Synthesis of 2-hydroxyarylaldehydes

Details Synthesis of 2-hydroxyarylaldehydes Synthesis of 2-hydroxyarylaldehydes

1998-12-10

2001-08-14

Padmanabhan, Sreeni (Department: 1621)

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

C568S437000, C568S426000

Reexamination Certificate

active

06274068

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to a process for making 2-hydroxyarylaldehydes by reacting an aryloxy magnesium compound with formaldehyde or a compound capable of generating formaldehyde in situ under certain reaction conditions.
BACKGROUND OF THE INVENTION
Ortho-formylated phenols and their derivatives are valuable intermediates in the chemical, pharmaceutical and mining industries. Therefore, processes for making hydroxyarylaldehydes, and in particular, 2-hydroxyarylaldehydes, have been well researched. It is well recognized that such hydroxyarylaldehydes can be made by reacting magnesium phenoxides with formaldehyde.
For instance, Casiraghi et al. described in J. C. S. Perkin I (1978) pp. 318 et seq. that aryloxymagnesium bromide alone or its complexes with hexamethylphosporamide (HMPA) can be reacted with formaldehyde in refluxing benzene and conclude that the absence of HMPA leads to the formation of dihydroxydiphenylmethanes whilst the formation of the desired 2-hydroxyarylaldehydes is promoted only by the presence of stoichiometric amounts of the HMPA ligand. This latter reaction is said to occur via an oxidation-reduction process, promoted by HMPA, between an intermediate 2-hydroxybenzyl alcohol intermediate and formaldehyde. The difference in acidity between the free and HMPA-complexed magnesium counterion is invoked to explain the two reaction pathways.
Similarly, Aldred et al. describe in J. C. S. Perkin I (1994) at pp. 1823 et seq. the deprotonation of phenols using magnesium methoxide, followed by distillative removal of free methanol and addition of paraformaldehyde to generate, by an ortho-specific magnesium-mediated formulation, the corresponding salicylaldehyde magnesium salts from which the salicylaldehydes are isolated by acidic work-up. They further disclose that addition of aqueous hydroxylamine sulphate to the salicylaldehyde magnesium salts, in place of the acid work-up, yields the corresponding salicylaldoximes.
Similar methods are also described in: U.S. Pat. No. 5,260,487 in which 2-hydroxyarylaldehyde is made by reacting a magnesium bis-hydrocarbyloxide, derived at least in part from a hydroxyaromatic compound having at least one free ortho position to the hydroxyl group with formaldehyde under substantially anhydrous conditions; and U.S. Pat. No. 5,354,920 in which 2-hydroxyarylaldehyde is made by reacting an aryloxymagnesium halide with formaldehyde under substantially anhydrous conditions in the presence of a polar organic solvent other than HMPA or 1,3-dimethyl-3,4,5,6-2(1H)-pyrimidone.
It has now been found and the present invention relates to a process in which 2-hydroxyarylaldehydes are made with an active species that contains only non-hydrocarbyloxy ligands attached to the magnesium aryloxide moiety.
SUMMARY OF THE INVENTION
The present invention comprises a process for the preparation of 2-hydroxyarylaldehydes from an aryloxy magnesium salt and formaldehyde, the process comprising reacting at a temperature from 40-120° C.
I. an aryloxy magnesium compound, having an aryloxy anion and a non-aryloxy anion and in which (a) the non-aryloxy anion is more basic than the aryloxy anion such that when the aryloxy magnesium compound is brought into contact with an acidic species, the acid reacts more preferentially with the non-aryloxy anion to form the desired aryloxy magnesium salt and (b) the aryloxy anion has at least one free position ortho to the hydroxyl group in the aryloxy anion, with
II. formaldehyde or a compound capable of giving rise to formaldehyde under the reaction conditions, in the presence of a polar co-solvent capable of providing the non-aryloxy anion in the aryloxy magnesium compound characterized in that the non-aryloxy anion is selected from the group consisting of an oxide, a hydroxide, a carboxylate, a sulphate an a nitrate.
The present invention relates to the creation of 2-hydroxyarylaldehydes. The present invention provides a process for making 2-hydroxyarylaldehydes by reacting an aryloxy magnesium compound with formaldehyde or a compound capable of generating formaldehyde in situ at a temperature from 40-120° C. by a process in which the active species that contains only non-hydrocarbyloxy ligands attached to the magnesium aryloxide moiety.
The present invention also has the ability to tolerate the presence of water.
Finally, the present invention allows the use of water as the acidic species in order to generate non-aryloxy anions in salt as eg. oxide or hydroxide.
DETAILED DESCRIPTION OF THE INVENTION
The aryloxy magnesium salt is suitable derived from an aryloxy magnesium compound which in turn is derived by reacting a phenolic compound which has at least one of the ortho positions, i.e. the 2- and/or 6-positions of the aromatic ring with respect to the carbon carrying the phenolic hydroxyl group, free. The meta and para positions in the aromatic nucleus may carry substituents which are inert under the reaction conditions. Suitable examples of such substituents include one or more of hydrogen atoms; halogen atoms; alkyl, cycloalkyl, and alicyclic groups, aryl groups, alkaryl groups, aralkyl groups having 1-36 carbon atoms; alkoxy groups, aryloxy groups which have from 1-30 carbon atoms; acyl groups which have from 1-24 carbon atoms; and any combinations thereof.
They aryloxy magnesium compound can be prepared by any of the methods known to those skilled in the art. For instance, magnesium in the form of its alkoxide, e.g. methoxide can be reacted with a reactant capable of providing the aryloxy group, i.e. a phenolic compound, such as e.g. paranonyl phenol, in the presence of a non-polar solvent, such as e.g. benzene, toluene, xylene or cyclohexane, optionally in the presence of a polar co-solvent. Examples of polar co-solvents that may be used include one or more of: lower C1-C4 alcohols such as, e.g., methanol and ethanol; amines such as e.g. triethylamine or pyridine; amides such as, e.g., dimethylformamide and N,N-dimethylacetamide; sulphoxides such as e.g., dimethyl sulphoxide; mono-glyme, di-glyme and tri-glyme; and ethers such as e.g., diethyl ether, diphenyl ether and tetrahydrofuran.
The reaction mixture is heated to reflux to allow the magnesium to dissolve. The phenolic compound, e.g. nonyl phenol, is then added to this solution of magnesium alkoxide in a non-polar solvent with agitation to ensure good mixing of the reactants. The mixture is suitably heated for a period to facilitate complete of the reaction. The temperature for this step is preferably within the range from 25° C. to the boiling point of the reaction mixture. The reaction is preferably run at or near the boiling point of the solvent used for the reaction. For example, if toluene is used as the solvent and magnesium methoxide is the alkoxide, the reaction mixture is preferably run at a temperature of about 65° C. The duration of the reaction is generally in the range from 30 minutes to several hours depending upon the reaction temperature employed. In general, lower temperatures will require longer reaction times to complete the conversion. When the reaction is run at or near the boiling point of the solvent system used, a reaction time of 30 to 60 minutes should be sufficient for completion of the conversion. The relative mole ratios of the phenolic compound to the magnesium alkoxide is suitable in the range from about 0.9:1 to about 1.1:1, and is preferably about 1:1. Subsequently, the non-polar solvent and the polar co-solvent are then removed as an azeotrope from the reaction mixture by fractional distillation. The reaction may be carried out at ambient or under reduced pressure, the latter being used to facilitate the removal of volatile by-products of the reaction. The resultant aryloxy magnesium compound is then reacted with a compound capable of providing the desired non-aryloxy anion such as e.g. an oxide, a hydroxide, a carboxylate, sulphate or a nitrate anion to form the desired aryloxy magnesium salt. An example of a compound capable of providing a carboxylate anion s glacial acetic, which provides an ac

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