Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-06-10
2001-04-17
Ambrose, Michael G. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C568S642000, C568S928000, C570S201000
Reexamination Certificate
active
06218564
ABSTRACT:
This invention relates to a process for preparing substituted aromatic compounds.
Many of the currently available processes for making substituted aromatic compounds necessarily rely upon coupling reactions involving bromo- and iodo-substituted intermediates. These intermediates can be difficult to prepare and expensive.
For example the paper by Suzuki et al in Synthetic Communications, 11(7), 513-519 (1981) describes the coupling of certain aryl boronic acids with iodo- or bromo-benzenes in the presence of Pd(0)(PPh
3
)
4
and Na
2
CO
3
. At the foot of page 515 and on page 516, lines 16-17, the paper teaches that the coupling does not work with chloroarenes and chlorobenzenes.
European Patent No. 0 470 795 B1 describes a process for the manufacture of biphenylcarbonitriles wherein certain phenylboronic acids are coupled with cyanophenyl compounds having a bromo, iodo or trifluoromethanesulphonyloxy group in the presence of specified catalysts.
We have now invented a process which uses chloroaromatic compounds and avoids the need for Pd(0)(PPh
3
)
4
, which is itself rather expensive. Chloroaromatic compounds are generally easier to prepare and cheaper than the corresponding bromo-, iodo- and trifluoromethanesulphonyloxy compounds.
According to the present invention there is provided a process for the preparation of a substituted aromatic compound comprising coupling a chloroaromatic compound and an alkyl-, alkenyl- or aryl-boronic acid, ester or anhydride in the presence of palladium and a phosphine selected from the group consisting of:
a) lipophilic aliphatic phosphines comprising at least one branched aliphatic group, and
b) lipophilic aliphatic bis(phosphines).
The chloroaromatic compound is preferably an optionally substituted chlorobenzene, chloropyridine, chiorotriazole, chlorobenzotriazole, chloronaphthalene, chlorothiophene, chloropyrimidine, chlorofuran or chlorobenzofuran, more preferably an optionally substituted chlorobenzene, especially an optionally substituted chlorobenzene which is free from iodo, bromo and trifluoromethanesulphonyloxy groups. Especially preferred substituted chlorobenzenes have one, two or three substituents selected from alkyl, preferably C
1-4
-alkyl; alkoxy, preferably C
1-4
-alkoxy; nitro; fluoro, chloro; cyano; carboxy; —OCF
3
; —NR
1
R
2
wherein R
1
and R
2
are each independently H, C
1-4
-alkyl or —CO—(C
1-4
-alkyl); —SR
1
; —SO
3
H; OH; OCOR
3
wherein R
3
is C
1-4
-alkyl or aryl; COR
1
, particularly formyl, and CF
3
.
Examples of chloroaromatic compounds include chlorobenzene, 2-chloronaphthalene, 2-cyano chlorobenzene, 4-formyl chlorobenzene, 2-chloropyridine, 2-chloropyrimidine, 2-chlorothiophene, methyl 2-chlorobenzoate, 4-chloroaniline, 1,4-dichlorobenzene, 1-chloro-3-nitrobenzene, 4-chloro-2-nitrophenol, 4-chloro-3-nitrobenzene sulphonic acid, 5-chlorobenzotriazole and 1-chloro-2,4-dinitrobenzene. Many more chioroaromatic compounds are known and may be used in the process. The most preferred chloroaromatic compound is 2-cyano chlorobenzene.
The alkyl-, alkenyl- or aryl-boronic acid, ester or anhydride is preferably of the Formula (1):
wherein:
R
4
is alkyl, alkenyl or aryl; and
Q
1
and Q
2
are each independently H, alkyl, alkenyl or aryl or Q
1
and Q
2
together with the —O—B—O— group which joins them forms a boroxin ring of the Formula (2) wherein R
4
is as hereinbefore defined:
When R
4
, Q
1
or Q
2
is alkyl it is preferably C
1-10
-alkyl more preferably C
1-4
-alkyl.
When R
4
, Q
1
or Q
2
is alkenyl it is preferably C
2-10
-alkenyl, more preferably C
2-4
-alkenyl, especially —CH═CH
2
or —C(CH
3
)═CH
2
.
When R
4
, Q
1
or Q
2
is aryl it is preferably optionally substituted phenyl, more preferably phenyl or phenyl bearing one, two or three substituents selected from those mentioned above for the chloroaromatic compound.
When R
4
, Q
1
or Q
2
is heteroaryl it is preferably pyridinyl, naphthalenyl, thiophenyl, pyrimidinyl or furanyl, optionally substituted by one or two substituents selected from those mentioned above for the chloroaromatic compound.
Preferably Q
1
and Q
2
are both H or Q
1
and Q
2
together with the —O—B—O— group which joins them forms a boroxin ring of the Formula (2) shown above. R
4
is preferably optionally substituted phenyl wherein the optional substituents are as described above.
Examples of preferred alkyl-, alkenyl- and aryl boronic acids include benzeneboronic acid, n-butaneboronic acid, thiophene-2-boronic acid, thiophene-3-boronic acid, 4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid, 3-aminobenzeneboronic acid monohydrate, 3-aminobenzeneboronic acid hemisulphate, 3-fluorobenzeneboronic acid, 4-fluorobenzeneboronic acid, 2-formylbenzeneboronic acid, 3-formylbenzeneboronic acid, 4-formylbenzeneboronic acid, 2-methoxybenzeneboronic acid, 3-methoxybenzeneboronic acid, 4-methoxybenzeneboronic acid, 4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid, benzo[b]furan-2-boronic acid, 4-carboxybenzeneboronic acid, 2,4,6-trimethylbenzeneboronic acid, 3-nitrobenzeneboronic acid, 4-(methylthio)benzeneboronic acid, 1-naphthaleneboronic acid, 2-naphthaleneboronic acid, 3-chloro-4-fluorobenzeneboronic acid, 3-acetamidobenzeneboronic acid, 3-trifluoromethylbenzeneboronic acid, 4-trifluoromethylbenzeneboronic acid, 2,4-dichlorobenzeneboronic acid, 3,5-dichlorobenzeneboronic acid, 4-bromobenzeneboronic acid, 3,5-bis(trifluoromethyl)benzeneboronic acid, 1,4-benzenediboronic acid, 4,4′-biphenyldiboronic acid, and the esters and anhydrides of such acids.
The boronic acids readily undergo dehydration to form cyclic trimeric anhydrides known as boroxines. This often occurs spontaneously at room temperature, but it does not affect the reaction because both the acid and anhydride and mixtures of the two will work in the process.
Compounds of Formula (1) are known and may be prepared as needed or purchased from commercial sources, for example Lancaster Synthesis, United Kingdom. Known synthetic methods include reaction of a trialkylboronate of the formula B(OR)
3
wherein R is a C
1-6
-alkyl group with a Grignard reagent or phenyl lithium compound of the R
4
group described above (e.g. R
4
Li or R
4
MgX wherein X is a halogen). Such procedures are described in our EP 0 470 795 B1, page 3, lines 23-38, which is incorporated herein by reference thereto. Aryl boronic acids of Formula (1) having a wide variety of substituents may also be prepared by functionalisation of the parent aryl boronic acid or ester, e.g. by nitration, oxidation and halogenation. Functionalisation methods are described by T. Onak in “Organoborane Chemistry”, Academic Press, New York, 1975, Page 222.
Lipophilic aliphatic phosphines can be obtained from commercial sources (e.g. Sigma, Aldrich, Fluka and other chemical catalogue companies) or they can be prepared using generally known processes. These phosphines are believed to act as ligands to the palladium thereby forming an effective catalyst for the coupling reaction.
The lipophilic aliphatic phosphines comprising at least one branched liphatic group or aliphatic bis(phopshines) preferably comprise from five to forty, preferably from five to thirty, especially from six to twenty five aliphatic carbon atoms. Most preferably, each of the phosphorus atoms is substituted by three aliphatic groups. The point of branching in the aliphatic groups is most commonly at the carbon alpha or beta to the phosphorus atom. Preferred lipophilic aliphatic phosphines are of the Formula (3) or (4):
wherein:
each R
5
, R
6
, R
7
, R
8
and R
9
independently is an alkyl or cycloalkyl group, provided that in the phosphines of formula (3), at least one of R
5-7
is branched; and
L is a divalent aliphatic linker group.
When R
5
, R
6
, R
7
, R
8
or R
9
is an alkyl group it is preferably straight chain or branched chain C
1-6
-alkyl, more preferably branched chain C
3-6
-alkyl.
When R
5
, R
6
, R
7
, R
8
or R
9
is a cycloalkyl group it is preferably cyclohexyl or cyclopentyl.
L is preferably a C
1-20
-alkylene group, more preferably a C
1-10
-alk
Ambrose Michael G.
Pillsbury & Winthrop LLP
Zeneca Limited
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