Note: Descriptions are shown in the official language in which they were submitted.
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RUTHENIUM METATHESIS CATALYSTS
The present invention relates to new compounds of formula 1, the preparation
thereof,
intermediate products for preparing them and the use of the compounds of
formula 1 as
catalysts in various metathesis reactions
R3
X'Ru_ a
Z
R O / b
I-
R10d c
1
BACKGROUND TO THE INVENTION
Ruthenium complexes of formula A are known from WO 02/14376 A2 and are
described as
active, air-stable and recoverable metathesis catalysts. Catalysts of this
kind which have an
even greater activity than A have also become known (Angew. Chem. 2002, 114,
No. 5, 832-
834; Angew. Chem. 2002, 114, No. 13, 2509-2511; Angew. Chem. 2002, 114, No.
21, 4210-
4212), and are described by the formulae B, C and D.
Mes-N. N-Mes
Mes-N~ N-Mes
/-\ CI.,,, ,
Mes-NON-Mes CIO': - CI'''=Ru_
CIS Mes-NvN-Mes
CL,,, Ru_ Pro \ / -
CI~ Pro _ ~Pr \ / CI.,,.
CI~Ru_ -
iPrO ~ / NOZ
A B C D
The improvement in the activity of B, C and D compared with A is due to steric
and
electronic effects of the substituents at the phenyl nucleus of the isopropoxy-
phenylmethylene
ligand. It has now been found, surprisingly, that a major increase in the
activity of metathesis
catalysts of type A can be achieved by making particular changes to the
aliphatic moiety of
the ether group.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new ruthenium complexes of formula 1 and
their use as
metathesis catalysts,
L R3
R a
XI
Rz O u_ b
d c
R10 0
1
wherein
X and X denote anionic ligands; preferably halogen, particularly preferably Cl
or
Br;
L denotes a neutral ligand;
a, b, c, d independently of one another denote H, -NO2, C1_12-alkyl, C1-12-
alkoxy
or phenyl, while phenyl may optionally be substituted by a group
selected from among C1_6-alkyl and C1_6-alkoxy;
R' denotes C1_12-alkyl, C5_6-cycloalkyl, C7_18-aralkyl, aryl;
R2 denotes H, C1_12-alkyl, C5_6-cycloalkyl, C7_18-aralkyl, aryl;
R3 denotes H, C1_12-alkyl, C2_12-alkenyl, C2_12-alkynyl, aryl.
Preferred compounds are the compounds of formula 1, wherein
X and X' denote halogen;
L denotes a neutral ligand;
a, b, c, d independently of one another denote H, -NO2, C 1.6-alkyl, C 1.6-
alkoxy or
phenyl, while phenyl may optionally be substituted by a group selected
from among C 1-4-alkyl and C 1 4-alkoxy;
R denotes C1_6-alkyl, C5_6-cycloalkyl, C7_11-aralkyl, aryl;
RZ denotes H, C1.6-alkyl, C5_6-cycloalkyl, C7_11-aralkyl, aryl;
R3 denotes H, C1_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, aryl;
particularly preferred compounds being the compounds of formula 1 wherein
X and X' denotes Cl or Br;
L denotes a neutral ligand;
a, b, c, d independently of one another denote H, -NO2, methyl, ethyl, iso-
propyl,
methoxy, or phenyl, while phenyl may optionally be substituted by a
group selected from among methyl and methoxy;
R' denotes methyl, ethyl , n-propyl, iso-propyl, n-butyl, sec-butyl, tert-
butyl, n-heptyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,4-
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dimethylcyclohexyl benzyl, 1-phenylethyl, 2-phenylethyl, phenyl, o-,
m-, p-tolyl and 3,5-dimethylphenyl.
R2 denotes H, methyl, ethyl , n-propyl, iso-propyl, n-butyl, sec-butyl, tert-
butyl, n-heptyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,4-
dimethylcyclohexyl benzyl, 1-phenylethyl, 2-phenylethyl, phenyl, o-,
m-, p-tolyl and 3,5-dimethylphenyl.
R3 denotes H, methyl, ethyl, phenyl .
Particularly preferred compounds among the above-mentioned compounds of
general formula
1 are those wherein R', R2, R3, X, X' and L may have the meanings specified
and
a, b, c denote H; and
d denotes phenyl which may be substituted by a group selected from
among C 1.6-alkyl and C 1.6-alkoxy;
or
a, c, d denote H; and
b denotes -NO2.
particularly preferred among the above-mentioned compounds of general formula
1 are
those wherein R', R2, R3, X, X', a, b, c and d may have the meanings specified
and
L denotes P(R4)3 or a ligand of formula L1, L2, L3 or L4, wherein
R7 R8 . R7 R8 Y Y' R8
1 H
RS NN-R8 R5 NON-R8 RS NON-R8 RS N ,N-R8
L' L2 L3 L4
R4 denotes C1-6-alkyl, cycloalkyl or aryl
R5 and R6 independently of one another denote H, C1.6-alkyl or aryl;
R7 and R8 independently of one another denote H, C1.6-alkyl, C2_6-alkenyl or
aryl;
or
R7 and R8 together form a 3- or 4-membered alkylene bridge; and
Y and Y' denote halogen; preferably Cl or Br.
Most preferred are compounds of general formula 1, wherein
X and X denote Cl;
L denotes L';
a, b, c, d -denote H;
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R' denotes methyl;
R2 denotes methyl;
R3 denotes H;
R5 and R6 denote mesityl;
R7 and R8 denote H.
The new compounds of formula 1 are obtained by reacting preligands of formula
2 with
ruthenium complexes of formula 3
R3
R11R12C- a
R2 0 b R9
Ru4 10
R,O O d c X R
2 L 3
where R3, a, b, c and d have the meanings given for formula 1 and
R1 denotes Ci_12-alkyl, C5-6-cycloalkyl, C7_18-aralkyl, aryl; preferably C1.6-
alkyl, C5-6-cycloalkyl, C7_11-aralkyl, aryl;
R2 denotes H, C1-12-alkyl, C5_6-cycloalkyl, C7_18-aralkyl, aryl; preferably
C1_6-alkyl, C5_6-cycloalkyl, C7.1t-aralkyl, aryl;
R" and R12 independently of one another denote H, C1_6-alkyl, optionally
substituted by one or more halogens, or aryl, optionally substituted by
one or more halogens or C 1.6-alkyl; preferably H, C 1.6-alkyl or aryl; in
particular and
L denotes a neutral ligand; preferably L', L2, L3 or L4;
R9 and R10 independently of one another denote H, C1-6-alkyl, optionally
substituted by one or more halogens, or aryl, optionally substituted by
one or more halogens or C1_6-alkyl; preferably H, C1.6-alkyl or aryl;
with the proviso that R1 and R2 cannot simultaneously represent methyl.
Therefore in another
aspect the invention relates to a compound of formula 2,
R3
R11R12C- a
R2 O b
II dc
RO 0 2
wherein R3, a, b, c and d have the meanings given in claim 1; and
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R1 denotes C1_12-alkyl, C5_6-cycloalkyl, C7_18-aralkyl, aryl;
R2 denotes H, C1_12-alkyl, C5_6-cycloalkyl, C7_18-aralkyl, aryl;
R" and R12 independently of one another denote H, C1.6-alkyl, optionally
substituted by one or more halogens, or aryl, optionally substituted by
one or more halogens or C1_6-alkyl;
with the proviso that R1 and R2 cannot simultaneously represent methyl.
Preferred compounds
are the compounds of formula 2, wherein
R1 denotes C1_6-alkyl, C5_6-cycloalkyl, C7_11-aralkyl, aryl;
R2 denotes H, C1_6-alkyl, C5_6-cycloalkyl, C7_11-aralkyl, aryl;
R11 and R12 independently of one another denote H, C14-alkyl, optionally
substituted by one or more halogens, or aryl, optionally substituted by
one or more halogens or methyl;
with the proviso that R1 and R2 cannot simultaneously represent methyl.
Particularly preferred are the compounds of formula 2 wherein
R1 denotes methyl, cyclohexyl, benzyl, phenyl;
R2 denotes H, methyl, cyclohexyl, benzyl, phenyl;
R11 denotes H;
R12 denotes H or methyl;
with the proviso that R1 and R2 cannot simultaneously represent methyl.
The ligands and complexes shown may occur as pure enantiomers or pairs of
enantiomers.
Within the scope of the invention therefore the pure enantiomers to certain
racemates may
also be present, which may transfer the enantiomerism to a substrate through
the stereocentre
during the catalysis.
In an additional aspect the invention relates to a process for carrying out
metathesis reactions,
in which two compounds are reacted each of which contains an olefinic double
bond or
wherein one of the compounds contains at least two olefinic double bonds and
wherein one of
the above-mentioned compounds of formula 1 is used as catalyst, or a process
for carrying out
ring-closing metathesis (RCM) or cross metathesis (CM) which involves a
compound which
contains two olefinic double bonds as substrate and one of the compounds of
formula 1 as
catalyst.
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TERMS AND DEFINITIONS USED
By "anionic ligands" (X or X') are meant, within the scope of the invention,
negatively
charged molecules or atoms with electron donor properties. Examples which may
be
mentioned here include halogens, such as fluorine, chlorine, bromine or
iodine.
By "neutral ligands" (L) are meant, within the scope of the invention,
uncharged or charge-
neutral molecules or atoms with electron donor properties. Examples which may
be
mentioned here include tertiary phosphines which contain aliphatic,
cycloaliphatic and
aromatic hydrocarbon groups, such as trioctylphosphine, tridodecylphosphine,
tricyclohexylphosphine, tris-(2-methylcyclohexyl)phosphine and tris-(o-tolyl)
phosphine.
Examples of particularly preferred neutral ligands include NHC ligands such as
e.g. the
compounds described by formulae L', L2, L3 and L4:
R7 R8 R7 R8 Y Y' R8
H RS NON-RB R5 NON-RB R5 NON-RB RS N jjN-RB
L' L2 L3 L4
wherein
R5 and R6 independently of one another denote H, C1.6-alkyl or aryl,
R7 and R8 independently of one another denote H, C1_6-alkyl, C1_6-alkenyl or
aryl or
together form a 3 or 4-membered alkylene bridge and
Y and Y' denote halogen.
By the term "C1_12-alkyl" (including those which are part of other groups) are
meant branched
and unbranched alkyl groups with 1 to 12 carbon atoms, and accordingly by the
term
"C1_6-alkyl" are meant branched and unbranched alkyl groups with I to 6 carbon
atoms and by
the term "C 1.4-alkyl" are meant branched and unbranched alkyl groups with I
to 4 carbon
atoms. Alkyl groups with 1 to 6 carbon atoms are preferred while those with 1
to 4 carbon
atoms are particularly preferred. Examples include: methyl, ethyl, n-propyl,
iso-propyl, n-
butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or
hexyl. In some cases
the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may be used for
the above-
mentioned groups. Unless stated otherwise, the definitions propyl, butyl,
pentyl and hexyl
include all the possible isomeric forms of the groups in question. Thus, for
example, propyl
includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-
butyl, etc.
By the term "C2_12-alkenyl" (including those which are part of other groups)
are meant
branched and unbranched alkenyl groups with 2 to 12 carbon atoms, provided
that they have
at least one double bond. Accordingly, the term "C2-6-alkenyl" denotes alkenyl
groups with 2
to 6 carbon atoms and the term "C24-alkenyl" denotes branched and unbranched
alkenyl
groups with 2 to 4 carbon atoms. Alkenyl groups with 2 to 6 carbon atoms are
preferred, those
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with 2 to 4 carbon atoms are particularly preferred. Examples include: ethenyl
or vinyl,
propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise specified, the
definitions propenyl,
butenyl, pentenyl and hexenyl include all possible isomeric forms of the
groups in question.
Thus for example propenyl includes 1-propenyl and 2-propenyl, butenyl includes
1, 2- and 3-
butenyl, 1-methyl- l -propenyl, 1-methyl-2-propenyl etc.
By the term "C2_12-alkynyl" (including those which are part of other groups)
are meant
branched and unbranched alkynyl groups with 2 to 12 carbon atoms, provided
that they have
at least one triple bond. Accordingly, the term "C2.6-alkynyl" refers to
alkynyl groups with 2
to 6 carbon atoms and the term "C2.4-alkynyl" refers to branched and
unbranched alkynyl
groups with 2 to 4 carbon atoms. Alkynyl groups with 2 to 6 carbon atoms are
preferred,
those with 2 to 4 carbon atoms are particularly preferred. The following are
mentioned by
way of example: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless
otherwise
specified, the definitions propynyl, butynyl, pentynyl and hexynyl include all
possible
isomeric forms of the groups in question. Thus for example propynyl includes 1-
propynyl and
2-propynyl, butynyl includes 1, 2- and 3-butynyl, 1-methyl-l-propynyl, 1-
methyl-2-propynyl,
etc.
By the term "C1_12-alkoxy" (including those which are part of other groups)
are meant
branched and unbranched alkoxy groups with 1 to 12 carbon atoms, and similarly
the term
"C1_6-alkoxy" denotes branched and unbranched alkoxy groups with 1 to 6 carbon
atoms and
the term "C1_4-alkoxy" denotes branched and unbranched alkoxy groups with 1 to
4 carbon
atoms. Alkoxy groups with I to 6 carbon atoms are preferred, those with I to 4
carbon atoms
are particularly preferred. The following are mentioned by way of example:
methoxy, ethoxy,
propoxy, butoxy or pentoxy. The abbreviations MeO, EtO, PrO, etc. may also be
used in
some cases for the above-mentioned groups. Unless otherwise specified, the
definitions
propoxy, butoxy and pentoxy include all possible isomeric forms of the groups
in question.
Thus for example propoxy includes n-propoxy and iso-propoxy, butoxy includes
iso-butoxy,
sec-butoxy and tert-butoxy etc.
By the term "CS_6-cycloalkyl" (including those which are part of other groups)
are meant
cyclic alkyl groups with 5 or 6 carbon atoms. The following are mentioned by
way of
example: cyclopentyl or cyclohexyl. Unless otherwise specified, the cyclic
alkyl groups may
be substituted by one or more groups selected from among methyl, ethyl, iso-
propyl, tert-
butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term "aryl" (including those which are part of other groups) are meant
aromatic ring
systems with 6 or 10 carbon atoms. The following are mentioned by way of
example: phenyl
or naphthyl, the preferred aryl group being phenyl. Unless otherwise
specified, the aromatic
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groups may be substituted by one or more groups selected from among methyl,
ethyl, iso-
propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term " C7_lg-aralkyl" (including those which are part of other groups)
are meant
branched and unbranched alkyl groups with 1 to 8 carbon atoms which are
substituted by an
aromatic ring system with 6 or 10 carbon atoms, and similarly the term "C7_1 I-
aralkyl" denotes
branched and unbranched alkyl groups with 1 to 4 carbon atoms which are
substituted by an
aromatic ring system with 6 carbon atoms. The following are mentioned by way
of example:
benzyl, 1- or 2-phenylethyl. Unless otherwise specified, the aromatic groups
may be
substituted by one or more groups selected from among methyl, ethyl, iso-
propyl, tert-butyl,
hydroxy, fluorine, chlorine, bromine and iodine.
PREPARATION OF THE COMPOUNDS
The reaction of the ruthenium complexes of formula 3 with the preligands of
formula 2 is
carried out in inert solvents, e.g. CH2C12 at approx. 0 to 80 C. It is
advantageous to add
CuCI to the reaction mixture. The reactants are generally used in equivalent
amounts, but in
order to increase the yield the more valuable component in each case may be
used in a smaller
amount. It may also be useful to produce the complex of formula 3 in situ from
other
ruthenium compounds and ligand pre-products, e.g. dihydroimidazolinium salts,
in order to
arrive at the new metathesis catalysts of formula 1 with the desired ligand
combination in
each case, via the resulting complexes of formula 3.
The metathesis catalysts of formula 1 prepared by ligand exchange reaction may
be separated
off from other reaction products which are insoluble in the reaction mixture,
by filtration of
the solution thereof and, after concentration of the solution, are obtained in
pure form by
chromatography or crystallisation. However, it is also possible to use the
crude products or
the catalysts produced in situ directly to carry out metathesis reactions.
The preligands of formula 2 may be prepared in a manner known per se from
aromatic
aldehydes which contain corresponding substituents, by reactions of
olefination, e.g. by
reaction with phosphorylidene according to Wittig.
Particularly preferred is a new combined process which starts from optionally
correspondingly substituted phenylallylethers, and leads by Claisen
rearrangement and
catalytic double bond isomerisation to optionally correspondingly substituted
2-alkenyl-
phenols which are subsequently reacted by alkylation with a-halocarboxylic
acid esters to
obtain compounds of formula 2.
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The alkylation of phenols to form alkyl-phenylethers is well known in the art
and is usually
carried out in a solvent in the presence of basic substances by reaction with
nucleophilic
reagents. The reaction with a-halocarboxylic acid esters proceeds particularly
smoothly and
with good yields. Suitable solvents include, for example, alcohols such as
ethanol or aprotic
polar solvents such as dimethylformamide. The alkylation may also be carried
out under
phase transfer conditions. Examples of basic substances include alkali metal
carbonates, and
similarly the alkali metal salts of the intermediate products which contain a
free aromatically
bound OH group may be used for this reaction.
In order to illustrate the sequence of synthesis which is preferably used to
prepare compounds
of formula 2, the preparation of (3-propenyl-biphen-2-yl) (1-methoxycarbonyl-
ethyl)ether
will now be described as a specific example:
Starting from 2-hydroxybiphenyl, 2-allyloxy-biphenyl is obtained by alkylation
with allyl
chloride in DMF as solvent in the presence of potassium carbonate. By thermal
rearrangement
at 190 C in trichlorobenzene, 3-allyl-2-hydroxy-biphenyl is then obtained,
which is
catalytically rearranged (RhCl3 H2O) in ethanolic solution in the presence of
p-
toluenesulphonic acid to form an E/Z mixture of 3-propenyl-2-hydroxybiphenyl.
Alkylation
of this intermediate product with methyl 2-bromopropionate yields the
preligand (3-propenyl-
biphen-2-yl)(I-methoxycarbonyl-ethyl)ether.
The compounds of formula 1 are highly active metathesis catalysts which may
also be
successfully used for carrying out difficult metathesis reactions, including
all types of
reactions of this kind (RCM, CM, ROMP etc.).
EXAMPLE I
Preparation of a metathesis catalyst of formula la.
1.1) Preparation of the new preligand of formula 2a:
A mixture of 500 mg (3.72 mmol) of 2-propenylphenol (E/Z mixture), prepared by
Claisen
rearrangement of phenylallylether followed by double bond isomerisation, 1.02
g of
potassium carbonate (0.74 mmol) and 745 mg of rac. methyl 2-bromopropionate
(4.46 mmol)
and 10 ml of dimethylformamide was stirred overnight at RT and then for 4
hours at 80 C.
The reaction mixture was then added to 40 ml of water and extracted three
times with 30 ml
diethyl ether. The organic phase was washed with 5% sodium hydroxide solution,
separated
off, dried with Na2SO4 and concentrated by evaporation. 685 mg (83.6% of
theory) of
virtually pure methyl 2-(2-propenyl-phenyloxy)propionate were obtained.
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a
b
-1O d c
MeO 0 2a
1.2) Preparation of the metathesis catalyst of formula la.
424 mg (0.5 mmol) of Grubb's catalyst, 2nd generation,
n
Mes-N,N-Mes
Cl 1,,. Ru_
CI.,,
PCy3
and 59 mg CuCI (0.6 mmol) were placed in a Schlenk tube, and under argon a
solution of 134
mg (0.6 mmol) of methyl 2-(2-propenyl-phenyloxy)propionate, dissolved in 10 ml
CH2C12,
was added. The mixture was stirred for 1 hour at 40 C, then evaporated down
i.v, the residue
was taken up in 20 ml of ethyl acetate and the cloudy solution obtained was
filtered. The
crude product obtained after evaporation of the solvent was purified by
chromatography
carried out twice (Merck silica gel type 9385, 1st eluent AcOEt / cyclohexane
3:7, 2nd eluent
AcOEt / cyclohexane 1:1). 193 mg (58 % of theory) of pure product were
obtained.
HRMS(El): C32H38N2O3C12Ru
Calculated: [M+]670.13030, found: 670.13467
Mes-NvN-Mes
CI,,,. Ru_
CIS '
O
MeO la
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EXAMPLE 2
Use of the catalyst of formula la prepared according to the invention and
comparison of its
activity with the known catalyst of formula A (see above).
2.1) Ring-closing metathesis (RCM) using 1a:
A solution of 2.7 mg (0.004 mmol) of the catalyst la obtained according to
Example I
in 1 ml dichloromethane at 25 C was added to a solution of 100 mg (0.4 mmol)
diethyl allyl-methallyl-malonate (substrate) in 20 ml of dichloromethane. The
reaction
mixture was kept at this temperature for 2 hours. After this time a sample was
taken,
the catalyst was destroyed by the addition of ethylvinylether and the sample
was
analysed by gas chromatography (comparison with substrate and ring-closing
product
prepared in known manner). The level of conversion of the substrate into the
metathesis product (1,1-bis-ethoxycarbonyl-3-methyl-cyclopent-3-ene) was 89%.
2.2) RCM using the known catalyst of formula A:
The same substrate was reacted as described in Example 2.1, but using 2.5 mol%
of
the known catalyst A. Investigation by gas chromatography showed that the
level of
conversion into the ring-closing product was 18%.
EXAMPLE 3
Use of the catalyst of formula la prepared according to the invention and
comparison of its
activity with the known catalyst of formula D (see above).
COzMe C%Me
O O,NH
O O,NH
1
No la or D No OYNH OYNH O&
11 O b-S-&Br O O-S Br
O O
4 5
4 is dissolved in 10 ml of degassed toluene and heated to 80 C, freshly
prepared catalyst is
added under nitrogen (1st) and the resulting mixture is stirred for 60 min at
80 C. The reaction
is tested by HPLC and a further amount of the catalyst is added (2"d). After
another 60 min
the reaction is tested once more by HPLC.
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Figure 1 shows the cyclisation rate of 4 (T = 0 min:0.4 mol%; T = 60 min:0.2
mol%). Table 1
shows the results of an HPLC analysis in which the results are compared with
the known
catalyst of formula D (Angew. Chem. Int. Ed. 2002, 41, 4038).
Table I
reaction [%peak at 200 nm]
Catalyst 1 t [mol%] 4 [mol] toluene [ml] 5 [60 min] 4 [60 min]
2d [mol%] 5 [120 min] 4 [120 min]
la 0.4 0.0075 554 82.8
0.2 94.6
D 0.4 0.015 1008 77.4 22.6
0.2 92.8 7.2
12
