (Iu.sub.3),
those which are preferred involve, as metals, lithium, sodium,
magnesium or zinc and X.sub.1 represents a chlorine atom.
[0235] The R.sup.42, R'.sup.42 and R''.sup.42 groups are
advantageously a C.sub.1-C.sub.4 alkyl group, a cyclohexyl group or
a phenyl group or said groups can form a benzene, cyclopentadiene,
pyridine or thiophene ring.
[0236] Mention may be made, as examples, of n-butyllithium,
t-butyllithium, phenyllithium, methyl- or ethyl- or phenylmagnesium
bromide or chloride, diphenylmagnesium, dimethyl- or diethylzinc,
cyclopentadienylzinc, or ethylzinc chloride or bromide.
[0237] Recourse may be had, as other nucleophilic compounds capable
of being employed, to boronic acids or their derivatives and more
particularly to those corresponding to the following formula
(Iv):
##STR00025##
in which: [0238] R.sup.43 represents a monocyclic or polycyclic
aromatic carbocyclic or heterocyclic group; and [0239] T.sup.1 and
T.sup.2, which are identical or different, represent a hydrogen
atom, a saturated or unsaturated, linear or branched aliphatic
group having from 1 to 20 carbon atoms or an R.sup.43 group.
[0240] More specifically, the boronic acid or its derivative
corresponds to the formula (Iv) in which the R.sup.43 group
represents an aromatic carbocyclic or heterocyclic group. Thus,
R.sup.43 can take the meanings given above for D in the formula
(Im.sub.1). However, R.sup.43 more particularly represents a
carbocyclic group, such as a phenyl or naphthyl group, or a
heterocyclic group, such as a pyrrolyl, pyridyl, pyrimidinyl,
pyridazinyl, pyrazinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl or
thienyl group.
[0241] The aromatic ring can also be substituted. The number of
substituents is generally at most 4 per ring but is most often
equal to 1 or 2. Reference may be made to the definition of
R.sup.32 of the formula (Ik) for examples of substituents.
[0242] The preferred substituents are alkyl or alkoxy groups having
from 1 to 4 carbon atoms, an amino group, a nitro group, a cyano
group, a halogen atom or a trifluoromethyl group.
[0243] As regards T.sup.1 and T.sup.2, which can be identical or
different, they more particularly represent a hydrogen atom or a
linear or branched acyclic aliphatic group which has from 1 to 20
carbon atoms and which is saturated or comprises one or more
unsaturations in the form of double and/or triple bond(s) in the
chain, preferably from 1 to 3 unsaturations, which are preferably
simple or conjugated double bonds.
[0244] T.sup.1 and T.sup.2 preferably represent an alkyl group
having from 1 to 10 carbon atoms, preferably from 1 to 4 carbon
atoms, or an alkenyl group having from 2 to 10 carbon atoms,
preferably a vinyl or 1-methylvinyl group.
[0245] T.sup.1 and T.sup.2 can additionally take the meanings given
for R.sup.43 and in particular any ring can also carry a
substituent as described above.
[0246] R.sup.43 preferably represents a phenyl group.
[0247] It will not be departing from the scope of the present
invention to resort to boronic acid derivatives, such as anhydrides
and esters, more particularly alkyl esters having from 1 to 4
carbon atoms.
[0248] Mention may in particular be made, as examples of
arylboronic acids, of benzeneboronic acid, 2-thiopheneboronic acid,
3-thiopheneboronic acid, 4-methylbenzeneboronic acid,
3-methylthiophene-2-boronic acid, 3-aminobenzeneboronic acid,
3-aminobenzeneboronic acid hemisulfate, 3-fluorobenzeneboronic
acid, 4-fluorobenzeneboronic acid, 2-formylbenzeneboronic acid,
3-formylbenzeneboronic acid, 4-formylbenzeneboronic acid,
2-methoxybenzeneboronic acid, 3-methoxybenzeneboronic acid,
4-methoxybenzeneboronic acid, 4-chlorobenzeneboronic acid,
5-chlorothiophene-2-boronic acid, benzo[b]furan-2-boronic acid,
4-carboxybenzeneboronic acid, 2,4,6-trimethylbenzeneboronic acid,
3-nitrobenzeneboronic acid, 4-(methyl-thio)benzeneboronic acid,
1-naphthaleneboronic acid, 2-naphthaleneboronic acid,
2-methoxy-1-naphthaleneboronic acid,
3-chloro-4-fluorobenzeneboronic acid, 3-acetamidobenzeneboronic
acid, 3-trifluoromethylbenzeneboronic acid,
4-trifluoromethylbenzeneboronic acid, 2,4-dichlorobenzeneboronic
acid, 3,5-dichlorobenzeneboronic acid,
3,5-bis(trifluoromethyl)benzeneboronic acid, 4,4'-biphenyldiboronic
acid and the esters and anhydrides of these acids.
[0249] The present description provides lists of nucleophilic
compounds but are not under any circumstances limiting and any type
of nucleophilic compound can be envisaged.
[0250] As indicated above and according to the process of the
present invention, a --C--C-- or --C-HE- bond (where HE represents
O, S, P, N, Si, B and others) can be created by reaction of a
nucleophilic compound, such as those which have just been described
above, with a compound carrying a leaving group, in particular a
compound comprising an unsaturated bond situated in the .alpha.
position with respect to a leaving group.
[0251] More specifically, the compound carrying a leaving group is
represented by the general formula (II):
Y--R.sup.0 (II)
in which formula R.sup.0 represents a hydrocarbon group comprising
from 2 to 20 carbon atoms and optionally has at least one
unsaturation (a double or triple bond) situated in the .alpha.
position with respect to a leaving group Y or represents a
monocyclic or polycyclic aromatic carbocyclic and/or heterocyclic
group.
[0252] In accordance with the process of the invention, the
compound of formula (I) is reacted with a compound of formula (II)
in which: [0253] R.sup.0 represents an aliphatic hydrocarbon group
optionally comprising a double bond and/or a triple bond in the
.alpha. position with respect to the leaving group or a cyclic
hydrocarbon group comprising an unsaturation carrying the leaving
group; or [0254] R.sup.0 represents a monocyclic or polycyclic
aromatic carbocyclic and/or heterocyclic group; [0255] Y represents
a leaving group, preferably a halogen atom or a sulfonic ester
group of formula --OSO.sub.2--R.sup.e, in which R.sup.e is a
hydrocarbon group.
[0256] The compound of formula (II) will be subsequently denoted by
"compound carrying a leaving group".
[0257] In the formula of the sulfonic ester group, R.sup.e is a
hydrocarbon group of any nature. However, given that Y is a leaving
group, it is advantageous from an economic viewpoint for R.sup.e to
be simple in nature and to more particularly represent a linear or
branched alkyl group having from 1 to 4 carbon atoms, preferably a
methyl or ethyl group; however, it can also represent, for example,
a phenyl or tolyl group or a trifluoromethyl group.
[0258] Among the Y groups, the preferred group is a triflate group,
which corresponds to an R.sup.e group representing a
trifluoromethyl group.
[0259] The choice is preferably made, as preferred leaving groups,
of a bromine or chlorine atom.
[0260] The compounds of formula (II) very particularly targeted
according to the process of the invention can be categorized into
three groups: [0261] (1) the compounds of aliphatic type carrying a
double bond and which can be represented by the formula (IIa):
##STR00026##
[0261] in which: [0262] R.sup.44, R.sup.45 and R.sup.46, which are
identical or different, represent a hydrogen atom or a hydrocarbon
group having from 1 to 20 carbon atoms which can be a saturated or
unsaturated, linear or branched aliphatic group, a saturated,
unsaturated or aromatic, monocyclic or polycyclic carbocyclic or
heterocyclic group, or any sequence of aliphatic and/or carbocyclic
and/or heterocyclic group(s) as mentioned above; and [0263] Y
symbolizes the leaving group as defined above; [0264] (2) compounds
of aliphatic type carrying a triple bond and which can be
represented by the formula (IIb):
[0264] R.sup.44--C.ident.C--Y (In)
in which: [0265] R.sup.44 has the meanings given in the formula
(IIa); and [0266] Y represents a leaving group as defined above;
[0267] (3) compounds of aromatic type which are subsequently
denoted by "halogenoaromatic compound" and which can be represented
by the formula (IIc):
##STR00027##
[0267] in which: [0268] E symbolizes the residue of a ring forming
all or part of a monocyclic or polycyclic aromatic carbocyclic
and/or heterocyclic system; [0269] R.sup.47, which are identical or
different, represent substituents on the ring; [0270] Y represents
a leaving group as defined above; and [0271] n'' represents the
number of substituents on the ring.
[0272] The invention applies to the unsaturated compounds
corresponding to the formulae (IIa) and (IIb) in which R.sup.44
preferably represents a saturated, linear or branched acyclic
aliphatic group preferably having from 1 to 12 carbon atoms.
[0273] The invention does not rule out the presence of another
unsaturated bond in the hydrocarbon chain, such as a triple bond or
else one or more double bonds, which can be conjugated or
nonconjugated.
[0274] The hydrocarbon chain can optionally be interrupted by a
heteroatom (for example oxygen or sulfur) or by a functional group,
insofar as the latter does not react, and mention may be made in
particular of a group such as especially --CO--.
[0275] The hydrocarbon chain can optionally carry one or more
substituents insofar as they do not react under the reaction
conditions and mention may in particular be made of a halogen atom,
a nitrile group or a trifluoromethyl group.
[0276] The saturated or unsaturated, linear or branched acyclic
aliphatic group can optionally carry a cyclic substituent. "Ring"
is understood to mean a saturated, unsaturated or aromatic
carbocyclic or heterocyclic ring.
[0277] The acyclic aliphatic group can be connected to the ring via
a valence bond, a heteroatom or a functional group, such as oxy,
carbonyl, carboxy, sulfonyl, and the like.
[0278] It is possible to envisage, as examples of cyclic
substituents, cycloaliphatic, aromatic or heterocyclic
substituents, in particular cycloaliphatic substituents comprising
6 carbon atoms in the ring, or benzenic substituents, these cyclic
substituents themselves optionally carrying any substituent,
insofar as they do not interfere in the reactions occurring in the
process of the invention. Mention may in particular be made of
alkyl or alkoxy groups having from 1 to 4 carbon atoms.
[0279] Among aliphatic groups carrying a cyclic substituent, the
aralkyl groups having from 7 to 12 carbon atoms, in particular the
benzyl or phenylethyl groups, are more particularly targeted.
[0280] In the formulae (IIa) and (IIb), R.sup.44 can also represent
a saturated or unsaturated carbocyclic group preferably having 5 or
6 carbon atoms in the ring, preferably a cyclohexyl group, a
saturated or unsaturated heterocyclic group comprising in
particular 5 or 6 atoms in the ring, including one or two
heteroatoms, such as nitrogen, sulfur and oxygen atoms, a
monocyclic aromatic carbocyclic group, preferably a phenyl group,
or a fused or nonfused polycyclic aromatic carbocyclic group,
preferably a naphthyl group.
[0281] With regard to R.sup.45 and R.sup.46, they preferably
represent a hydrogen atom or an alkyl group having from 1 to 12
carbon atoms, a phenyl group or an aralkyl group having from 7 to
12 carbon atoms, preferably a benzyl group.
[0282] In the formulae (IIa) and/or (IIb), R.sup.44, R.sup.45 and
R.sup.46 more particularly represent a hydrogen atom or else
R.sup.44 represents a phenyl group and R.sup.45 and R.sup.46
represent a hydrogen atom.
[0283] It should be noted that R.sup.34 and R.sup.35 can also
represent a functional group, insofar as they do not interact in
the coupling reaction. Mention may be made, as examples of such
functional groups, of the amido, ester, ether or cyano groups.
[0284] Mention may in particular be made, as examples of compounds
corresponding to the formulae (IIa) and (IIb), of vinyl chloride or
vinyl bromide, or .beta.-bromostyrene or .beta.-chlorostyrene, or
bromoalkyne or iodoalkyne.
[0285] The invention applies in particular to the halogenoaromatic
compounds corresponding to the formula (IIc) in which E is the
residue of an optionally substituted cyclic compound preferably
having at least 4 atoms in the ring, preferably 5 or 6 atoms, and
representing at least one of the following rings: [0286] a
monocyclic or polycyclic aromatic carbocycle, that is to say a
compound composed of at least two aromatic carbocycles which form,
with one another, ortho- or ortho- and peri-fused systems or a
compound composed of at least two carbocycles, only one of which
among them is aromatic, which form, with one another, ortho- or
ortho- and peri-fused systems; [0287] a monocyclic aromatic
heterocycle comprising at least one of the heteroatoms P, O, N
and/or S or a polycyclic aromatic heterocycle, that is to say a
compound composed of at least two heterocycles comprising at least
one heteroatom in each ring, at least one of the two rings of which
is aromatic, which form, with one another, ortho- or ortho- and
peri-fused systems, or a compound composed of at least one
carbocycle and at least one heterocycle, at least one of the rings
of which is aromatic, which form, with one another, ortho- or
ortho- and peri-fused systems.
[0288] More particularly, the optionally substituted residue E
preferably represents the residue of an aromatic carbocycle, such
as benzene, of an aromatic bicycle comprising two aromatic
carbocycles, such as naphthalene, or of a partially aromatic
bicycle comprising two carbocycles, one of the two of which is
aromatic, such as 1,2,3,4-tetrahydronaphthalene.
[0289] The invention also envisages the fact that E can represent
the residue of a heterocycle insofar as it is more electrophilic
than the compound corresponding to the formula (Ik).
[0290] Mention may be made, as specific examples, of an aromatic
heterocycle, such as furan or pyridine, an aromatic bicycle
comprising an aromatic carbocycle and an aromatic heterocycle, such
as benzofuran or benzopyridine, a partially aromatic bicycle
comprising an aromatic carbocycle and a heterocycle, such as
methylenedioxybenzene, an aromatic bicycle comprising two aromatic
heterocycles, such as 1,8-naphthylpyridine, or a partially aromatic
bicycle comprising a carbocycle and an aromatic heterocycle, such
as 5,6,7,8-tetrahydroquinoline.
[0291] In the process of the invention, use is preferably made of a
halogenoaromatic compound of formula (IIc) in which E represents an
aromatic nucleus, preferably a benzenic or naphthalenic
nucleus.
[0292] The aromatic compound of formula (IIc) can carry one or more
substituents.
[0293] In the present text, "more" is understood to mean generally
less than four R.sup.47 substituents on an aromatic nucleus.
Reference may be made to the definitions of the R.sup.42 group in
the formula (Ik) for various examples of substituents.
[0294] R.sup.47 can also represent a saturated, unsaturated or
aromatic heterocycle comprising 5 or 6 atoms and comprising sulfur,
oxygen and/or nitrogen as heteroatom(s). In this respect, mention
may in particular be made of the pyrazolyl or imidazolyl
groups.
[0295] In the formula (IIc), n'' is equal to 0, 1, 2, 3 or 4,
preferably equal to 1 or 2.
[0296] Mention may in particular be made, as examples of compounds
corresponding to the formula (IIc), of para-chlorotoluene,
para-bromoanisole or para-bromo-trifluorobenzene.
[0297] The amount of the compound carrying a leaving group of
formula (II), preferably of formula (IIa) or (Iib) or (IIc),
employed is generally expressed with respect to the amount of
nucleophilic compound and can vary within wide proportions;
generally, it is in the vicinity of stoichiometry.
[0298] Thus, the ratio of the number of moles of the compound
carrying the leaving group to the number of moles of the
nucleophilic compound generally varies between 0.1 and 2.0,
preferably between 0.5 and 1.5, more preferably between 0.8 and 1.2
and more preferentially between 0.9 and 1.1.
[0299] In accordance with the process of the invention, the
nucleophilic compound, preferably corresponding to the formulae
(Ia) to (Iv), is reacted with a compound carrying a leaving group,
preferably corresponding to the formula (II), more preferably to
the formulae (IIa) or (IIb) or (IIc), in the presence of an
effective amount of a catalytic system comprising a
copper/butadienylphosphine complex as defined according to the
invention.
[0300] This is because it has been discovered that it is possible
to carry out coupling reactions, such as defined supra, between
nucleophilic compounds and compounds carrying a leaving group by
using a catalytic system comprising a copper/butadienylphosphine
complex as defined according to the invention.
[0301] Mention may be made, as examples of catalytic systems
capable of being employed, of those comprising at least one
copper/butadienylphosphine complex, such as those defined supra
under the generic term Pho-Bu/Cu, that is to say complexes of
copper with at least one butadienylphosphine of formula (1)
according to the invention.
[0302] Mention may be made, as example of complex of Pho-Bu/Cu type
particularly suitable for the coupling reactions defined above, of
the phenylbutadienyldiphenylphosphine/copper iodide monomer complex
[Ph-CH.dbd.CH--CH.dbd.CH--PPh.sub.2].sub.2CuI, where Ph represents
the phenyl radical. As also indicated above, the Pho-Bu/Cu complex
can be prepared in situ, in the reaction medium for the coupling
reaction.
[0303] The total amount of copper/butadienylphosphine complex
catalyst employed in the process of the invention, expressed by the
molar ratio of the number of moles of complex, expressed as copper,
to the number of moles of compound carrying a leaving group,
generally varies between 0.001 and 0.5, preferably between 0.01 and
0.1.
[0304] According to an alternative form, the invention does not
exclude the copper being combined with a small amount of another
metal element denoted by M. The metal element M is chosen from
Group VIII, Ib and IIb of the Periodic Table of the Elements, as
defined above.
[0305] Mention may be made, as examples of metals M, of silver,
palladium, cobalt, nickel, iron and/or zinc.
[0306] Use is advantageously made of a mixture comprising palladium
and copper. The palladium can be introduced in the form of a finely
divided metal or in the form of an inorganic derivative, such as an
oxide or a hydroxide. It is possible to resort to an inorganic
salt, preferably nitrate, sulfate, oxysulfate, halide, oxyhalide,
silicate or carbonate, or to an organic derivative, preferably
cyanide, oxalate, acetylacetonate, alkoxide, more preferably still
methoxide or ethoxide, or carboxylate, more preferably still
acetate.
[0307] It is also possible to employ complexes, in particular
chlorine- or cyanide-comprising complexes, of palladium and/or of
alkali metals, preferably sodium or potassium, or of ammonium.
Mention may in particular be made, as examples of compounds capable
of being employed in the preparation of the catalysts of the
invention, of palladium(II) bromide, palladium(II) chloride,
palladium(II) iodide, palladium(II) cyanide, palladium(II) nitrate
hydrate, palladium(II) oxide, palladium(II) sulfate dihydrate,
palladium(II) acetate, palladium(II) propionate, palladium(II)
butyrate or palladium benzoate.
[0308] Mention may be made, as specific examples of nickel
derivatives, of nickel(II) halides, such as nickel(II) chloride,
bromide or iodide, nickel(II) sulfate, nickel(II) carbonate, salts
of organic acids comprising from 1 to 18 carbon atoms, such as, in
particular, acetate or propionate, nickel(II) complexes, such as
nickel(II) acetylacetonate,
dibromobis(triphenylphosphine)nickel(II) or
dibromobis(bipyridine)nickel(II), or nickel(0) complexes, such as
bis(1,5-cyclooctadiene)nickel(0) or
[bis(diphenylphosphino)ethane]nickel(0).
[0309] Recourse may also be had to derivatives based on iron or on
zinc, generally in the oxide or hydroxide form or in the form of
salts, such as halides, preferably chloride, nitrates and
sulfates.
[0310] The amount of the metal element M represents less than 50
mol %, preferably less than 25 mol %, advantageously less than 10
mol %, with respect to the number of moles of copper.
[0311] More preferably still, use is made of a catalyst in the form
of a complex with a butadienylphosphine comprising only copper.
[0312] A base, the function of which is to scavenge the leaving
group, is also involved in the process of the invention.
[0313] The bases suitable for the process of the invention can be
characterized by their pKa, which is advantageously at least
greater than or equal to 2, preferably between 4 and 30.
[0314] The pKa is defined as the ionic dissociation constant of the
acid/base pair when water is used as solvent. Reference may be
made, for the choice of a base having a pKa as defined by the
invention, inter alia, to the Handbook of Chemistry and Physics,
66.sup.th edition, pp. D-161 and D-162.
[0315] Mention may be made, among the bases which can be used,
inter alia, of inorganic bases, such as carbonates,
hydrogencarbonates, phosphates or hydroxides of alkali metals,
preferably sodium, potassium or cesium, or of alkaline earth
metals, preferably calcium, barium or magnesium.
[0316] Recourse may also be had to alkali metal hydrides,
preferably sodium hydride, or to alkali metal alkoxides, preferably
sodium alkoxides or potassium alkoxides, and more preferably to
sodium methoxide, ethoxide or tert-butoxide.
[0317] Organic bases, such as tertiary amines, are also suitable
and mention may more particularly be made of triethylamine,
tri(n-propyl)amine, tri(n-butyl)amine, methyldibutylamine,
methyldicyclohexylamine, ethyldiisopropylamine,
N,N-diethylcyclohexylamine, pyridine, 4-(dimethylamino)pyridine,
N-methylpiperidine, N-ethylpiperidine, N-(n-butyl)piperidine,
1,2-dimethylpiperidine, N-methylpyrrolidine and
1,2-dimethyl-pyrrolidine.
[0318] The choice is preferably made, among the bases, of alkali
metal carbonates.
[0319] The amount of base employed is such that the ratio of the
number of moles of base to the number of moles of the compound
carrying the leaving group preferentially varies between 1 and 4,
preferably in the vicinity of 2.
[0320] The coupling reaction, in particular arylation or vinylation
or alkynylation reaction, carried out according to the invention is
generally carried out in the presence of an organic solvent.
Recourse is preferably had to an organic solvent which does not
react under the conditions of the reaction.
[0321] Recourse is preferably had, as types of solvents employed in
the process of the invention, to a polar organic solvent and
preferably a polar aprotic organic solvent.
[0322] Nonlimiting examples of solvents which can be employed in
the process of the invention are chosen from: [0323] linear or
cyclic carboxamides, such as N,N-dimethylacetamide (DMAC),
N,N-diethylacetamide, dimethylformamide (DMF), diethylformamide or
1-methyl-2-pyrrolidinone (NMP); [0324] dimethyl sulfoxide (DMSO);
[0325] hexamethylphosphoramide (HMPT); [0326] tetramethylurea;
[0327] nitro compounds, such as nitromethane, nitroethane,
1-nitropropane, 2-nitropropane and their mixtures, or nitrobenzene;
[0328] aliphatic or aromatic nitriles, such as acetonitrile,
propionitrile, butanenitrile, isobutanenitrile, pentanenitrile,
2-methylglutaronitrile or adiponitrile; [0329] tetramethylene
sulfone (sulfolane); [0330] organic carbonates, such as dimethyl
carbonate, diisopropyl carbonate or di(n-butyl) carbonate; [0331]
alkyl esters, such as ethyl acetate or isopropyl acetate; [0332]
halogenated or nonhalogenated aromatic hydrocarbons, such as
chlorobenzene or toluene; [0333] ketones, such as acetone, methyl
ethyl ketone, methyl isobutyl ketone, cyclopentanone or
cyclohexanone; [0334] nitrogenous heterocycles, such as pyridine,
picoline and quinolines.
[0335] Use may also be made of a mixture of two or more solvents
chosen in particular from those listed above.
[0336] The preferred solvents are carboxamides, such as DMF,
acetonitrile, DMSO, NMP and DMAC.
[0337] The amount of organic solvent to be employed is determined
according to the nature of the organic solvent chosen. It is
determined so that the concentration of the compound carrying the
leaving group in the organic solvent is preferably between 5% and
40% by weight.
[0338] According to an alternative form, the nucleophilic compound
and/or the compound carrying the leaving group can be used as
solvent(s) for the reaction, in which case it is not necessary to
add an additional solvent to the reaction medium.
[0339] The coupling reaction, that is to say the reaction for the
creation of a C--C or C-HE bond according to the process of the
invention, is generally carried out at a temperature which is
advantageously situated between 0.degree. C. and 200.degree. C.,
preferably between 20.degree. C. and 170.degree. C. and more
preferably still between 25.degree. C. and 140.degree. C.
[0340] Said reaction is generally carried out at atmospheric
pressure but higher pressures, which can, for example, reach 10
bar, can also be used.
[0341] From a practical viewpoint, the reaction is simple to carry
out.
[0342] The order in which the reactants are employed is not
critical. Preferably, the copper/butadienylphosphine complex
catalytic system, the nucleophilic compound, preferably of formula
(Ia) to (Iv), the base, the compound carrying the leaving group,
preferably of formula (II), more preferably of formula (IIa), (Iib)
or (IIc), and optionally the organic solvent are charged. The
reaction medium is then brought to the desired temperature.
[0343] As mentioned above, it is possible, in an alternative form,
to introduce the copper and at least one butadienylphosphine as
ligand, in order to form the copper/butadienylphosphine complex in
situ.
[0344] The progress of the reaction is monitored by following the
disappearance of the compound carrying the leaving group. At the
end of the reaction, a product of the R-Q-R.sup.0 type is obtained,
R, Q and R.sup.0 being as defined above.
[0345] The compound obtained is recovered according to the
conventional techniques used, in particular by crystallization from
an organic solvent.
[0346] Mention may in particular be made, as more specific examples
of such organic solvents which can be used in the crystallization
stage, of aliphatic or aromatic hydrocarbons, which may or may not
be halogenated, carboxamides and nitriles. Mention may in
particular be made of cyclohexane, toluene, dimethylformamide or
acetonitrile.
[0347] Examples of the implementation of the invention are given
below. These examples are given by way of indication, without a
limiting nature.
EXAMPLES
Examples A
Syntheses of the butadienylphosphines
[0348] The reactions are carried out under a pure and dry nitrogen
atmosphere. 40 ml (2 equivalents, 58.44 mmol) of n-butyllithium
(n-BuLi; 1.6 M) are added at -50.degree. C. to a solution of 10 g
(29.22 mmol) of dimethyldiphenylphosphonium iodide
[Ph.sub.2P(CH.sub.3).sub.2].sup.+I.sup.- in 300 ml of anhydrous
tetrahydrofuran (THF) and then the reaction mixture is brought to
-10.degree. C. over one hour (yellow solution). 5.2 ml (1
equivalent, 29.22 mmol) of chlorodiphenylphosphine are added at the
same temperature. The reaction mixture is left stirring in order to
return to ambient temperature over one hour (orange solution) and
then one equivalent (or more, if necessary) of the
.alpha.,.beta.-unsaturated aldehyde is added. The reaction mixture
is kept stirred at ambient temperature overnight. The THF is
evaporated and then the residue is dissolved in dichloromethane.
The organic phase obtained is subsequently washed three times with
water, dried over anhydrous magnesium sulfate (MgSO.sub.4) and
concentrated under vacuum. The products are separated, with
satisfactory yields, by chromatography on a silica or alumina
column with a mixture of hexane/dichloromethane eluant appropriate
for each product.
Example A-1
Cinnamic butadienylphosphine Ph(C.sub.4H.sub.4)PPh.sub.2
[0349] The general procedure described above was followed using 4
ml (29.22 mmol) of cinnamaldehyde (trans). The two isomers are
separated on an alumina column with a mixture of
hexane/dichloromethane (95/5) eluant. The reaction yield is 90%
(E/Z=21/79).
Example A-1-1
Cinnamic butadienylphosphine (Z)-Ph(C.sub.4H.sub.4)PPh.sub.2
[0350] Identification
##STR00028##
[0351] Empirical formula: C.sub.22H.sub.19P
[0352] Molecular weight: 314.19
[0353] Melting point: 83-86.degree. C. (hexane/dichloromethane)
[0354] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-28.08 (s,
1P)
[0355] .sup.1H NMR (CDCl.sub.3): .delta.=6.22 (dd, 1H, H.sub.1,
.sup.2J.sub.H1P=0.80 Hz); 6.60 (broad d, 1H, H.sub.4,
.sup.3J.sub.H4H3=15.26 Hz); 6.97 (quintet, 1H, H.sub.2,
.sup.3J.sub.H2H1=11.25 Hz, .sup.3J.sub.H2H3=11.15 Hz,
.sup.3J.sub.H2P=22.47 Hz); 7.48 (m, 1H, H.sub.3,
.sup.4J.sub.H3H1=0.91 Hz, .sup.3J.sub.H3H4=15.26 Hz,
.sup.4J.sub.H3P=0.0023 Hz), 7.37-7.14 (m, 15H, 3Ph).
[0356] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=143.96 (d, 1C,
C.sub.2, .sup.2J.sub.CP=20.47 Hz); 138.98 (d, 2C, C.sub.ips,
.sup.1J.sub.CipsP=8.56 Hz); 136.87 (s, 1C, C.sub.5); 136.31 (s, 1C,
C.sub.4); 132.68 (d, 4C, C.sub.o, .sup.2J.sub.CoP=18.98 Hz); 129.70
(d, 4C, C.sub.3, .sup.3J.sub.C3P=13.90 Hz); 128.60 (d, 4C, C.sub.m,
.sup.3J.sub.CmP=6.58 Hz); 128.48 (s, 2C, C.sub.p,
.sup.4J.sub.CpP=5.12 Hz); 128.14 (s, 2C, C.sub.6-10); 126.89 (s,
2C, C.sub.7-9); 126.21 (d, 1C, C.sub.1, .sup.1J.sub.C1P=23.82
Hz).
[0357] IR (KBr): v (cm.sup.-1)=3020 s, 3010 m, 1620 m, 1570 m, 1470
m, 1430 vs, 1300 w, 1250 w, 1180 m, 1090 s, 1020 s, 980 s, 950 s,
690 vs.
Example A-1-2
Cinnamic butadienylphosphine (E)-Ph(C.sub.4H.sub.4)PPh.sub.2
[0358] Identification
##STR00029##
[0359] Empirical formula: C.sub.22H.sub.19P
[0360] Molecular weight: 314.19
[0361] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-11.32 (s,
1P)
[0362] .sup.1H NMR (CDCl.sub.3): .delta.=6.68 (m, 3H, 3CH);
7.45-7.26 (m, 15H, 3Ph); 7.79 (qdd, 1H, CH)
[0363] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=147.55 (d, 1C,
C.sub.3, .sup.3J.sub.C3P=3.52 Hz); 143.74 (d, 1C, C.sub.2,
.sup.2J.sub.CP=27.98 Hz); 138.15 (d, 2C, C.sub.ips,
.sup.1J.sub.CipsP=9.56 Hz); 136.87 (s, 1C, C.sub.4); 134.39 (d, 2C,
C.sub.6-10, .sup.6J.sub.CP=1.46 Hz); 133.18 (d, 4C, C.sub.o,
.sup.2J.sub.CoP=19.02 Hz); 129.25 (d, 1C, C.sub.1,
.sup.1J.sub.C1P=12.98 Hz); 128.73 (S, 2C, C.sub.p); 128.69 (d, 4C,
C.sub.m, .sup.3J.sub.CmP=16.40 Hz); 126.70 (s, 2C, C.sub.7-9);
126.06 (s, 1C, C.sub.8).
[0364] IR (KBr): v (cm.sup.-1)=3040 s, 3010 s, 1640 s, 1580 s, 1470
s, 1430 vs, 1390 w, 1190 s, 1115 s, 1090 m, 1030 m, 980 vs, 850 m,
720 s, 690 vs.
Example A-2
Crotonic butadienylphosphine CH.sub.3(C.sub.4H.sub.4)PPh.sub.2
[0365] The general procedure was followed using 2.4 ml (29.22 mmol)
of crotonaldehyde (trans-2-butanal). The two isomers are separated
on an alumina column with a mixture of hexane/dichloromethane
(97/3) eluant. The reaction yield is 80% (E/Z=25/75).
Example A-2-1
Crotonic butadienylphosphine
(Z)--CH.sub.3(C.sub.4H.sub.4)PPh.sub.2
[0366] Identification:
##STR00030##
[0367] Empirical formula: C.sub.17H.sub.17P
[0368] Molecular weight: 252.14
[0369] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-28.90 (s,
1P)
[0370] .sup.1H NMR (CDCl.sub.3): .delta.=1.65 (d, 3H, CH.sub.3,
.sup.3J.sub.H3H4=6.62 Hz); 5.73 (m, 1H, H.sub.3); 5.94 (dd, 1H,
H.sub.1; .sup.3J.sub.H1H2=10.42 Hz, .sup.3J.sub.H1P=2.02 Hz);
6.79-6.69 (m, 2H, H.sub.2 and H.sub.4); 7.62-7.11 (m, 10H,
2Ph).
[0371] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=144.60 (d, 1C,
C.sub.2, .sup.2J.sub.C2P=21.59 Hz); 139.39 (d, 2C, C.sub.ips,
.sup.1J.sub.CipsP=8.56 Hz); 134.53 (s, 1C, C.sub.4); 132.66 (d, 4C,
C.sub.o, .sup.2J.sub.CoP=18.61 Hz); 129.36 (d, 1C, C.sub.1,
.sup.1J.sub.C1P=23.82 Hz); 128.53 (d, 4C, C.sub.m,
.sup.3J.sub.CmP=6.70 Hz); 128.37 (s, 2C, C.sub.p); 126.18 (d, 1C,
C.sub.3, .sup.3J.sub.C3P=12.66 Hz); 18.47 (s, 1C, C.sub.5).
[0372] IR (CCl.sub.4): v (cm.sup.-1)=3060 s, 3040 s, 3000 s, 2915
s, 1690 vs, 1580 s, 1560 m, 1480 s, 1430 vs, 1370 m, 1300 w, 1100
m, 1030 s, 990 s, 950 s, 930 m, 820 s, 730 vs, 690 vs.
Example A-2-2
Crotonic butadienylphosphine
(E)-CH.sub.3(C.sub.4H.sub.4)PPh.sub.2
[0373] Identification
##STR00031##
[0374] Empirical formula: C.sub.17H.sub.17P
[0375] Molecular weight: 252.14
[0376] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-12.58 (s,
1P)
[0377] .sup.1H NMR (CDCl.sub.3): .delta.=1.65 (d, 3H, CH.sub.3,
.sup.4J.sub.H5H3=1.51 Hz, .sup.3J.sub.H5H4=7.07 Hz); 5.80 (sextet,
1H, H.sub.3, .sup.3J.sub.H3H2=10.42 Hz, .sup.4J.sub.H3H1=6.82 Hz);
6.11 (m, 2H, H.sub.1 and H.sub.4); 6.47 (m, 1H, H.sub.2,
.sup.3J.sub.H2H1=16.27 Hz, .sup.4J.sub.H2H4=9.60 Hz,
.sup.3J.sub.H2P=1.26 Hz); 7.35-7.14 (m, 10H, 2Ph).
[0378] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=144.88 (d, 10,
C.sub.2, .sup.2J.sub.CP=31.35 Hz); 138.70 (d, 2C, C.sub.ips,
.sup.1J.sub.CP=9.86 Hz); 132.94 (d, 4C, C.sub.o,
.sup.2J.sub.CP=18.82 Hz); 132.56 (s, 10, C.sub.4); 132.39 (d, 10,
C.sub.1, .sup.1J.sub.CP=17.31 Hz); 128.52 (s, 4C, C.sub.m); 128.39
(s, 2C, C.sub.p); 127.12 (d, 10, C.sub.3, .sup.3J.sub.CP=9.41 Hz);
18.22 (s, 10, C.sub.5).
[0379] IR (CCl.sub.4): v (cm.sup.-1)=3060 s, 3040 s, 3000 s, 2900
s, 1640 vs, 1580 s, 1475 s, 1430 vs, 1370 m, 1290 m, 1255 w, 1180
w, 1090 s, 1070 s, 1030 vs, 990 vs, 930 w, 690 vs.
Examples B
Preparations of the Copper/Butadienylphosphine complexes
[0380] The butadienylphosphine and the copper salt in the solid
form are successively introduced into a Schlenk tube purged three
times via vacuum/nitrogen cycles. The reactor is purged under
vacuum and then again filled with nitrogen. The solvent
(acetonitrile) is then added using a syringe. The reactor is
stirred at ambient temperature for 30 min.
[0381] When the metal salt is liquid, it is added after the solvent
using a syringe.
Example B-1
(Z)-Cinnamic phosphine/CuI complex
[0382] The general procedure described above was followed using 300
mg (0.954 mmol) of (Z)-cinnamic butadienylphosphine (example
A-1-1), 91 mg (0.477 mmol) of cuprous iodide (CuI) and 10 ml of
acetonitrile. The white precipitate formed is filtered off and then
recrystallized from acetonitrile.
[0383] Yield: 383 mg (98%)
[0384] Identification:
##STR00032##
[0385]
Iododi{.eta.-[(4-phenyl-1,3-butadienyl)diphenylphosphine]}copper
complex
[0386] Empirical formula: C.sub.44H.sub.38CuIP.sub.2
[0387] Molecular weight: 818.82
[0388] Melting point: 200-203.degree. C. (acetonitrile)
[0389] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-21.86 (s,
1P)
[0390] .sup.1H NMR (CDCl.sub.3): .delta.=6.03 (dd, 1H, H.sub.1,
.sup.3J.sub.H1H2=11.83 Hz, .sup.2J.sub.H1P=6.36 Hz); 6.47 (d, 1H,
H.sub.4, .sup.3J.sub.H4H3=15.26 Hz); 6.83 (quintet, 1H, H.sub.2,
.sup.3J.sub.H2P=11.34 Hz); 7.13 (dd, 1H, H.sub.3,
.sup.3J.sub.H2H3=11.59 Hz); 7.33-7.18 (m, 15H, 3Ph).
[0391] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=143.70 (d, 1C,
C.sub.2, .sup.2J.sub.CP=4.09 Hz); 137.95 (s, 1C, C.sub.4); 136.30
(s, 1C, C.sub.5); 134.16 (d, 2C, C.sub.i, .sup.1J.sub.CiP=28.66
Hz); 133.29 (d, 4C, C.sub.o, .sup.2J.sub.CoP=13.77 Hz); 129.55 (s,
10, C.sub.8); 128.57 (d, 4C, C.sub.m, .sup.3J.sub.CmP=8.05 Hz);
128.46 (s, 2C, C.sub.9); 128.27 (s, 2C, C.sub.6-10); 127.60 (s, 2C,
C.sub.7-9); 126.15 (d, 10, C.sub.3, .sup.3J.sub.C3P=13.40 Hz);
123.45 (d, 10, C.sub.1, .sup.1J.sub.C1P=23.08 Hz).
[0392] FAB-MS (positive mode): m/z=691
[(Ph(C.sub.4H.sub.4)PPh.sub.2).sub.2Cu].sup.+, 377
[(Ph(C.sub.4H.sub.4)PPh.sub.2) Cu].sup.+.
[0393] IR (KBr): v (cm.sup.-1)=3066 vw, 3023 vw, 1618 m, 1595 w,
1576 m, 1478 m, 1446 m, 1431 s, 1420 s, 1364 w, 1303 m, 1180 vw,
1156 m, 1096 m, 1066 m, 987 s, 943 s, 755 m, 740 vs, 732 vs, 711
vs, 697 vs, 627 m, 616 w.
[0394] X-ray Structure:
##STR00033##
[0395] Two phosphine-butadiene ligands are bonded to the copper
solely via the doublet of the phosphorus. The double bonds are not
involved in the coordination. The third ligand is iodine.
[0396] The values of the C1-C2 (1.343 .ANG.) and C3-C4 (1.339
.ANG.) bonds indicate that the double bonds are not involved in the
coordination. This is because these values correspond to that of a
double bond, diphenylstyrylphosphine (table below).
TABLE-US-00001 ##STR00034## Bond Length (.ANG.) C2-C211 1.467 (2)
C1-C2 1.339 (2) P1-C121 1.8385 (14) P1-C1 1.8412 (15) P1-C1 1.8140
(16)
Example B-2
(Z)-Crotonic phosphine/CuI complex
[0397] The general procedure described above was followed using 80
mg (0.317 mmol) of (Z)-crotonic butadienylphosphine (example
A-2-1), 30 mg (0.158 mmol) of cuprous iodide (CuI) and 5 ml of
acetonitrile. After treatment, the residue obtained was dissolved
in a minimum amount of dichloromethane and then precipitated from
pentane.
[0398] Yield: 82 mg (75%).
[0399] Identification:
##STR00035##
[0400] Empirical formula: C.sub.34H.sub.34CuIP.sub.2
[0401] Molecular weight: 694.38
[0402] Melting point: 94-96.degree. C. (pentane)
[0403] .sup.31P {.sup.1H} NMR (CDCl.sub.3): .delta.=-23.36 (s,
2P)
[0404] .sup.1H NMR (CDCl.sub.3): .delta.=1.61 (d, 6H, 2CH.sub.3);
5.98-5.65 (m, 4H, 2H.sub.1 and 2H.sub.3); 6.97-6.53 (m, 4H,
2H.sub.2 and 2H.sub.4); 7.35-7.15 (m, 120H, 4Ph).
[0405] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=18.29 (s, 2C,
2C.sub.5); 120.78 (d, 2C, 2C.sub.1, .sup.1J.sub.C1P=21.6 Hz);
128.51 (d, 8C, 8C.sub.m, .sup.3J.sub.CmP=8.9 Hz); 129.35 (s, 4C,
4C.sub.p); 129.67 (s, 2C, 2C.sub.3); 133.04 (d, 8C, 8C.sub.o,
.sup.2J.sub.CoP=14.9 Hz); 134.82 (d, 4C, .sup.4C.sub.i,
.sup.1J.sub.CiP=25.7 Hz); 136.55 (s, 2C, 2C.sub.4); 144.74 (d, 2C,
2C.sub.2, .sup.2J.sub.C2P=9.7 Hz)
[0406] FAB-MS (positive mode): m/z=567
[{CH.sub.3(C.sub.4H.sub.4)PPh.sub.2}.sub.2Cu].sup.+, 315
[CH.sub.3(C.sub.4H.sub.4)PPh.sub.2Cu].sup.+
[0407] IR (KBr): v (cm.sup.-1)=3060 vw, 3000 vw, 2900 vw, 1640 m,
1560 w, 1540 w, 1480 m, 1430 s, 1370 w, 1310 w, 1100 m, 1035 w, 990
s, 950 m, 930 m, 825 w, 750 s, 730 w, 690 vs
Examples C
Arylation reactions in the presence of the butadienylphosphine and
a copper salt
[0408] General Procedure
[0409] The copper salt, the butadienylphosphine (ligand), the
nucleophile and the base are successively introduced into a 35 ml
Schlenk tube purged three times via vacuum/nitrogen cycles. The
arylating agent and then the solvent (acetonitrile) are then added
using syringes. The reaction mixture is brought to the desired
temperature and stirred at this temperature for the duration
shown.
Example C-1
Arylation of pyrazole
[0410] The general procedure described above (solvent:
acetonitrile; reaction temperature: 82.degree. C.; duration of the
reaction: 12 hours, or 30 hours in the case of bromobenzene) was
followed using 9.52 mg (0.05 mmol) of copper iodide CuI, 32 mg (0.1
mmol) of (Z)-cinnamic butadienylphosphine of example A-1-1, 68 mg
(0.75 mmol) of pyrazole, 326 mg (1 mmol) of cesium carbonate
(Cs.sub.2CO.sub.3), 56 .mu.l (0.5 mmol) of iodobenzene (or 53 .mu.l
of bromobenzene) and 500 .mu.l of acetonitrile. The oil obtained
after treatment (dichloromethane/water extraction) was purified by
chromatography on a silica column (eluant: dichloromethane/hexane
50/50).
[0411] Yield: 70 mg of colorless oil (98%)
[0412] Identification:
##STR00036##
[0413] .sup.1H NMR (CDCl.sub.3): .delta.=7.95-7.96 (dd, 1H,
H.sub.7); 7.71-7.75 (m, 3H, H.sub.2, 6, 9); 7.47-7.50 (m, 2H,
H.sub.3, 5); 7.28-7.34 (m, 1H, H.sub.4); 6.49-6.50 (dd, 1H,
H.sub.8).
[0414] .sup.13C NMR (CDCl.sub.3): .delta.=141.09 (C.sub.9); 140.22
(C.sub.1); 129.45 (C.sub.3, 5); 126.75 (C.sub.7); 126.46 (C.sub.4);
119.23 (C.sub.2, 6); 107.61 (C.sub.8)
[0415] IR (Kbr): v (cm.sup.-1)=3142; 3050; 2924; 1600; 1520; 1500;
1393; 1332; 1198; 1120; 1046; 936; 914; 755; 689; 654; 610; 515
[0416] GC/MS: rt=14.53 min, m/z=144
[0417] HRMS: 145.0766 (M+H). Theory: 145.0766
Example C-2
Arylation of 3,5-dimethylphenol
[0418] The general procedure (acetonitrile, 82.degree. C., 12 hours
or hours in the case of bromobenzene) was followed using 9.52 mg
(0.05 mmol) of copper iodide CuI, 31.4 mg (0.1 mmol) of
(Z)-cinnamic butadienylphosphine of example A-1-1, 91.62 mg (0.75
mmol) of 3,5-dimethylphenol, 212 mg (1 mmol) of potassium phosphate
(K.sub.3PO.sub.4), 56 .mu.l (0.5 mmol) of iodobenzene (53 .mu.l of
bromobenzene) and 500 .mu.l of acetonitrile. The oil obtained after
treatment (dichloromethane/water extraction) was purified by
chromatography on a silica column (eluant: hexane).
[0419] Yield: 89 mg of colorless oil (90%)
[0420] Identification
##STR00037##
[0421] .sup.1H NMR (CDCl.sub.3): .delta.=7.28-7.42 (m, 2H);
7.12-7.17 (m, 1H); 7.03-7.14 (m, 2H); 6.79 (m, 1H); 6.69 (m, 2H);
2.33 (s, 6H, CH.sub.3).
[0422] .sup.13C {.sup.1H} NMR (CDCl.sub.3): .delta.=157.50 (Cq);
157.22 (Cq); 139.61 (2 Cq); 129.70 (2 CH); 125.04 (CH); 123.02
(CH); 118.89 (2 CH); 116.67 (2 CH); 21.35 (2 CH.sub.3)
[0423] GC/MS: rt=18.24 min, m/z=198
[0424] Rf: 0.22 (eluant: hexane)
Example C-3
Arylation of ethyl cyanoacetate
[0425] Preparation of 2-phenylethyl cyanoacetate
[0426] The general procedure (acetonitrile, 82.degree. C., 12 hours
with iodobenzene; 30 hours in the case of bromobenzene) was
followed using 9.52 mg (0.05 mmol) of copper iodide CuI, 31.4 mg
(0.1 mmol) of (Z)-cinnamic butadienylphosphine of example A-1-1, 80
ml (0.75 mmol) of ethyl cyanoacetate, 318 mg (1.5 mmol) of
potassium phosphate (K.sub.3PO.sub.4), 56 .mu.l (0.5 mmol) of
iodobenzene (53 .mu.l of bromobenzene) and 500 .mu.l of
acetonitrile. The residue obtained after treatment
(dichloromethane/water extraction) was purified by chromatography
on a silica column (gradient: hexanes/CH.sub.2Cl.sub.2 100:0 to
75:25).
[0427] Yield: 94%
[0428] .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. (ppm)=7.37-7.45
(m, 5H); 4.71 (s, 1H); 4.25 (q, .sup.3J=7.1 Hz, 2H); 1.28 (t,
.sup.3J=7.1 Hz, 3H).
[0429] .sup.13C {.sup.1H} NMR (50 MHz, CDCl.sub.3): .delta.
(ppm)=165.0 (Cq); 130.0 (Cq); 129.3 (2 CH); 129.2 (CH); 127.9 (2
CH); 115.7 (CN); 63.3 (CH.sub.2); 43.7 (CH); 13.9 (CH.sub.3)
[0430] GC/MS (EI): rt=15.24 min, m/z: 189
[0431] Rf: 0.22 (hexanes/CH.sub.2Cl.sub.2 3:1)
Examples D
Arylation reactions in the presence of the (Z)-cinnamic
phosphine/CuI complex obtained in example B-1
[0432] General Procedure
[0433] The complex, the base, the nucleophile and the arylating
agent are successively introduced into a 35 ml Schlenk tube purged
three times via vacuum/nitrogen cycles and then the solvent
(acetonitrile) are then added using syringes. The tube is sealed
under nitrogen pressure and then stirred and brought to 82.degree.
C. for the time shown in the table. After cooling to ambient
temperature, the mixture is diluted with dichloromethane
(approximately 20 ml) and filtered through Celite (registered brand
name). The precipitate is then washed several times with
dichloromethane, the filtrate is washed with water, the organic
phases are combined and dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum, and then the crude products obtained are
purified on a chromatography column, elution being carried out with
a hexane/dichloromethane mixture.
[0434] For a complete characterization of the products obtained,
which are all known, see the following papers: arylpyrazoles
(Cristau, H. J., Cellier, P. P., Spindler, J.-F.; Taillefer, M.,
Chemistry, a European Journal, 10, 2004, 5607, or European Journal
of Organic Chemistry, 2004, 695), diaryl ethers (ibid, Organic
Letters, 6, 2004, 913), vinylpyrazoles and vinyl aryl ethers (Ouali
A., Renard B., Spindler, J.-F., Taillefer, M., Chemistry, a
European Journal, 2006, 20, 5301).
[0435] The reactions carried out are combined in the following
table:
TABLE-US-00002 ##STR00038## ArX NuH Time [h] Yield [%] ##STR00039##
##STR00040## 4 98 ##STR00041## ##STR00042## 4 97 ##STR00043##
##STR00044## 4 98 ##STR00045## ##STR00046## 10 .sup. 91.sup.[a]
##STR00047## ##STR00048## 24 .sup. 70.sup.[b] .sup.[a]base:
K.sub.3PO.sub.4. .sup.[b]DMF, 140.degree. C.
Examples E
Vinylation reactions in the presence of (Z)-cinnamic phosphine/CuI
complex obtained in example B-1
[0436] The reactions combined in the following table were carried
out according to the general procedure described in examples D.
TABLE-US-00003 ##STR00049## vinylBr NuH Time [h] Yield [%]
##STR00050## ##STR00051## 4 100 ##STR00052## ##STR00053## 10 95
* * * * *