U.S. patent application number 10/529361 was filed with the patent office on 2006-06-15 for compositions containing ionic liquids and uses thereof, especially in organic synthesis.
Invention is credited to Said Gmouth, Michel Vaultier.
Application Number | 20060128996 10/529361 |
Document ID | / |
Family ID | 31985248 |
Filed Date | 2006-06-15 |
United States Patent
Application |
20060128996 |
Kind Code |
A1 |
Vaultier; Michel ; et
al. |
June 15, 2006 |
Compositions containing Ionic liquids and uses thereof, especially
in organic synthesis
Abstract
The invention relates to the use of an ionic liquid as a matrix
liquid for organic synthesis in a homogeneous phase on a soluble
medium, said ionic liquid being present in the form of a liquid or
solid at room temperature, having formula
A.sub.1.sup.+X.sub.1.sup.-, .sub.1.sup.+ representing a functional
or non-functional cation or a mixture of cations wherein none of
said cations are functional or at least one of the cations is
functional, and X.sub.1.sup.- a functional or non-functional anion
or a mixture of anions wherein none of the anions are functional or
at least one of the anions is functional.
Inventors: |
Vaultier; Michel;
(Chateaugiron, FR) ; Gmouth; Said; (Casablaca,
MA) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET
2ND FLOOR
ARLINGTON
VA
22202
US
|
Family ID: |
31985248 |
Appl. No.: |
10/529361 |
Filed: |
September 23, 2003 |
PCT Filed: |
September 23, 2003 |
PCT NO: |
PCT/FR03/02795 |
371 Date: |
November 3, 2005 |
Current U.S.
Class: |
568/312 ;
502/150; 546/347; 548/110; 564/281 |
Current CPC
Class: |
B01J 31/0281 20130101;
C07B 37/02 20130101; C07B 37/12 20130101; C07C 67/03 20130101; B01J
31/04 20130101; C07C 67/343 20130101; C07C 67/347 20130101; C07C
67/03 20130101; C07C 67/03 20130101; B01J 2231/4266 20130101; C07C
2602/42 20170501; C07C 67/03 20130101; C07C 67/343 20130101; B01J
31/30 20130101; B01J 31/0224 20130101; B01J 2231/341 20130101; B01J
2231/4211 20130101; C07C 67/343 20130101; C07C 67/343 20130101;
B01J 2231/4261 20130101; C07C 67/03 20130101; C07C 67/343 20130101;
C07B 37/04 20130101; B01J 2231/326 20130101; C07C 67/343 20130101;
C07C 67/347 20130101; B01J 31/0239 20130101; C07C 67/03 20130101;
B01J 31/0288 20130101; C07C 69/753 20130101; C07C 67/03 20130101;
C07C 69/753 20130101; C07C 69/618 20130101; C07C 69/734 20130101;
C07C 69/732 20130101; C07C 69/732 20130101; C07C 69/76 20130101;
C07C 69/65 20130101; C07C 69/618 20130101; C07C 69/734 20130101;
C07C 69/76 20130101; C07C 69/65 20130101 |
Class at
Publication: |
568/312 ;
502/150; 548/110; 546/347; 564/281 |
International
Class: |
B01J 31/00 20060101
B01J031/00; C07C 45/46 20060101 C07C045/46; C07D 213/20 20060101
C07D213/20; C07F 5/02 20060101 C07F005/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 26, 2002 |
FR |
02/11910 |
Claims
1-32. (canceled)
33. A method of organic synthesis in homogeneous phase on soluble
support, without volatile organic solvent, comprising the use of an
ionic liquid, as liquid matrix, said ionic liquid being presented
in liquid or solid form at ambient temperature, of formula
A.sub.1.sup.+X.sub.1.sup.-, A.sub.1.sup.+ representing a cation,
functional or non-functional, or a mixture of cations in which
either none of the cations is functional or at least one of the
cations is functional, and X.sub.1.sup.- an anion, functional or
non-functional, or a mixture of anions in which either none of the
anions is functional or at least one of the anions is
functional.
34. The method of claim 33, characterized in that A.sub.1.sup.+
represents a non-functional cation or a mixture of non-functional
cations and X.sub.1.sup.- a non-functional anion or a mixture of
non-functional anions.
35. The method of claim 33, characterized in that A.sub.1.sup.+
represents a functional cation or a mixture of cations at least one
of which is functional, and/or X.sub.1.sup.- represents a
functional anion or a mixture of anions at least one of which is
functional, said functional cations and functional anions
corresponding to an ionic entity, namely cationic or anionic
respectively, linked to at least one function F.sub.i, F.sub.i
varying from F.sub.0 to F.sub.n, n being an integer varying from 1
to 10.
36. The method of claim 33, for the preparation of a stable
composition containing in solution: at least said ionic liquid of
formula A.sub.1.sup.+X.sub.1.sup.-, playing the role of liquid
matrix and, at least one functionalized salt (salt with a dedicated
task), in particular functionalized onium salt, of formula
A.sub.2.sup.+X.sub.2.sup.-, as reaction support, the functionalized
salt, in particular the functionalized onium salt, being dissolved
in the liquid matrix, in order to form a homogeneous phase,
A.sub.1.sup.+ representing a non-functional cation or a mixture of
cations in which none of the cations is functional, and
X.sub.1.sup.- representing a non-functional anion or a mixture of
anions in which none of the anions is functional, A.sub.2.sup.+
representing a cation, functional or non-functional, or a mixture
of cations in which none of the cations is functional or in which
at least one of the cations is functional, and X.sub.2.sup.-
representing an anion, functional or non-functional, or a mixture
of anions in which none of the anions is functional or in which at
least one of the anions is functional, provided that A.sub.2.sup.+
and/or X.sub.2.sup.- represent(s) or comprise(s) a functional
cation and a functional anion respectively, said functional cations
and functional anions corresponding to an ionic entity Y--, namely
cationic Y.sup.+-- or anionic Y.sup.--- respectively, linked,
optionally via an L arm, in particular an alkyl group comprising 1
to 20 carbon atoms, to at least one function F.sub.i, F.sub.i
varying from F.sub.0 to F.sub.n, n being an integer varying from 1
to 10, the functional cation being representable in the form
Y.sup.+-L-F.sub.i, and the functional anion in the form
Y.sup.--(L).sub.k-F.sub.i, k being equal to 0 or 1, and the
functional anion possibly representing, when k is equal to 0, a
single anion, corresponding to Y.sup.---F.sub.i, in particular
chosen from: OH.sup.-, F.sup.-, CN.sup.-, RO.sup.- or RS.sup.-, R
representing an alkyl group comprising 1 to 20 carbon atoms or an
aryl group comprising 6 to 30 carbon atoms.
37. The method of claim 35, for the preparation of a stable
composition containing in solution: at least one first part of said
ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.-, the cation
and/or the anion of which correspond(s) to an ionic entity linked
to one or more initial functions F.sub.0, playing the role of
liquid matrix, and at least one second part of said ionic liquid of
formula A.sub.1.sup.+X.sub.1.sup.-, in which said initial function
or functions Fo are converted into first novel functions,
conferring upon said second part of said ionic liquid the role of
functionalized salt and of reaction support, the functionalized
salt and the liquid matrix forming a homogeneous phase, the
abovementioned first novel functions of the second part of said
ionic liquid being capable of being converted subsequently into
other functions, without affecting the initial function or
functions Fo of the first part of said ionic liquid.
38. The method of claim 36, characterized in that the A.sub.2.sup.+
cation and/or the X.sub.2.sup.- anion of the functionalized salt or
salts, corresponding to a Y-- ionic entity linked to at least one
function F.sub.i, are immobilized in the liquid matrix and cannot
be extracted from the liquid matrix by standard extraction means,
in particular by solvent, and in which the function(s) F.sub.i of
the functionalized salt or salts can be converted at the end of at
least one reaction resulting from the addition of at least one
reagent to said composition.
39. The method of claim 38, characterized in that several
functionalized salts are immobilized.
40. The method of claim 36, characterized in that the A.sub.2.sup.+
cation is functional.
41. The method of claim 36, characterized in that the X.sub.2.sup.-
anion is functional.
42. The method of claim 36, characterized in that A.sub.2.sup.+ and
X.sub.2.sup.- are functional.
43. The method of claim 33, characterized in that: either the ionic
liquid of formula A.sub.1.sup.+X.sub.1.sup.- is solid at ambient
temperature and is liquefiable within a temperature range from
approximately 25.degree. C. to approximately 250.degree. C., in
particular from approximately 30.degree. C. to approximately
150.degree. C., and the A.sub.2.sup.+X.sub.2.sup.- functionalized
salt is solid at ambient temperature and is soluble in the
liquefied A.sub.1.sup.+X.sub.1.sup.- ionic liquid, in order to form
a homogeneous phase, or the ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.- is solid at ambient temperature and is
liquefiable within a temperature range from approximately
25.degree. C. to approximately 250.degree. C., in particular from
approximately 30.degree. C. to approximately 150.degree. C., and
the A.sub.2.sup.+X.sub.2.sup.- functionalized salt is liquid at
ambient temperature, and is miscible with the liquefied
A.sub.1.sup.+X.sub.1.sup.- ionic liquid, in order to form a
homogeneous phase, or the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
is liquid at ambient temperature and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is liquid at ambient temperature and miscible
with the A.sub.1.sup.+X.sub.1.sup.- ionic liquid, in order to form
a homogeneous phase, or the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
is liquid at ambient temperature and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is solid at ambient temperature and is soluble
or partially soluble in the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
within a temperature range from approximately 25.degree. C. to
approximately 250.degree. C., in particular from approximately
30.degree. C. to approximately 150.degree. C., in order to form a
homogeneous phase.
44. The method of claim 37, characterized in that: either the ionic
liquid of formula A.sub.1.sup.+X.sub.1.sup.- is liquid at ambient
temperature, or the ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.- is solid at ambient temperature and is
liquefiable within a temperature range from approximately
25.degree. C. to approximately 250.degree. C., in particular from
approximately 30.degree. C. to approximately 150.degree. C.
45. The method of claim 33, characterized in that the ionic liquid
of formula A.sub.1.sup.+X.sub.1.sup.-, playing the role of liquid
matrix, has a viscosity less than or equal to approximately 1500 cp
(15 N.s/m.sup.2), in particular less than approximately 500 cp (5
N.s/m.sup.2) and preferably less than approximately 200 cp (2
N.s/m.sup.2).
46. A stable composition containing in solution: at least said
ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.-, playing the
role of liquid matrix and, at least one functionalized salt (salt
with a dedicated task), in particular functionalized onium salt, of
formula A.sub.2.sup.+X.sub.2.sup.-, as reaction support, the
functionalized salt, in particular the functionalized onium salt,
being dissolved in the liquid matrix, in order to form a
homogeneous phase, A.sub.1.sup.+ representing a non-functional
cation or a mixture of cations in which none of the cations is
functional, and X.sub.1.sup.- representing a non-functional anion
or a mixture of anions in which none of the anions is functional,
A.sub.2.sup.+ representing a cation, functional or non-functional,
or a mixture of cations in which none of the cations is functional
or in which at least one of the cations is functional, and
X.sub.2.sup.- representing an anion, functional or non-functional,
or a mixture of anions in which none of the anions is functional or
in which at least one of the anions is functional, provided that
A.sub.2.sup.+ and/or X2.sup.- represent(s) or comprise(s) a
functional cation and a functional anion respectively, said
functional cations and functional anions corresponding to an ionic
entity Y--, namely cationic Y.sup.+-- or anionic Y.sup.---
respectively, linked, optionally via an L arm, in particular an
alkyl group comprising 1 to 20 carbon atoms, to at least one
function F.sub.i, F.sub.i varying from F.sub.0to F.sub.n, n being
an integer varying from 1 to 10, the functional cation being
representable in the form Y.sup.+-L-F.sub.i, and the functional
anion in the form Y.sup.--(L).sub.k-F.sub.i, k being equal to 0 or
1, and the functional anion possibly representing, when k is equal
to 0, a single anion, corresponding to Y.sup.---F.sub.i, in
particular chosen from: OH.sup.-, F.sup.-, CN.sup.-, RO.sup.- or
RS.sup.-, R representing an alkyl group comprising 1 to 20 carbon
atoms or an aryl group comprising 6 to 30 carbon atoms.
47. A stable composition containing in solution: at least one first
part of said ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.-,
the cation and/or anion of which correspond(s) to an ionic entity
linked to one or more initial functions F.sub.0, playing the role
of liquid matrix, and at least one second part of said ionic liquid
of formula A.sub.1.sup.+X.sub.1.sup.-, in which said initial
function or functions F.sub.0 are converted into first novel
functions, conferring on said second part of said ionic liquid the
role of functionalized salt and reaction support, the
functionalized salt and the liquid matrix forming a homogeneous
phase, the abovementioned first novel functions of the second part
of said ionic liquid being capable of being subsequently converted
to other functions, without affecting the initial function or
functions F.sub.0 of the first part of said ionic liquid.
48. The composition of claim 46, characterized in that the
A.sub.2.sup.+ cation and/or the X.sub.2.sup.- anion of the
functionalized salt or salts, corresponding to a Y-- ionic entity
linked to at least one function F.sub.i, are immobilized in the
liquid matrix and cannot be extracted from the liquid matrix by
standard extraction means, in particular by solvent.
49. The composition of claim 46 characterized in that the liquid
matrix is non-reactive vis-a-vis the functionalized salt.
50. The composition of claim 46, characterized in that
A.sub.2.sup.+ is a functional cation.
51. The composition of claim 50, characterized in that the
X.sub.1.sup.- and X.sub.2.sup.- anions are identical.
52. The composition of claim 50, characterized in that: the
X.sub.1.sup.- and X.sub.2.sup.- anions are chosen from the
following two families: the non-complex anions, chosen in
particular from the BF.sub.4.sup.-, PF.sub.6.sup.-,
CF.sub.3SO.sub.3.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
.sup.-N(SO.sub.2CF.sub.3).sub.2 (or NTf.sub.2.sup.-) anion the
halides, the BR.sub.4.sup.-, RCO.sub.2.sup.- or RSO.sub.3.sup.-
anions, R being an alkyl group comprising 1 to 20 carbon atoms or
an aryl group comprising 6 to 30 carbon atoms, said R group also
possibly representing a perfluorinated or partially fluorinated
group, or the R'SO.sub.4.sup.- anions, R' being a hydrogen atom, a
methyl group or an ethyl group; the complex anions, resulting from
the combination of a Lewis acid and a halide, preferably Cl.sup.-
or F.sup.-, of general formula MXj, j being an integer comprised
between 1 and 7, and M representing a metal, in particular chosen
from aluminium, tin, zinc, bismuth, manganese, iron, copper,
molybdenum, antimony, gallium or indium; the A.sub.1.sup.+ and
A.sub.2.sup.+ cations are chosen from the onium cations, such as
the substituted or non-substituted pyridinium, imidazolium,
ammonium, phosphonium or sulphonium cations, and preferably
ammonium or phosphonium.
53. The composition of claim 46, characterized in that the
A.sub.2.sup.+ functional cation corresponds to a Y.sup.+-- cationic
entity, linked, via an L arm, in particular an alkyl group
comprising 1 to 20 carbon atoms, to a function F.sub.0, said
function F.sub.0 being chosen from the standard functions of
organic chemistry, such as the hydroxyl, carboxylic, amide,
sulphone, primary amine, secondary amine, aldehyde, ketone,
ethenyl, ethynyl, dienyl, ether, epoxide, phosphine (primary,
secondary or tertiary), azide, imine, ketene, cumulene,
heterocumulene, thiol, thioether, sulphoxide, phosphorus-containing
moieties, heterocycles, sulphonic acid, silane, stannane or
functional aryl functions.
54. The composition of claim 46, characterized in that the ionic
liquid is chosen from the following: ##STR252## R.sub.a and R.sub.b
representing linear or branched alkyl groups, comprising 1 to 20
carbon atoms, in particular an ethyl, propyl, butyl, pentyl, hexyl,
heptyl or octyl group, or functional alkyl groups comprising 1 to
20 carbon atoms, or functional or non-functional aryl groups
comprising 6 to 30 carbon atoms, Bu.sub.3P.sup.+--Me,
X.sub.1.sup.-.sup..sym.P(C.sub.6H.sub.13).sub.3C.sub.14H.sub.29,
X.sub.1.sup.- (C.sub.8H.sub.17).sub.3N.sup.+Me, X.sub.1.sup.-
X.sub.1.sup.- being in particular chosen from: NTf.sub.2.sup.-,
PF.sub.6.sup.-, BF.sub.4.sup.- or CF.sub.3SO.sub.3.sup.-.
55. The composition of claim 46, characterized in that the
functionalized salt is chosen from the following: ##STR253##
X.sub.2.sup.- being chosen from: NTf.sub.2.sup.-, PF.sub.6.sup.-,
BF.sub.4.sup.-, Cl.sup.-, Br.sup.-, I.sup.-,
CF.sub.3SO.sub.3.sup.-, MeSO.sub.4.sup.-, EtSO.sub.4.sup.-,
MeSO.sub.3.sup.-, C.sub.6H.sub.5SO.sub.3.sup.-,
pMeC.sub.6H.sub.4SO.sub.3.sup.-, m being an integer comprised
between 0 and 20, R.sub..beta. representing a substituted or
non-substituted vinyl group, functional aryl group comprising 1 to
20 carbon atoms, or functional alkyl group comprising 6 to 30
carbon atoms, and R.sub.a representing a branched or non-branched
alkyl group comprising 1 to 20 carbon atoms, in particular an
ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group.
56. The composition of claim 46, characterized in that
X.sub.2.sup.- is a functional anion, corresponding in particular to
an anion the pK.sub.A of the conjugated acid of which is less than
30, and is chosen in particular from the following anions:
OH.sup.-, F.sup.-, R.sub.cBZ.sub.3.sup.-, N.sub.3.sup.-, CN.sup.-,
or W{overscore (C)}R.sub.cV Z representing an --F, --OH, --OR
group, R representing an alkyl group comprising 1 to 20 carbon
atoms, V and W representing, independently of each other, an
electroattractive group, in particular a cyano, alkoxycarbonyl
moiety comprising 2 to 20 carbon atoms, acyl moiety comprising 2 to
20 carbon atoms, benzoyl, alkyl sulphonyl moiety comprising 1 to 20
carbon atoms, aryl sulphonyl moiety comprising 6 to 30 carbon
atoms, dialkoxyphosphonyl moiety comprising 2 to 20 carbon atoms,
R.sub.c representing a branched or non-branched, cyclic or
non-cyclic alkyl moiety, comprising 1 to 20 carbon atoms, or an
aryl moiety comprising 6 to 30 carbon atoms, and in that the
A.sub.2.sup.+ cation is chosen from the ammonium and phosphonium
cations, in particular from the following cations:
Me.sub.3N.sup.+--R.sub.dEt.sub.3N.sup.+--R.sub.dBu.sub.4P.sup.+--R.sub.d
R.sub.d being an alkyl group comprising 1 to 20 carbon atoms.
57. A method of continuous, discontinuous, combinatorial, or
parallel organic synthesis, and/or for the preparation of libraries
of products, comprising the use of the composition of claim 46.
58. A method for the implementation of the preparation of a
molecule G, comprising the use of the composition of claim 46, said
molecule G having an initial function F.sub.0, linked, optionally
via an L arm, in particular an alkyl group comprising 1 to 20
carbon atoms, to a Y.sup.+-- ionic entity, forming part of the
A.sub.2.sup.+ cation of the A.sub.2.sup.+X.sub.2.sup.-, and/or
Y.sup.--- functionalized salt, forming part of the X.sub.2.sup.-
anion of the A.sub.2.sup.+X.sub.2.sup.- functionalized salt, the
cation being in the form Y.sup.+-L-F.sub.0 and/or the anion being
in the form Y.sup.--(L).sub.k-F.sub.0, k being equal to 0 or 1,
which method comprises the stages: of a first addition of a reagent
B.sub.1 into the abovementioned composition and the reaction
between said function F.sub.0, and the reagent B.sub.1, leading to
a function F.sub.1, linked to the Y.sup.+-- ionic entity, forming
part of the A.sub.2.sup.+ cation of the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt, and/or to the Y.sup.--- ionic entity, forming
part of the X.sub.2.sup.- anion of the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt, according to one of the following reaction
diagrams: ##STR254## of n-1 successive additions of B.sub.i
reagents, 1<i.ltoreq.n, n varying from 2 to 10, to the
abovementioned composition, allowing, at each addition, the
reaction between the reagent B.sub.i and a function F.sub.i-1,
leading to the obtaining of a function F.sub.i, the (n-1).sup.th
addition of the reagent B.sub.n to the function F.sub.n-1 leading
to the obtaining of the function F.sub.n, the n-1 additions being
representable according to one of the following reaction diagrams:
##STR255## of cleavage of the function F.sub.n, linked to the
Y.sup.+-- or Y.sup.--- ionic entity respectively of the
A.sub.2.sup.+ cation and/or of the X.sub.2.sup.- anion, making it
possible to recover on the one hand the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt in the form Y.sup.+-L-F.sub.0, X.sub.2.sup.- or
A.sub.2.sup.+, Y.sup.--(L).sub.k-F.sub.0, in solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid matrix, or in the form
Y.sup.+-L-F'.sub.0, X.sub.2.sup.- or A.sub.2.sup.+ ,
Y.sup.--(L).sub.k-F'.sub.0, in which F'.sub.0 represents a function
different from F.sub.0, and on the other hand the molecule G,
according to one of the following reaction diagrams: ##STR256##
59. The method of claim 58 for implementation of the Diels-Alder
reaction, according to one of the following reaction diagrams:
##STR257## p being an integer varying from 0 to 2, Y.sup.+--
representing an onium cation such as the substituted or
non-substituted pyridinium, imidazolium, ammonium, phosphonium or
sulphonium cations, and preferably ammonium or phosphonium of claim
52, and preferably being a trimethylalkylammonium,
triethylalkylammonium or tributylalkylphosphonium cation, L
representing an arm, in particular a linear or branched alkyl group
comprising 1 to 20 carbon atoms, or an optionally functional
aralkyl group, comprising 6 to 30 carbon atoms, and preferably
being a linear alkyl group preferably a linear alkyl group of
(CH2)r type, r varying from 1 to 20, and preferably from 3 to 6,
X.sub.2.sup.- being an anion, functional or non-functional, or a
mixture of anions in which either none of the anions is functional
or at least one of the anions is functional, and being in
particular NTf.sub.2.sup.-, BF.sub.4.sup.-, PF.sub.6.sup.-,
Cl.sup.-, Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms, said R group also possibly representing a
perfluorinated or partially fluorinated group, or the
R'SO.sub.4.sup.- anions, R' being a hydrogen atom, a methyl group
or an ethyl group, the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
being in particular in the form: ##STR258## R.sub.a and R.sub.b
representing linear or branched alkyl groups, comprising 1 to 20
carbon atoms, in particular an ethyl, propyl, butyl, pentyl, hexyl,
heptyl or octyl group, or functional alkyl groups comprising 1 to
20 carbon atoms, or functional or non-functional aryl groups
comprising 6 to 30 carbon atoms, and preferably representing alkyl
groups comprising 1 to 20 carbon atoms, X.sub.1.sup.- being chosen
from: BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-,
Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being as defined in claim
20, the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below: F.sub.0 corresponds to a -.chi..sub.1H group, in which
.chi..sub.1 represents an oxygen atom or an --NR.sub.f group,
R.sub.f corresponding to a linear or branched alkyl group,
comprising 1 to 20 carbon atoms, or an aryl group comprising 6 to
30 carbon atoms, F.sub.1 corresponds to the following formula:
##STR259## .chi..sub.1 being as defined above, F.sub.2 corresponds
to the following formula: ##STR260## .chi..sub.1 being as defined
above, G corresponding to the following formula: ##STR261## in
which .chi..sub.2 represents either an OR.sub.g group, R.sub.g
representing a hydrogen atom or an alkyl group comprising 1 to 20
carbon atoms, or an --NR.sub.hR.sub.u group, R.sub.h and R.sub.u
representing independently of each other a hydrogen atom, an alkyl
group comprising 1 to 20 carbon atoms or an aryl group comprising 6
to 30 carbon atoms, ##STR262## Y.sup.+--, L, X.sub.2.sup.- and the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid being as defined
previously, the functions F.sub.0, F.sub.1 and F.sub.2 being as
defined below: F.sub.0 represents any function making it possible
to attach a 1,3-diene, and is in particular chosen from the
carbonyl, amine, alkoxy, silane, stannane and borane functions,
comprising 1 to 20 carbon atoms, F.sub.1 corresponds to the
following formula: ##STR263## p being an integer varying from 0 to
2, F.sub.2 corresponds to the following formula: ##STR264##
.chi..sub.3 representing an electroattractive group, in particular
chosen from the cyano, alkoxycarbonyl groups, comprising 1 to 20
carbon atoms, acyl groups comprising 2 to 20 carbon atoms, benzoyl,
sulphonyl, dialkoxyphosphonyl groups comprising 1 to 10 carbon
atoms, G corresponding to the following formula: ##STR265##
.chi..sub.3 being as defined above.
60. The method of claim 58 for implementation of Heck's reaction,
according to the following reaction diagram: ##STR266## Y.sup.+--
representing an onium cation as defined in claim 53, and preferably
being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation, L representing an arm, in
particular a linear or branched alkyl group comprising 1 to 20
carbon atoms, or an optionally functional aralkyl group comprising
1 to 20 carbon atoms, and preferably being a linear alkyl group
preferably a linear alkyl group of (CH.sub.2).sub.r type, r varying
from 1 to 20, and preferably from 3 to 6, X.sub.2.sup.- being an
anion, functional or non-functional, or a mixture of anions in
which either none of the anions is functional or at least one of
the anions is functional, and being in particular BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-, Cl.sup.-,
Br.sup.-, or I.sup.-, the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
being in particular in the form: ##STR267## R.sub.a and R.sub.b
representing linear or branched alkyl groups, comprising 1 to 20
carbon atoms, in particular an ethyl, propyl, butyl, pentyl, hexyl,
heptyl or octyl group, or functional alkyl groups comprising 1 to
20 carbon atoms, or functional or non-functional aryl groups
comprising 6 to 30 carbon atoms, and preferably representing alkyl
groups comprising 1 to 20 carbon atoms, X.sub.1.sup.- being chosen
from: BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-,
Br.sup.--, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being as defined in claim
20, the functions F.sub.0, F.sub.1, F'.sub.1, F.sub.2 and F'.sub.2
being as defined below: F.sub.0 corresponds to a -.chi..sub.1H
group, in which .chi..sub.1 represents an oxygen atom or an
--NR.sub.f group, R.sub.f corresponding to a linear or branched
alkyl group, comprising 1 to 20 carbon atoms, or an aryl group
comprising 6 to 30 carbon atoms, F.sub.1 corresponds to the
following formula: ##STR268## .chi..sub.1 being as defined above,
F.sub.2 corresponds to the following formula: ##STR269##
.chi..sub.1 being as defined above, G corresponding to the
following formula: ##STR270## in which .chi..sub.2 represents
either an --OR.sub.g group, R.sub.g representing a hydrogen atom or
an alkyl group comprising 1 to 20 carbon atoms, or an
--NR.sub.hR.sub.u group, R.sub.h and R.sub.u representing
independently of each other a hydrogen atom, an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms, .chi..sub.3 representing a leaving moiety, in
particular chosen from the halides I, Cl and Br, the mesylate,
tosylate, triflate, sulphonate, sulphate or phosphate groups,
T.sub.1, T.sub.2, T.sub.3, T.sub.4 and T.sub.5 representing
independently of one another a hydrogen atom, a linear or branched
alkyl group, comprising 1 to 20 carbon atoms or an aryl group
comprising 6 to 30 carbon atoms, or a functional group in
particular chosen from NO.sub.2, CN, COOR, OR, COR, NHCOR, NRR'',
SO.sub.2R, I, Br, R and R'' representing independently of each
other an alkyl group comprising 1 to 20 carbon atoms or an aryl
group comprising 6 to 30 carbon atoms, the entity ##STR271##
representing in particular the following groups: ##STR272##
F'.sub.1 corresponds to the following formula: ##STR273##
.chi..sub.1 and .chi..sub.3 being as defined above, F'.sub.2
corresponds to the following formula: ##STR274## .chi..sub.1 being
as defined above, G' corresponding to the following formula:
##STR275## .chi..sub.2 being as defined above.
61. The method of claim 58 for implementation of the Baylis-Hillman
reaction, according to the following reaction diagram: ##STR276##
Y.sup.+-- representing an onium cation as defined in claim 53, and
preferably being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation, L representing an arm, in
particular a linear or branched alkyl group comprising 1 to 20
carbon atoms, or an optionally functional aralkyl group, comprising
6 to 30 carbon atoms, and preferably being a linear alkyl group
preferably a linear alkyl group of (CH.sub.2).sub.r type, r varying
from 1 to 20, and preferably from 3 to 6, X.sub.2.sup.- being an
anion, functional or non-functional, or a mixture of anions in
which either none of the anions is functional or at least one of
the anions is functional, and being in particular BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, CF.sub.3SO.sub.3.sup.--, Cl.sup.-,
Br.sup.-, I.sup.-, CH.sub.3CO.sub.2.sup.- or
CF.sub.3CO.sub.2.sup.-, the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
being in particular in the form: ##STR277## R.sub.a and R.sub.b
representing linear or branched alkyl groups, comprising 1 to 20
carbon atoms, in particular an ethyl, propyl, butyl, pentyl, hexyl,
heptyl or octyl group, or functional alkyl groups comprising 1 to
20 carbon atoms, or functional or non-functional aryl groups
comprising 6 to 30 carbon atoms, and preferably representing alkyl
groups comprising 1 to 20 carbon atoms, X.sub.1.sup.- being chosen
from: BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-,
Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R an alkyl group comprising
1 to 20 carbon atoms or an aryl group comprising 6 to 30 carbon
atoms, said R group also possibly representing a perfluorinated or
partially fluorinated group, or the R'SO.sub.4.sup.- anions, R'
being a hydrogen atom, a methyl group or an ethyl group, the
functions F.sub.0, F.sub.1 and F.sub.2 being as defined below:
F.sub.0 represents an --OH group, F.sub.1 corresponds to the
following formula: ##STR278## F.sub.2 corresponds to the following
formula: ##STR279## G corresponding to the following formula:
##STR280## .chi..sub.1 representing an --OH group, or an --OR.sub.g
group, R.sub.g representing a linear or branched alkyl group,
comprising 1 to 20 carbon atoms, Ar representing a substituted or
non-substituted, aromatic or heteroaromatic group, ArCHO being in
particular chosen from: ##STR281##
62. The method of claim 58 for implementation of Suzuki coupling,
according to one of the following reaction diagrams: ##STR282##
R.sub.3 being chosen from the substituted or non-substituted aryl,
heteroaryl, ethenyl, dienyl, allyl, ethynyl groups, comprising 2 to
30 carbon atoms, R.sub.7 represents a branched or linear alkyl
group or a cycloalkyl group comprising 1 to 12 carbon atoms,
Y.sup.+-- representing an onium cation as defined in claim 53, and
preferably being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation, L representing an arm, in
particular a linear or branched alkyl group comprising 1 to 20
carbon atoms, or an optionally functional aralkyl group comprising
6 to 30 carbon atoms, and preferably being a linear alkyl group
preferably a linear alkyl group of (CH.sub.2).sub.r type, r varying
from 1 to 20, and preferably from 3 to 6, X.sub.2.sup.- being as an
anion, functional or non-functional, or a mixture of anions in
which either none of the anions is functional or at least one of
the anions is functional, and being in particular NTf.sub.2.sup.-,
BF.sub.4.sup.-, PF.sub.6.sup.-, Cl.sup.-, Br.sup.-,
CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-,
BR.sub.4.sup.-, R being an alkyl group comprising 1 to 20 carbon
atoms or an aryl group comprising 6 to 30 carbon atoms, said R
group also possibly representing a perfluorinated or partially
fluorinated group, or the R'SO.sub.4.sup.- anions, R' being a
hydrogen atom, a methyl group or an ethyl group, the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid being in particular in the
form: ##STR283## R.sub.a and R.sub.b being representing linear or
branched alkyl groups, comprising 1 to 20 carbon atoms, in
particular an ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl
group, or functional alkyl groups comprising 1 to 20 carbon atoms,
or functional or non-functional aryl groups comprising 6 to 30
carbon atoms, and preferably representing alkyl groups comprising 1
to 20 carbon atoms, X.sub.1.sup.- being chosen from:
BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-,
Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms, said R group also possibly representing a
perfluorinated or partially fluorinated group, or the
R'SO.sub.4.sup.- anions, R' being a hydrogen atom, a methyl group
or an ethyl group, the functions F.sub.0, F.sub.1 and F.sub.2 being
as defined below: F.sub.0 is in the form -.chi..sub.1H, .chi..sub.1
representing an oxygen atom or an --NR.sub.f group, R.sub.f
corresponding to a linear or branched alkyl group, comprising 1 to
20 carbon atoms, or an aryl group comprising 6 to 30 carbon atoms,
F.sub.1 is in the form --R.sub.e-.chi., R.sub.e representing an
aromatic or heteroaromatic group comprising 6 to 30 carbon atoms,
.chi. representing a leaving group preferably chosen from Cl, Br,
I, OTf, O--CO.sub.2R.sup.5 or OSO.sub.3--R.sup.5, R.sup.5
representing an alkyl group comprising 1 to 10 carbon atoms or an
aralkyl group comprising 6 to 30 carbon atoms, F.sub.1 preferably
corresponding to the following formula: ##STR284## F.sub.2 is in
the form --R.sub.e--R.sub.2, R.sub.e being as defined above and
R.sub.2 being chosen from the substituted or non-substituted aryl,
heteroaryl, ethenyl, dienyl, allyl, ethynyl groups, comprising 2 to
30 carbon atoms, F.sub.2 preferably corresponding to the following
formula: ##STR285## Ar.sub.1 representing an aromatic group
preferably chosen from: ##STR286## the G molecule being in the form
R.sub.2--R.sub.3, R.sub.2 and R.sub.3 being as defined above, and
corresponds in particular to the following formula: ##STR287## in
which .chi..sub.2 represents either an --OR.sub.g group, R.sub.g
representing a hydrogen atom or an alkyl group comprising 1 to 20
carbon atoms, i.e. an --NR.sub.hR.sub.u group, R.sub.h and R.sub.u
representing independently of each other a hydrogen atom, an alkyl
group comprising 1 to 20 carbon atoms or an aryl group comprising 6
to 30 carbon atoms, Ar.sub.1 is as defined above, ##STR288##
Y.sup.+--, L, X.sub.2.sup.-, A.sub.1.sup.+X.sub.1.sup.- and R.sub.2
being as defined above, the functions F.sub.0, F.sub.1 and F.sub.2
being as defined below: F.sub.0 is in the form -.chi..sub.1H,
.chi..sub.1 being as defined above, F.sub.1 is in the form
--R.sub.q--B(OR.sub.7).sub.2, R.sub.7 being as defined above, and
R.sub.q corresponding to an aryl group comprising 6 to 30 carbon
atoms, heteroaryl group comprising 4 to 20 carbon atoms, ethenyl
group comprising 2 to 20 carbon atoms, dienyl group comprising 3 to
20 carbon atoms, allyl group comprising 3 to 20 carbon atoms,
ethynyl group comprising 2 to 20 carbon atoms, substituted or
non-substituted, F, preferably corresponding to the following
formula: ##STR289## Ar.sub.2 corresponding to a substituted or
non-substituted aryl group comprising 6 to 30 carbon atoms, F.sub.2
is in the form --R.sub.q--R.sub.e, R.sub.q and R.sub.e being as
defined above, F.sub.2 preferably corresponding to the following
formula: ##STR290## Ar.sub.1 representing an aromatic group
preferably chosen from: ##STR291## the G molecule being in the form
R.sub.2--R.sub.3, R.sub.2 and R.sub.3 being as defined above, and
corresponding in particular to the following formula: ##STR292## in
which .chi..sub.2, Ar.sub.1 and Ar.sub.2 are as defined above,
##STR293## Y.sup.+--, L, X.sub.2.sup.-, A.sub.1.sup.+X.sub.1.sup.-,
R.sub.2 and R.sub.3 being as defined above, R.sub.3 preferably
being a phenyl group, ##STR294## A.sub.2.sup.+ being an
(R.sub.a).sub.3N.sup.+R.sub.b ammonium or
(R.sub.a).sub.3P.sup.+R.sub.b phosphonium cation, preferably
tetrabutylammonium and tetramethylammonium, R.sub.a and R.sub.b
being as defined above, X.sub.2.sup.- being in particular chosen
from OH.sup.-, F.sup.-, CN.sup.-, R.sub.aO.sup.--, R.sub.aS.sup.-,
preferably OH.sup.- or F.sup.-, R.sub.s representing an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms, R.sub.3 and R.sub.4 being as defined above, R.sub.6
and R.sub.7 representing independently of each other an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms, the boronic molecule of formula
R.sub.3R.sub.7R.sub.6B being a trialkyl or aryl borane, the alkyl
group comprising 1 to 20 carbon atoms and the aryl group comprising
6 to 30 carbon atoms, a boronic acid or ester, preferably a boronic
acid or ester chosen as being phenyl boronic acid, R.sub.2 and
.chi. are as defined previously, R.sub.2.chi. preferably
corresponding to an aryl halide chosen from: ##STR295##
63. The method of claim 33 for the synthesis of molecule libraries
according to the parallel synthesis technique, according to the
following diagram: ##STR296## characterized in that the
Y.sup.+-L-F.sub.1, X.sub.2.sup.- functionalized salt in the
A.sub.1.sup.+, X.sub.1.sup.- ionic liquid is separated into n
approximately equal parts, n varying from 2 to 1024, and in that
each of these parts is then converted according to an organic
synthesis reaction, preferably a Heck or Suzuki coupling reaction,
each using a different reagent B.sub.i in order to produce n
solutions each containing a defined Y.sup.+-L-F.sub.2.sup.i,
X.sub.2.sup.- compound, F.sub.2.sup.i representing a function
chosen from the functions as defined in claim 53, i varying from 1
to n, each solution being treated in order to release the G.sub.i
molecules, i varying from 1 to n, which are each isolated and
purified, constituting a molecule library.
64. The method of claim 33, for implementation of the synthesis of
molecule libraries by the split-and-mix technique according to the
following diagram: ##STR297## characterized in that: n fractions of
the Y.sup.+-L-F.sub.1, X.sub.2.sup.- solution, obtained from the
starting Y.sup.+-L-F.sub.0, X.sub.2.sup.- functionalized salt, in
the A.sub.1.sup.+X.sub.1.sup.- ionic liquid are converted in
parallel according to an organic chemistry reaction, preferably a
Heck or Suzuki coupling reaction, each using a different reagent
B.sub.i in order to produce n solutions each containing a defined
Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.- compound, i varying from 1
to n, n varying from 2 to 1024, preferably from 2 to 96,
F.sub.2.sup.i representing a function chosen from the standard
functions of organic chemistry, such as the hydroxyl, carboxylic,
amide, sulphone, primary amine, secondary amine, aldehyde, ketone,
ethenyl, ethynyl, dienyl, ether, epoxide, phosphine (primary,
secondary or tertiary), azide, imine, ketene, cumulene,
heterocumulene, thiol, thioether, sulphoxide, phosphorus-containing
moieties, heterocycles, sulphonic acid, silane, stannane or
functional aryl functions, the n solutions obtained in the
preceding stage are mixed in order to produce a solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid containing the n
Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.- products, i varying from 1
to n, annotated i = 1 i = n .times. .times. Y + - L - F 2 .times. i
, ##EQU13## X.sub.2.sup.-, and this solution is subjected to a
cleavage stage, preferably a transesterification or a
transamidation, in order to obtain in solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid, a mixture of the n G.sub.i
molecules, i varying from 1 to n, and the starting
Y.sup.+-L-F.sub.0, X.sub.2.sup.- functionalized salt the mixture as
obtained in the preceding stage is separated from the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid and from the starting
Y.sup.+-L-F.sub.0, X.sub.2.sup.- functionalized salt by the usual
separation methods, preferably by vacuum distillation, by
extraction with a standard solvent such as heptane or toluene
followed by evaporation of the solvent, by chromatography on a
column, plates or under pressure, in order to obtain a library
containing n G.sub.i molecules, this sequence of stages mentioned
above being possibly repeated j times, j being comprised between 2
and 10, in order to obtain j different libraries of n products.
Description
[0001] The present invention relates to compositions containing
ionic liquids, as well as their uses, in particular in organic
synthesis.
[0002] Synthesis on solid support has become a very effective
method often used for the production of combinatorial libraries of
products (Wilson et al., 1997; Charken et al., 1996; Sammelson et
al., 2001; Gravet et al., 1997; Wentworth et al., 1999). Thanks to
the development of high-throughput tests for biological evaluation
and the discovery of new biologically-active products,
combinatorial libraries have become very important in
pharmaceutical chemistry and in agricultural chemistry. The use of
suitably functionalized Merrifield resins has made it possible to
develop a multitude of methodologies for synthesis on solid support
(Thompson et al., 1996; Dorwald, 2000). These solid-support
methodologies have numerous advantages such as easy purification by
simple washing, the possibility of using various techniques such as
parallel or "split-and-mix" synthesis making it possible to
simultaneously produce a large quantity of products. However,
numerous problems are associated with these methods, such as the
price of the functionalized resins and their low specific load
which is very often less than 1 mmol/g of resin and only very
rarely reaches 2 mmol/g of resin. Another difficulty is due to the
fact that the reactions take place in heterogeneous phase, which
requires a particular development in each case, the reaction
conditions being generally different from those used in solution.
Moreover, there are few effective means of analysis for monitoring
the reactions. Other difficulties can arise in particular during
the release of the products sought and it is difficult to use
high-temperature reactions, conditions which destroy the solid
supports, as well as, moreover, unsuitable magnetic or mechanical
stirring.
[0003] The use of soluble polymers (Sammelson et al., 2001; Gravet
et al., 1997) proves to be a useful alternative. In fact, the
substitution of insoluble resins by a soluble polymer such as
polyethylene glycol or PEG, makes it possible to go back to
experimental procedures familiar to chemistry in solution, whilst
preserving simple purification. Moreover, it is possible to use the
different methods of analysis for the characterization of the
product obtained, without prior release from the support. However,
various problems are associated with this methodology such as the
high mass of polymers comprised between 2000 and 20,000 daltons.
The direct consequence is a low specific load since a decimolar
solution already contains 500 grams of polymer per liter for a PEG
with a mass of 5000 which would at the most produce one decimole of
expected product per one liter of solution. Such concentrations are
used only rarely as they lead to problems of viscosity of the
medium. Another problem is the purification of the products and the
recycling of PEGs. Thus, there exists a real need for new supports
for supported organic synthesis.
[0004] For the last few years, ionic liquids (Welton et al., 1999;
Wasserscheid et al., 2000) have increasingly been used in organic
synthesis and in catalysis as they have a certain number of useful
and important physico-chemical properties such as their high
thermal stability, their low volatilities and their very low vapor
pressures, their low inflammability, their strong solubilization
power of the salts as well as of the neutral organic molecules and
polymers and finally the possibility of easy recycling.
[0005] One object of the present invention is to provide a novel
use of ionic liquids as novel matrices for organic synthesis in
homogeneous phase on soluble support(s).
[0006] One object of the present invention is to provide novel
matrices for the organic synthesis on soluble support(s), which are
easily recyclable, liquid in a very broad range of temperature,
having a very low vapor pressure and possessing a very strong
solubilization power.
[0007] One object of the present invention is to provide novel
matrices for organic synthesis on soluble support(s), said soluble
support(s) being dissolved in said matrices.
[0008] One object of the present invention is to provide novel
matrices for organic synthesis on soluble support(s) in place of
the resins but without the drawbacks linked to reactions in
heterogeneous phase on solid support.
[0009] One object of the present invention is to provide a novel
use of ionic liquids, by conferring resin-type properties on these
ionic liquids.
[0010] The present invention relates to the use of an ionic liquid,
as liquid matrix for organic synthesis in homogeneous phase on
soluble support, without volatile organic solvent, said ionic
liquid being presented in liquid or solid form at ambient
temperature, of formula A.sub.1.sup.+X.sub.1.sup.-, A.sub.1.sup.+
representing a cation, functional or non-functional, or a mixture
of cations in which either none of the cations is functional or at
least one of the cations is functional, and X.sub.1.sup.- an anion,
functional or non-functional, or a mixture of anions in which
either none of the anions is functional or at least one of the
anions is functional.
[0011] The expression "ionic liquid" designates a salt or a mixture
of salts the melting point of which is comprised between
-100.degree. C. and 250.degree. C.
[0012] The expression "liquid matrix" designates an ionic liquid
capable of solubilizing one or more chemical species such as
mineral or organic salts, organic molecules, polymers of natural or
synthetic origin. The expression "liquid matrix" therefore
designates a solvent constituted by an ionic liquid. These novel
solvents are non-volatile and have a very low vapor pressure. They
are also polar and have the ability to dissolve functional onium
salts which can then serve as soluble supports.
[0013] The expression "soluble support" designates a salt dissolved
in the ionic liquid matrix carrying one or more functions allowing
the catching of molecules and their subsequent functionalization as
well as the release at the end of the reaction sequence.
[0014] The expression "organic synthesis in homogeneous phase on
soluble support" designates the conversion(s) of the chemical
function(s) carried by the soluble support without modifying the
liquid matrix, followed by a cleavage reaction releasing the sought
molecule(s).
[0015] The expression "functional cation" designates a molecular
group which possesses at least one chemical function, part of this
group carrying a positive charge.
[0016] The expression "functional anion" designates a molecular
group which possesses at least one chemical function, part of this
group carrying a negative charge.
[0017] The expression "non-functional cation" designates a
molecular group which possesses no chemical function, part of this
group carrying a positive charge.
[0018] The expression "non-functional anion" designates a molecular
group which possesses no chemical function, part of this group
carrying a negative charge.
[0019] When the A.sub.1.sup.+X.sub.1.sup.- matrix comprises no
functional ion, it serves as a reaction medium which is inert
vis-a-vis reagents but is capable of dissolving them.
[0020] When the A.sub.1.sup.+X.sub.1.sup.- matrix comprises at
least one functional ion, it can serve on the one hand as a
reaction medium and on the other hand as a soluble support.
[0021] The A.sub.1.sup.+X.sub.1.sup.- matrix can contain several
non-functional cations and/or anions for the following reasons:
[0022] On the one hand, the mixture of cations can originate from
industry. In fact, numerous detergents based on ammonium or
phosphonium cations are mixtures of salts produced as such by
synthesis. They correspond to cuts. Thousands of tons are thus
produced at a low price. The benefit of using such mixtures within
the framework of the present invention is therefore economic.
[0023] The fact of having mixtures is not a problem, if all the
constituents of the mixture are chemically inert under conditions
of use. For example, a mixture of tetralkylammonium or phosphonium
non-functional salts can be used.
[0024] On the other hand, the melting point of a mixture is lower
than the melting point of the constituent of the mixture which
melts at the lowest temperature. It can therefore be very important
to resort to a mixture in order to have an ionic liquid at a
reasonable melting temperature.
[0025] Certain functionalized salts, in particular those with large
anions such as NTf.sub.2.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.- or
CF.sub.3SO.sub.3.sup.-, can be liquid at ambient temperature or can
melt at low temperature, for example ##STR1## NTf.sub.2.sup.- is
liquid at ambient temperature. This ionic liquid is prepared by
alkylation of Me.sub.3N according to the following reaction:
##STR2##
[0026] The present invention relates to the use as defined above,
characterized in that A.sub.1.sup.+ represents a non-functional
cation or a mixture of non-functional cations and X.sub.1.sup.- a
non-functional anion or a mixture of non-functional anions.
[0027] The present invention also relates to the use as defined
above, characterized in that:
[0028] A.sub.1.sup.+ represents a functional cation or a mixture of
cations at least one of which of is functional,
[0029] and/or X.sub.1.sup.- represents a functional anion or a
mixture of anions at least one of which is functional,
[0030] said functional cations and functional anions corresponding
to an ionic entity, namely respectively cationic or anionic, linked
to at least one function F.sub.i, F.sub.i varying from F.sub.0 to
F.sub.n, n being an integer varying from 1 to 10.
[0031] The expression "ionic entity" designates the part of the
cation or of the anion, which carries the charge, respectively
positive or negative.
[0032] The function F.sub.i is in particular chosen from the
following functions:
[0033] hydroxyl, carboxylic, amide, sulphone, primary amine,
secondary amine, aldehyde, ketone, ethenyl, ethynyl, dienyl, ether,
epoxide, phosphine (primary, secondary or tertiary), azide, imine,
ketene, cumulene, heterocumulene, thiol, thioether, sulphoxide,
phosphorus-containing groups, heterocycles, sulphonic acid, silane,
stannane or functional aryl, and any function resulting from a
chemical, thermal, photochemical conversion or a conversion by
micro-wave irradiation of the preceding functions.
[0034] The present invention relates to the use of an ionic liquid
as defined above, for the preparation of a stable composition
containing in solution: [0035] at least said ionic liquid of
formula A.sub.1.sup.+X.sub.1.sup.-, playing the role of liquid
matrix and, [0036] at least one functionalized salt (salt with a
dedicated task), in particular functionalized onium salt, of
formula A.sub.2.sup.+X.sub.2.sup.-, as reaction support,
[0037] the functionalized salt, in particular the functionalized
onium salt, being dissolved in the liquid matrix, in order to form
a homogeneous phase,
[0038] A.sub.1.sup.+ representing a non-functional cation or a
mixture of cations in which none of the cations is functional, and
X.sub.1.sup.- representing a non-functional anion or a mixture of
anions in which none of the anions is functional,
[0039] A.sub.2+ representing a cation, functional or
non-functional, or a mixture of cations in which none of the
cations is functional or in which at least one of the cations is
functional, and X.sub.2.sup.- representing an anion, functional or
non-functional, or a mixture of anions in which none of the anions
is functional or in which at least one of the anions is
functional,
[0040] provided that A.sub.2.sup.+ and/or X.sub.2.sup.-
represent(s) or comprise(s) a functional cation and a functional
anion respectively,
[0041] said functional cations and functional anions corresponding
to a ionic entity Y--, namely cationic Y.sup.+-- or anionic
Y.sup.--- respectively, optionally linked via an L arm, in
particular an alkyl group comprising 1 to 20 carbon atoms, to at
least one function F.sub.i, F.sub.i varying from F.sub.0 to
F.sub.n, n being an integer varying from 1 to 10, the functional
cation being representable in the form Y+-L-Fi, and the functional
anion in the form Y.sup.--(L).sub.k-F.sub.i, k being equal to 0 or
1, and the functional anion possibly representing, when k is equal
to 0, a single anion, corresponding to Y.sup.---F.sub.i, in
particular chosen from: OH.sup.-, F.sup.-, CN.sup.-, RO.sup.- or
RS.sup.-, R representing an alkyl group comprising 1 to 20 carbon
atoms or an aryl group comprising 6 to 30 carbon atoms.
[0042] The expression "stable composition" designates the
homogeneous mixture composed of the A.sub.1.sup.+X.sub.1.sup.-
liquid matrix and of the A.sub.2+X.sub.2.sup.- functionalized
salt(s). This composition is described as stable to the extent that
it does not undergo spontaneous conversions over time.
[0043] It can be verified that this composition is stable by
spectroscopic analysis using NMR, IR, visible V, of the mass
spectrometry or chromatography methods.
[0044] The expression "functionalized salt (salt with a dedicated
task)" designates an entity of type A.sub.2.sup.+X.sub.2.sup.- in
which the cation and/or the anion carries a function F.sub.i as
previously defined. This function confers chemical and/or
physico-chemical properties upon said functionalized salt and upon
the stable composition, of which it forms part.
[0045] The expression "functionalized onium salt" designates
ammonium, phosphonium, sulphonium salts, as well as all the salts
resulting from the quaternization of an amine, a phosphine, a
thioether or a heterocycle containing one or more of these
heteroatoms, and carrying at least one function F.sub.i. This
expression also designates an onium salt the cation of which as
defined above is not functionalized but the anion of which carries
a function F.sub.i. This expression can also designate a salt the
anion and the cation of which carry a function F.sub.i.
[0046] A preferred functionalized onium salt is in particular
chosen from the following: ##STR3##
[0047] m being an integer from 0 to 20.
[0048] A preferred non-functionalized onium salt is in particular
chosen from the following: imidazolium, pyridinium
Me.sub.3N.sup.+--Bu or Bu.sub.3P.sup.+--Me cations,
NTf.sub.2.sup.-, PF.sub.6.sup.- or BF.sub.4.sup.- anions.
[0049] The expression "reaction support" designates any salt of
A.sub.2.sup.+X.sub.2.sup.- type functionalized by a function
F.sub.i which can be converted and cleaved in order to release the
sought molecule at the end of the reaction sequence. This
expression designates in particular any salt of
A.sub.2.sup.+X.sub.2.sup.- type functionalized by a function
F.sub.n (last function in the reaction chain) which can be cleaved
in order to release the sought molecule at the end of the reaction
sequence.
[0050] In the term "Y.sup.---", the dash "--" represents the
optional bond between the ionic entity and the L arm.
[0051] In the term "Y.sup.+--", the dash "--" represents the
optional bond between the cationic entity and the L arm.
[0052] In the term "Y.sup.---", the dash "--" represents the
optional bond between the anionic entity and the L arm.
[0053] The term "L arm" designates an alkyl or aralkyl chain which
can contain one or more heteroatoms such as nitrogen, phosphorus,
sulphur, oxygen, silicon, tin, containing between 1 and 30 carbon
atoms, and said arm is in particular chosen from an alkyl chain
containing 2 to 10 carbon atoms and 1 to 6 oxygen or nitrogen
atoms.
[0054] In this embodiment of the invention, the ionic matrix is
non-functional and it is necessary that the
A.sub.2.sup.+X.sub.2.sup.- onium salt be functionalized, either via
the A.sub.2.sup.+ cation, or via the X.sub.2.sup.- anion, or via
the A.sub.2.sup.+ cation and the X.sub.2.sup.- anion.
[0055] The functionalization of the cation alone means that the
anion is simply a "spectator" during the functional modifications
and is there only to ensure electric neutrality. The fact of only
having a function on the cation with an inert anion leads to a
simplification of the control of the reactions. Similarly, if the
cation is chemically inert, it is possible to modify the anion
without worrying about the cation. The use of a functional anion
has additional benefits:
[0056] a simplicity of synthesis of the functionalized salt by
simple neutralization or metathesis of the anion, for example:
##STR4## [0057] the ammonium carboxylate solution thus obtained can
be used directly in a Heck or Suzuki coupling;
[0058] in terms of cleavage, it is sufficient to wash with a
solution of HCl, in particular in order to release, in the case of
the abovementioned example, a carboxylic acid: ##STR5## compound
obtained after a
[0059] Heck coupling [0060] this example relates to a Bronsted
acid; [0061] the anion can also react by neutralization of a Lewis
acid for example:
Bu.sub.4N.sup.+OH.sup.-+Ar.sub.1B(OH).sub.2.fwdarw.Bu.sub.4N.su-
p.+Ar.sub.1{overscore (B)}(OH).sub.3
[0062] the anion thus obtained can then serve as a reaction
intermediate, in particular in Suzuki coupling, according to the
following reaction:
Bu.sub.4N.sup.+OH.sup.-+Ar.sub.1B(OH).sub.2.fwdarw.Bu.sub.4N.sup.+Ar.sub.-
1{overscore (B)}(OH).sub.3
[0063] it can be noted that this coupling is "releasing" to the
extent that there is no need for a cleavage reaction in order to
recover the final product.
[0064] The use of a functionalized salt involving both the anion
and the cation is useful in more complicated sequences. It is
possible to selectively modify the cation or the anion and to give
rise to the reaction of the anion with the cation in a final
conversion via the functions that carry the cation and the anion.
It is also possible to start from a functionalized salt only the
cation of which is functionalized. The function F.sub.0 is modified
in order to obtain the function F.sub.i and, by metathesis, a
functional anion is introduced the function of which can react with
the function F.sub.i carried by the functionalized cation.
[0065] The present invention relates to the use as defined above,
for the preparation of a stable composition containing in
solution:
[0066] at least one first part of said ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.-, the cation and/or the anion of which
correspond(s) to an ionic entity linked to one or more initial
functions F.sub.0, playing the role of liquid matrix, and
[0067] at least one second part of said ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.-, in which said initial function(s)
F.sub.0 are converted into first novel functions, conferring upon
said second part of said ionic liquid the role of functionalized
salt and of reaction support,
[0068] the functionalized salt and the liquid matrix forming a
homogeneous phase,
[0069] the abovementioned first novel functions of the second part
of said ionic liquid being capable of subsequently being converted
into other functions, without affecting one or more initial
functions F.sub.0 of the first part of said ionic liquid.
[0070] The expression "without affecting one or more initial
functions F.sub.0 of the first part of said ionic liquid" means
that the first novel functions of the second part of said ionic
liquid are subsequently converted into other functions, by
chemoselective conversions.
[0071] This particular embodiment of the invention corresponds to
the case where the A.sub.1.sup.+X.sub.1.sup.- ionic liquid plays
the role of both liquid matrix and functionalized salt.
[0072] The case where the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
plays the role of both liquid matrix and functionalized salt is
useful to the extent that one starts with a single initial product.
Moreover, after reaction, during cleavage by transesterification or
transamidation, for example, the starting salt is regenerated and
therefore recycled. Moreover, the function F.sub.0 of the starting
salt can confer particular reaction activation properties on the
medium, for example by hydrogen bonding or by any other activation
dependent on the function F.sub.0.
[0073] The present invention relates to the use of an ionic liquid
as defined above, characterized in that the A.sub.2.sup.+ cation
and/or the X.sub.2.sup.- anion of the functionalized salt(s),
corresponding to a Y-- ionic entity linked to at least one function
F.sub.i, are immobilized in the liquid matrix and cannot be
extracted from the liquid matrix by standard extraction means, in
particular by solvent, and in which the function(s) F.sub.i of the
functionalized salt(s) can be converted at the end of at least one
reaction resulting from the addition of at least one reagent to
said composition.
[0074] The term "immobilized" means that the functionalized salt
cannot be extracted from the matrix by standard means such as
extraction or distillation.
[0075] The expression "cannot be extracted from the liquid matrix
by standard extraction means" designates the fact that the mixture
formed by the liquid matrix and the functionalized salt can be
washed using standard solvents or heated under vacuum without loss
of said functionalized salt. This allows in particular the use of
an excess of reagents which can be eliminated when the reaction is
completed as in the case of resins.
[0076] The present invention is based on the unexpected feature
according to which the mixture of a functionalized salt in a
A.sub.1.sup.+X.sub.1.sup.- liquid matrix results in the
immobilization of said functionalized salt in said liquid
matrix.
[0077] The present invention relates to the use of an ionic liquid
as defined above, characterized in that several functionalized
salts are immobilized.
[0078] It is possible to confer on a solution of several salts in
an ionic liquid matrix several properties that can be used in a
cascade or multicomponent.
[0079] The present invention relates to the use as defined above,
characterized in that the A.sub.2+ cation is functional.
[0080] According to an advantageous embodiment, the present
invention relates to the use as defined above, characterized in
that the A.sub.2+ cation is functional and the X.sub.2.sup.- anion
is non-functional.
[0081] The present invention relates to the use as defined above,
characterized in that the X.sub.2.sup.- anion is functional.
[0082] According to an advantageous embodiment, the present
invention relates to the use as defined above, characterized in
that the X.sub.2.sup.- cation is functional and the A.sub.2+ anion
is non-functional.
[0083] The present invention relates to the use as defined above,
characterized in that A.sub.2+ and X.sub.2.sup.- are
functional.
[0084] The present invention relates to the use as defined above,
characterized in that:
[0085] either the ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.- is solid at ambient temperature and is
liquefiable within a temperature range from approximately
25.degree. C. to approximately 250.degree. C., in particular from
approximately 30.degree. C. to approximately 150.degree. C., and
the A.sub.2.sup.+X.sub.2.sup.- functionalized salt is solid at
ambient temperature and is soluble in the liquefied
A.sub.1.sup.+X.sub.1.sup.- ionic liquid, in order to form a
homogeneous phase,
[0086] or the ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.- is
solid at ambient temperature and is liquefiable within a
temperature range from approximately 25.degree. C. to approximately
250.degree. C., in particular from approximately 30.degree. C. to
approximately 150.degree. C., and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is liquid at ambient temperature, and is
miscible with the liquefied A.sub.1.sup.+X.sub.1.sup.- ionic
liquid, in order to form a homogeneous phase,
[0087] or the A.sub.1.sup.+X.sub.1.sup.- ionic liquid is liquid at
ambient temperature and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is liquid at ambient temperature and miscible
with the A.sub.1.sup.+X.sub.1.sup.- ionic liquid, in order to form
a homogeneous phase,
[0088] or the A.sub.1.sup.+X.sub.1.sup.- ionic liquid is liquid at
ambient temperature and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is solid at ambient temperature and is soluble
or partially soluble in the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
within a temperature range from approximately 25.degree. C. to
approximately 250.degree. C., in particular from approximately
30.degree. C. to approximately 150.degree. C., in order to form a
homogeneous phase.
[0089] When the ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.-
and the A.sub.2.sup.+X.sub.2.sup.- functionalized salt are solid at
ambient temperature, after the conversions of the initial function
F.sub.0 to functions F.sub.i and cleavage, a mixture formed from a
solid and the sought molecule is obtained, from which it is
possible to extract this molecule, by simple addition of a solvent
solubilizing the molecule and not the functionalized salts, and by
simple filtration. This embodiment therefore makes it possible to
add a few advantages specific to the solid-support technique,
whilst preserving the advantages of the soluble-support
reactions.
[0090] When the ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.-
is solid at ambient temperature and the functionalized salt
A.sub.2.sup.+X.sub.2.sup.- is liquid at ambient temperature, this
is the case where a liquid functionalized salt is added to a solid
matrix at ambient temperature. A homogeneous phase is obtained on
melting of the mixture which can either remain liquid, or produce a
solid, or produce a solid/liquid heterogeneous mixture.
[0091] The case where the A.sub.1.sup.+X.sub.1.sup.- ionic liquid
and the A.sub.2.sup.+X.sub.2.sup.- functionalized salt are liquids
at ambient temperature corresponds to the standard case making it
possible to carry out reactions at ambient or sub-ambient
temperature.
[0092] When the A.sub.1.sup.+X.sub.1.sup.- ionic liquid is liquid
at ambient temperature and the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt is solid at ambient temperature, several
distinct cases can be encountered, and in particular:
[0093] either the A.sub.2.sup.+X.sub.2.sup.- solid is soluble in
A.sub.1.sup.+X.sub.1.sup.- and the operation is carried out in
solution as in the preceding case; this case is very frequent due
for example to the use of chlorides, bromides or iodides which are
solid at ambient temperature, inexpensive and easy to purify by
recrystallization;
[0094] or the solid A.sub.2.sup.+X.sub.2.sup.- is soluble in
A.sub.1.sup.+X.sub.1.sup.- at a temperature higher than ambient
temperature, which makes it necessary to work at this temperature
in order to obtain a homogeneous phase and to avoid
reprecipitation; if not, once the functionalized salt is dissolved,
a solution is recovered at ambient temperature without
reprecipitation;
[0095] or it is necessary to dissolve the
A.sub.2.sup.+X.sub.2.sup.- functionalized salt in a standard
solvent, to mix the solution with liquid
A.sub.1.sup.+X.sub.1.sup.-, then to eliminate the solvent under
vacuum in order to obtain a solution of
A.sub.2.sup.+X.sub.2.sup.-.
[0096] The present invention relates to the use as defined above,
characterized in that:
[0097] either the ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.- is liquid at ambient temperature,
[0098] or the ionic liquid of formula A.sub.1.sup.+X.sub.1.sup.- is
solid at ambient temperature and is liquefiable within a
temperature range from approximately 25.degree. C. to approximately
250.degree. C., in particular from approximately 30.degree. C. to
approximately 150.degree. C.
[0099] The present invention also relates to the use as defined
above, characterized in that the ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.-, playing the role of liquid matrix, has
a viscosity less than or equal to approximately 1500 cp (15
N.s/m.sup.2), in particular less than approximately 500 cp (5
N.s/m.sup.2) and preferably less than approximately 200 cp (2
N.s/m.sup.2).
[0100] Thus, the table below corresponds to the viscosities at
23.degree. C. of the preferred ionic liquids of the invention.
TABLE-US-00001 Ionic liquid Viscosity in (cP) at 23.degree. C.
[btma][NTf.sub.2] 58 [htma][NTf.sub.2] 64 [C.sub.3OHtma][NTf.sub.2]
94.3 [C.sub.3CNtma][NTf.sub.2] 62 [C.sub.3CNtma][NTf.sub.2] 69
[btma][NTf.sub.2] = [C.sub.4tma][NTf.sub.2] = [Me.sub.3N.sup.+ -
C.sub.4H.sub.9][N.sup.-(SO.sub.2CF.sub.3).sub.2] [htma][NTf.sub.2]
= [C.sub.6tma][NTf.sub.2] = [Me.sub.3N.sup.+ -
C.sub.6H.sub.11][N.sup.-(SO.sub.2CF.sub.3).sub.2]
[C.sub.3OHtma][NTf.sub.2] = [Me.sub.3N.sup.+ -
(CH.sub.2).sub.2CH.sub.2OH][N.sup.-(SO.sub.2CF.sub.3).sub.2]
[C.sub.3OHtma][NTf.sub.2] = [Me.sub.3N.sup.+ -
(CH.sub.2).sub.2CH.sub.2CH][N.sup.-(SO.sub.2CF.sub.3).sub.2]
[C.sub.3OHtma][NTf.sub.2] = [Me.sub.3N.sup.+ -
(CH.sub.2).sub.2CH.sub.4CH][N.sup.-(SO.sub.2CF.sub.3).sub.2]
[0101] Method and Apparatus for Measuring Dynamic Viscosity:
[0102] Dynamic viscosity measurements were carried out at
23.degree. C. on a Rheolyst AR 1000 type microviscosimeter (TA
instruments) equipped with a steel cone-plate with a diameter P=40
mm and angle t=1 degree I minute. The procedure is applied from
0.06 to 200s.sup.-1 for 3 minutes with 20 points per decade. The
device is computer-controlled with Rheology Advantage Instrument
Control AR software.
[0103] The present invention relates to a stable composition
containing in solution: [0104] at least said ionic liquid of
formula A.sub.1.sup.+X.sub.1.sup.-, playing the role of liquid
matrix and, [0105] at least one functionalized salt (salt with a
dedicated task), in particular functionalized onium salt, of
formula A.sub.2.sup.+X.sub.2.sup.-, as reaction support,
[0106] the functionalized salt, in particular the functionalized
onium salt, being dissolved in the liquid matrix, in order to form
a homogeneous phase,
[0107] A.sub.1.sup.+ representing a non-functional cation or a
mixture of cations in which none of the cations is functional, and
X.sub.1.sup.- representing a non-functional anion or a mixture of
anions in which none of the anions is functional,
[0108] A.sub.2.sup.+ representing a cation, functional or
non-functional, or a mixture of cations in which none of the
cations is functional or in which at least one of the cations is
functional, and X.sub.2.sup.- representing an anion, functional or
non-functional, or a mixture of anions in which none of the anions
is functional or in which at least one of the anions is
functional,
[0109] provided that A.sub.2.sup.+ and/or X.sub.2.sup.-
represent(s) or comprise(s) a functional cation and a functional
anion respectively,
[0110] said functional cations and functional anions corresponding
to an ionic entity Y--, namely cationic Y.sup.+-- or anionic
Y.sup.--- respectively, optionally linked via an L arm, in
particular an alkyl group comprising 1 to 20 carbon atoms, to at
least one function F.sub.i, F.sub.i varying from F.sub.0 to
F.sub.n, n being an integer varying from 1 to 10, the functional
cation being representable in the form Y.sup.+-L-F.sub.i, and the
functional anion in the form Y.sup.--(L).sub.k-F.sub.i, k being
equal to 0 or 1, and the functional anion possibly representing,
when k is equal to 0, a single anion, corresponding to
Y.sup.--F.sub.i, in particular chosen from: OH.sup.-, F.sup.-,
CN.sup.-, RO.sup.- or RS.sup.-, R representing an alkyl group
comprising 1 to 20 carbon atoms or an aryl group comprising 6 to 30
carbon atoms.
[0111] The present invention relates to a stable composition
containing in solution:
[0112] at least one first part of said ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.-, the cation and/or anion of which
correspond(s) to an ionic entity linked to one or more initial
functions F.sub.0, playing the role of liquid matrix, and
[0113] at least one second part of said ionic liquid of formula
A.sub.1.sup.+X.sub.1.sup.-, in which said initial function or
functions F.sub.0 are converted into first novel functions,
conferring on said second part of said ionic liquid the role of
functionalized salt and reaction support,.
[0114] the functionalized salt and the liquid matrix forming a
homogeneous phase,
[0115] the abovementioned first novel functions of the second part
of said ionic liquid being capable of being subsequently converted
to other functions, without affecting the initial function or
functions F.sub.0 of the first part of said ionic liquid.
[0116] According to an advantageous embodiment of the present
invention, a composition of the invention is characterized in that
the A.sub.2.sup.+ cation and/or the X.sub.2.sup.- anion of the
functionalized salt or salts, corresponding to an ionic entity Y--
linked to at least one function F.sub.i, are immobilized in the
liquid matrix and cannot be extracted from the liquid matrix by
standard means of extraction, in particular by solvent.
[0117] An advantageous composition of the present invention is
characterized in that the liquid matrix is non-reactive vis-a-vis
the functionalized salt.
[0118] The property of non-reactivity of the matrix vis-a-vis the
salt is verified for example using the usual spectroscopic
techniques such as .sup.1H, .sup.13C NMR, mass spectrometry, or
HPLC analysis.
[0119] Another advantageous composition of the present invention is
characterized in that A.sub.2.sup.+ is a functional cation.
[0120] Another advantageous composition of the present invention is
characterized in that the X.sub.1.sup.- and X.sub.2.sup.- anions
are identical.
[0121] This particular case relates in particular to the case of
large anions such as NTf.sub.2.sup.-, BF.sub.4.sup.-,
PF.sub.6.sup.-, CF.sub.3SO.sub.3.sup.- commonly used for the
preparation of ionic liquids. This particular embodiment also
promotes the solubility of one salt in another.
[0122] Another advantageous composition of the present invention is
characterized in that the X.sub.1.sup.- and X.sub.2.sup.- anions
are different. This particular case relates to the general case
where a functionalized salt, for example a halide (Cl.sup.-,
Br.sup.-, I.sup.-, F.sup.-) is dissolved in an ionic liquid matrix.
This particular embodiment has the particular advantage of allowing
the dissolution of inexpensive salts.
[0123] According to an advantageous embodiment, a composition
according to the present invention is characterized in that: [0124]
the X.sub.1.sup.- and X.sub.2.sup.- anions are chosen from the
following two families: [0125] non-complex anions, chosen in
particular from the BF.sub.4.sup.-, PF.sub.6.sup.-,
CF.sub.3SO.sub.3.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
.sup.--N(SO.sub.2CF.sub.3).sub.2 (or NTf.sub.2.sup.-) anions, the
halides, the BR.sub.4.sup.-, RCO.sub.2.sup.- or RSO.sub.3.sup.-
anions, R being an alkyl group comprising 1 to 20 carbon atoms or
an aryl group comprising 6 to 30 carbon atoms, said R group also
possibly representing a perfluorinated or partially fluorinated
group, or the R'SO.sub.4.sup.- anions, R' being a hydrogen atom, a
methyl group or an ethyl group;
[0126] * complex anions, resulting from the combination of a Lewis
acid and a halide, preferably Cl.sup.- or F.sup.-, of general
formula MX.sub.j, j being an integer comprised between 1 and 7, and
M representing a metal, in particular chosen from aluminium, tin,
zinc, bismuth, manganese, iron, copper, molybdenum, antimony,
gallium or indium; [0127] the A.sub.1.sup.+ and A.sub.2.sup.+
cations are chosen from the onium cations, such as the pyridinium,
imidazolium, ammonium, phosphonium or sulphonium cations,
substituted or non-substituted, and preferably ammonium or
phosphonium.
[0128] An advantageous composition of the present invention is
characterized in that the A.sub.2.sup.+ functional cation
corresponds to a Y.sup.+-- cationic entity, linked, optionally via
an L arm, in particular an alkyl group comprising 1 to 20 carbon
atoms, to a function F.sub.0, said function F.sub.0 being chosen
from the standard functions of organic chemistry, such as the
hydroxyl, carboxylic, amide, sulphone, primary amine, secondary
amine, aldehyde, ketone, ethenyl, ethynyl, dienyl, ether, epoxide,
phosphine (primary, secondary or tertiary), azide, imine, ketene,
cumulene, heterocumulene, thiol, thioether, sulphoxide,
phosphorus-containing groups, heterocycles, sulphonic acid, silane,
stannane or functional aryl functions.
[0129] According to an advantageous embodiment, a composition of
the invention is characterized in that the ionic liquid is chosen
from the following: ##STR6##
[0130] R.sub.a and R.sub.b representing linear or branched alkyl
groups, comprising 1 to 20 carbon atoms, in particular an ethyl,
propyl, butyl, pentyl, hexyl, heptyl or octyl group, or functional
alkyl groups comprising 1 to 20 carbon atoms, or functional or
non-functional aryl groups comprising 6 to 30 carbon atoms,
Bu.sub.3P.sup.+--Me, X.sub.1.sup.-
.sup..sym.P(C.sub.6H.sub.13).sub.3C.sub.14H.sub.29, X.sub.1.sup.-
(C.sub.8H.sub.17).sub.3N.sup.+Me, X.sub.1.sup.-
[0131] X.sub.1.sup.- being in particular chosen from:
NTf.sub.2.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.- or
CF.sub.3SO.sub.3.sup.-.
[0132] An advantageous composition of the invention is
characterized in that the functionalized salt is chosen from the
following: ##STR7##
[0133] X.sub.2.sup.- being chosen from: NTf.sub.2.sup.-,
PF.sub.6.sup.-, BF.sub.4.sup.-, Cl.sup.-, Br.sup.-, I.sup.-,
CF.sub.3SO.sub.3.sup.-, MeSO.sub.4.sup.-, EtSO.sub.4.sup.-,
MeSO.sub.3.sup.-, C.sub.6H.sub.5SO.sub.3.sup.-,
pMeC.sub.6H.sub.4SO.sub.3.sup.-,
[0134] m being an integer comprised between 0 and 20,
[0135] R.sub..beta. representing a substituted or non-substituted
vinyl group, functional aryl group comprising 1 to 20 carbon atoms,
or functional alkyl group comprising 6 to 30 carbon atoms,
[0136] and R.sub.a representing a branched or non-branched alkyl
group comprising 1 to 20 carbon atoms, in particular an ethyl,
propyl, butyl, pentyl, hexyl, heptyl or octyl group.
[0137] According to an advantageous embodiment, a composition of
the invention is characterized in that X.sub.2.sup.- is a
functional anion, corresponding in particular to an anion the
pK.sub.A of the conjugated acid of which is less than 30, and is
chosen in particular from the following anions: OH.sup.-, F.sup.-,
R.sub.cBZ.sub.3.sup.-, N.sub.3.sup.-, CN.sup.-, or
[0138] Z representing an --F, --OH, --OR moiety, R representing an
alkyl group comprising 1 to 20 carbon atoms,
[0139] V and W representing, independently of one another, an
electroattractive moiety, in particular a cyano, alkoxycarbonyl
moiety comprising 2 to 20 carbon atoms, acyl moiety comprising 2 to
20 carbon atoms, benzoyl, alkyl sulphonyl moiety comprising 1 to 20
carbon atoms, aryl sulphonyl moiety comprising 6 to 30 carbon
atoms, dialkoxyphosphonyl moiety comprising 2 to 20 carbon
atoms,
[0140] R.sub.c representing a branched or non-branched, cyclic or
non-cyclic alkyl moiety comprising 1 to 20 carbon atoms, or an aryl
moiety comprising 6 to 30 carbon atoms,
[0141] and in that the A.sub.2.sup.+ cation is chosen from the
ammonium and phosphonium cations, in particular from the following
cations:
Me.sub.3N.sup.+--R.sub.dEt.sub.3N.sup.+--R.sub.dBu.sub.4P.sup.+--R.sub.d
[0142] R.sub.d being an alkyl group comprising 1 to 20 carbon
atoms.
[0143] The present invention also relates to the use of a
composition as defined above, for continuous, discontinuous,
combinatorial, or parallel organic synthesis, and/or for the
preparation of libraries of products.
[0144] The present invention also relates to the use of a
composition as defined above, for the implementation of a process
for the preparation of a molecule G of an initial function F.sub.0,
linked, optionally via an L arm, in particular an alkyl group
comprising 1 to 20 carbon atoms, to a Y.sup.+-ionic entity, forming
part of the A.sub.2.sup.+ cation of the A.sub.2.sup.+X.sub.2.sup.-,
and/or Y.sup.--- functionalized salt, forming part of the
X.sub.2.sup.- anion of the A.sub.2.sup.+X.sub.2.sup.-
functionalized salt, the cation being in the form Y.sup.+-L-F.sub.0
and/or the anion being in the form Y.sup.--(L).sub.k-F.sub.0, k
being equal to 0 or 1, which process comprises the steps: [0145] of
a first addition of a reagent B.sub.1 into the abovementioned
composition and the reaction between said function F.sub.0, and the
reagent B.sub.1, leading to a function F.sub.1, linked to the
Y.sup.+-- ionic entity, forming part of the A.sub.2+ cation of the
A.sub.2+X.sub.2.sup.- functionalized salt, and/or to the ionic
entity Y.sup.---, forming part of the X.sub.2.sup.- anion of the
A.sub.2.sup.+X.sub.2.sup.- functionalized salt, according to one of
the following reaction diagrams: ##STR8## [0146] of n-1 successive
additions of B.sub.i reagents, 1<i.ltoreq.n, n varying from 2 to
10, to the abovementioned composition, allowing, at each addition,
the reaction between the reagent B.sub.i and a function F.sub.i-1,
leading to the obtaining of a function F.sub.i, the (n-1).sup.th
addition of the reagent B.sub.n to the function F.sub.n-1 leading
to the obtaining of the function F.sub.n, the n-1 additions being
representable according to one of the following reaction diagrams:
##STR9## [0147] of cleavage of the function F.sub.n, linked to the
Y.sup.+-- or Y.sup.--- ionic entity respectively of the
A.sub.2.sup.+ cation and/or of the X.sub.2.sup.- anion, making it
possible to recover [0148] on the one hand the
A.sub.2.sup.+X.sup.2.sup.- functionalized salt in the form
Y.sup.+-L-F.sub.0, X.sub.2.sup.- or A.sub.2.sup.+,
Y.sup.--(L).sub.k-F.sub.0, in solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid matrix, or in the form
Y.sup.+-L-F'.sub.0, X.sub.2.sup.- or A.sub.2.sup.+,
Y.sup.--(L).sub.k-F'.sub.0, in which F'.sub.0 represents a
different function from F.sub.0, [0149] and on the other hand the
molecule G, [0150] according to one of the following reaction
diagrams: ##STR10##
[0151] The use of the ionic liquids in such a reaction chain has
the following advantages:
[0152] the reactions are carried out in solution, and therefore all
the analysis techniques, including .sup.1H, .sup.13C, .sup.19F,
.sup.31P, .sup.11B, .sup.15N NMR etc., HPLC, FTIR, UV, visible,
fluorescence, electrochemical techniques, electrophoresis, mass
spectrometry etc., can be used under normal conditions without
particular complications;
[0153] the reactions are carried out at the usual concentrations of
0.5 to 1 mole per litre (or even more), which represents a huge
advantage in terms of specific load;
[0154] recycling of the functionalized salt solution is easy;
[0155] the solutions are easily transferable using syringe and (or)
pumping techniques;
[0156] synthesis of the ionic liquids and the functionalized salts
is very simple and certain of these are commercially available;
[0157] an immense variety of ionic liquids and functionalized salts
is easily accessible;
[0158] the solutions readily lend themselves to partition
techniques and therefore to parallel or combinatorial synthesis
techniques, which makes it possible to access product
libraries;
[0159] novel reactivities and selectivities have been observed in
these media;
[0160] scaling up does not pose any problems different from those
observed during operations in the usual solvents;
[0161] a parallel is easily established between this novel
technology and solid-support synthesis and soluble-polymers
synthesis techniques. It is immediately and obviously deduced that
the salts functionalized identically to Wang, Rink, silylalkyl,
carbonate, carboxylic, formyl, hydroxy, amino, oxime resins etc.
can be used much more readily and advantageously.
[0162] The present invention relates to the use as defined above,
for implementation of the Diels-Alder reaction, according to one of
the following reaction diagrams: ##STR11##
[0163] p being an integer varying from 0 to 2,
[0164] Y.sup.+-- representing an onium cation as defined above, and
preferably being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation,
[0165] L representing an arm, in particular a linear or branched
alkyl group comprising 1 to 20 carbon atoms, or an optionally
functional aralkyl group, comprising 6 to 30 carbon atoms, and
preferably being a linear alkyl group preferably a linear alkyl
group of (CH.sub.2).sub.r type, r varying from 1 to 20, and
preferably from 3 to 6,
[0166] X.sub.2.sup.- being as defined above, and being in
particular NTf.sub.2.sup.-, BF.sub.4.sup.-, PF.sub.6.sup.-,
Cl.sup.-, Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being as defined
above,
[0167] the A.sub.1.sup.+X.sub.1.sup.- ionic liquid being in
particular in the form: ##STR12##
[0168] R.sub.a and R.sub.b being as defined above, and preferably
representing alkyl groups comprising 1 to 20 carbon atoms,
[0169] X.sub.1.sup.- being chosen from: BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-, Br.sup.-,
CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-,
BR.sub.4.sup.-, R being as defined above,
[0170] the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below:
[0171] F.sub.0 corresponds to a -.chi..sub.1H group, in which
.chi..sub.1 represents an oxygen atom or an --NR.sub.f group,
R.sub.f corresponding to a linear or branched alkyl group,
comprising 1 to 20 carbon atoms, or an aryl group comprising 6 to
30 carbon atoms,
[0172] F.sub.1 corresponds to the following formula: ##STR13##
.chi..sub.1 being as defined above,
[0173] F.sub.2 corresponds to the following formula: ##STR14##
.chi..sub.1 being as defined above,
[0174] G corresponding to the following formula: ##STR15##
[0175] in which .chi..sub.2 represents either an OR.sub.g group,
R.sub.g representing a hydrogen atom or an alkyl group comprising 1
to 20 carbon atoms, or an --NR.sub.hR.sub.u group, R.sub.h and
R.sub.u representing independently of one another a hydrogen atom,
an alkyl group comprising 1 to 20 carbon atoms or an aryl group
comprising 6 to 30 carbon atoms, ##STR16##
[0176] the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below:
[0177] F.sub.0 represents any function making it possible to attach
a 1,3-diene, and is in particular chosen from the carbonyl, amine,
alkoxy, silane, stannane and borane functions, comprising 1 to 20
carbon atoms,
[0178] F.sub.1 corresponds to the following formula: ##STR17## p
being an integer varying from 0 to 2,
[0179] F.sub.2 corresponds to the following formula: ##STR18##
.chi..sub.3 representing an electroattractive group, in particular
chosen from the cyano, alkoxycarbonyl groups, comprising 1 to 20
carbon atoms, acyl group comprising 2 to 20 carbon atoms, benzoyl,
sulphonyl, dialkoxyphosphonyl groups comprising 1 to 10 carbon
atoms,
[0180] G corresponding to the following formula: ##STR19##
.chi..sub.3 being as defined above.
[0181] The present invention also relates to the use as defined
above, for implementation of Heck's reaction, according to the
following reaction diagram: ##STR20##
[0182] Y.sup.+-- representing an onium cation as defined above, and
preferably being a trimethylalkylammonium, triethylalkylanimonium
or tributylalkylphosphonium cation,
[0183] L representing an arm, in particular a linear or branched
alkyl group comprising 1 to 20 carbon atoms, or an optionally
functional aralkyl group comprising 1 to 20 carbon atoms, and
preferably being a linear alkyl group preferably a linear alkyl
group of type (CH.sub.2).sub.r, r varying from 1 to 20, and
preferably of 3 to 6,
[0184] X.sub.2.sup.- being as defined above, and being in
particular BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, Cl.sup.-, Br.sup.-, or I.sup.-,
[0185] the ionic liquid A.sub.1.sup.+X.sub.1.sup.- being in
particular in the form: ##STR21##
[0186] R.sub.a and R.sub.b being as defined above, and preferably
representing alkyl groups comprising 1 to 20 carbon atoms,
[0187] X.sub.1.sup.- being chosen from: BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-, Br.sup.-,
CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-,
BR.sub.4.sup.-, R being as defined above,
[0188] the functions F.sub.0, F.sub.1, F'.sub.1, F.sub.2 and
F'.sub.2 being as defined below:
[0189] F.sub.0 corresponds to a -.chi..sub.1H group, in which
.chi..sub.1 represents an oxygen atom or a --NR.sub.f group,
R.sub.f corresponding to a linear or branched alkyl group,
comprising 1 to 20 carbon atoms, or an aryl group comprising 6 to
30 carbon atoms,
[0190] F.sub.1 corresponds to the following formula: ##STR22##
.chi..sub.1 being as defined above,
[0191] F.sub.2 corresponds to the following formula: ##STR23##
.chi..sub.1 being as defined above,
[0192] G corresponding to the following formula: ##STR24##
[0193] in which .chi..sub.2 represents either an --OR.sub.g group,
R.sub.g representing a hydrogen atom or an alkyl group comprising 1
to 20 carbon atoms, or an --NR.sub.hR.sub.u group, R.sub.h and
R.sub.u representing independently of one another a hydrogen atom,
an alkyl group comprising 1 to 20 carbon atoms or an aryl group
comprising 6 to 30 carbon atoms,
[0194] .chi..sub.3 representing a leaving group, in particular
chosen from the halides I, Cl and Br, the mesylate, tosylate,
triflate, sulphonate, sulphate or phosphate groups,
[0195] T.sub.1, T.sub.2, T.sub.3, T.sub.4 and T.sub.5 representing
independently of one another a hydrogen atom, a linear or branched
alkyl group, comprising 1 to 20 carbon atoms or an aryl group
comprising 6 to 30 carbon atoms, or a functional group in
particular chosen from NO.sub.2, CN, COOR, OR, COR, NHCOR, NRR'',
SO.sub.2R, I, Br, R and R'' representing independently of one
another an alkyl group comprising 1 to 20 carbon atoms or an aryl
group comprising 6 to 30 carbon atoms,
[0196] the entity ##STR25## representing in particular the
following groups: ##STR26##
[0197] F'.sub.1 corresponds to the following formula: ##STR27##
.chi..sub.1 and .chi..sub.3 being as defined above,
[0198] F'.sub.2 corresponds to the following formula: ##STR28##
.chi..sub.1 being as defined above,
[0199] G' corresponding to the following formula: ##STR29##
.chi..sub.2 being as defined above.
[0200] The present invention relates to the use as defined above,
for implementation of the Baylis-Hillman reaction, according to the
following reaction diagram: ##STR30##
[0201] Y.sup.+-- representing an onium cation as defined above, and
preferably being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation,
[0202] L representing an arm, in particular a linear or branched
alkyl group comprising 1 to 20 carbon atoms, or an optionally
functional aralkyl group, comprising 6 to 30 carbon atoms, and
preferably being a linear alkyl group preferably a linear alkyl
group of (CH2).sub.r type, r varying from 1 to 20, and preferably
from 3 to 6,
[0203] X.sub.2.sup.- being as defined above, and being in
particular BF.sub.4.sup.-, PF.sub.6.sup.-, NTf.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, Cl.sup.-, Br.sup.-, I.sup.-,
CH.sub.3CO.sub.2.sup.- or CF.sub.3CO.sub.2.sup.-,
[0204] the A.sub.1.sup.+X.sub.1.sup.- ionic liquid being in
particular in the form: ##STR31##
[0205] R.sub.a and R.sub.b being as defined above, and preferably
representing alkyl groups comprising 1 to 20 carbon atoms,
[0206] X.sub.1.sup.- being chosen from: BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-, Br.sup.-,
CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-,
BR.sub.4.sup.-, R being as defined above,
[0207] the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below:
[0208] F.sub.0 represents an --OH group,
[0209] F.sub.1 corresponds to the following formula: ##STR32##
[0210] F.sub.2 corresponds to the following formula: ##STR33##
[0211] G corresponding to the following formula: ##STR34##
.chi..sub.1 representing an --OH group, or an --OR.sub.g group,
R.sub.g representing a linear or branched alkyl group, comprising 1
to 20 carbon atoms,
[0212] Ar representing a substituted or non-substituted, aromatic
or heteroaromatic group ArCHO being in particular chosen from:
##STR35##
[0213] The present invention relates to use as defined above, for
implementation of Suzuki coupling, according to one of the
following reaction diagrams: ##STR36##
[0214] R.sub.3 being chosen from the substituted or non-substituted
aryl, heteroaryl, ethenyl, dienyl, allyl, ethynyl groups,
comprising 2 to 30 carbon atoms,
[0215] R.sub.7 represents a branched or linear alkyl group or a
cycloalkyl group comprising 1 to 12 carbon atoms,
[0216] Y.sup.+-- representing an onium cation as defined above, and
preferably being a trimethylalkylammonium, triethylalkylammonium or
tributylalkylphosphonium cation,
[0217] L representing an arm, in particular a linear or branched
alkyl group comprising 1 to 20 carbon atoms, or an optionally
functional aralkyl group comprising 6 to 30 carbon atoms, and
preferably being a linear alkyl group, preferably a linear alkyl
group of (CH.sub.2).sub.r type, r varying from 2 to 20, and
preferably from 3 to 6,
[0218] X.sub.2.sup.- being as defined above, and being in
particular NTf.sub.2.sup.-, BF.sub.4.sup.-, PF.sub.6.sup.-,
Cl.sup.-, Br.sup.-, CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-,
CF.sub.3SO.sub.3.sup.-, BR.sub.4.sup.-, R being as defined
above,
[0219] the A.sub.1.sup.+X.sub.1.sup.- ionic liquid being in
particular in the form: ##STR37##
[0220] R.sub.a and R.sub.b being as defined above, and preferably
representing alkyl groups comprising 1 to 20 carbon atoms,
[0221] X.sub.1.sup.- being chosen from: BF.sub.4.sup.-,
PF.sub.6.sup.-, NTf.sub.2.sup.-, Cl.sup.-, Br.sup.-,
CH.sub.3COO.sup.-, CF.sub.3CO.sub.2.sup.-, CF.sub.3SO.sub.3.sup.-,
BR.sub.4.sup.-, R being as defined above,
[0222] the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below:
[0223] F.sub.0 is in the form -.chi..sub.1H, .chi..sub.1
representing an oxygen atom or an --NR.sub.f group, R.sub.f
corresponding to a linear or branched alkyl group, comprising 1 to
20 carbon atoms, or an aryl group comprising 6 to 30 carbon
atoms,
[0224] F.sub.1 is in the form --R.sub.e.chi., R.sub.e representing
an aromatic or heteroaromatic group comprising 6 to 30 carbon
atoms, .chi. representing a leaving group preferably chosen from
Cl, Br, I, OTf, O--CO.sub.2R.sup.5 or OSO.sub.3--R.sup.5, R.sup.5
representing an alkyl group comprising 1 to 10 carbon atoms or an
aralkyl group comprising 6 to 30 carbon atoms, F.sub.1 preferably
corresponding to the following formula: ##STR38##
[0225] F.sub.2 is in the form --R.sub.e--R.sub.2, R.sub.e being as
defined above and R.sub.2 being chosen from the substituted or
non-substituted aryl, heteroaryl, ethenyl, dienyl, allyl, ethynyl
groups, comprising 2 to 30 carbon atoms, F.sub.2 preferably
corresponding to the following formula: ##STR39##
[0226] Ar.sub.1 representing an aromatic group preferably chosen
from: ##STR40##
[0227] the G molecule being in the form R.sub.2--R.sub.3, R.sub.2
and R.sub.3 being as defined above, and corresponds in particular
to the following formula: ##STR41##
[0228] in which .chi..sub.2 represents either an --OR.sub.g group,
R.sub.g representing a hydrogen atom or an alkyl group comprising 1
to 20 carbon atoms, or an --NR.sub.hR.sub.u group, R.sub.h and
R.sub.u representing independently of one another a hydrogen atom,
an alkyl group comprising 1 to 20 carbon atoms or an aryl group
comprising 6 to 30 carbon atoms,
[0229] Ar.sub.1 is as defined above, ##STR42##
[0230] Y.sup.+--, L, X.sub.2.sup.-, A.sub.1.sup.+X.sub.1.sup.- and
R.sub.2 being as defined above,
[0231] the functions F.sub.0, F.sub.1 and F.sub.2 being as defined
below:
[0232] F.sub.0 is in the form -.chi..sub.1H, .chi..sub.1 being as
defined above,
[0233] F.sub.1 is in the form --R.sub.q--B(OR.sub.7).sub.2, R.sub.7
being as defined above, and R.sub.q corresponding to a substituted
or non-substituted aryl group comprising 6 to 30 carbon atoms,
heteroaryl group comprising 4 to 20 carbon atoms, ethenyl group
comprising 2 to 20 carbon atoms, dienyl group comprising 3 to 20
carbon atoms, allyl group comprising 3 to 20 carbon atoms, ethynyl
group comprising 2 to 20 carbon atoms, F.sub.1 preferably
corresponding to the following formula: ##STR43##
[0234] Ar.sub.2 corresponding to a substituted or non-substituted
aryl group comprising 6 to 30 carbon atoms,
[0235] F.sub.2 is in the form --R.sub.q--R.sub.e, R.sub.q and
R.sub.e being as defined above, F.sub.2 preferably corresponding to
the following formula: ##STR44##
[0236] Ar.sub.1 representing an aromatic group preferably chosen
from: ##STR45##
[0237] the G molecule being in the form R.sub.2--R.sub.3, R.sub.2
and R.sub.3 being as defined above, and corresponding in particular
to the following formula: ##STR46## in which .chi..sub.2, Ar.sub.1
and Ar.sub.2 are as defined above, ##STR47##
[0238] Y.sup.+--, L, X.sub.2.sup.-, A.sub.1.sup.+X.sub.1.sup.-,
R.sub.2 and R.sub.3 being as defined above,
[0239] R.sub.3 preferably being a phenyl group, ##STR48##
[0240] A.sub.2.sup.+ being an (R.sub.a).sub.3N.sup.+R.sub.b
ammonium or (R.sub.a).sub.3P.sup.+R.sub.b phosphonium cation,
preferably tetrabutylammonium and tetramethylammonium, R.sub.a and
R.sub.b being as defined above,
[0241] X.sub.2.sup.- being in particular chosen from OH.sup.-,
F.sup.-, CN.sup.-, RO.sup.-, RS.sup.-, preferably OH.sup.- or
F.sup.-, R.sub.s representing an alkyl group comprising 1 to 20
carbon atoms or an aryl group comprising 6 to 30 carbon atoms,
[0242] R.sub.3 and R.sub.4 being as defined above,
[0243] R.sub.6 and R.sub.7 representing independently of one
another an alkyl group comprising 1 to 20 carbon atoms or an aryl
group comprising 6 to 30 carbon atoms,
[0244] the boronic molecule of formula R.sub.3R.sub.7R.sub.6B being
a trialkyl or aryl borane, the alkyl group comprising 1 to 20
carbon atoms and the aryl group comprising 6 to 30 carbon atoms, a
boronic acid or ester, preferably a boronic acid or ester chosen as
being phenyl boronic acid,
[0245] R.sub.2 and .chi. are as previously defined, R.sub.2.chi.
preferably corresponding to an aryl halide chosen from:
##STR49##
[0246] The present invention also relates to the use as defined
above, for the synthesis of libraries of molecules according to the
parallel-synthesis technique, according to the following diagram:
##STR50##
[0247] characterized in that the Y.sup.+-L-F.sub.1, X.sub.2.sup.-
functionalized salt in the A.sub.1.sup.+, X.sub.1.sup.- ionic
liquid is separated into n approximately equal parts, n varying
from 2 to 1024, and in that each of these parts is then converted
according to an organic-synthesis reaction, preferably a Heck or
Suzuki coupling reaction, each using a different reagent B.sub.i in
order to produce n solutions each containing a defined
Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.- compound, F.sub.2.sup.i
representing a function chosen from the functions as defined above,
i varying from 1 to n, each solution being treated in order to
release the G.sub.i molecules, i varying from 1 to n, which are
each isolated and purified, constituting a molecule library.
[0248] The parallel-synthesis technique consists of preparing in
parallel and simultaneously libraries of perfectly identified
single products at a rate of one product per reactor or per well,
after a sequence of reactions carried out with reagents specific to
each prepared product.
[0249] The expression "approximately equal" designates partition
into equal volumes, allowing for experimental errors.
[0250] The expression "molecule library" designates a set of
products all identified, not mixed, each of them being arranged in
its own container. This type of molecule library results from
parallel synthesis. This expression can also designate a mixture of
products identified by analysis techniques at the disposal of
chemists and resulting from the reaction of a mixture of reagents
with a single product or of a mixture of products with a single
reagent according to the split-and-mix technique.
[0251] The present invention also relates to the use as defined
above, for implementation of the synthesis of molecule libraries by
the split-and-mix technique according to the following diagram:
##STR51##
[0252] characterized in that:
[0253] n fractions of the Y.sup.+-L-F.sub.1, X.sub.2.sup.-
solution, obtained from the starting Y.sup.+-L-F.sub.0,
X.sub.2.sup.- functionalized salt, in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid are converted in parallel
according to an organic chemistry reaction, preferably a Heck or
Suzuki coupling reaction, each using a different reagent B.sub.i in
order to produce n solutions each containing a defined
Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.- compound, i varying from 1
to n, n varying from 2 to 1024, preferably from 2 to 96,
F.sub.2.sup.i representing a function chosen from the functions as
defined above,
[0254] the n solutions obtained in the preceding step are mixed in
order to produce a solution in the A.sub.1.sup.+X.sub.1.sup.- ionic
liquid containing the n Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.-
products, i varying from 1 to n, annotated i = 1 i = n .times.
.times. Y + - L - F 2 i , X 2 - , ##EQU1## and this solution is
subjected to a cleavage step, preferably a transesterification or a
transamidation, in order to obtain in solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid, a mixture of the n G.sub.i
molecules, i varying from 1 to n, and the starting
Y.sup.+-L-F.sub.0, X.sub.2.sup.- functionalized salt,
[0255] the mixture as obtained in the preceding step is separated
from the A.sub.1.sup.+X.sub.1.sup.- ionic liquid and from the
starting Y.sup.+-L-F.sub.0, X.sub.2.sup.- functionalized salt by
the usual separation methods, preferably by vacuum distillation, by
extraction with a standard solvent such as heptane or toluene
followed by evaporation of solvent, by chromatography on a column,
plates or under pressure, in order to obtain a library containing n
G.sub.i molecules,
[0256] this sequence of steps mentioned above being possibly
repeated j times, j being comprised between 2 and 10, in order to
obtain j different libraries of n products.
[0257] The split-and-mix technique (O'Brecht et al., 1998) consists
of reacting n fractions of a solution of a product, each with a
different reagent leading to n novel products which are mixed after
identification. This novel mixture is separated into m fractions
which are then reacted in parallel each with a different reagent
leading to m mixtures of n novel products, i.e. m.times.n products.
These operations are repeated as many times as necessary.
[0258] According to an advantageous embodiment, the solution in the
A.sub.1.sup.+X.sub.1.sup.- ionic liquid containing the n
Y.sup.+-L-F.sub.2.sup.i, X.sub.2.sup.- products, i varying from 1
to n, as obtained after the mixing stage, and annotated i = 1 i = n
.times. .times. Y + - L - F 2 .times. i , ##EQU2##
[0259] X.sub.2.sup.- is separated into m parts, m varying from 2 to
1024. Each of said parts is then treated respectively by a reagent
B'.sub.j, j varying from 2 to m, according to the following
diagram: TABLE-US-00002 i = 1 i = n .times. Y + - L - F 2 i , X 2 -
##EQU3## ##STR52## i = 1 i = n .times. Y + - L - F 3 i , 1 , X 2 -
##EQU4## i = 1 i = n .times. Y + - L - F 3 i , 2 , X 2 - ##EQU5## i
= 1 i = n .times. Y + - L - F 3 i , m , X 2 - ##EQU6## ##STR53## i
= 1 i = n .times. G i 1 ##EQU7## i = 1 i = n .times. G i 2 ##EQU8##
i = 1 i = n .times. G i m ##EQU9## ##STR54## i = 1 i = n .times. G
i 1 ##EQU10## i = 1 i = n .times. G i 2 ##EQU11## i = 1 i = n
.times. G i m ##EQU12##
[0260] Thus, m novel G.sub.i.sup.j libraries of n new products are
obtained.
DESCRIPTION OF THE FIGURES
[0261] FIG. 1 represents proton NMR spectra recorded at 200 MHz in
acetone D6, corresponding to monitoring of the Heck coupling
reaction between the supported acrylate 6 and
1-iodonaphthalene.
[0262] FIG. 2 represents a chromatogram corresponding to the
mixture of the nine methyl esters 13a to 13i the mass spectra of
which are described in Table II.
[0263] FIG. 3 represents a chromatogram corresponding to the
mixture of the nine ethyl esters 14a to 14i the mass spectra of
which are described in Table III.
[0264] FIG. 4 represents a chromatogram corresponding to the
mixture of the nine propyl esters 15a to 15i the mass spectra of
which are described in Table IV.
[0265] FIG. 5 represents a chromatogram corresponding to the
mixture of the nine butyl esters 16a to 16i the mass spectra of
which are described in Table V.
[0266] FIG. 6 represents proton NMR spectra recorded at 200 MHz in
acetone D6, corresponding to monitoring of the Heck coupling
reaction between the supported aryl iodide 7 and tertbutyl
acrylate.
[0267] The upper spectrum corresponds to the spectrum of 7b in 0.85
M solution in Me.sub.3N--(CH.sub.2).sub.2Me,NTf.sub.2.sup.-. The
lower spectrum is that of the reaction mixture once the Heck
coupling is finished.
[0268] FIG. 7 represents a chromatogram corresponding to the
mixture of the biaryl propyl esters 23a to 23i the mass spectra of
which are described in Table XI.
[0269] FIG. 8 represents a chromatogram corresponding to the
mixture of the biaryl methyl esters of Table XII.
[0270] FIG. 9 represents a chromatogram corresponding to the
mixture of the biaryl ethyl esters of Table XIII.
[0271] FIG. 10 represents proton NMR spectra recorded at 200 MHz in
acetone D6, corresponding to monitoring of Grieco's reaction with
supported aniline 1 and 4-nitrobenzaldehyde.
[0272] FIG. 11 represents proton NMR spectra recorded at 200 MHz in
acetone D6, corresponding to monitoring of Sonogashira coupling
with R=phenyl.
[0273] FIG. 12 represents a chromatogram corresponding to the
mixture of the methyl esters the mass spectra of which are
described in Table XX.
[0274] FIG. 13 represents a chromatogram corresponding to the
mixture of the ethyl esters the mass spectra of which are described
in Table XXI.
EXPERIMENTAL PART
Preparation of the Compounds
I) Synthesis of the Functionalized Salts:
[0275] 1/Alcohols 1: TABLE-US-00003 (1) ##STR55## 1a m = 1; X.sub.2
= Cl 1b m = 3; X.sub.2 = Cl 1c m = 1; X.sub.2 = PF.sub.6 1d m = 1;
X.sub.2 = NTf.sub.2 1e m = 3; X.sub.2 = NTf.sub.2 1f m = 1; X.sub.2
= BF.sub.4
*1a:
[0276] 25 g (0.1 mol) of 3-chloropropanol, 30 ml of a 45% solution
of trimethyl amine in water (0.2 mol) are introduced into a 250-ml
flask, as well as 100 ml of acetonitrile in order to homogenize the
medium. The mixture is then taken to reflux for 36 hours. The
water/acetonitrile mixture is evaporated under vacuum and the white
solid obtained is washed twice with 30 ml of ether.
White solid Yield=82% M.p.=158-160.degree. C.
[0277] .sup.1H NMR (200 MHz, D.sub.2O): 1.80-2.05 (m, 2H); 3.00 (s,
9H); 3.20-3.41 (m, 2H); 3.60 (t, 2H, J=7.1 Hz)
[0278] .sup.13C NMR (50 MHz, D2O): 25.68; 53.31 (t, J.sub.C--N=4.1
Hz); 58.52; 64.52.
*1b:
[0279] 5 g (36 mmol) of 6-chlorohexanol, 10 ml of a 45% solution of
trimethyl amine in water (0.1 mol) are introduced into a 250-ml
flask as well as 100 ml of acetonitrile in order to homogenize the
medium. The mixture is then taken to reflux for 36 hours. The
water/acetonitrile mixture is evaporated under vacuum and the white
solid obtained is washed twice with 30 ml of ether.
White solid Yield=62% M.p.=178-180.degree. C.
[0280] .sup.1H NMR (200 MHz, MeOH): 1.30-1.65 (m, 6H); 1.80-1.95
(m, 2H); 3.18 (s, 9H); 3.4-3.6 (m, 2H); 3.55 (t, 2H, J=6.1 Hz).
[0281] .sup.13C NMR (50 MHz, MeOH): 22.93; 25.48; 26.15; 32.35;
52.60 (t; J=4.1 Hz); 61.67; 66.76.
*1c:
[0282] A mixture of a solution of 10 g (65.3 mol) of
N,N',N''-trimethyl-3-hydroxypropylammonium chloride in 15 ml of
water and 13.23 ml (0.15 mol) of 60% hexafluorophosphoric acid in
solution in water is stirred at ambient temperature for 2 hours.
The medium immediately becomes heterogeneous and the formed
precipitate is filtered and washed with ether. The white solid
obtained is dried under vacuum.
White solid Yield=67% M.p.=124-126.degree. C.
[0283] .sup.1H NMR (200 MHz, CD.sub.3CN): 1.70 (m, 2H); 2.82 (s,
9H); 3.15 (m, 2H); 3.40 (t, 2H, J=6.1 Hz).
[0284] .sup.13C NMR (50 MHz, CD.sub.3CN): 25.44,; 52.59 (t, J=4.2
Hz); 57.67; 64.26 (t, J=3.8 Hz).
*1d:
[0285] A solution of 10 g of ammonium salt (1a) (65.3 mol) in 10 mL
of water is prepared in a beaker. In another beaker, 20 g of
lithium bis-trifluoromethanesulphonamide (71.9 mmol) is dissolved
in the same manner. The two solutions are mixed and stirred for 2
hours at ambient temperature in order for the exchange to be
complete. The two phases obtained are separated in a separating
funnel, and the aqueous phase is extracted twice with 15 ml of
methylene chloride. Finally, the solvent is evaporated and the
product is dried under vacuum.
Colorless viscous oil Yield=86%
[0286] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.00-2.21 (m, 2H);
3.25 (s, 9H); 3.50-3.80 (m, 4H).
[0287] .sup.13C NMR (50 MHz, Acetone D.sub.6): 29.14; 54.27(t;
J.sub.C--N=4.1 Hz); 60.05; 66.09; 121.05 (q, J=321.2 Hz).
*1e:
[0288] A mixture of a solution of 10 g (51.2 mmol) of
N,N',N''-trimethyl-4-hydroxybutylammonium chloride in 15 ml of
water and 18.7 g (6.66 mmol) of lithium trifluoromethane
sulphonamide is stirred at ambient temperature. The medium
immediately becomes heterogeneous, and the two phases are separated
in a separating funnel. The colorless oil obtained is then washed
twice with 3 ml of water and dried at 50.degree. C. under high
vacuum.
Colorless oil Yield=93%.
[0289] .sup.1HNMR (200 MHz, Acetone, D6): 1.41-1.60 (m, 6H);
1.88-2.01 (m, 2H); 3.30 (s, 9H); 3.50-3.65.(m, 4H); 3.55 (t, 2H,
J=6.1 Hz).
[0290] .sup.13C NMR (50 MHz, Acetone, D6): 23.02; 25.60; 26.22;
53.01 (t, J=4.1 Hz); 61.73; 66.99; 121.05 (q, J=324.2 Hz).
*1f:
[0291] A mixture of a solution of 10 g (65 mmol) of
N,N',N''-trimethyl-3-hydroxypropylammonium chloride in 15 ml of
water and 9.1 ml (0.15 mol) of 50% tetrafluoroboric acid in water
is stirred at ambient temperature. The medium remains homogeneous.
After 12 hours, the water is evaporated to dryness, the white solid
obtained is washed twice with 15 ml of anhydrous ether.
White solid Yield=92% M.p.=110-112.degree. C.
[0292] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.10-2.241 (m, 2H);
3.05 (s, 9H); 3.24-3.45 (m, 4H); 3.61 (t, J=7.1 Hz, 2H).
[0293] .sup.13C NMR (50 MHz, Acetone D.sub.6): 27.52; 53.35 (t,
J.sub.C--N=4.1 Hz); 58.25.05 ? ?; 64.58.
[0294] 2/Carboxylic Acid 2: TABLE-US-00004 (2a) ##STR56## 2a
X.sub.2 = Br 2b X.sub.2 = NTf.sub.2
*2a:
[0295] A mixture of 30 ml of a 6.65 molar aqueous solution (0.2
mol) and 14.3 ml (0.1 mol) of ethyl bromobutyrate is taken to
reflux for 24 hours. The solvent is then evaporated to dryness and
the white solid obtained is washed with 3 times 25 ml of ether.
[0296] The solid thus obtained is dissolved in 15 ml of a solution
of hydrobromic acid (6 N), then taken to reflux for 12 hours,
followed by evaporation to dryness. The solid obtained is washed in
ether and then dried under vacuum.
White solid Yield=75% M.p.=188-190.degree. C.
[0297] .sup.1H NMR (200 MHz, CD.sub.3OD): 1.95-2.21 (m, 2H); 2.49
(t, 2H, J=7.0 Hz); 3.25 (s, 9H); 3.45-3.55 (m, 2H).
[0298] .sup.13C NMR (50 MHz, CD.sub.3OD): 18.58; 30.04; 52.86 (t,
J=4.1 Hz); 65.84 (t, J=4.1 Hz); 174.40.
*2b:
[0299] 4 g of N,N',N''-trimethyl-3-butanoic acid (2a) (17.7 mmol)
is dissolved in 10 mL of water in a beaker. 5.6 g of LiNTf.sub.2
(19.5 mmoles) is dissolved in the same manner in another beaker and
the 2 solutions are mixed. The medium becomes cloudy and the
appearance of 2 phases is observed. Stirring is maintained for 2
hours at ambient temperature in order for the exchange to be
complete. The content of the beaker is decanted into a separating
funnel and left to settle until there are 2 well-separated phases.
The ionic liquid (lower phase) is extracted and the aqueous phase
is washed twice with 20 ml of methylene chloride. Finally, the
flask is placed under vacuum in order to dry the product after
evaporation of the solvent.
Colorless viscous oil Yield=88%
[0300] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.15-2.30 (m, 2H);
2.5 (t, J=6.7 Hz, 2H); 3.40 (s, 9H); 3.55-3.70 (m, 2H)
[0301] .sup.13C NMR (50 MHz, Acetone D.sub.6): 19.52; 23.73; 54.09
(t, J.sub.C--N=4.0 Hz); 67.02 (t, J.sub.C--N=3.0 Hz); 118.4
(q.sub.C--F, J=324.0 Hz); 172.89.
[0302] 3/Halide 3: TABLE-US-00005 (3) ##STR57## 3a m = 1; X.sub.2 =
Br 3b m = 3; X.sub.2 = Br 3c m = 1; X.sub.2 = NTf.sub.2 3d m = 1;
X.sub.2 = PF.sub.6 3e m = 3; X.sub.2 = PF.sub.6 3f m = 3; X.sub.2 =
BF.sub.4
[0303] 1) X.sub.2.dbd.Br:
[0304] 41 ml (0.6 mol) of a 45% aqueous solution of trimethylamine
is introduced into a 100-mL single-necked flask surmounted by a
condenser. It is stirred and the oil bath is heated to a
temperature of 40.degree. C. At the condenser outlet, the
trimethylamine vapors pass through a trap with KOH pellets in order
to retain the traces of water present in the vapors and are bubbled
through a two-necked flask containing 0.2 mole of dibromoalkane
dissolved in 100 mL of anhydrous THF under stirring.
[0305] The contents of the flask are filtered and the solid is
washed with ether. The white solid thus obtained is dried under
vacuum.
*3a:
White solid Yield=99% M.p.=212-215.degree. C.
[0306] .sup.1H NMR (200 MHZ, CD.sub.3OD): 2.31-2.59 (m, 2H); 3.32
(s, 9H); 3.52-3.69 (m, 4H)
[0307] .sup.13C NMR (50 MHz, CD.sub.3OD): 26.42; 28.96; 53.11 (t,
J.sub.C--N=4.0 Hz); 65.50 (t, J=3.6 Hz).
*3b:
White solid Yield=96% M.p.=139-140.degree. C.
[0308] .sup.1HNMR (200 MHz, D.sub.2O): 1.50-1.75 (m, 2H); 1.85-2.15
(m, 4H); 3.25 (s, 9H); 3.4-3.55 (m, 2H); 3.65 (t, J=6.6 Hz, 2H)
[0309] .sup.13C NMR (50 MHz, D.sub.2O): 21.91; 24.51; 31.72; 34.61;
53.22 (t, J.sub.C--N=4.0 Hz); 66.80
[0310] 2) X.sub.2.dbd.NTf.sub.2:
[0311] 5.5 g of LiNTf.sub.2 (19 mmoles) are dissolved in 10 mL of
water in a beaker. In the same manner, approximately 17.3 mmoles of
corresponding bromide is dissolved in water in another beaker. The
two solutions are mixed and left under stirring for two hours.
[0312] The contents of the beaker are decanted into a separating
funnel. The aqueous phase is extracted with twice 15 mL of
methylene chloride. The organic phases are collected and dried over
MgSO.sub.4. The solvent is then evaporated to dryness and the
product is dried under vacuum.
*3c:
Colorless viscous oil Yield=84%.
[0313] .sup.1H NMR (200 MHz, Acetone D.sub.6): 1.40-1.70 (m, 2H);
1.90-2.20 (m, 4H); 3.35 (s, 9H); 3.50-3.70 (m, 4H)
[0314] .sup.13C NMR (50 MHz, Acetone D.sub.6): 23.13; 25.86; 33.24;
34.58; 54.06 (t, J.sub.C--N=4.0 Hz); 67.65; 121.37 (q,
J.sub.C--F=320.9 Hz)
[0315] 3) X.sub.2.dbd.PF.sub.6:
[0316] 23 mmoles of the bromide is dissolved in 10 mL of water in a
beaker, and 6 mL (68 mmol) of 60% HPF.sub.6 in water is added.
Stirring is maintained for 2 hours at ambient temperature in order
for the exchange to be complete then the precipitate is filtered.
The filtrate is then washed twice with 15 ml of methylene chloride.
The solvent is evaporated to dryness and the solid obtained is
added to the starting precipitate. Finally, the white solid
obtained is washed with ether and dried under vacuum.
*3d:
White powder Yield=88% M.p.=144-146.degree. C.
[0317] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.1-2.5 (m, 2H);
3.05 (s, 9H); 3.4-3.6 (m, 4H)
[0318] .sup.13C NMR (50 MHz, Acetone D.sub.6): 27.29; 30.27; 54.27
(t, J.sub.C--N=4.1 Hz); 66.54 (t, J.sub.C--N=3.5 Hz)
[0319] .sup.19F NMR (282 MHz, Acetone D.sub.6): -71.65 (d, J=7.07
Hz)
[0320] .sup.31P NMR spectrum (300 MHz, Acetone D.sub.6): -142.69
(septuplet, J=708.2 Hz)
*3e:
White solid Yield=97% M.p.=139-140.degree. C.
[0321] .sup.1H NMR (200 MHz, D.sub.2O): 1.30-1.55 (m, 2H);
1.61-1.93 (m, 4H); 3.05 (s, 9H); 3.10-3.30 (m, 2H); 3.45 (t, J=6.7
Hz, 2H)
[0322] .sup.13C NMR (50 MHz, D.sub.2O): 21.89; 24.49; 31.69; 34.54;
53.18 (t, J.sub.C--N=4.0 Hz); 66.78
[0323] .sup.19F NMR (282 MHz, D.sub.2O): -71.78 (d, J=703 Hz)
[0324] .sup.31P NMR spectrum (300 MHz, D.sub.2O): -144.38
(septuplet, J=703 Hz)
[0325] 4) X.sub.2.dbd.BF.sub.4
[0326] 5 g of bromide (3b)(17.3 mmol) is dissolved in 10 mL of
water in a beaker. 2.1 mL (34.6 mmol) of a 50% solution of
HBF.sub.4 is added and stirring is maintained at ambient
temperature for approximately 2 hours in order for the reaction to
be complete. The contents of the beaker are decanted into a flask
and the water is evaporated to dryness in a rotary evaporator,
followed by finally drying under high vacuum.
*3f:
Orange-colored viscous oil Yield=78%.
[0327] .sup.1H NMR (200 MHz, D.sub.2O): 1.31-1.53 (m, 2H);
1.60-1.94 (m, 4H); 3 (s, 9H); 3.15-3.32 (m, 2H); 3.45 (t, J=6.7 Hz,
2H)
[0328] .sup.13C NMR (50 MHz, D.sub.2O): 21.92; 24.55; 31.79; 34.85;
53.23 (t, J.sub.C--N=3.5 Hz); 66.72 (t, J.sub.C--N=3.02 Hz)
[0329] 4/Amine 4: TABLE-US-00006 (4) ##STR58## 1) X.sub.2 = Br
[0330] 10 mmol of bromide (3a or 3b) and 30 ml of a 25% aqueous
solution of ammonium hydroxide are introduced into a 250-mL
single-necked flask. A condenser is fitted and the reaction mixture
is taken to reflux overnight (14 hours). The solution is left to
cool down to ambient temperature, and 5 ml of a solution of NaOH (1
N) is added, then the water and the excess of ammonium hydroxide
are evaporated to dryness.
[0331] The solid obtained is dissolved in acetone, filtered on
MgSO.sub.4, and evaporated to dryness. A white solid is obtained
which is dried in a desiccator under vacuum in the presence of
P.sub.2O.sub.5.
*4a:
White solid Yield=82% M.p.=172-174.degree. C.
[0332] .sup.1H NMR (200 MHz, D.sub.2O): 1.55-1.63 (m, 2H); 2.85 (t,
J=6.5 Hz, 2H); 3.21 (s, 9H); 3.35-3.60 (m, 2H).
[0333] .sup.13C NMR (50 MHz, D.sub.2O): 27.95; 34.85; 52.65 (t,
J.sub.C--N=3.4 Hz); 63.58 (t, J.sub.C--N=3 Hz).
*4b:
White solid Yield=95% M.p.=132-134.degree. C.
[0334] .sup.1H NMR (200 MHz, D.sub.2O): 1.30-1.52 (m, 2H);
1.64-1.90 (m, 4H); 3.07 (s, 9H); 3.15-3.33 (m, 2H); 3.45 (t, J=6.7
Hz, 2H)
[0335] .sup.13C NMR (50 MHz, D.sub.2O): 21.92; 24.55; 31.79; 34.85;
53.23 (t, J.sub.C--N=3.5 Hz); 66.72 (t, J.sub.C--N=3.0 Hz).
[0336] 2) X.sub.2.dbd.NTf.sub.2:
[0337] 5.5 g of LiNTf.sub.2 (19 mmoles) is dissolved in 10 mL of
water in a beaker. In the same manner, approximately 17.3 mmoles of
corresponding ammonium bromide is dissolved in water in another
beaker. The two solutions are mixed and left under stirring for two
hours.
[0338] The contents of the beaker are decanted into a separating
funnel and the aqueous phase is extracted with twice 15 mL of
methylene chloride. The 2 organic phases are collected and dried
over MgSO.sub.4. The solvent is then evaporated to dryness and the
product is dried under vacuum.
*4c:
Viscous orange oil Yield=87%
[0339] .sup.1H NMR (200 MHz, Acetone): 1.41-1.70 (m, 2H); 1.95-2.15
(m, 4H); 2.82 (broad s, 2H); 3.35 (s, 9H); 3.25-3.40 (m, 2H);
3.50-3.70 (m, 2H).
[0340] .sup.13C NMR (50 MHz, Acetone): 23.02; 26.45; 30.79; 35.64;
53.56 (t, J.sub.C--N=3.5 Hz); 67.82 (t, J.sub.C--N=3.0 Hz); 121.65
(q, J=321 Hz)
[0341] 5/Diethanolamine 5: TABLE-US-00007 (5) ##STR59## 5a X.sub.2
= NTf.sub.2 5b X.sub.2 = BF.sub.4 5c X.sub.2 = PF.sub.6
[0342] 10 g of the salt ((III) with X.sub.2.dbd.Br and m=3), 40 mL
of ethanol and 1 equivalent of diethanolamine are introduced into a
50-mL single-necked flask. A condenser is fitted and the reaction
mixture is taken to 90.degree. C. overnight (14 hours). The
assembly is then cooled down to ambient temperature, and a solution
of NaOH (1N) is added until a basic pH is reached. The
(water/ethanol) mixture is then evaporated to dryness and the flask
is placed under high vacuum until the water is completely
eliminated. The white paste obtained is then washed with 3 times 30
ml of anhydrous acetone in order to extract the maximum amount of
product. Finally, the solvent is evaporated to dryness.
*5a:
Viscous orange oil Yield=91%.
[0343] .sup.1H NMR (200 MHz, D.sub.2O): 1.25-1.5 (m, 2H); 1.55-1.95
(m, 4H); 2.8-2.95 (m, 4H); 3.0 (t, J=5.8 Hz, 4H); 3.05 (s, 9H);
3.2-3.35 (m, 2H); 3.75 (t, J=5.7 Hz, 4H).
[0344] .sup.13C NMR (50 MHz, D.sub.2O): 21.26; 22.31; 23.17; 48.31;
51.86 (t, J.sub.C--N=4.0 Hz); 52.83; 54.05; 56.60; 56.80;
65.53.
*5b:
White paste Yield=91%.
[0345] .sup.1H NMR (200 MHz, D.sub.2O): 1.25-1.45 (m, 2H);
1.55-1.90(m, 4H); 2.8-2.95 (m, 4H); 3.05 (s, 9H); 3.25 (t, J=8.7
Hz, 2H); 3.80 (t, J=5.8 Hz, 4H); 2.95-3.15 (m, 4H)
[0346] .sup.13C NMR (50 MHz, D.sub.2O): 22.41; 23.37; 23.93; 49.42;
53.15; 53.95; 55.22; 57.19; 57.53; 66.68.
[0347] .sup.19F NMR (282 MHz, D.sub.2O): -71.64 (d,
J.sub.P--F=707.6 Hz).
[0348] .sup.31P NMR spectrum: (300 MHz, D.sub.2O): -144.35.
*5c:
Colorless viscous oil Yield=94%.
[0349] .sup.1H NMR (200 MHz, D.sub.2O): 1.25-1.65 (m, 4H);
1.67-1.95 (m, 4H); 3.05 (s, 9H); 3.15 (t, J=5.6 Hz, 2H); 3.2-3.3
(m, 4H); 3.4-3.5 (m, 2H); 3.8 (t, J=5.6 Hz, 4H)
[0350] .sup.13C NMR (50 MHz, D.sub.2O): 21.90; 22.32; 28.47; 31.75;
34.63; 49.29; 53.17 (t, J.sub.C--N=4.0 Hz); 56.87; 66.58;
70.30.
[0351] .sup.19F NMR (282 MHz, D.sub.2O): -149.98 (t,
J.sub.B--F=1.13 Hz).
II) Functionalization of the Preceding Salts:
[0352] A) Acrylic Ester 6:
[0353] General Procedure of Esterification by Acrylic Acid:
TABLE-US-00008 6 ##STR60## 6a X.sub.2 = NTf.sub.2 6b X.sub.2 = Cl
6c X.sub.2 = BF.sub.4
[0354] A solution of N,N',N''-trimethyl-3-hydroxypropylammonium
salt and 3 equivalents of acryloyl chloride in acetonitrile is
stirred in the presence of 5 equivalents of solid K.sub.2CO.sub.3
for 2 hours at a temperature comprised between 18 and 22.degree. C.
The mixture is then filtered and placed under vacuum in order to
eliminate the solvent and the excess of the reagent. The ammonium
acrylate thus obtained is stable at 4.degree. C. and can be stored
for several months.
*6a:
Colorless oil Yield=100%
[0355] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.22 -2.25 (m, 2H);
3.25 (s, 9H); 3.60 -3.75 (m, 2H); 4.15 (t, 2H, J=6.0 Hz); 5.80 (dd,
1H, J.sub.1=1.92, J.sub.2=10.68 ); 6.05 (dd, 1H, J.sub.1=17.2,
J.sub.2=10.7); 6.15 (dd, 1H, J.sub.1=1.9, J.sub.2=17.2).
[0356] .sup.13C NMR (50 MHz, Acetone D.sub.6): 29.17; 54.16 (t,
J=4.0); 65.16; 65.23; 121.05 (q, J.sub.CF=374.2 Hz); 129.40;
132.15; 165.61
[0357] .sup.19F NMR (282 MHz, Acetone D.sub.6): -79.8
[0358] Mass spectrometry (FAB) for C.sub.9H.sub.18NO.sub.2
(C.sup.+) [0359] Calculated theoretical mass 172.13375 [0360] Mass
found: 172.1346 *6b: White solid Yield=100% M.P.=175-177.degree.
C.
[0361] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.15-2.20 (m, 2H);
3.15 (s, 9H); 3.48 -3.52 (m, 2H); 4.18 (t, 2H, J=6.0 Hz); 5.75 (dd,
1H, J.sub.1=1.92 Hz, J.sub.2=10.5 Hz); 6.15 (dd, 1H, J.sub.1=10.5
Hz, J.sub.2=17.3 Hz); 6.15 (dd, 1H, J.sub.1=1.9 Hz, J.sub.2=17.3
Hz)
[0362] .sup.13C NMR (50 MHz, Acetone D.sub.6): 21.74; 52.23 (t,
J=4.2 Hz); 60.44 (t, J=3.02); 62.6; 127.41; 130.65; 165.04
*6c:
Colorless oil Yield=93%
[0363] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.28 -3.31 (m, 2H);
3.32 (s, 9H); 3.06 -3.15 (m, 2H); 4.52 (t, 2H, J=6.6 Hz); 5.80 (dd,
1H, J.sub.1=1.9 Hz, J.sub.2=10.0 Hz); 6.05 (dd, 1H, J.sub.1=18.3
Hz, J.sub.2=10.0 Hz); 6.15 (dd, 1H, J.sub.1=1.9 Hz, J.sub.2=18.3
Hz)
[0364] .sup.13C NMR (50 MHz, Acetone D.sub.6): 22.8 1,; 53.28;
61.46; 63.83; 128.51; 131.72; 167.31.
[0365] B/3-iodobenzoic esters 7: TABLE-US-00009 (7) ##STR61## 7a
X.sub.2 = Cl 7b X.sub.2 = NTf.sub.2
*7a:
[0366] 1.3 g (8.4 mmol) of
N,N',N''-trimethyl-3-hydroxypropylamrnmonium chloride, 10 ml of
acetonitrile, 6.5 g of K.sub.2CO.sub.3 and 3 g of 3-iodobenzoic
acid chloride are introduced into a 100-ml flask. After stirring
overnight at ambient temperature, the reaction medium is filtered
and K.sub.2CO.sub.3 is washed with 3 times 15 ml of methylene
chloride. After evaporation of the latter, the product is isolated
by filtration after crystallization from acetone. The white solid
thus obtained is washed with 3.times.10 ml of ether in order to
eliminate the remaining traces of acid.
White solid Yield=85% M.p.=180-182.degree. C.
[0367] .sup.1H NMR (200 MHz, D.sub.2O): 2.15 (m, 2H); 3.01 (s, 9H);
3.25-3.45 (m, 2H); 4.10-4.20 (t, 2H, J=6.6 Hz); 7.05 (t, 1H, J=7.1
Hz); 7.75 (dd, 2H, J.sub.1=7.1 Hz, J.sub.2=2Hz); 8.0 (d, 1H, J=2.0
Hz).
[0368] .sup.13C NMR (50 MHz, D.sub.2O): 22.56; 53.35 (t,
J.sub.C--N=4.1 Hz); 62.83; 64.15 (t, J.sub.C--N=3.3 Hz); 93.87;
129.07; 130.72; 131.08; 138.31; 142.83; 166.91.
*7b:
[0369] 0.7 g (1.8 mmol) of the chloride (VII) with X.sub.2.dbd.Cl)
is solubilized in 5 ml of water in a 100-ml flask. 0.8 g (2.8 mmol)
of LiNTf.sub.2 in 3 ml of water is added to this solution. The
reaction mixture is stirred for 2 hours at ambient temperature
before extracting the product from the water with methylene
chloride. After evaporation of the latter, a white solid is
obtained.
White solid Yield=88% M.p.=78-80.degree. C.
[0370] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.20-2.30 (m, 2H);
3.31 (s, 9H); 3.65-3.77 (m, 2H); 4.39 (t, 2H, J=6.7 Hz); 7.21 (t,
1H, J=7.1 Hz); 7.90 (dd, 2H, J.sub.1=7.1 Hz, J.sub.2=1.9 Hz); 8.22
(d, 1H, J=1.9 Hz)
[0371] .sup.13C NMR (50 MHz, Acetone D.sub.6): 23.97; 54.23 (t,
J.sub.C--N=4.1 Hz); 55.40; 63.27; 65.31 (t, J.sub.C--N=3.3 Hz);
94.70; 121.17 (q, J.sub.C--F=320.9 Hz); 130.11; 131.94; 133.29;
139.32; 143.37; 165.65
[0372] .sup.19F NMR (282 MHz, Acetone D.sub.6): -79.23
[0373] Mass spectrometry (FAB) for
C.sub.15H.sub.19F.sub.6N.sub.2O.sub.6S.sub.2
[0374] Theoretical mass calculated for (2C.sup.+,A): 976.0094
[0375] Mass found: 976.0094
[0376] C/4-bromobenzoic esters 8: TABLE-US-00010 (8) ##STR62## 8a
X.sub.2 = Cl 8b X.sub.2 = NTf.sub.2 8c X.sub.2 = PF.sub.6 8d
X.sub.2 = BF.sub.4
*8a:
[0377] 2 g (13.1 mmol) of
N,N',N''-trimethyl-3-hydroxypropylammonium chloride, 25 ml of
acetonitrile, 20 g of K.sub.2CO.sub.3 in powder and 4 g (17.5 mmol)
of 4-bromobenzoic acid chloride are introduced into a 250-ml flask.
After stirring overnight at ambient temperature, the reaction
medium is filtered and K.sub.2CO.sub.3 is washed with 3 times 15 ml
of methylene chloride and finally evaporated to dryness. After
taking up in water the excess of the 4-bromobenzoic acid which
crystallizes by filtration is eliminated. The product is then
crystallized from acetone after evaporation of water.
White solid Yield=60% M.p.=164-166.degree. C.
[0378] .sup.1H NMR (200 MHz, D.sub.2O): 2.21-2.34 (m, 2H); 3.12 (s,
9H); 3.30-3.58 (m, 2H); 4.35 (t, 2H, J=6.8 Hz); 7.57 (d, 2H, J=7.4
Hz); 7.80 (d, 2H, J.sub.1=7.4 Hz)
[0379] .sup.13C NMR (50 MHz, D.sub.2O): 22.55; 30.61; 53.34 (t,
J.sub.C--N=4.2 Hz); 62.69; 64.41 (t, J.sub.C--N=4.09 Hz); 128.34;
128.66; 131.37; 132.20; 167.84
[0380] Mass spectrometry (FAB) for C.sub.11H.sub.19NO.sub.2Cl
[0381] Theoretical mass for (C.sup.+): 302.0580
[0382] Mass found: 302.0585
*8b:
[0383] In this case the synthesis of substrate was envisaged
according to two approaches: by direct esterification of
N,N,N-trimethyl-3-hydroxypropylammonium
bis-trifluoromethanesulphonamide or by metathesis from the
corresponding chloride.
[0384] Esterification:
[0385] 4 g (10.5 mmol) of the alcohol, 20 ml of acetonitrile, 2 ml
of a saturated solution of NaCO.sub.3 in water and 4 g (17.5 mmol)
of 4-bromobenzoic acid chloride are introduced into a 250-ml flask.
The reaction mixture is heated at 60.degree. C. overnight followed
by evaporation to dryness, and the residue obtained is solubilized
in methylene chloride. This solution is washed successively with
2.times.20 ml of water, 2.times.20 ml of a soda solution (1N) and
finally with 2.times.20 ml of water. The solution is dried over
magnesium sulphate and the solvent is evaporated to dryness. After
taking up in acetone, the remaining traces of acids are eliminated
by precipitation at 4.degree. C. After evaporation of the latter, a
pure white solid is obtained.
[0386] Yield=90 %
[0387] Metathesis
[0388] 1 g (2.98 mmol) of (8a) is solubilized in 5 ml of water in a
100-ml flask. 1.1 g (3.19 mmol) of lithium
bis-trifluoromethanesulphonamide (LiNTf.sub.2) in solution in 3 ml
of water is added to this solution. The reaction mixture is stirred
for 2 hours at ambient temperature before extracting our product
with 20 ml of methylene chloride. After evaporation of the latter,
a white solid is obtained which is dried under vacuum.
White solid Yield=90% M.p.=86-88.degree. C.
[0389] .sup.1HNMR (200 MHz, Acetone D.sub.6): 2.64-2.83 (m, 2H);
3.59 (s, 9H); 3.96-4.06 (m, 2H); 4.71 (t, 2H, J=6.76 Hz); 7.90 (d,
2H, J=8.9 Hz); 8.19 (dd, 2H, J=8.9 Hz).
[0390] .sup.13C NMR (50 MHz, Acetone D.sub.6): 23.96; 54.24 (t,
J.sub.C--N=4.2 Hz); 63.09; 65.35 (t, J.sub.C--N=4.0 Hz); 121.46 (q,
J.sub.C--F=322.0 Hz); 128.95; 130.42; 132.58; 133.12; 166.34.
[0391] Mass spectrometry (FAB) for
C.sub.15H.sub.19F.sub.6N.sub.2O.sub.6S.sub.2
[0392] Theoretical mass calculated for (2C.sup.+, A): 880.03713
[0393] Mass found: 880.0375
*8c:
[0394] 0.5 ml (5.7 mmol) of 60% HPF.sub.6 in water is added to a
solution of 1 g (2.98 mmol) of (8a) in 3 ml of water. The reaction
mixture is left under stirring for two hours at ambient temperature
in order for the exchange to be complete. The white solid obtained
after filtration is washed with water then twice with 30 ml of
ether and finally dried under vacuum.
White solid Yield=96% M.P.=154-156.degree. C.
[0395] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.45-2.59 (m, 2H);
3.40 (s, 9H); 3.79-3.85 (m, 2H); 4.50 (t, 2H, J=5.96 Hz), 7.55 (dd,
2H, J.sub.1=1.91 Hz, J.sub.2=7.73 Hz); 8.00 (dd, 2H, J.sub.1=1.91
Hz, J.sub.2=7.74 Hz)
[0396] .sup.13C NMR (50 MHz, Acetone D.sub.6): 22.96; 53.23 (t,
J=4.01 Hz); 62.31; 64.34; 128.06; 129.48; 131.79; 132.25;
165.63
[0397] .sup.19F NMR (282 MHz, Acetone D.sub.6): -71.6 (d, J=707.3
Hz; P--F)
[0398] .sup.31P NMR (Acetone, 121.5 Mhz) .delta.: -142 (m, J=0.7
Hz, P--F.sub.6)
[0399] Mass spectrometry (FAB) for
C.sub.15H.sub.19F.sub.6NO.sub.2P
[0400] Theoretical mass calculated for (2C.sup.+, A.sup.-):
747.0822
[0401] Mass found: 747.0824
*8d:
[0402] 1 ml of HBF.sub.4 in 40% solution in water is added to a
solution of 1 g (2.98 mmol) of (8a) in 3 ml of water. After the
addition of the latter, the formation of a white solid is observed.
The reaction mixture is left under stirring for two hours at
ambient temperature. The white solid obtained after filtration is
washed with water (in order to eliminate the excess of HBF.sub.4)
then twice with 30 ml of ether and finally dried under vacuum.
White solid Yield=98% Mip.=154-156.degree. C.
[0403] .sup.1H NMR (200 MHz, Acetone D.sub.6): 2.39-2.57 (m, 2H);
3.35 (s, 9H); 3.70-3.87 (m, 2H); 4.50 (t, 2H, J=5.91 Hz); 7.73 (dd,
2H, J.sub.1=1.97 Hz, J.sub.2=6.77 Hz); 8.02 (dd, 2H, J.sub.1=1.77
Hz, J.sub.2=6.47 Hz)
[0404] .sup.13C NMR (50 MHz, Acetone D.sub.6): 22.96; 53.14 (4.1
Hz); 62.35; 64.29; 128.01; 129.52; 131.85; 132.24; 165.61.
[0405] .sup.19F NMR (282 MHz, Acetone D.sub.6): -150.16 (s,
B--F)
[0406] Mass spectrometry (FAB) for
C.sub.15H.sub.19F.sub.4NO.sub.2B
[0407] Theoretical mass calculated for (2C.sup.+, A.sup.-):
689.1214
[0408] Mass found: 689.1211
D/Boratrane 9:
[0409] 1/Grafting on the Cation: TABLE-US-00011 (9) ##STR63## 9a
X.sub.2 = NTf.sub.2 9b X.sub.2 = BF.sub.4 9c X.sub.2 = PF.sub.6
[0410] 2 g of (5a to 5c) and a magnetic stirrer are introduced into
a 150-mL single-necked flask. The flask is placed under high vacuum
for approximately 3 hours at a temperature of 50.degree. C. The
flask is then place under argon, and approximately 2.8 ml of
isopropanol is added in order to solubilize the salt. 1 g of
phenylboronic acid is dissolved in 60 mL of chloroform in another
flask and under argon. Then this solution is added to the first.
And finally, 43 mL of anhydrous ether is added and stirring is
maintained for 18 hours at ambient temperature.
[0411] The medium becomes biphasic, the upper phase is eliminated
and the white paste is washed 3 times with 20 ml of anhydrous
ether.
*9a:
Light Yellow Viscous Oil.
[0412] .sup.1H NMR (200 MHz, Acetone D.sub.6): 1.40-2.20 (m, 6H);
3.30 (s, 9H); 3.35-3.70 (m, 6H); 3.95-4.10 (m, 6H); 7.25-7.5 (m,
3H); 7.70-7.90 (m, 2H)
[0413] .sup.13C NMR (50 MHz, Acetone D.sub.6): 24.14; 26.58; 30.24;
56.7; 57.05; 60.7; 64.04; 66.8; 67.3; 67.8; 128.97; 135.45
[0414] .sup.11B NMR spectrum (96.25 MHz, Acetone): 13.06
*9b:
White Paste
[0415] .sup.1H NMR (200 MHz, Acetone. D.sub.6): 1.42-2.25 (m, 6H);
3.01 (s, 9H); 3.29-3.62 (m, 6H); 3.95-4.1 (m, 6H); 7.23-7.58 (m,
3H); 7.70-7.91 (m, 2H)
[0416] .sup.11B NMR (96.25 MHz, Acetone): 29.96 (60%); 4.40
(40%)
*9c:
White Paste
[0417] .sup.1H NMR (200 MHz, Acetone): 1.40-2.21 (m, 6H); 3.16 (s,
9H); 3.34-3.73 (m, 6H); 3.91-4.12 (m, 6H); 7.25-7.51 (m, 3H);
7.72-7.89 (m, 2H)
2/Grafting on the Anion:
[0418] a- Quaternization by a Hydroxyl ##STR64##
[0419] 0.1 g (0.38 mmol) of tetrabutylammonium hydroxide is
dissolved in 0.6 g of N,N',N''-trimethylbutylammonium
bis-trifluoromethanesulphonamide as matrix in a 5-ml flask. 47 mg
(0.38 mmol) of phenylboronic acid and finally 0.5 mL of THF
(anhydrous) are added to this solution. The solution is left under
stirring for 2 hours at ambient temperature. Then the THF is
evaporated to dryness and the solution is dried under vacuum.
Tinted Viscous Oil.
[0420] .sup.1H NMR (200 MHz, Acetone D.sub.6): 0.9-1.05 (m, 12H);
1.21-1.52 (m, 8H); 1.5-1.8 (m, 8H); 3.0 (broad singlet, 8H);
6.90-7.30 (m, 3H); 7.60-7.70 (m, 2H).
[0421] .sup.13C NMR (50 MHz, Acetone D.sub.6): 14.21; 20.50; 24.78;
25.75; 26.56; 53.78; 59.67; 67.45; 68.56; 127.94; 134.60
[0422] .sup.17B NMR spectrum (96.25 MHz, Acetone): 3.97 b-
Quaternization by the Fluoride: ##STR65##
[0423] 0.1 g (2.1 mmol) of anhydrous tetramethylammoniun fluoride
is introduced into a 10-mL single-necked flask, then 1 mL of THF
(anhydrous) is added and the solution is homogenized while heating
if necessary. Finally, 0.13 g of phenylboronic acid (2.1 mmol) is
introduced. Stirring is maintained for approximately 2 hours at
ambient temperature.
[0424] After stirring for 2 hours, anhydrous ether is added for
better crystallization and the solid is filtered on sintered glass.
The solid is washed 2 to 3 times with 20 ml of ether. And finally,
the solid is placed under vacuum in order to dry it.
White solid Yield=82% M.p.=162-164.degree. C.
[0425] .sup.1H NMR (200 MHz, Acetone D.sub.6): 3.15 (s, 12H);
6.8-7.4 (m, 3H); 7.50-7.70 (m, 2H)
[0426] .sup.13C NMR (50 MHz, Acetone D.sub.6): 56.19 (t,
J.sub.C--N=3.97 Hz); 127.47; 128.36; 130.91; 132.98; 135.96.
[0427] .sup.19F NMR spectrum (282 MHz, Acetone D.sub.6): -136.40
(multiplet).
[0428] .sup.11B NMR spectrum (96.25 MHz, Acetone D.sub.6): 4.66 (D,
J.sub.B--F=27.2 Hz)(56%); 28.5 (44%).
E/Synthesis of the Supported Triethylamine (STEA)(12):
[0429] 3 g (6.1 mmol) of (3b), 12 mL of ethanol and 13 g (18 mmol)
of diethylamine are introduced into a single-necked flask. A
condenser is fitted and the reaction mixture is then taken to
reflux for approximately 14 hours. After which, the ethanol and the
excess diethylamine are evaporated off. The oil obtained is
dissolved in dichloromethane and the solution is washed with twice
5 mL of diluted K.sub.2CO.sub.3. The organic phase is separated,
dried over MgSO.sub.4 and the solvent evaporated to dryness.
Orange Viscous Oil Yield=83%
[0430] .sup.1H NMR spectrum (200 MHz, Acetone D.sub.6): 1.05 (t,
J=7.1 Hz, 2H); 1.40-1.70 (m, 2H); 1.90-2.10 (m, 4H); 2.50-2.70 (m,
6H); 3.35 (s, 9H); 3.50-3.70 (m, 2H).
[0431] .sup.13C NMR spectrum (50 MHz, Acetone): 12.34; 23.813;
25.08; 27.48; 48.140; 53.543; 54.04 (t, J.sub.C--N=4.02 Hz); 67.93;
124.594 (q, J=319.9 Hz)
EXAMPLES
[0432] The different functionalized salts used were prepared
according to the procedures described in the literature.
[0433] In order to illustrate this principle, we chose to
support:
[0434] an acryl ester via an ammonium salt the preparation of which
is described in the diagram below; this salt was then involved in
three examples of reactions of great interest in organic chemistry;
##STR66##
[0435] an acryl ester substituted by a halogen prepared according
to the reaction diagram below, which was tested in two examples of
coupling reactions; ##STR67##
[0436] an arylboronic acid ester in the form of boratrane
(functionalization of the cationic part) or in the form of borate
(functionalization of the anionic part of the functionalized
salt).
[0437] The synthesis of functionalized salts and of ionic
substrates is described in detail in the experimental part which
follows.
Example 1
Heck Reaction
[0438] The formation of carbon-carbon bonds is a fundamental
operation in organic chemistry. Among the large number of possible
reactions, the methods using organometallic catalysts are extremely
important. In particular, we used the principle of the invention of
organic synthesis supported on ionic liquid (OSSIL) in the coupling
of alkenes catalyzed by palladium with aryl iodides of known by the
name of Heck coupling.
[0439] This reaction has been the subject of several works using
ionic liquids as solvents (Abbott et al., 2002; Murphy et al.,
2000; Fraga-Dubreuil et al., 2001; Visser et al., 2002; Visser et
al., 2001). In 1999, Xiao J. et al., have shown the possibility of
the recycling of the catalytic system and the effect of the anion
on the kinetics and the selectivity of the reaction (Jeffery et
al., 1996; Howarth et al., 2000; Bayer et al., 1991).
[0440] In this example acryl ester and an acryl ester substituted
by an iodine atom are separately used as substrates.
[0441] 1--Acryl Ester:
[0442] The acrylate (6) was involved in Heck in the presence of
palladium acetate as catalyst, potassium bicarbonate as base and an
aryl iodide in large excess as reagent (see diagram hereafter).
##STR68##
[0443] All the coupling reactions were carried out at 80.degree. C.
with A.sub.1.sup.+X.sub.1.sup.-.dbd.Me.sub.3N.sup.+Bu,
.sup.-NTf.sub.2 as liquid matrix. The monitoring of the reactions
was carried out by proton NMR at 200 MHz and FIG. 1 shows the
example of the reaction of the salt 6
(X.sub.2.sup.-.dbd.NTf.sub.2.sup.-) in solution in
trimethylbutylammonium triflimide with 1-iodonaphthalene (test 10
in Table I below).
[0444] According to FIG. 1, it is noted that it is possible and
simple to monitor the reaction by .sup.1H NMR. In fact, the total
disappearance of signals between 5.9 and 6.5 ppm is noted
corresponding to the three protons of the double bond of the
substrate 6, and the appearance of signals of the double bond of
the product resulting from the Heck coupling 12.
[0445] This type of monitoring is impossible in the case of the use
of an insoluble solid support and less evident in the case of the
soluble support (PEG) described in the literature due to broad NMR
signals.
[0446] The results obtained for a reaction time of 2 hours at
80.degree. C. are collected in Table I below: TABLE-US-00012 TABLE
I Solvent or ionic Conversion E/Z.sup.iii test Ar X.sup.i
matrix.sup.i (%).sup.ii Ratio 1 ##STR69## -- CH.sub.3CN 26 >98/2
2 ##STR70## NTf.sub.2 CH.sub.3CN 70 88/12 3 ##STR71## BF.sub.4
##STR72## 75 84/16 4 ##STR73## NTf.sub.2 ##STR74## 100 >99/1 5
##STR75## NTf.sub.2 ##STR76## 100 >99/1 6 ##STR77## NTf.sub.2
##STR78## 100 >99/1 7 ##STR79## NTf.sub.2 ##STR80## 100 >99/1
8 ##STR81## NTF.sub.2 ##STR82## 100 >99/1 9 ##STR83## NTF.sub.2
##STR84## 100 >99/1 10 ##STR85## NTF.sub.2 ##STR86## 100
>99/1 11 ##STR87## NTF.sub.2 ##STR88## 100 >99/1 12 ##STR89##
NTF.sub.2 ##STR90## 100 >99/1 13 ##STR91## NTF.sub.2 ##STR92##
100 >99/1 .sup.iNTf.sub.2 = N(SO.sub.2CF.sub.3).sub.2
.sup.iidetermined by NMR .sup.iiidetermined by NMR and confirmed by
GC.
[0447] The results of the table above show that the use of the
supported substrate makes it possible to have a better reactivity
in comparison with the use of a standard substrate (compare tests 1
and 2).
[0448] The use of the ionic liquid as solvent has distinctly
increased the reaction speed and made it possible to have a better
stereoselectivity compared with acetonitrile which is often used as
solvent for this reaction (tests 2 and 4).
[0449] A direct relationship is noted between the
reactivity/selectivity and the nature of the anion of the supported
substrate (tests 4 and 5).
[0450] The nature of the reagent seems to have no influence on the
reaction.
[0451] In the last stage for this example, the product is released
from the support by transesterification with an alcohol (Diagram
below), and the possibility of adapting this methodology to the
combinatorial technique was tested. ##STR93##
[0452] Thus, transesterification was carried out with different
alcohols on a mixture of the products 12a to 12i isolated during
the last stage, according to the procedure below. The alcohols used
are methanol, ethanol, propanol and butanol.
[0453] Procedure:
[0454] Four synthetic mixtures constituted by 100 mg from each of
the tests: 5, 6, 7, 8, 9, 10, 11, 12, 13 (Table I) are dissolved in
5 ml of methanol, ethanol, propanol and butanol respectively. 5
drops of concentrated hydrochloric acid (12N) are then added to
each solution following by taking to reflux for 12 hours. The
monitoring of the reaction is carried out by .sup.1H NMR where a
difference is observed in the chemical shifts between the protons
of the salts with a dedicated task 12 and 1, as represented
hereafter: ##STR94##
[0455] After 12 hours, each solution is evaporated to dryness and
the different mixtures are separately extracted with 3 times 15 ml
of diethyl ether. The products extracted are then analyzed in
MS-GPC, and the chromatograms corresponding to each mixture are
presented below.
[0456] In the chromatograms represented in FIGS. 2 to 5, the 36
expected-products are found (13a to 13i; 14a to 14i; 15a to 15i;
16a to 16i). This validates the OSSIL principle and demonstrates
its applicability to combinatorial synthesis.
[0457] Compounds 13a to 13i corresponds to the product of formula
##STR95## in which R is a methyl group.
[0458] Table II below shows these 9 methyl esters, indicating for
each the meaning of Ar. This table corresponds to the chromatogram
of FIG. 2. TABLE-US-00013 TABLE II Retention time (min) Mass found
13 Ar 12.50 180 13a ##STR96## 12.55 162 13b ##STR97## 13.22 13.38
13.47 176 13c 13d 13e ##STR98## 14.69 240 13f ##STR99## 14.80 192
13g ##STR100## 15.47 207 13h ##STR101## 17.91 212 13i
##STR102##
[0459] Compounds 14a to 14i correspond to the product of formula
##STR103## in which R is an ethyl group.
[0460] Table III below shows these 9 ethyl esters, indicating for
each the meaning of Ar. This table corresponds to the chromatogram
of FIG. 3. TABLE-US-00014 TABLE III Retention time (min) Mass found
14 Ar 13.136 194 14a ##STR104## 13.196 176 14b ##STR105## 13.800
13.980 14.087 190 14c 14d 14e ##STR106## 15.475 254 14f ##STR107##
15.577 206 14g ##STR108## 16.318 221 14h ##STR109## 19.434 226 14i
##STR110##
[0461] Compounds 15a to 15i correspond to the product of formula
##STR111## in which R is a propyl group. Ar
[0462] Table IV below shows these 9 propyl esters, indicating for
each the meaning of Ar. This table corresponds to the chromatogram
of FIG. 4. TABLE-US-00015 TABLE IV Retention time (min) Mass found
15 Ar 13.902 208 15a ##STR112## 13.992 1190 15b ##STR113## 14.608
14.859 14.973 204 15c 15d 15e ##STR114## 16.731 270 15f ##STR115##
16.905 120 15g ##STR116## 17.814 234 15h ##STR117## 22.264 240 15i
##STR118##
[0463] Compounds 16a to 16i correspond to the product of formula
##STR119## in which R is a butyl group.
[0464] Table V below shows these 9 butyl esters, indicating for
each the meaning of Ar. This table corresponds to the chromatogram
of FIG. 5. TABLE-US-00016 TABLE V Retention time (min) Mass found
16 Ar 14.752 222 16a ##STR120## 14.853 204 16b ##STR121## 15.625
15.930 116.109 218 16c 16d 16e ##STR122## 18.544 284 16f ##STR123##
18.783 234 16g ##STR124## 19.931 249 16h ##STR125## 26.390 254 16i
##STR126##
[0465] 2--Iodo-arylic ester:
[0466] The second example of functionalized salt which was tested
in the Heck reaction is an aryl iodide supported on (TMHPA,
NTf.sub.2) (1) according to the following diagram: ##STR127##
[0467] During this example, we took to 80.degree. C. for 3 hours a
mixture constituted:
[0468] by a solution of 0.85% molar of the salt 7 dissolved in
trimethylbutylammonium trifluoromethanesulphonamide (TMBA,
NTf.sub.2) as matrix,
[0469] tertbutyl acrylate as alkene,
[0470] palladium acetate as catalyst
[0471] solid K.sub.2CO.sub.3 as base
[0472] The reaction corresponds to the following diagram:
##STR128##
[0473] The monitoring of the reaction is carried out by .sup.1H and
.sup.13C NMR and FIG. 6 illustrates and confirms the simplicity of
monitoring by this analysis technique, a more difficult matter in
the case of the solid or soluble supports described in the
literature.
[0474] 3--Test on 6 Grams (15 mmol) of Functionalized Salt 6a.
[0475] All the coupling tests were carried out on very small
quantities. For the purpose of showing that the OSSIL principle can
be extrapolated to the gram scale or even to large quantities
("large scale"), we tested the Heck coupling reaction on 6 g (15
mmol) of acryl ester (6a), under the same operating conditions as
those described in the first part of this example, using
iodobenzene as substrate (5 eq), butylmethyl imidazolium
hexafluorophosphate [BMIM][PF.sub.6] as matrix (11 g), and
palladium acetate as catalyst (25 mg). After 3 hours, the proton
spectrum NMR shows that the reaction is complete.
[0476] After washing with ether in order to eliminate the excess of
iodobenzene, transesterification by methanol was carried out.
[0477] The yield of pure isolated product is 86%.
[0478] The first recycling of the functionalized salt leads to a
yield of 88%.
Example 2
Diels-Alder Reaction
[0479] The richness and the potential of the Diels-Alder reaction
have encouraged chemists to research methods making it possible to
increase on the one hand speed and yield, on the other hand regio-
and stereoselectivity. Recently, works using ionic liquids as
solvent have shown the influence of their polarity on the endo/exo
ratio (Xiao et al., 2000). This reaction is the second example
chosen in order to show the benefit of the strategy of organic
synthesis supported on OSSIL ionic liquid.
[0480] The Diels-Alder reaction between a dienophile 6 and
cyclopentadiene was therefore studied. The diagram hereafter
represents the different stages. ##STR129##
[0481] Procedure:
[0482] A solution of (6) and 10 equivalents of cyclopentadiene, in
a solvent or in an ionic matrix, is stirred for two hours at
ambient temperature. The excess of the reagent is then eliminated
under vacuum and the reaction product thus obtained is put into
solution in methanol, ethanol or butanol in the presence of five
drops of 12 N hydrochloric acid.
[0483] After twelve hours under reflux, transesterification is
complete and the product is then extracted with pentane. The
results obtained are shown in Table VI below: TABLE-US-00017 TABLE
VI Conv. Endo/ Solvent or rate exo test N X.sub.2 Liquid matrix R
(%) % 1 4 NTf.sub.2 ##STR130## Me 85 80/20 2 1 NTf.sub.2 ##STR131##
Me 94 81/19 3 1 NTf.sub.2 Without solvent.sup.i Me 96 83/17 4 1
NTf.sub.2 CH.sub.2Cl.sub.2 Me 86 80/20 5 1 NTf.sub.2 ##STR132## Me
93 80/20 6 1 NTf.sub.2 ##STR133## Me 95 82/18 7 1 NTf.sub.2 '' Et
89 82/18 8 1 NTf.sub.2 '' Pr 97 81/19 9 1 Cl '' Me 95 78/22 10 1
BF.sub.4 '' Me 92 80/20 .sup.i2, .sup.-N(SO.sub.2CF.sub.3).sub.2 is
liquid at ambient temperature.
[0484] The results of this table show that the length of the alkyl
chain of the L arm influences the reaction speed. In fact, by
increasing the chain by 3 carbon atoms, the reaction speed is
reduced without inhibiting it (compare tests 1 and 2). Conversely,
no influence on reactivity and selectivity is observed for the
different ionic matrices and anions of the support (tests 5 to
10).
[0485] The regiospecificity of this reaction is comparable to that
observed in the case of the non-supported substrate, i.e. methyl
acrylate.
[0486] Finally, we tested the possibility of recycling the ionic
support solution, in two different cases. The results that we
obtained are shown in Table VII which follows: TABLE-US-00018 TABLE
VII test X.sub.2 Liquid matrix Yield of 2 stages 1.sup.st reaction
NTf.sub.2 ##STR134## 78 1.sup.st recycling NTf.sub.2 ##STR135## 75
2.sup.nd NTf.sub.2 ##STR136## 77 3.sup.rd NTf.sub.2 ##STR137## 81
1.sup.st reaction Cl ##STR138## 83 1.sup.st recycling Cl ##STR139##
80 2.sup.nd Cl ##STR140## 85
[0487] Whatever the nature of the anion the yields of isolated
product 18 are identical as well as the percentage of the two
isomers. It should also be noted that in the second case (6b),
after three recycling processes, more than 85% of the
functionalized salt 1a is isolated from the matrix by simple
filtration after precipitation in acetone. This recovery operation
of the functionalized salt can prove useful for the recycling of
the matrix and of the functionalized salt.
Example 3
Baylis-Hillman Reaction
[0488] The third example used in order to validate the OSSIL
principle is the Baylis-Hillman reaction, which consists of the
condensation of an aldehyde on the double bond of the acrylic
substrate 6 in the presence of 3-hydroxyquinuclidine (see diagram
hereafter). ##STR141##
[0489] General Procedure:
[0490] A mixture of 2 mmol of 6 and 10 mmoles of aldehyde in a
solvent or an ionic matrix is stirred at ambient temperature in the
presence of 2 mmoles of 3-nuclidine hydroxyquinuclidine as
base.
[0491] After 24 hours, washing in ether is carried out in order to
eliminate the excess reagent and the conversion rate is determined
by NMR. The results are shown in Table VIII which follows.
TABLE-US-00019 TABLE VIII % Solvent or Yield test Ar liquid matrix
in 19.sup.i 9 ##STR142## C.sub.2H.sub.5OH 40 1 ##STR143##
##STR144## 45 2 ##STR145## ##STR146## 42 3 ##STR147## ##STR148## 65
4 ##STR149## ##STR150## 75 5 ##STR151## ##STR152## 64 6 ##STR153##
'' 60 7 ##STR154## '' 75 8.sup.ii ##STR155## ##STR156## 39 10
##STR157## ##STR158## 50 11 ##STR159## ##STR160## 46 12 ##STR161##
##STR162## 60 13 ##STR163## ##STR164## 71 14 ##STR165## ##STR166##
55 15 ##STR167## ##STR168## 25 .sup.iyield of isolated product
after transesterification. .sup.iitest with methyl acrylate as
substrate.
[0492] Better reactivity of the ionic substrate 6 is noted compared
with the results achieved with methyl acrylate as substrate in an
ionic liquid as solvent (compare tests 8 and 10). The nature of the
latter distinctly influences the reaction speed. In fact, the use
of an ionic matrix carrying an alcohol function increases
reactivity (compare tests 10, 11 and 12, 13).
[0493] The influence of the nature of the reagent on yields is very
considerable, it is comparable to that described in works related
to the non-supported substrates or during the use of the solid
supports. It should however be noted that the yields which we
obtained are distinctly better compared with the latter.
Example 4
Suzuki Coupling
[0494] Another example where we applied the OSSIL principle is the
Suzuki coupling reaction which consists of the coupling of an aryl
halide and an aryl boronic acid.
[0495] This study was carried out according to two distinct
approaches:
[0496] 1--using a supported aryl halide;
[0497] 2--using a supported boronic acid.
[0498] A--Supported Aryl Halide:
[0499] In this study 3-iodobenzoic acid and 4-bromobenzoic acid
were used as supported aryl halide. In a first phase and in order
to develop the optimal conditions, the influence of the different
parameters on the coupling reaction was studied. The effect of the
ionic matrix, the temperature and the counter-ion of the ionic
support was therefore studied.
[0500] These different studies were carried out using phenylboronic
acid and palladium acetate as catalyst, according to the following
reaction diagram: ##STR169##
[0501] 1--Effect of the Matrix:
[0502] The coupling reaction was carried out with
N,N,N-trimethylpropylammonium 4-bromobenzoate bis-trifluoromethane
sulphonamide and solid K.sub.2CO.sub.3 or K.sub.2CO.sub.3 in
aqueous solution as base. The results obtained after 18 hours of
stirring at ambient temperature are shown in the following Table
IX: TABLE-US-00020 TABLE IX Conversion rate Ar--Ar' Ar--Ar
(homocoupling) test Matrix (%) (%) (%) 1 ##STR170## 45.5 34.9 10.6
2 ##STR171## 76.5 64.9 10.6 3 ##STR172## 62.3 51.6 10.7 4
##STR173## 20 < to 2% 2.2 5 ##STR174## 20.7 < to 2% 4.73 6
##STR175## 30.2 19.7 10.56 7 ##STR176## 50.7 47.9 3.3 8 ##STR177##
73 62.4 8.45
[0503] Examination of the preceding table shows that the use of the
matrices with the bis-trifluromethanesulphonamide (NTf.sub.2) anion
makes it possible to observe better reactivity compared with the
use of hexafluorophosphate (PF.sub.6) as anion (compare tests 3 and
4). Similarly, in the case of the matrices composed of ammonium and
phosphonium cations, reactivity is distinctly better than that
observed in the case of the imidazolium cations (compare tests 2, 8
and 3, 4, 5).
[0504] It should however be noted that the presence of an alcohol
function on the ionic matrix also makes it possible both to improve
the conversion rate from 45 to 76% and to reduce the level of the
homocoupling product from 10 to 1% (compare tests 1 and 2).
[0505] Finally, this preliminary study shows that the nature of the
ionic matrix influences reactivity. Thorough study allows the
choice of an appropriate matrix.
[0506] 2--Effect of the Support Anion, the Temperature and the
Base:
[0507] In this part, we are interested in studying the influence of
a few parameters on the reactivity of substrates supported on an
ionic support. All things being equal besides, the temperature, the
base and/or the medium were varied.
[0508] The different tests carried out are shown in the following
Table X: TABLE-US-00021 TABLE X Solvent or Conv. rate Ar--Ar'
Ar--Ar test X.sub.2 T (.degree. C.) base liquid matrix.sup.ii (%)
(%) (%).sup.i 1 NTf.sub.2 20 K.sub.2CO.sub.3(s) ##STR178## 28.0
20.6 7.4 2 PF.sub.6 20 K.sub.2CO.sub.3(s) ##STR179## 100 91.6 8.4 3
BF.sub.4 20 K.sub.2CO.sub.3(s) ##STR180## 100 99.0 0.1 4 Cl 20
K.sub.2CO.sub.3(s) ##STR181## 23.4 16.2 7.1 5 NTf.sub.2 20
K.sub.2CO.sub.3(l) ##STR182## 65.0 55.1 9.8 6 NTf.sub.2 20 NaOAc(s)
##STR183## 30.1 25.4 4.6 7 NTf.sub.2 20 TEA.sup.ii ##STR184## 63.0
56.1 6.9 8 NTf.sub.2 20 TEAS.sup.iv ##STR185## 59.3 50.5 8.9 11
NTf.sub.2 80 K.sub.2CO.sub.3(s) ##STR186## 40.6 26.5 14.1
.sup.iHomocoupling product. .sup.iithe functionalized salt is used
pure and serves as ionic matrix. .sup.iiiTEA: triethylamine.
.sup.ivTEAS: tertiary amine of formula:
Me.sub.3N.sup.+(CH.sub.2).sub.2CH.sub.2NEt.sub.2,
NTf.sub.2.sup.-
[0509] During this study N,N',N''-trimethyl-3-hydroxypropylammonium
bis-trifluoromethanesulphonamide was used as matrix. In contrast,
in the case of the use of DMF as solvent, the ionic support is used
pure, i.e. the salt functionalized by the 4-bromobenzoate group is
dissolved in pure DMF. During this study in addition to the
standard bases, triethylamine supported on a salt (TEAS) was used,
which was synthesized by simple condensation of diethylamine on the
salt (3c) according to the following reaction diagram:
##STR187##
[0510] In order to have a conclusive comparative study the reaction
time was reduced to 10 hours in the tests carried out at ambient
temperature (tests 1 to 8), and to 5 hours for those taken to
80.degree. C. (test 11).
[0511] Tests 1 to 4 show that the reactivity of the functionalized
salts (ionic supports) the anion of which is tetrafluoroborate or
hexafluorophosphate is much greater than that observed with a
chloride or bis-trifluoromethanesulphonamide anion. The fact that
all the ionic supports are dissolved in the same matrix proves
that, from the point of view of the mechanism, it is the ionic part
of the support which is probably involved at the level of the
palladium. This observed reactivity is moreover accompanied by a
very great selectivity in the case of the tetrafluoroborate
anion.
[0512] In addition to the results already observed during the study
of the effect of the matrix, tests 1 to 4 show that the mixture of
salts carrying different cations or anions do not at all reduce
either the reactivity or the selectivity, which offers a wide
choice and makes it possible to reduce the cost of the cations and
of anions which is sometimes considerable: a chloride costs perhaps
50 times less, for example, than a triflimide.
[0513] It is also noted that the presence of water in the medium
distinctly increases the reaction speed. In fact, the conversion
rate passes from 28 to 64% in the presence of solid K.sub.2CO.sub.3
and of a solution of K.sub.2CO.sub.3 in water (tests 1 and 5)
respectively, which can be explained by better homogeneity of the
medium in the presence of water. Similarly, the use of
triethylamine as base makes it possible to observe a reactivity
comparable to that in the presence of water (compare tests 5 and
7). The grafting of the latter on an ionic support does not
influence its reactivity too much. In fact, the result obtained
during test 8 is comparable to that of test 7, whether in terms of
reactivity or in terms of selectivity. This represents a major
result, knowing that recycling of this form of base is easy. In
fact, a simple washing with a basic solution makes it possible to
regenerate the TEAS, which will therefore simultaneously reduce the
cost and harmful waste.
[0514] 3--Application in Combinatorial Chemistry:
[0515] This library of biaryl esters was prepared by operating as
in the case of Example 1.
[0516] In a first phase we carried out a series of coupling
reactions in parallel with 9 arylboronic acids and supported
4-bromobenzoic acid. Then, the 9 reactions were mixed in order to
form a homogeneous solution, which was then divided into three
equal portions, after which each of the solutions was solubilized
in an alcohol. Then a few drops of concentrated hydrochloric acid
(12 N) were added and the alcohol was taken to reflux for 18 hours.
After evaporation of the alcohol, the mixture of the biarylesters
was extracted with ether. 3 series of 9 esters were therefore
obtained which were then analyzed by GC/MS. The different expected
biarylesters were all identified without ambiguity.
[0517] All the results are represented in the form of tables below.
A chromatogram corresponding to the mixture of the biaryl propyl
esters is represented below.
[0518] 1/Biaryl Propyl Esters:
[0519] Table XI hereafter corresponds to the chromatogram of FIG.
7. TABLE-US-00022 TABLE XI Library of the propyl esters 23
Retention time in minutes R and seconds Molecular mass ##STR188##
26.42; 27.36 270 ##STR189## 28.13 268 ##STR190## 32.29 285
##STR191## 19.28 258 ##STR192## 28.96 265 ##STR193## 22.82 254
##STR194## 19.53 240 ##STR195## 34.52 290
[0520] 2/Biaryl Methyl Esters: TABLE-US-00023 TABLE XII Library of
the methyl esters R Retention time Molecular mass ##STR196## 21.31;
22.35 242 ##STR197## 23.24 240 ##STR198## 28.58 257 ##STR199##
16.28 230 ##STR200## 24.23 237 ##STR201## 18.25 226 ##STR202##
16.41 212 ##STR203## 27.74 262
[0521] 3/Biaryl Ethyl Esters: TABLE-US-00024 TABLE XIII Library of
the ethyl esters Ar Retention time Molecular mass ##STR204## 23.76;
24.73 256 ##STR205## 25.19 254 ##STR206## 28.72 271 ##STR207##
17.33 244 ##STR208## 25.95 251 ##STR209## 19.82 240 ##STR210##
17.50 226 ##STR211## 30.12 276
B--Supported Aryl Halide:
[0522] In a second phase, an attempt was made to graft an
arylboronic acid on a salt in order to involve it in a Suzuki
coupling reaction. This study can be carried out according to two
different approaches:
[0523] the first one is to support an arylboronic acid on the
cation of the salt functionalized by diethanolamine in order to
form boratranes (see below): ##STR212##
[0524] the second one is to support it by means of the anion of the
functionalized salt. In fact, if the X.sub.2.sup.- anion of the
functionalized salt serving as support is nucleophilic enough, it
will react with phenylboronic acid, quaternizing the boron atom in
order to produce a borate: ##STR213##
[0525] I--Functionalized Cation Salt:
[0526] 1) Synthesis of the Functionalized Salts:
[0527] The functionalized salts were synthesized according to the
following reaction diagram: ##STR214##
[0528] The condensation reaction of trimethylamine on an alkyl
dibromide is carried out under anhydrous conditions with very good
yields (>95%). The ammonium bromide thus obtained undergoes an
anion-exchange reaction (metathesis) under standard conditions. The
second stage was carried out in the presence of an equivalent of
diethanolamine with a quantitative yield. Similarly, the stage of
grafting of the arylboronic acid was carried out with good yields
and makes it possible to obtain a product in two different forms.
In fact, as a function of the solvent and of the anion of the
support, equilibrium is or is not obtained between the tri- and
tetravalent borons. Thus, if the operation is carried out in THF
and in the presence of a bis-trifluoromethanesulphonamide anion the
equilibrium obtained is 80/20 in favor of the tetravalent boron.
Conversely, the use of an ether, chloroform and isopropanol mixture
exclusively leads to the tetravalent boron (boratrane). Under the
same conditions and in the presence of the tetrafluoroborate anion,
a 60/40 equilibrium is obtained in favor of the trivalent boron,
according to the following diagram: ##STR215##
[0529] It should be noted that the chemical shifts of the boron
obtained depend on the nature of the anion. In fact, in the case of
bis-trifluoromethanesulphonamide the signal of the tetravalent
boron appears at 13.06 ppm. On the other hand, with the
tetrafluoroborate anion it appears at 4 ppm. This shows that the
nature of the counter-ion also influences the nature of the bond
between the nitrogen and boron atoms, and therefore the transfer of
electrons from the nitrogen to the boron.
[0530] Then, the synthesized boratranes were involved in the Suzuki
coupling reaction according to the following reaction diagram:
##STR216## 0.85 M solution in (Me).sub.3N.sup.+Bu,
N.sup.-Tf.sub.2
[0531] A solution of boratrane (0.85 mol/l) in
N,N',N''-trimethylbutylammonium bis-trifluoromethanesulphonamide
serving as matrix is brought into contact with
1-bromo-3-methoxybenzene, in the presence of solid K.sub.2CO.sub.3
as base and palladium acetate as catalyst. The mixture is heated at
80.degree. C. for 18 hours. The results obtained are shown in the
following Table XIV: TABLE-US-00025 TABLE XIV test boratrane
Conversion rate ##STR217## ##STR218## 1 ##STR219## 72% 66.8% 5.1% 2
##STR220## 82% 64.4% 18.0% 3 ##STR221## 54% 32.3% 22.1%
[0532] The preliminary tests which were carried out show that the
supported boronic acids can be subjected to Suzuki coupling. In
contrast, this reaction requires an energy supply, as at ambient
temperature no reaction was observed for the different
substrates.
[0533] On the other hand, at 80.degree. C. as indicated in the
preceding table the reaction takes place and depends on the nature
of the counter-ion of the support. The influence of the latter on
selectivity (test 1 and 2) is also noted. It should however be
pointed out that this reactivity can be influenced by the nature of
the equilibrium existing between the tri- and tetravalent borons,
which can explain the weak reactivity of the boratrane possessing
the tetrafluoroborate as counter-ion compared with that observed in
the case of the presence of an equilibrium displaced towards the
tetravalent boron (case of bis-trifluoromethane sulphonamide).
[0534] II--Functionalized Anion Salt:
[0535] In the preceding case, the cationic part of the salt with a
dedicated task was functionalized in order to support an
arylboronic acid in the form of a boratrane with a tetravalent
boron atom. The latter represents the intermediate species in the
Suzuki coupling reaction. It is also possible to envisage the use
of salts with nucleophilic anions (OH.sup.- and F.sup.-) capable of
quaternizing the boron atom of arylboronic acid in order to produce
borates, derivatives of tetravalent boron, an intermediate in the
Suzuki coupling reaction. The following commercial ammonium salts
were therefore used:
[0536] tetrabutylammonium hydroxide: ##STR222##
[0537] tetramethylammonium fluoride: ##STR223##
[0538] 1) Case of Bu.sub.4N.sup.+OH.sup.-:
[0539] The synthesis of the supported substrate is carried out
according to the following reaction diagram: ##STR224##
[0540] The Bu.sub.4N.sup.+OH.sup.-, dried under vacuum after
evaporation of the water, is solubilized in the TMBA
bis-trifluoromethanesulphonamide serving as matrix in order to
produce a 0.85 mol/l solution. A stoichiometric quantity of
phenylboronic acid in solution in anhydrous THF is added to this
solution at ambient temperature. The monitoring of the reaction by
.sup.11B NMR after evaporation of the THF shows that it is complete
after two hours. A single signal is then observed at 3.97 ppm
corresponding to a borate.
[0541] 2) Case of Me.sub.4N.sup.+F.sup.-:
[0542] In the same manner as in the case of the hydroxide, the
phenylboronic acid is quaternized by Me4N.sup.+F.sup.- according to
the following diagram: ##STR225##
[0543] For this reaction, the salt was solubilized in THF
(anhydrous) at ambient temperature, then phenylboronic acid was
added. After 18 hours of stirring of the mixture at ambient
temperature, the precipitate which forms is filtered then washed
with ether. The yield of isolated product depends on the quantity
of phenylboronic acid used. In fact, in the presence of an excess
of the latter, an 82% yield is obtained. On the other hand a
deficiency causes it to drop to less than 50%. The monitoring of
this reaction is carried out using NMR of the boron and of the
fluorine. Table XV below shows the results obtained: TABLE-US-00026
TABLE XV number of boronic acid test equivalents Yield(%) NMR
Analyses 1 1 eq 65% .sup.11 B NMR Spectrum: (Acetone), .delta. ppm:
B.sub.4 = 4.66 ppm (60%) B.sub.3 = 28.5 ppm (40%) .sup.19F NMR
Spectrum: (Acetone), .delta. ppm: -136.4 ppm 2 0.75 eq 48% .sup.11
B NMR Spectrum: (Acetone), .delta. ppm: B.sub.4 = 4.76 ppm (60%)
B.sub.3 = 28.5 ppm (40%) .sup.19F NMR Spectrum: (Acetone), .delta.
ppm: -136.05 ppm 3 2 eq 82% .sup.11B NMR Spectrum: (Acetone),
.delta. ppm: B.sub.4 = 4.4 ppm (60%) B.sub.3 = 28.5 ppm (40%)
[0544] In the different cases, the NMR of the boron shows the
presence of an equilibrium between the tri- and tetravalent forms
and in favor of the latter (Diagram) ##STR226##
[0545] a/-Suzuki Coupling Reactions with
[TEMA][PhB(OH).sub.2F]:
[0546] The protocol is the same as that used in the preceding part
and is carried out according to the following reaction diagram:
##STR227##
[0547] The reaction was carried out at two distinct temperatures in
order to study the effect of the temperature both on reactivity,
and on selectivity. See Table XVI hereafter: TABLE-US-00027 TABLE
XVI test T.degree. C. Conversion rate in (%) ##STR228## ##STR229##
1 AT 92.4% 86.3% 5.7% 2 80.degree. C. 96% 77.7% 18.3%
[0548] It is noted that the yield obtained at 80.degree. C. is
close to that obtained at ambient temperature. By contrast, the
percentage of homocoupling product is less at ambient temperature
than at 80.degree. C. (tests 1 and 2).
[0549] b-/Coupling Reaction with [TEBA][PhB((OH).sub.3]:
##STR230##
[0550] As in the preceding cases, the same protocol was used and
the best operating conditions were developed in order to be able to
initiate a combinatorial chemistry test.
[0551] For this purpose, the influence of several parameters was
tested, namely temperature and the addition of a solvent such as
DMF.
[0552] The results are shown in the following Table XVII:
TABLE-US-00028 TABLE XVII test Aryl Conversion rate T (.degree. C.)
solvent ##STR231## ##STR232## 1 ##STR233## 51% 40.degree. C.
[TMBA][X.sup.-] 44.2% 6.4% 5 ##STR234## 66% AT [TMBA][X.sup.-]
55.4% 10.2%
Example 5
Use of the Solid [Matrix+Functionalized Salt] Combination at
Ambient Temperature
[0553] In the different examples that we have studied to date, only
ionic matrices which are liquid at ambient temperature have been
used. However, the possibility of using a matrix which is solid at
ambient temperature has been tested and demonstrated.
[0554] In fact, the use of an ionic liquid the melting temperature
of which is higher than ambient, diversifies the choice of matrix
and broadens the scope of the OSSIL principle. Matrices which are
solid at ambient temperature can have a very considerable
additional benefit: the crystallization of the medium simplifies
the recovery of both the excess of reagents and the reaction
products. The choice of the solid matrix can be carried out
according to the following criteria:
[0555] in the absence of standard organic solvent, the melting
point of the functionalized ionic salt/ionic matrix mixture must be
below the reaction temperature,
[0556] in the presence of a standard organic solvent, a matrix with
a dedicated task (ionic matrix+functionalized salt) must preferably
be soluble in the solvent.
[0557] In order to illustrate this example the Heck coupling test
was carried out using a matrix which is solid at ambient
temperature, according to the following diagram: ##STR235##
[0558] In this test the Heck coupling was carried out using
supported aryl iodide as substrate and tert-butyl acrylate as
alkene under the same conditions as those described in the examples
where ionic matrices which are liquid at ambient temperature were
used.
[0559] In this case N-methyl, N'-ethylimidazolium
hexafluorophosphate (EMIM, PF.sub.6) was used as ionic matrix, the
melting point of which is of the order of 56.degree. C.
[0560] Procedure:
[0561] 1 mmol of functionalized ionic salt (7a) is mixed with 1 g
of the ionic matrix and heated to 70.degree. C. in order to obtain
a solution. On cooling down, this homogeneous mixture is solid at
ambient temperature. On reheating and from 65.degree. C., the
medium again becomes liquid and completely homogeneous. The base
and the catalyst are added to this solution like for the different
tests mentioned above, followed by heating to 80.degree. C. After 5
hours the .sup.1H NMR of the mixture shows complete disappearance
of the starting iodide.
[0562] The reaction mixture is cooled down to ambient temperature
and a heterogeneous (solid/liquid) mixture is obtained. Then, ether
is added and the solid is filtered out, then washed again in order
to extract all of the acrylate. The product is then released from
the functionalized salt by transesterification according to the
procedure described in the different examples mentioned above.
After elimination under vacuum of the excess methanol, the cinnamic
ester is isolated by the addition of ether and filtration of the
solid mixture constituted by the functionalized salt and the
starting solid matrix which can be reused.
[0563] In conclusion this test shows that the application of the
OSSIL principle to ionic matrices with a dedicated task, which are
solid at ambient temperature is perfectly possible, and as a result
makes it possible to broaden the choice of the nature of the anion;
Moreover, this system with a mixture which is solid at ambient
temperature opens up new horizons and in addition will make it
possible to easily adapt the OSSIL principle to all the
technologies already developed in the case of solid supports.
[0564] The very wide variety of easily accessible onium salts and
more particularly phosphonium, ammonium, pyridinium and imidazolium
salts will be noted.
Example 6
Sonogashira Coupling
[0565] Another example of coupling where the OSSIL principle was
tested is that of Sonogashira which consists of a coupling of an
aryl halide and a true alkyne.
[0566] This study was carried out supporting 4-iodobenzoic acid on
a salt with a dedicated task. Several tests are carried out for the
purpose of determining the influence of the nature of the anion of
the support and that of the matrix on this coupling reaction (see
diagram below). ##STR236##
[0567] The results shown in Table XIX below were determined by
means of monitoring of the reactions by .sup.1H NMR. TABLE-US-00029
TABLE XIX Time Conv. Input X R matrix (h) (%) Yield (%) 1 OTf Ph
[tmba][NTf.sub.2] 1 75 72 2 NTf.sub.2 Ph [tmba][NTf.sub.2] 1 78 77
3 NTf.sub.2 Ph [bmim][BF.sub.4] 1 70 66 4 NTf.sub.2 Ph
[tmba][NTf.sub.2] 2 100 95 5 NTf.sub.2 CH.sub.3OCH.sub.2
[tmba][NTf.sub.2] 2 92 92 6 NTf.sub.2 CH.sub.3(CH.sub.2).sub.3
[tmba][NTf.sub.2] 2 100 98 7 NTf.sub.2 CH.sub.3(CH.sub.2).sub.4
[tmba][NTf.sub.2] 2 94 90 8 NTf.sub.2 CH.sub.3(CH.sub.2).sub.6
[tmba][NTf.sub.2] 2 93 88 ##STR237##
[0568] The results shown in the table show that the nature of the
anion of the support and of the matrix does not influence the
reaction speed and the yields of isolated product too much. FIG. 11
illustrates the simplicity of the monitoring of the reaction by
proton NMR (Case of R.dbd.Ph).
[0569] The cleavage of the products after coupling was carried out
by two transesterification processes, one by methanol, the other by
ethanol. For this purpose the products of tests 4, 5, 6, 7 and 8
are mixed and reacted according to the "split-and-mix" principle in
the presence of alcohol and a catalytic quantity of hydrochloric
acid. This stage also allows the recycling of the salt with a
dedicated task as well as that of the matrix used for the
reaction.
[0570] After 12 hours the two reactions are complete, the products
are isolated by extraction with ether then injected into GC/MS. In
both cases the four products were detected.
1/Methyl Esters:
[0571] Table XX hereafter corresponds to the chromatogram of FIG.
12. TABLE-US-00030 TABLE XX Library of the methyl esters Retention
time R in minutes Molecular mass ##STR238## 14.57 204 ##STR239##
15.35 216 ##STR240## 16.56 230 ##STR241## 20.53 236 ##STR242##
21.16 258
2/Ethyl Esters:
[0572] The table XXI hereafter corresponds to the chromatogram of
FIG. 13. TABLE-US-00031 TABLE XXI Library of the ethyl esters
Retention time R in minutes Molecular mass ##STR243## 15.24 218
##STR244## 16.18 230 ##STR245## 17.68 244 ##STR246## 22.77 250
##STR247## 23.57 272
Procedure:
[0573] Alkyne (0.64 mmol) and copper iodide (0.8 mg; 0.04 mmol) are
added to a mixture constituted by a 0.85 M solution of
[3-(4-iodobenzoyloxy)-propyl]-trimethylammonium (100 mg; 0.156
mmol) in an ionic liquid (matrix) and triethylamine (0.92 ml),
followed by stirring at ambient temperature for 5 minutes then the
palladium complex PdCl.sub.2(Ph.sub.3P).sub.2 (1.4 mg; 0.02 mmol)
is added. The reaction medium is left under stirring at ambient
temperature for 2 hours. The medium is then washed several times
with ether and dried under vacuum.
Example 7
Multi-Component Reactions (MCRs)
[0574] Multi-component reactions simultaneously bring at least
three reaction partners into contact under experimental conditions
which do not vary over time and allow the creation of several
covalent bonds in a single stage, unlike standard reactions where
two reagents lead to a product by the creation of new bonds. Thus
it is possible to access a highly functionalized molecule from
relatively simple entities in a single stage. Moreover, the MCRs
combine convergence and economy of atoms, two fundamental
principles in organic synthesis which are important for
combinatorial chemistry. Finally it should be pointed out that
these reactions generally take place with a high yield, since they
avoid the succession of stages which, at each step, causes the
yield to drop.
[0575] The best known and most highly developed MCRs are those of
Passerini and Ugi (Ugi, 1976). One of the key elements of these
reactions is an isonitrile, the electronic structure of which,
comprising a doublet and an electron hole, allows the passage of a
formally divalent carbon atom to a tetravalent carbon atom by
adding an electrophile and a nucleophile. The diagram below
presents an example of a Passerini reaction. ##STR248##
[0576] Of course the MCRs were transposed onto solid support, for
example a resin with an amine termination was used in an Ugi-type
reaction in order to produce, after cleavage, a series of
high-purity adducts with yields ranging from average to excellent
(see diagram below) (Lhoel and Nielsen, 1999). ##STR249##
[0577] Although the Ugi and Passerini reactions are the best known
and most highly developed, other MCRs exist, which correspond to
the essential criteria, namely: all the reagents are present from
the start of the reaction and the conditions do not vary during the
latter. Unlike the Ugi and Passerini reactions, these other
reactions are not based on the use of an isonitrile as one of the
central players in the creation of new covalent bonds. These
different types of reactions make it possible to access highly
functionalized varying structures in a single stage.
[0578] The substituted quinolines are useful pharmacophores. Their
synthesis on solid support was carried out by a so-called Doebner
MCR, involving an aniline, an aldehyde and an
.alpha.-dicarbonylated compound (see diagram hereafter) (Gopalsamy
and Pallai, 1997). The quinolines are obtained with a high purity
and very good yields. ##STR250##
[0579] The principle of the present invention was applied within
the framework of Grieco-type MCRs (Grieco and Bahas, 1988). This
example has been the subject of several works described by W.
Armstrong et al. (Kiselyov et al., 1998) on solid support and it
has allowed the preparation of a library of 80 products with yields
ranging from 50 to 93%.
[0580] In order to do this, the aniline 1 was supported and used
with an aldehyde and cyclopentadiene in the presence of
butyltrimethylammoniumtriflimide as matrix in order to produce
tetrahydroquinolines (see diagram hereafter). This example with
three components, consists of a first condensation of the aldehyde
and the aniline in order to produce the imine. The latter then
reacts in what is formally a Diels-Alder reaction with
cyclopentadiene in the presence of a catalytic quantity of
trifluoroacetic acid. ##STR251##
[0581] The monitoring of the different reactions was carried out by
.sup.1H NMR and we observed conversion ranging from 80% to 100%
according to the nature of the aldehyde. Thus, in the presence of
4-nitrobenzaldehyde, the reaction is complete at the end of 30
minutes whereas it is only 75% in the case of
4-methoxy-benzaldehyde (electron-rich aldehyde). FIG. 10
illustrates the case of 4-nitrobenzaldehyde, after washing with
ether in order to eliminate the excess of the two reagents and the
trifluoroacetic acid. This figure also shows that the monitoring of
a reaction which leads to complex compounds is possible and with
remarkable clarity. It should also be noted that
transesterification by methanol leads to very clean products which
are extracted with ether and purified by filtration on silica.
[0582] The different examples carried out and the results obtained
are shown in Table XVIII below. TABLE-US-00032 TABLE XVIII reaction
time conversion rate R matrix (min) (%) H [tmba][NTf.sub.2] 30 100
H [C.sub.3OHtma][NTf.sub.2] 30 100 NO.sub.2 [tmba][NTf.sub.2] 30
100 Cl [tmba][NTf.sub.2] 30 100 Br [tmba][NTf.sub.2] 30 100 OMe
[tmba][NTf.sub.2] 75 82 [tmba] = [Me.sub.3N.sup.+ - Bu]
[C.sub.3OHtma] = [Me.sub.3N.sup.+ - (CH.sub.2).sub.2CH.sub.2OH]
[0583] During this work no effect of the nature of matrix was
observed. On the other hand, the presence of the latter distinctly
influences the reaction speed and allows complete conversion in
less than an hour, whereas, in the case of the works described in
the literature on solid support, this conversion rate is obtained
only after 12 hours.
[0584] Procedure of the Grieco Reaction:
[0585] A 0.85 M solution of
[3-(4-aminobenzoyloxy)-propyl]-trimethylammonium (100 mg; 0.2 mmol)
in an ionic liquid (matrix) is placed under vacuum then under
argon. Aldehyde (0.5 mmol), cyclopentadiene (132 mg, 2 mmol) and
trifluoroacetic acid TFA (20 .mu.l; 0.27 mmol) are added. The
mixture is stirred at ambient temperature. At the end of the
reaction, the medium is washed several times with ether and dried
under vacuum.
[0586] The viscous oil obtained is then dissolved in methanol and
taken to reflux in the presence of 3 drops of concentrated
hydrochloric acid. After 12 hours the product is extracted with
ether (2.times.30 ml) after evaporation of the methanol.
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