Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-01-24
2002-05-07
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C568S426000, C568S442000, C568S051000, C568S033000, C568S648000
Reexamination Certificate
active
06384273
ABSTRACT:
The present invention relates to a process for the metallation of a carbocyclic aromatic derivative.
The invention is preferably directed towards the ortho-metallation of 1,3-dimethoxybenzene and more particularly to the preparation of 2,6-dimethoxybenzoic acid.
An o-metallation conventionally denotes a reaction leading to the generation of an anion in an ortho position relative to an electron-donating group present on an aromatic system.
More specifically, the present invention relates to an electrophilic addition to aromatic systems bearing an anion. This mechanism requires, in a first step, the loss of a leaving group, commonly a proton, prior to the addition of the electrophilic group which takes place in a consecutive step.
One of the approaches conventionally adopted for carrying out the first step consists in placing the aromatic derivative which it is desired to functionalize in contact with an organometallic compound in order to metallate it.
The usual reagent proposed for this reaction is butyllithium.
The major drawback of this metallation is precisely the use of butyllithium, which is an expensive reagent.
The reaction of sodium on 1,3-dimethoxybenzene in the presence of chlorobenzene, followed by a carboxylation has also been disclosed (G. Erhardt; Chem. Ber. 2042 (1963)). However, the reaction yield in terms of expected product remains very low on account of the formation of side products.
The object of the present invention is thus to propose a novel route for the metallation of aromatic derivatives which is more advantageous in terms of cost and yield than those mentioned above.
Consequently, a first subject of the present invention is a process for the ortho-metallation of a carbocyclic aromatic derivative bearing at least one electron-donating group, characterized in that the said carbocyclic aromatic derivative is reacted with an effective amount of at least one alkali metal in the presence of a compound of formula (I):
RX (I)
in which
R represents a hydrocarbon-based radical containing from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic radical; a saturated, unsaturated, monocyclic or polycyclic cycloaliphatic radical; or a saturated or unsaturated, linear or branched aliphatic radical bearing a cyclic substituent; and
X represents a bromine or chlorine atom.
In the account which follows of the present invention, the term “aromatic” means the conventional notion of aromaticity as defined in the literature, in particular by Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, 1992, pp. 40 et seq.
More specifically, a subject of the present invention is a process for the ortho-metallation of a carbocyclic aromatic derivative of general formula (II):
in which:
A symbolizes the residue of a ring forming all or part of a monocyclic or polycyclic aromatic carbocyclic system, this system comprising at least one group R′, the said cyclic residue possibly bearing one or more substituents,
R′ represents one or more substituents, which may be identical or different, of electron-donating nature, which are optionally linked together, and
n is a non-zero integer less than or equal to 4.
The electron-donating nature of the radicals R′ is assessed in the context of the present invention according to the scale of electronegativity established by Jerry March, “Advanced Organic Chemistry”, 4th edition, John Wiley and Sons, 1992, pp. 14 et seq. The electronegative nature of a radical is evaluated with regard to that of the hydrogen atom, the value of which is 2.176.
As an illustration of the radicals which may be represented by R′ in the general formula (II), mention may be made in particular of:
a linear or branched alkyl radical containing from 1 to 12 carbon atoms, the hydrocarbon-based chain possibly being interrupted with a hetero atom (for example oxygen), with a functional group (for example —CO—) and/or bearing a substituent such as, for example, an aromatic or non-aromatic cyclic substituent. It may be in particular a linear or branched alkyl radical containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or a linear or branched alkenyl radical containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl or allyl, or a C
1
to C
12
arylalkyl radical such as benzyl,
a carbocyclic radical which is saturated or which comprises 1 or 2 unsaturations in the ring, generally containing from 3 to 8 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted with substituents such as R′. It may be in particular a cycloalkyl group containing from 3 to 8 carbon atoms, such as a cyclohexyl group, and
an aromatic carbocyclic radical, preferably a monocyclic radical, generally containing at least 4 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted. It may in particular be phenyl;
Z(R
1
) with Z representing an oxygen or sulphur atom and R
1
corresponding to the definition proposed for R′ above and preferably featuring
a hydrogen atom,
a linear or branched C
1
to C
6
and preferably C
1
to C
4
alkyl radical such as methyl, ethyl, propyl, ispropyl, butyl, isobutyl, sec-butyl or tert-butyl;
a C
3
to C
8
cycloalkyl radical such as cyclohexyl;
a fused or non-fused C
5
to C
12
aryl radical such as phenyl;
a C
1
to C
12
arylalkyl radical such as benzyl, and
a trialkylsilyl radical,
—R
2
COOR
1
,
—R
2
CO—N(R
3
)
2
,
—R
2
—N(R
3
)
2
,
—R
2
—CF
3
;
with R
2
representing a valency bond or a linear or branched, saturated or unsaturated divalent hydrocarbon-based radical containing from 1 to 6 carbon atoms, such as, for example, methylene, ethylene, propylene, isopropylene or isopropylidene, and the radicals R
3
, which may be identical or different, representing a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, or alternatively
two groups R′ can be linked and form alkylenedioxy or alkylenedithio groups, preferably a methylenedioxy, ethylenedioxy, methylenedithio or ethylenedithio group.
It is understood that the list of examples of substituents R′ given above has no limiting nature. Any substituent can be present on the ring provided that it remains inert under the reaction conditions, i.e. it does not interfere with the ortho-metallation reaction.
In the general formula (II) of the aromatic derivatives, the residue A can represent the residue of a monocyclic aromatic carbocyclic compound containing at least 4 carbon atoms and preferably 6 carbon atoms, or the residue of a polycyclic carbocyclic compound which can consist of at least 2 aromatic carbocycles and together forming ortho- or ortho- and peri-fused systems, or can consist of at least 2 carbocycles, at least one of which is aromatic, and together forming ortho- or ortho- and peri-fused systems. A naphthalene residue may be mentioned more particularly.
Residue A can bear one or more radicals R′ on the aromatic ring.
The process of the invention applies most particularly to carbocylic aromatic derivatives substituted with at least one electron-donating radical featured by a group OR
1
.
In the present text, the expression “alkoxy groups” denotes, in a simplified manner, groups of the type —O—R
1
in which R
1
has the meaning given above. R
1
thus represents either a saturated, unsaturated or aromatic, acyclic aliphatic or cycloaliphatic radical or a saturated or unsaturated aliphatic radical bearing an aromatic or non-aromatic, cyclic substituent, or alternatively a trialkylsilyl radical.
The carbocyclic aromatic ether which is involved in the process of the invention preferably corresponds to formula (II) in which R
1
in OR
1
, represents a saturated or unsaturated, linear or branched acyclic aliphatic radical.
More preferably, R
1
of the aromatic ether represents a linear or branched alkyl radical containing from 1 to 12 carbon atom
Desmurs Jean Roger
Gissot Arnaud
Mioskowski Charles
Pevere Virginie
Wagner Alain
Killos Paul J.
Rhodia Chimie
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