U.S. patent application number 10/425389 was filed with the patent office on 2003-11-27 for process for the preparation of substituted phenylboronic acids.
This patent application is currently assigned to Clariant GmbH. Invention is credited to Haber, Steffen, Meudt, Andreas, Scherer, Stefan, Vollmueller, Frank.
Application Number | 20030220516 10/425389 |
Document ID | / |
Family ID | 7905289 |
Filed Date | 2003-11-27 |
United States Patent
Application |
20030220516 |
Kind Code |
A1 |
Haber, Steffen ; et
al. |
November 27, 2003 |
Process for the preparation of substituted phenylboronic acids
Abstract
Compounds of the formula (I) 1 in which Q.sup.1 and Q.sup.2 are
each OH or form a trimeric boric anhydride, Z is CHO, CH.sub.2Y, X
or a protected aldehyde group, and X is CN, COOH, COCl, CONH.sub.2
or C(OR).sub.3, and Y is OH or NH.sub.2, and Z is in the o-, m- or
p-position to the boronic acid radical, are prepared by a) reacting
a compound of the formula (II) 2 with Mg in the presence of an
anthracene compound and, if desired, a transition-metal halide and,
if desired, an Mg halide or in the presence of a transition-metal
halide and, if desired, an Mg halide, to give the corresponding
arylmagnesium chloride, b) reacting the latter with a borate of the
formula B(OR').sub.3 and hydrolyzing the product, with removal of
the aldehyde protecting group, c) and, if desired, oxidizing or
reducing the free aldehyde group.
Inventors: |
Haber, Steffen;
(Landau/Pfalz, DE) ; Meudt, Andreas;
(Floersheim-Weilbach, DE) ; Scherer, Stefan;
(Buettelborn, DE) ; Vollmueller, Frank; (Mainz,
DE) |
Correspondence
Address: |
CLARIANT CORPORATION
INTELLECTUAL PROPERTY DEPARTMENT
4000 MONROE ROAD
CHARLOTTE
NC
28205
US
|
Assignee: |
Clariant GmbH
|
Family ID: |
7905289 |
Appl. No.: |
10/425389 |
Filed: |
April 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10425389 |
Apr 29, 2003 |
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09553036 |
Apr 20, 2000 |
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6576789 |
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Current U.S.
Class: |
558/287 ;
260/665G; 556/403; 564/305 |
Current CPC
Class: |
C07F 5/025 20130101;
Y02P 20/55 20151101; C07F 3/02 20130101 |
Class at
Publication: |
558/287 ;
260/665.00G; 556/403; 564/305 |
International
Class: |
C07F 005/02; C07F
005/04; C07F 007/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 21, 1999 |
DE |
199 17 979.4 |
Claims
1. A process for the preparation of a compound of the formula (I)
19in which Q.sup.1 and Q.sup.2 are each OH or together are a
divalent radical of the formula (Ib) 20Z is --CHO, D, --CH.sub.2Y
or X, where D is a protected aldehyde group, Y is hydroxyl or
amino, and X is cyano, COOH, COCl, CONH.sub.2 or C(OR).sub.3, where
R is C.sub.1-C.sub.5-alkyl or phenyl, and where Z is in the ortho-,
meta- or para-position to the boronic acid radical; R.sup.1 to
R.sup.4, independently of one another, are hydrogen,
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, N(alkyl).sub.2, N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2
or CF.sub.3, or R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4, or
R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4 together form a 5- or
6-membered aliphatic or aromatic ring; which comprises a) reacting
a compound of the formula (II) 21 with magnesium in the presence of
i) an anthracene compound and, optionally a transition-metal halide
and, optionally, a magnesium halide; or ii) a transition-metal
halide and, optionally, 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) 22b)
reacting the compound of the formula (III) with a borate of the
formula B(OR').sub.3, in which R' are identical to or different
from one another and are straight-chain or branched
(C.sub.1-C.sub.8)-alkyl radicals, phenyl radicals which are
unsubstituted or substituted by one or two (C.sub.1-C.sub.4)-alkyl
groups or (C.sub.1-C.sub.4)-alkoxy groups, and hydrolyzing the
product to give a compound of the formula (IV) 23in which D.sup.1
is CHO or D; Q.sup.1 and Q.sup.2 are each OH or together are a
divalent radical of the formula (IVb) 24c) optionally oxidizing the
compound of the formula (IV) or (IVb) in which D.sup.1 is CHO to
give a compound of the formula (I) in which Z is X, or optionally
reducing the compound of the formula (IV) or (IVb) to give a
compound of the formula (I) in which Z is CH.sub.2Y.
2. The process as claimed in claim 1, wherein R.sup.1 to R.sup.4
are hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, butoxy or fluorine.
3. The process as claimed in claim 1, wherein D is an acetal of the
formula (V) or (VI) 25in which R.sup.5 to R.sup.8 are identical or
different and are hydrogen, C.sub.1-C.sub.12-alkyl or phenyl, or
R.sup.6 and R.sup.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) 26in which R.sup.9 is
C.sub.1-C.sub.6-alkyl, phenyl or benzyl, unsubstituted or
substituted on the aromatic ring.
4. The process as claimed in claim 1, wherein the borate
B(OR').sub.3 is trimethyl borate, triethyl borate, tri-n-propyl
borate, triisopropyl borate, tri-n-butyl borate and triisobutyl
borate.
5. The process as claimed in claim 1, wherein step a) is carried
out in the presence of anthracene, Mg anthracene,
9,10-diphenylanthracene or Mg 9,10-diphenylanthracene.
6. The process as claimed in claim 1, wherein step a) is carried
out in the presence of MgCl.sub.2 or MgBr.sub.2, and in the
presence of FeCl.sub.2, MnCl.sub.2, FeBr.sub.2 oder MnBr.sub.2.
7. The process as claimed in claim 1, wherein the compound of the
formula (IV) is esterified using an alcohol of the formula
HO-(C.sub.1-C.sub.12)-alkyl, HO-(C.sub.2-C.sub.12)-alkenyl,
HO-(C.sub.2-C.sub.12)-alkynyl, HO-aryl, HO-alkylaryl,
(C.sub.3-C.sub.12)-cycloalkane-1,2-diol, cycloalkane-1,2-diol,
(C.sub.5-C.sub.12)-cycloalkene-1,2-diol,
(C.sub.5-C.sub.12)-cycloalkane-1- ,3-diol,
(C.sub.5-C.sub.12)-cycloalkene-1,3-diol or using an alcohol of the
formulae (1) to (6) 27in which R.sub.1a to R.sub.8a, independently
of one another, are hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-hydroxyalkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, chlorine, NH.sub.2, NH(alkyl), N(alkyl).sub.2,
N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2 or CF.sub.3, two adjacent
radicals R.sub.1a to R.sub.8a together optionally form a 5- or
6-membered aliphatic or aromatic ring, and in which n is an integer
from 2 to 12.
8. The process as claimed in claim 1, wherein the compound of the
formula (I) is esterified using an alcohol of the formula
HO-(C.sub.1-C.sub.12)-a- lkyl, HO-(C.sub.2-C.sub.12)-alkenyl,
HO-(C.sub.2-C.sub.12)-alkynyl, HO-aryl, HO-alkylaryl,
(C.sub.3-C.sub.12)-cycloalkane-1,2-diol, cycloalkane-1,2-diol,
(C.sub.5-C.sub.12)-cycloalkene-1,2-diol,
(C.sub.5-C.sub.12)-cycloalkane-1,3-diol,
(C.sub.5-C.sub.12)-cycloalkene-1- ,3-diol or using an alcohol of
the formulae (1) to (6) 28in which R.sub.1a to R.sub.8a,
independently of one another, are hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-hydroxyalkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, chlorine, NH.sub.2, NH(alkyl), N(alkyl).sub.2,
N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2 or CF.sub.3, two adjacent
radicals R.sub.1a to R.sub.8a together optionally form a 5- or
6-membered aliphatic or aromatic ring, and in which n is an integer
from 2 to 12.
9. The process as claimed in claim 7, wherein, after the
esterification, the aldehyde group is oxidized to the carboxyl,
nitrile or carbonyl chloride group.
10. The process as claimed in claim 7, wherein, after the
esterification, the aldehyde group is reduced to the methylamino or
hydroxymethyl group.
11. An arylmagnesium chloride of the formula (III) 29in which
R.sup.1 to R.sup.4, independently of one another, are hydrogen,
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkyny- l, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, N(alkyl).sub.2, N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2
or CF.sub.3, or R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4, or
R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4 together form a 5- or
6-membered aliphatic or aromatic ring, and D is a protected
aldehyde group.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] The present invention is described in the German priority
application No. DE 199 17 979.4, filed Apr. 21, 1999, which is
hereby incorporated by reference as is fully disclosed herein.
BACKGROUND OF THE INVENTION
[0002] 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).
[0003] 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.
[0004] 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).
[0005] 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
[0006] 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
[0007] This object is achieved by a process for the preparation of
a compound of the formula (I) 3
[0008] in which
[0009] Q.sup.1 and Q.sup.2 are each OH or together are a divalent
radical of the formula (Ib) 4
[0010] Z is --CHO, D, --CH.sub.2Y or X, where D is a protected
aldehyde group, Y is hydroxyl or amino, and X is cyano, COOH, COCl,
CONH.sub.2 or C(OR).sub.3, where R is C.sub.1-C.sub.5-alkyl or
phenyl, and where Z is in the ortho-, meta- or para-position to the
boronic acid radical;
[0011] R.sup.1 to R.sup.4, independently of one another, are
hydrogen, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkyny- l, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, N(alkyl).sub.2, N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2
or CF.sub.3, or R.sup.1 and R.sup.2, and/or R.sup.3 and R.sup.4,
together form a 5-or 6-membered aliphatic or aromatic ring;
[0012] which comprises
[0013] a) reacting a compound of the formula (II) 5
[0014] with magnesium in the presence of
[0015] i) an anthracene compound and, if desired, a
transition-metal halide and, if desired, a magnesium halide; or
[0016] 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,
[0017] to give an arylmagnesium chloride of the formula (III) 6
[0018] b) reacting the compound of the formula (III) with a borate
of the formula B(OR').sub.3, in which R' are identical to or
different from one another and are straight-chain or branched
(C.sub.1-C.sub.8)-alkyl radicals, phenyl radicals which are
unsubstituted or substituted by one or two (C.sub.1-C.sub.4)-alkyl
groups or (C.sub.1-C.sub.4)-alkoxy groups, in particular
straight-chain or branched (C.sub.1-C.sub.4)-alkyl radicals or
unsubstituted phenyl radicals, and hydrolyzing the product to give
a compound of the formula (IV) 7
[0019] in which
[0020] D.sup.1 is CHO or D;
[0021] Q.sup.1 and Q.sup.2 are each OH or together are a divalent
radical of the formula (IVb) 8
[0022] c) if desired oxidizing the compound of the formula (IV) or
(IVb) in which D.sup.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.sub.2Y.
[0023] In the above definitions, alkyl is preferably
C.sub.1-C.sub.4-alkyl, aryl is preferably phenyl, alkylaryl is
preferably benzyl, and alkoxy is preferably
C.sub.1-C.sub.4-alkoxy.
[0024] Preferred radicals R (Z is --C(OR).sub.3) are
C.sub.1-C.sub.4-alkyl, in particular methyl, ethyl or phenyl.
[0025] Preferred radicals R.sup.1 to R.sup.4 are hydrogen, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy and
fluorine.
[0026] The radical D is preferably an acetal of the formula (V) or
(VI) 9
[0027] in which R.sup.5 to R.sup.8 are identical or different and
are hydrogen, C.sub.1-C.sub.12-alkyl or phenyl, or R.sup.6 and
R.sup.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) 10
[0028] in which R.sup.5 to R.sup.8 are as defined above, and
R.sup.9 is C.sub.1-C.sub.6-alkyl, phenyl or benzyl, unsubstituted
or substituted on the aromatic ring.
[0029] 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.
[0030] Preferred borates B(OR').sub.3 are trimethyl borate,
triethyl borate, tri-n-propyl borate, triisopropyl borate,
tri-n-butyl borate and triisobutyl borate.
[0031] 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.sup.1 is D, to obtain a compound of the
formula (IV) in which D.sup.1 is --CHO.
[0032] It is likewise possible, by reacting compounds of the
formula (IV) with alcohols of the formula
HO-(C.sub.1-C.sub.12)-alkyl, HO-(C.sub.2-C.sub.12)-alkenyl,
HO-(C.sub.2-C.sub.12)-alkynyl, HO-aryl or HO-alkylaryl, to prepare
acyclic boronates of the formula (IVa) 11
[0033] in which Q.sup.3 and Q.sup.4 are a radical of said
alcohols,
[0034] or, by reaction with the polyhydric alcohols
(C.sub.3-C.sub.12)-cycloalkane-1,2-diol,
(C.sub.5-C.sub.12)-cycloalkene-1- ,2-diol,
(C.sub.5-C.sub.12)-cycloalkane-1,3-diol, (C.sub.5-C.sub.12)-cyclo-
alkene-1,3-diol or with the alcohols of the formulae (1) to (6)
12
[0035] in which R.sub.1a to R.sub.8a, independently of one another,
are hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-hydroxyalkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, C.sub.3-C.sub.12-cycloalkyl,
(C.sub.1-C.sub.12)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, chlorine, NH.sub.2, NH(alkyl), N(alkyl).sub.2,
N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2 or CF.sub.3, and/or two
adjacent radicals R.sub.1a to R.sub.8a together form a 5- or
6-membered aliphatic or aromatic ring, and in which n is an integer
from 2 to 12,
[0036] to prepare a cyclic borate of the formula (IVa) in which
Q.sup.3 and Q.sup.4 together are a divalent radical of said
polyhydric alcohols.
[0037] The compounds of the formula (IVa) can be converted back
into compounds of the formula (IV) by acidic hydrolysis.
[0038] The compounds of the formula (I) in which Z is CHO, X or
--CH.sub.2Y can likewise be converted into the compounds of the
formula (la) by reaction with the above-mentioned alcohols. 13
[0039] The compounds of the formula (la) can be converted back into
compounds of the formula (I) by acidic hydrolysis.
[0040] The reaction of the compound of the formula (I) or of the
formula (IV) with the alcohols on which the radicals Q.sup.3 and
Q.sup.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.degree.
C. to the boiling point of the solvent used. In the case of diols
or other polyhydric alcohols, it is also possible to use methanol,
ethanol, n- or isopropanol as inert solvent. The diol on which the
radicals Q.sup.3 and Q.sup.4 are based is advantageously employed
in an equimolar amount, based on the boronic acid.
[0041] Preferred radicals Q.sup.3 and Q.sup.4 are
--O-(C.sub.1-C.sub.6)alk- yl, --O-(C.sub.2-C.sub.6)alkenyl,
--O-(C.sub.3-C.sub.6)-alkynyl, --O-phenyl, --O-benzyl, or Q.sup.3
and Q.sup.4, together with the boron atom, form a cyclic boronate
with the alcohols ethylene glycol, 1,2-propanediol,
1,3-propanediol, 1,4-butanediol, 2,2-dimethylpropane-1,3- -diol,
pyrocatechol, pinacol, 2,3-dihydroxynaphthalene,
1,2-dihydroxycyclohexane, 1,3-dihydroxycyclopentane or
1,2-dihydroxycyclooctane.
[0042] Particularly preferred radicals Q.sup.3 and Q.sup.4,
together with the boron atom, form a cyclic boronate with the
alcohols ethylene glycol, 1,3-propanediol, 2,2-dimethyl-1,3-diol,
pinacol and pyrocatechol.
[0043] The trimeric compounds of the formula (Ib) or (IVb) can be
prepared from the corresponding monomeric compounds of the formula
(I) or (IV) respectively, for example by heating at from 40 to
100.degree. C., preferably from 50 to 75.degree. C.
[0044] The process according to the invention is shown in Scheme 1
below: 14
[0045] The aldehyde group is firstly converted into a
magnesium-unreactive form, for example into a cyclic or a cyclic
acetal, preferably ethylene glycol acetal, dimethyl or diethyl
acetal, an oxazolidine or an oxazoline.
[0046] Chlorobenzaldehydes can be reacted with 1,2-diols by
conventional methods to give correspondingly substituted
1,3-dioxolanes of the general formula (V) or with trialkyl
ortho-esters, such as trimethyl orthoformate, triethyl
orthoformate, triisopropyl orthoformate or corresponding
orthoacetates, to give acyclic acetals of the general formula (VI).
Preference is given here to the reactions with ethylene glycol,
pyrocatechol, trimethyl orthoformate, triethyl orthoformate or
triisopropyl orthoformate.
[0047] Chlorobenzaldehydes can be reacted with 1,2-aminoalcohols
which are monosubstituted on the nitrogen to give correspondingly
substituted oxazolidines of the general formula (VII) by azeotropic
distillation of the water of reaction (T. H. Fife, L. Hagopian, J.
Am. Chem. Soc. 1968, 1007-1014). Preferred aminoalcohols are
N-methyl-2-aminoethanol, N-ethyl-2-aminoethanol,
N-propyl-2-aminoethanol, N-butyl-2-aminoethanol,
N-phenyl-2-aminoethanol, N-benzyl-2-aminoethanol,
N-methyl-2-aminopropano- l, N-ethyl-2-aminopropanol,
N-propyl-2-aminopropanol, N-butyl-2-aminopropanol, particularly
preferably N-ethyl-2-aminoethanol, N-butyl-2-aminoethanol,
N-phenyl-2-aminoethanol, N-benzyl-2-amino-ethanol- .
[0048] It is furthermore possible to react the correspondingly
substituted chlorobenzoyl chloride with 1,2-aminoalcohols by a
method described in J. Org. Chem. 1988, 53, 345-352, to give
oxazolines. 15
[0049] Preference is given here to 2-amino-2-methylpropan-1-ol and
2-aminoethanol.
[0050] The compound of the formula (II) is converted in accordance
with the invention into the Grignard compound of the formula (III)
using Mg powder or turnings in the presence of
[0051] i) an anthracene compound or ii) an anthracene compound and
a transition-metal halide or iii) an anthracene compound and a
magnesium halide or iv) an anthracene compound, a transition-metal
halide and a magnesium halide or v) a transition-metal halide or
vi) a transition-metal halide and a magnesium halide.
[0052] The anthracene compounds employed can be unsubstituted
anthracene or Mg anthracene, substituted, for example by 1 to 4
(C.sub.1-C.sub.4)-alkyl groups or phenyl groups, anthracene or Mg
anthracene, in particular 9,10-diphenylanthracene or Mg
9,10-diphenylanthracene. The anthracene compounds can be added in
amounts of from 0.5 to 100 mol %, preferably from 1 to 10 mol %,
based on the haloaromatic compounds, or alternatively formed in
situ.
[0053] The transition-metal halides are preferably chlorides or
bromides, in particular FeCl.sub.2, MnCl.sub.2, FeBr.sub.2 or
MnBr.sub.2. The transition-metal halides can be added in amounts of
from 0.5 to 100 mol %, preferably from 1 to 10 mol %, based on the
haloaromatic compounds.
[0054] Suitable magnesium halides are MgCl.sub.2 and MgBr.sub.2.
They can be added in amounts of from 0.5 to 100 mol %, preferably
from 1 to 10 mol %, based on the haloaromatic compounds.
[0055] The Grignard reaction is preferably carried out at the
boiling point of the corresponding solvent and under a
protective-gas atmosphere. Suitable solvents are usually
tetrahydrofuran, diethyl ether, monoglyme and diglyme and a
solution of N,N,N',N'-tetramethylethylenediamine in toluene. It may
be advantageous before commencement of the reaction to activate the
magnesium by a method described in Y.-H. Lai, Synthesis 585-604
(1981) or to carry out the Grignard reaction in the presence of
small amounts, for example from 0.01 to 10 mol %, preferably from
0.1 to 1 mol %, based on the haloaromatic compounds, of a
haloalkane, such as, for example, 1,2-dibromoethane, bromoethane or
iodomethane.
[0056] The compound of the formula (III) is novel and is likewise a
subject-matter of the present invention. The compound of the
formula (III) can be isolated by removing the solvent by
distillation under a protective-gas atmosphere.
[0057] In order to obtain phenylboronic acids, the compound of the
formula (III) is reacted, preferably without interim isolation,
with the borate of the formula B(OR').sub.3, in particular with
B(OCH.sub.3).sub.3, B(OEt).sub.3 or B(OiPr).sub.3, and subsequently
hydrolyzed under aqueous conditions to give a compound of the
formula (IV). The reaction with the borate is advantageously
carried out at a temperature of from -80.degree. C. to +20.degree.
C., preferably from -50.degree. C. to +10.degree. C., in particular
from -25.degree. C. to 0.degree. C.
[0058] The borate is advantageously employed in a 1- to 1.5-fold
molar amount, based on the Grignard compound.
[0059] The compound of the formula (IV) can subsequently be
hydrolyzed under acidic conditions, for example using sulfuric acid
at pH 0 to 3. If D is an acetal or oxazolidine group, a preferred
procedure is, when the addition of the borate is complete, to add
the reaction mixture to ice-water and to set the pH of the
suspension to from 1 to 2, for example using sulfuric acid, giving
the compound of the formula (IV) in which D.sup.1 is CHO and
Q.sup.1 and Q.sup.2 are each OH.
[0060] Oxazolines, i.e. D is a radical of the formula (VIII), can
be converted into the aldehyde by a method described in J. Am.
Chem. Soc. 1983, 105, 1586-1590, by alkylation on the nitrogen
using alkyl halides, for example methyl iodide, methyl bromide,
ethyl iodide or ethyl bromide, or using dialkyl sulfates, for
example dimethyl sulfate or diethyl sulfate, hydrogenation using
complex metal hydrides, such as LiAlH.sub.4, NaBH.sub.4 or
NaBH.sub.3(CN), followed by acidic hydrolysis. 16
[0061] During the hydrolysis, the aldehyde predicting group is
removed and the boronate is converted into the free boronic acid.
The formylphenylboronic acid of the formula (I) in which Z is CHO
can be isolated from the organic phase of the reaction mixture.
[0062] Secondary products can be prepared as shown in Scheme 2 by
oxidation or reduction of the aldehyde. In this scheme, Q.sub.10
and Q.sub.20 are Q.sub.1 and Q.sub.2, or Q.sub.3 and Q.sub.4 if the
formylphenylboronic acid is esterified, before the oxidation or
reduction, by the above-described method using an alcohol on which
the radicals Q.sub.3 and Q.sub.4 are based, in an inert organic
solvent. This is particularly advantageous if oxidation is
subsequently carried out. 17
[0063] a) From formylphenylboronic acid and its borates, the
corresponding cyanophenylboronic acid of the formula (I) in which Z
is CN is obtained by reaction with hydroxylamine or
hydroxylammonium salts followed by dehydration of the oxime formed.
The dehydration can be carried out by heating in glacial acetic
acid or in acetic anhydride (J. Chem. Soc. 1933, IX, 43). By a
method proposed in EP-A1-0 790 234, the nitrile function is
obtained by reaction of the benzaldehyde derivative with
hydroxylamine sulfate in the presence of a tertiary amine base and
azeotropic distillation of the water of reaction.
[0064] b) The corresponding carboxyphenylboronic acid of the
formula (I) in which Z is COOH can be prepared by oxidation of
formylphenylboronic acid using barium permanganate or potassium
permanganate, for example in accordance with U.S. Pat. No.
5,631,364.
[0065] c) The compound of the formula (I) in which Z=CH.sub.2OH can
be obtained by reduction using Raney nickel/hydrogen or using
complex metal hydrides, such as LiAlH.sub.4 or NaBH.sub.4.
[0066] d) The compound of the formula (I) in which Z=COCl can be
obtained by a method described in Ginsburg, D., J. Amer. Chem.
Soc., 1951, 73, 702-704, by reaction of formylphenylboronic acid
with t-BuOCl in carbon tetrachloride.
[0067] Starting from cyanophenylboronic acid or borates, further
secondary products can be prepared in accordance with Scheme 3.
EXAMPLES
[0068] 18
[0069] e) Carboxyphenylboronic acids can be obtained by hydrolysis
of cyanophenylboronic acid, for example analogously to M. V.
Sargent, J. Chem. Soc. Perkin Trans. 1, 1987 (1), 231.
[0070] f) Carboxamidophenylboronic acids can be prepared by a
method described in Liu, K.-T.; et al., Synthesis 1988 (9), 715,
starting from cyanophenylboronic acid using MnO.sub.2 on silica gel
and water in an organic solvent.
[0071] g) Carboxylic acid orthoester phenylboronic acids can be
prepared by a method described in P. Hamann et al., Synthetic
Commun. (1989) 19 (9-10.), 1509-1518, from cyanophenylboronic acid
using the corresponding alcohol ROH with addition of anhydrous
hydrogen chloride to give the corresponding orthoester, in which R
can be C.sub.1-C.sub.12-alkyl or aryl, preferably methyl, ethyl or
phenyl.
[0072] h) Methyleneaminophenylboronic acids can be prepared by a
method described in B. S. Biggs et al., Org. Synth. 1947, 27, by
hydrogenation using hydrogen and Raney nickel as catalyst.
Example 1
[0073] 2.7 g (110 mmol) of magnesium turnings were added to a
solution of 2 g (11 mmol) of anthracene in 100 ml of THF, and a few
drops of 1,2-dibromoethane were added. After the mixture had been
stirred at room temperature for about 2 hours, the bright orange
precipitate of magnesium anthracene had formed. A solution of 19 g
(100 mmol) of 4-chlorobenzaldehyde dimethyl acetal in 100 ml of THF
was added to the refluxing suspension over the course of 1 hour.
After the mixture had refluxed for 4 hours, the yield of Mg
4-chlorobenzaldehyde dimethyl acetal according to GC analysis
(determined as benzaldehyde after hydrolysis using dilute HCl) was
90%.
Example 2
[0074] 100 ml of THF, 1.18 g (5.5 mmol) of anhydrous iron(II)
bromide, 1.01 g (5.5 mmol) of magnesium bromide and a few drops of
dibromoethane were added to 2.7 g (110 mmol) of magnesium turnings.
After the mixture had been stirred at room temperature for about 2
hours, the mixture had become a dark-brown to black color. A
solution of 19 g (100 mmol) of 4-chlorobenzaldehyde dimethyl acetal
in 100 ml of THF was added to the refluxing suspension over the
course of 1 hour. After the mixture had refluxed for 4 hours, the
yield of Mg 4-chlorobenzaldehyde dimethyl acetal according to GC
analysis (determined as benzaldehyde after hydrolysis using dilute
HCl) was 95%.
Example 3
4-Formylboronic Acid
[0075] A Grignard solution as obtained from Example 1 or 2 was
added dropwise at -50.degree. C. to a suspension of 10.4 g (100
mmol) of trimethyl borate in 300 ml of THF over the course of 3
hours. When the addition was complete, the white suspension was
poured into 200 g of ice-water. The suspension was adjusted to pH 1
to 2 using conc. H.sub.2SO.sub.4. When the hydrolysis was complete,
the phases were separated, giving 12.45 g (83 mmol) of
4-formylboronic acid.
Example 4
[0076] Example 3 was repeated with a reaction temperature of
-15.degree. C.: yield 11.85 g (79 mmol) of 4-formylboronic
acid.
Example 5
4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)benzaldehyde
[0077] A suspension of 5 g (33.3 mmol) of 4-formylphenylboronic
acid and 3.93 g (33.3 mmol) of pinacol in 25 ml of toluene was
refluxed on a water separator. When all the water of reaction had
been removed, a clarifying filtration was carried out, and the
solvent was removed by distillation until the product started to
crystallize, giving 7.2 g (31 mmol) of product.
Example 6
4-Cyanophenylboronic Acid
[0078] 17 g (100 mmol) of hydroxylamine sulfate were added at
70.degree. C. to 15 g (100 mmol) of 4-formylphenylboronic acid, 10
g of water, 5 g (60 mmol) of pyridine and 200 ml of toluene. The
mixture was then refluxed on a water separator. When all the water
had been removed, the pyridinium salts were separated off, giving
12.7 g (87%) of 4-cyanophenylboronic acid.
Example 7
Pinacolyl 4-cyanophenylboronate
[0079] 17 g (100 mmol) of hydroxylamine sulfate were added at
70.degree. C. to 23.2 g (100 mmol) of pinacolyl
4-formylphenylboronate, 10 g of water, 5 g (60 mmol) of pyridine
and 200 ml of toluene. The mixture was then refluxed on a water
separator. When all the water had been removed, the pyridinium
salts were separated off, giving 20.8 g (91%) of pinacolyl
4-cyanophenylboronate.
Example 8
4-Carboxyphenylboronic Acid
[0080] 14.5 g (100 mmol) of 4-cyanophenylboronic acid were
dissolved in a mixture of 11 g (200 mmol) of potassium hydroxide
and 10 g of water in 100 ml of methanol, and the mixture was
refluxed until the evolution of ammonia gas was complete, giving
14.9 g (90 mmol) of 4-carboxyphenylboronic acid.
Example 9
Esterification of 4-carboxyphenylboronic Acid
[0081] 4-Carboxyphenylboronic acid and an equimolar amount of the
appropriate diol shown in Table 1 were refluxed in 200 ml of
toluene. When all the water formed had been removed on a water
separator (after about 1 hour), the solution was filtered through a
suction filter while still hot. The solvent was subsequently
removed by distillation.
1TABLE 1 Amount of starting Diol material Product Yield Pinacol 30
g 4-(4,4,5,5-Tetramethyl- 43.1 g (97%) (180
[1,3,2]dioxaborolan-2-yl)- mmol) benzoic acid Neopentyl 16.6 g
4-(5,5-Dimethyl- 22 g (94%) glycol (100 [1,3,2]dioxaborinan-2-yl)-
mmol) benzoic acid Ethylene glycol 200 g
4-[1,3,2]Dioxaborolan-2-yl- 227.1 g (98%) (1.2 mol) benzoic acid
Diethanolamine 20 g 4-[1,3,6,2]Dioxazaborocan- 27.5 g (98%) (120
2-yl-benzoic acid mmol)
Example 10
4-Carboxamidophenylboronic Acid
[0082] 10 g (68 mmol) of 4-cyanophenylboronic acid were refluxed
for 6 hours in a mixture of 12 g (135 mmol) of manganese dioxide,
10 g of water and 150 ml of cyclohexane. 9.6 g (58 mmol) of
4-carboxamidophenylboronic acid were isolated.
Example 11
4-(Trimethoxymethyl)phenylboronic Acid
[0083] 30 g (203 mmol) of 4-cyanophenylboronic acid were dissolved
in 200 ml of methanol, and 200 ml of 1 M hydrogen chloride solution
in diethyl ether were added. The reaction mixture was refluxed for
8 hours, giving 38.5 g (170 mmol) 4-(trimethoxymethyl)phenylboronic
acid
Example 12
4-(Methylamino)phenylboronic Acid
[0084] 30 g (203 mmol) of 4-cyanophenylboronic acid were dissolved
in 200 ml of tetrahydrofuran, and 0.5 g of Raney nickel were added.
A stream of hydrogen was passed through the reaction mixture for 8
hours, giving 29.8 g (199 mmol) of 4-(methylamino)phenylboronic
acid.
Example 13
4-(Hydroxymethyl)phenylboronic Acid
[0085] 15 g (100 mmol) of 4-formylphenylboronic acid were dissolved
in 200 ml of tetrahydrofuran, and 0.25 g of Raney nickel were
added. A stream of hydrogen was passed through the reaction mixture
for 8 hours, giving 14.8 g (97 mmol) of
4-(hydroxymethyl)phenylboronic acid.
Example 14
Pinacolyl 4-(hydroxymethyl)phenylboronate
[0086] Analogously to Example 12, 12 g (52 mmol) of pinacolyl
4-formylphenylboronate were hydrogenated in 100 ml of methanol,
giving 11.7 g (50 mmol) of 4-(hydroxymethyl)phenylboronic acid.
* * * * *