INTERMEDIATES USEFUL IN THE PRODUCTION OF PESTICIDES

Abstract: A process for the production of a boronic acid of formula III, in which an organometallic of formula IV in which formula IV, M represents a metallic moiety such as -MgX, X being a halogen or an alkali metal is treated with a trialkoxy borane of formula B(OH)₃, R representing an alkyl group and the product is hydrolysed.

Description: This invention relates to production of intermediates useful in the manufacture of pesticides. In International Patent Application No. GB 85/00146 there are disclosed methods for the preparation of compounds of formula I I R A CR₃=CR₄CHDR B in which formula: RA represents a group ArCR₁R₂ - in which Ar represents a phenyl or naphthyl group optionally substituted by one or more halogen, alkoxy, haloalkoxy, methylenedioxy, C₁-C₆ alkyl or haloalkyl groups; R₁ and R₂ together with the carbon to which they are attached represent a C₃-C₆ cycloalkyl group optionally substituted by one or more halogen atoms or C₁-C₆ alkyl groups. R₃ and R₄ which may be identical or differ, represent hydrogen, halogen or C₁-C₆ alkyl groups and R B represents the residue of an alcohol R B CHDOH in which D is hydrogen or cyano and of which the [IR, cis ] 2,2-dimethyl-3-(2,2-dibromovinyl) cyclopropane carboxylic ester is significantly insecticidal, the configuration of R A and CHDR B about the double bond being mutually trans . Compounds I in which R B represents 4-fluoro-3-phenoxyphenyl are of particular interest and may be prepared inter alia by reaction of the Grignard reagent, 4-fluoro-3-phenoxyphenyl magnesium bromide with a suitable substrate. The bromide required for preparation of this Grignard reagent (5-bromo-2-fluorodiphenyl ether) (II), has, however, been available hitherto only with difficulty. It has now however been found that the bromide and other intermediates can be generated in good yield from 2,4-dibromofluorobenzene, which is available commercially although generally contaminated with the isomer 3,4-dibromofluorobenzene. Accordingly, the present invention comprises a process for the production of a boronic acid of formula III, convertible into 5-bromo-2-fluorodiphenyl ether (II), in which an organometallic of formula IV, obtainable from 2,4-dibromofluorobenzene, in which formula IV M represents a metallic moiety such as -MgX, (X being a halogen) or an alkali metal such as lithium is treated with a trialkoxy borane of formula B(OR)₃, R representing an alkyl group (e.g. a C₁-6₆ alkyl group which is preferably methyl) and the product is hydrolysed. It has been found that the boronic acid III crystallizes readily and that the crystals are substantially free of impurities and particularly isomers of the acid III derived from metallation at the 4-bromo position of 2,4-dibromofluorobenzene or derived from 3,4-dibromofluorobenzene impurity in the starting material. Accordingly, in a preferred embodiment of the present process, the boronic acid III is crystallised and the crystals are isolated prior to further treatment. Although US Patents Nos. 3090801 and 2898365 describe the production of arene boronic acids by a Grignard reaction the teaching relates to the use as starting materials of halides which can yield only one isomer whereas in the present case two can be produced, theoretically. Although it was not predictable which isomer could predominate it has been found that bromine adjacent flourine reacts in preference to the other bromine in 2,4-dibromofluorobenzene and that 2,4-dibromofluorobenzene reacts in preference to any contaminating 3,4-dibromofluorobenzene present. The amount of the metal or metal alkyl used to treat 2,4-dibromofluorobenzene and thus produce the organometallic IV may be reduced to 80% or less of the stoichiometric amount. Under these conditions bromine at the 2-position in 2,4-dibromofluorobenzene may react in preference to bromine at the 4-position and 2,4-dibromofluorobenzene may react in preference to 3,4-dibromofluorobenzene present as a contaminant, so that a good yield of the desired isomer of formula IV is obtained. Amounts less than 60% of stoichiometric are undesirable as the yield is unnecessarily decreased. The boronic acid III may be converted into the intermediate 5-bromo-2-fluorodiphenyl ether II, by oxidation, suitably using hydrogen peroxide, to the corresponding phenol V a corresponding alkali metal phenoxide of which VI reacts with a halobenzene, in which the halogen is chlorine, bromine or iodine, under Ullmann conditions e.g. in the presence of a copper catalyst such as copper bronze or a Cu I or Cu II halide to give II The present invention includes in a further aspect an organometallic of formula IV, a boronic acid III, a phenol V, a phenoxide VI and processes as hereinbefore described for the conversion of 2,4-dibromofluorobenzene to the organometallic IV, of the boronic acid III to the phenol V, of the phenol V to the phenoxide VI and of the phenoxide VI to the intermediate 5-bromo-2-fluorodiphenyl ether. The invention is illustrated by the following Example: Dihydroxy-(5-bromo-2-fluorophenyl)-borane A solution of 2,4-dibromofluorobenzene (12.7g,containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15g) in dry THF (50ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7ml) in dry diethyl ether (80ml) under an atmosphere of nitrogen and cooled at -78°C. The mixture is stirred at -78°C for a further 15 min. and glacial acetic acid (6ml) added followed by water (50ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30ml) and then cooled at 0°C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8g m.pt. 173-174°C. 5-Bromo-2-fluorophenol To a stirred solution of dihydroxy-(5-bromo-2-fluorophenyl)-borane (2g) in diethyl ether (10ml) is added chloroform (10ml) and 30% hydrogen peroxide (10ml). The mixture is stirred for 18 hours at room temperature, diluted with water, extracted with diethyl ether (x3) and back extracted with 2M NaOH (or, in an alternative embodiment producing relatively increased yields, with stronger sodium hydroxide, e.g. 5M NaOH). The aqueous layer is acidified with aqueous 2N HCI extracted with diethyl ether (x3), dried and the solvent evaporated to give 5-bromo-2-fluorophenol, yield 1.25g. A sample is purified by t.l.c. on silica gel eluted with 30% diethyl ether in petroleum ether b.p. 60-80°C n D 1.5564. Alternatively, the product is distilled b.p. 52-54°/0.2 mm Hg. 5-Bromo-2-fluoro-diphenyl ether Sodium hydride (0.2g of 60% dispersion in oil) is added in small portions to a stirred solution of 5-bromo-2-fluorophenol (1g) in 2-methoxyethyl ether (1ml) under nitrogen and cooled in a water bath. Cuprous bromide (0.09g) and a solution of bromobenzene (1.5ml) in 2-methoxymethyl ether (2ml) were added and the mixture refluxed for 6 hours. The mixture was poured onto water, extracted with petroleum ether b.p. 60-80°(x3), washed with water, dried, solvent evaporated and the residue distilled at 0.02 mm Hg b.pt. 80-82°C n D 1.5708, Yield 0.55g.

Claims: A process for the production of a boronic acid of formula III, in which an organometallic of formula IV, in which formula IV, M represents a metallic moiety such as -MgX, X being a halogen or an alkali metal is treated with a trialkoxy borane of formula B(OR)₃, R representing an alkyl group and the product is hydrolysed. A process according to Claim 1, in which M in the compound of formula IV represents -MgBr. A process according to Claim 1, in which M in the compound of formula II represents an alkali metal which is lithium. A process according to any preceding Claim, in which R in the compound of Claim 1 represents a C₁-C₆ alkyl group. A process according to any preceding Claim, in which the boronic acid (III) is crystallised substantially free of any isomers thereof. A process according to any preceding Claim, in which the compound IV is produced by metallation at the 4-bromo position 2,4-dibromofluorobenzene using metal or metal alkyl in an amount which is no greater than 80% of the stoichiometric amount required. A process for the production of 5-bromo-2-fluorodiphenyl ether in which a boronic acid III produced in accordance with any preceding Claim is oxidised to 5-bromo-2-fluorophenol the alkali metal phenoxide of which is reacted with a halobenzene under Ulmann conditions. An organometallic compound of formula IV as defined in Claim 1. A boronic acid of formula III as defined in Claim 1. 5-bromo-2-fluorophenol. An alkali metal phenoxide of 5-bromo-2-fluorophenol.

Inventors: ELLIOTT, MICHAEL, JANES, NORMAN FRANK, KHAMBAY, BHUPINDER PALL SINGH
Applicants: NATIONAL RESEARCH DEVELOPMENT CORPORATION
Application year: 1987
Main classification: C07F5
IPC codes: C07C27, C07F5, C07F3, C07F1, C07C41, C07C43, C07C39, C07B49, C07C67