Process for the preparation of substituted phenylboronic acids

Details Process for the preparation of substituted phenylboronic acids Process for the preparation of substituted phenylboronic acids

2000-04-20

2003-06-10

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Boron acids or salts thereof

C558S287000

Reexamination Certificate

active

06576789

ABSTRACT:

BACKGROUND OF THE INVENTION
Substituted phenylboronic acids, for example cyanophenylboronic acids, are of considerable-industrial importance as precursors for active compounds, in particular as precursors for correspondingly substituted biphenyl derivatives, which are used as AT(II) antagonists, or as precursors for liquid-crystalline compounds, as liquid crystals or as a constituent of liquid-crystalline mixtures. Phenylboronic acids can be coupled to haloaromatic compounds with transition-metal catalysis to give biphenyl derivatives with the aid of methods described in the literature (N. Miyaura et al., Tetrahedron Lett., 3437 (1979); A. L. Casalnuovo et al., J. Amer. Chem. Soc. 112, 4324 (1990), N. Miyaura et al., Chem. Rev. 95 (1995), 2457-2483).
The conventional synthetic routes for cyanophenylboronic acids, either starting from carboxyphenylboronic acid via the formation of the acid amide with subsequent formation of the cyano compound or starting from the correspondingly substituted bromobenzonitrile by reaction with organolithium compounds, such as butyllithium, followed by reaction with a trialkyl borate, do not achieve the object of an economical synthesis of cyanophenylboronic acids which is simple to carry out industrially, since firstly the synthetic route contains too many steps, and secondly, organolithium compounds are very expensive and hazardous to handle.
The Grignard reaction with chlorobenzaldehyde proceeds in low yields and very slowly, meaning that for industrial purposes, it was hitherto necessary to use expensive bromobenzaldehyde (H. Jendralla et al., Liebigs Ann. 1995, 1253-1257).
WO 98/02 443 uses transition-metal compounds, if necessary in combination with co-catalysts, for activating aromatic chlorine compounds for Grignard reactions, but not for chlorinated aromatic aldehydes or protected derivatives thereof. Rather, it is known that ether and acetal protecting groups considerably reduce the reactivity of the magnesium by forming complexes at the magnesium surface (D. E. Pearson et al., J. Org. Chem., 1959, 24, 504-509).
SUMMARY OF THE INVENTION
Owing to the interest in this class of substances, there is a need for an economical synthesis of substituted phenylboronic acids, in particular of cyanophenylboronic acids, which is simple to carry out industrially.
DESCRIPTION OF THE PREFERRED EMBODIMENTS This object is achieved by a process for the preparation of a compound of the formula (I)
in which
Q
1
and Q
2
are each OH or together are a divalent radical of the formula (Ib)
Z is —CHO, D, —CH
2
Y or X, where D is a protected aldehyde group, Y is hydroxyl or amino, and X is cyano, COOH, COCl, CONH
2
or C(OR)
3
, where R is C
1
-C
5
-alkyl or phenyl, and where Z is in the ortho-, meta- or para-position to the boronic acid radical;
R
1
to R
4
, independently of one another, are hydrogen, C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
2
-C
12
-alkynyl, C
3
-C
12
-cycloalkyl, (C
1
-C
12
-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl, fluorine, N(alkyl)
2
, N[Si(C
1
-C
4
-alkyl)
3
]
2
or CF
3
, or R
1
and R
2
, and/or R
3
and R
4
, together form a 5- or 6-membered aliphatic or aromatic ring; which comprises
a) reacting a compound of the formula (II)
 with magnesium in the presence of
i) an anthracene compound and, if desired, a transition-metal halide and, if desired, a magnesium halide; or
ii) a transition-metal halide and, if desired, a magnesium halide, where the anthracene compound is a compound from the group consisting of anthracene, Mg anthracene, substituted anthracene and substituted Mg anthracene,
to give an arylmagnesium chloride of the formula (III)
b) reacting the compound of the formula (III) with a borate of the formula B(OR′)
3
, in which R′ are identical to or different from one another and are straight-chain or branched (C
1
-C
8
)-alkyl radicals, phenyl radicals which are unsubstituted or substituted by one or two (C
1
-C
4
)-alkyl groups or (C
1
-C
4
)-alkoxy groups, in particular straight-chain or branched (C
1
-C
4
)-alkyl radicals or unsubstituted phenyl radicals, and hydrolyzing the product to give a compound of the formula (IV)
 in which
D
1
is CHO or D;
Q
1
and Q
2
are each OH or together are a divalent radical of the formula (IVb)
c) if desired oxidizing the compound of the formula (IV) or (IVb) in which D
1
is CHO to give a compound of the formula (I) in which Z is X, or if desired reducing the compound of the formula (IV) or (IVb) to give a compound of the formula (I) in which Z is CH
2
Y.
In the above definitions, alkyl is preferably C
1
-C
4
-alkyl, aryl is preferably phenyl, alkylaryl is preferably benzyl, and alkoxy is preferably C
1
-C
4
-alkoxy.
Preferred radicals R (Z is —C(OR)
3
) are C
1
-C
4
-alkyl, in particular methyl, ethyl or phenyl.
Preferred radicals R
1
to R
4
are hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy and fluorine.
The radical D is preferably an acetal of the formula (V) or (VI)
in which R
5
to R
8
are identical or different and are hydrogen, C
1
-C
12
-alkyl or phenyl, or R
6
and R
7
together form a 5- or 6-membered aliphatic or aromatic ring; or D is an oxazolidine of the formula (VII) or an oxazoline of the formula (VIII)
in which R
5
to R
8
are as defined above, and R
9
is C
1
-C
6
-alkyl, phenyl or benzyl, unsubstituted or substituted on the aromatic ring.
It was surprising that compounds of the formula (I) can be prepared in good yields by the process according to the invention starting from ortho-, meta- or para-chlorobenzaldehyde,.
Preferred borates B(OR′)
3
are trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate and triisobutyl borate.
The group D is, if desired, converted into a compound of the formula (I) in which Z is —CHO by acidic hydrolysis or (in the case of the oxazolines) by reduction followed by acidic hydrolysis. It is also possible to remove the aldehyde protecting group in a one-pot process and, without prior isolation of a compound of the formula (IV) in which D
1
is D, to obtain a compound of the formula (IV) in which D
1
is —CHO.
It is likewise possible, by reacting compounds of the formula (IV) with alcohols of the formula HO-(C
1
-C
12
)-alkyl, HO-(C
2
-C
12
)-alkenyl, HO-(C
2
-C
12
)-alkynyl, HO-aryl or HO-alkylaryl, to prepare acyclic boronates of the formula (IVa)
in which Q
3
and Q
4
are a radical of said alcohols, or, by reaction with the polyhydric alcohols (C
3
-C
12
)-cycloalkane-1,2-diol, (C
5
-C
12
)-cycloalkene-1,2-diol, (C
5
-C
12
)-cycloalkane-1,3-diol, (C
5
-C
12
)-cycloalkene-1,3-diol or with the alcohols of the formulae (1) to (6)
in which R
1
a to R
8
a, independently of one another, are hydrogen, C
1
-C
12
-alkyl, C
1
-C
12
-hydroxyalkyl, C
2
-C
12
-alkenyl, C
2
-C
12
-alkynyl, C
3
-C
12
-cycloalkyl, (C
1
-C
12
)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl, fluorine, chlorine, NH
2
, NH(alkyl), N(alkyl)
2
, N[Si(C
1
-C
4
-alkyl)
3
]
2
or CF
3
, and/or two adjacent radicals R
1
a to R
8
a together form a 5- or 6-membered aliphatic or aromatic ring, and in which n is an integer from 2 to 12,
to prepare a cyclic borate of the formula (IVa) in which Q
3
and Q
4
together are a divalent radical of said polyhydric alcohols.
The compounds of the formula (IVa) can be converted back into compounds of the formula (IV) by acidic hydrolysis.
The compounds of the formula (I) in which Z is CHO, X or —CH
2
Y can likewise be converted into the compounds of the formula (Ia) by reaction with the above-mentioned alcohols.
The compounds of the formula (Ia) can be converted back into compounds of the formula (I) by acidic hydrolysis.
The reaction of the compound of the formula (I) or of the formula (IV) with the alcohols on which the radicals Q
3
and Q
4
are based is advantageously carried out in the presence of an organic solvent which is inert toward the reaction participants, such as tetrahydrofuran, methyl tert-butyl ether, toluene, o-, m- or p-xylene, hexane or heptane, at a temperature of from 20° C. to the boiling point

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