CATALYTIC OXIDATIVE PROCESS FOR PREPARING CARBOXYLIC ACIDS FROM ALCOHOLS OR ALDEHYDES

Abstract: A process for preparing a carboxylic acid of formula R<1>CO2H, wherein R<1> is optionally substituted aryl, optionally substituted heteroaryl or alkenyl optionally substituted by aryl; the process comprising reacting an alcohol of formula R<1>CH2OH or an aldehyde of formula R<1>CHO with oxygen in the presence of a base, a catalytic amount of a copper salt and a suitable ligand; optionally in the presence of an additive.

Description: CATALYTIC OXIDAΗVE PROCESS FOR PREPARING CARBOXYLIC ACIDS FROM ALCOHOLS OR ALDEHYDES The present invention concerns a catalytic oxidative process for preparing carboxylic acids from alcohols or aldehydes. Acids are important intermediates and products in the chemical industry. The present invention provides a process for preparing a carboxylic acid of formula R'CO^, wherein R 1 is optionally substituted aryl, optionally substituted heteroaryl or alkenyl optionally substituted by aryl; the process comprising reacting an alcohol of formula R ! CH OH or an aldehyde of formula R'CHO with oxygen in the presence of a base, a catalytic amount of a copper salt and a suitable ligand. The suitable ligand is a ligand suitable for copper, and is preferably an amine. It is preferably a bidentate ligand such as 1,10-phenanthroline, a substituted 1,10-phenanthroline (for example 5-nitro-l,10-phenanthroline, 5-chloro-l,10-phenanthroline or 5,6-dioxo-l,10- phenanthroline), a pyridine derivative (such as 2,2'-bipyridine, 4,4'-dimethyl-2-2'-bipyridine, 4,4'-bipyridine, 2,2':6',2"-terpyridine or 2,2'-dipyridylamine) or a diamine (such as N,N,N,N-tetramethylethylenediamine or ethylenediamine). Alternatively the ligand is as described and is bound to a polymer support. Oxygen can be supplied in pure form or in the form of air. It is preferred that the base is a strong base such as a hydroxide or an alkoxide (provided the alkoxide is not oxidisable under the reaction conditions, for example tert-butoxide). The alkoxide is, for example, an alkali metal (such as sodium or potassium) Cι-6 alkoxide. It is preferred that a hydroxide is an alkali metal (such as sodium or potassium) hydroxide. When an alcohol of formula R'CI^OH is being oxidised the alkoxide can be prepared in situ. For example a suitable hydride (preferably sodium hydride) or suitable organometallic (such as an alkyl lithium or a Grignard reagent) is added at the beginning of the process and reacts with a quantity of the alcohol of formula R 1 CH 2 OH to provide an alkoxide of formula R'CEkOTvT (wherein M is, preferably, an alkali metal [such as lithium, sodium or potassium] or a Grignard residue [ + MgHalide]) which acts as a base in the processs of the invention. Preferred bases are potassium tert-butoxide, sodium hydroxide or potassium hydroxide. A catalytic amount of a copper salt in a sub-stoichiometric amount, preferably 0.9 equivalents or less, more preferably 0.5 equivalents or less. It is preferred that the molar ratio of copper sal bidentate ligand is about 1:1. In one particular aspect the present invention provides a process wherein the molar ratio of alcohol of formula R'CE^OH or aldehyde of formula R'CHO opper salt:ligand is in the range 1:(0.01-0.10):(0.01-0.10), especially about 1:0.05:0.05. It is preferred that the copper salt is a copper (I) salt. Preferred counter ions are triflate, acetate, cyanide and, especially, chloride. The copper salt and ligand interact to form a complex. Thus, in a further aspect the present invention provides a process for preparing a carboxylic acid of formula R^O^ comprising reacting an alcohol of formula R'CJ^OH or an aldehyde of formula R^HO with oxygen in the presence of a base and a complex of a copper salt and a suitable ligand. The process of the present invention is preferably carried out in the presence of a solvent. Suitable solvents include aromatic solvents (such as benzene, toluene, p-xylene, fluorobenzene, perfluorobenzene, iso-butyl benzene or mesitylene), nitriles (such as acetonitrile), hydrocarbon solvents (such as petroleum fractions), halogenated solvents (such as dichloromethane, tetrachloroethylene or 1,2-dichloroethane) or esters (such as methyl or ethyl acetate). Preferred solvents are aromatic solvents (such as fluorobenzene, toluene, p-xylene, iso-butyl benzene or mesitylene) or hydrocarbon solvents (such as petroleum fractions). The process of the present invention produces water and in some circumstances it may be beneficial to remove excess water while carrying out the process. This can be done by azeotropic removal (for example using a Dean and Stark, or similar, apparatus) or the process can be conducted in the presence of a drying agent (such as potassium carbonate, magnesium sulphate, sodium sulphate or molecular sieves). It is preferred that the process of the invention is carried out at elevated temperature, such as in the range 0-140°C, particularly 30-120°C, especially 60-110°C. The process of the present invention can be carried out at atmospheric pressure, at elevated pressure of up to 10 atmospheres or at autogenic pressure. Alkenyl groups have straight or branched chains and, unless stated otherwise, preferably contain from 2 to 24, especially from 2 to 10, carbon atoms. The alkenyl groups contain one or more (preferably 1, 2, 3 or 4) double bonds. It is preferred that alkenyl optionally substituted by aryl is a β-aryl alkene (that is an alkene of formula aryl(R 2 )C=C(H)CH 2 OH, wherein R 2 is hydrogen or the residue of the alkene group) and, therefore, R ! CO 2 H includes cinnamic acid. Aryl and heteroaryl groups are optionally substituted with one or more of the following: halogen, Ci-io alkyl (especially methyl and ethyl), C 2 .ιo alkenyl (especially allyl), C 2 -ιo alkynyl (especially propargyl), Ci-io alkoxy (especially methoxy), C 2 - 10 alkenyloxy (especially allyloxy), C 2 -ιo alkynyloxy (especially propargyloxy), halo(Cι-ιo)alkyl (especially trifluoromethyl), halo(Cι-ιo)alkoxy (especially trifluoromethoxy), Ci-io alkylthio (especially methylthio), halo(C M0 )alkylthio, Cι- 4 alkoxy(Cι-ιo)alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkyl(C 1 . 10 )alkyl, optionally substituted methylenedioxy (especially optionally substituted with fluorine or C MO alkyl), optionally substituted aryl (especially optionally substituted phenyl), optionally substituted aryloxy (especially optionally substituted phenoxy), optionally substituted aryl(C 1 . 1 o)alkyl (especially optionally substituted benzyl, optionally substituted phenethyl and optionally substituted phenyl n-propyl), optionally substituted aryl(C 2 .ιo)alkenyl (especially optionally substituted phenylethenyl), optionally substituted aryl(Cι-ιo)alkoxy (especially optionally substituted benzyloxy), optionally substituted aryloxy(Cι-ιo)alkyl (especially phenoxymethyl), acyloxy (including Ci-io alkanoyloxy (especially acetyloxy) and benzoyloxy), cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CONR'R", -COOR', -OSO 2 R', -SO 2 R', -COR, -CR=NR" or -N=CR'R" in which R and R" are independently hydrogen, Cι- 4 alkyl, C M alkoxy, C alkylthio, C 3 - 7 cycloalkyl, C 3 - cycloalkyl(Cι- 10 )alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, Ci-io alkyl or Cι-ι 0 alkoxy; or two substituents, when they are in adjacent positions on the aryl or heteroaryl ring can join to form a fused ring (especially to form a fused 5-, 6- or 7-membered ring optionally substituted with aryl (which may be fused), heteroaryl or non-aromatic heterocycle). Substituents which may be present in the aryl or heteroaryl ring of any of the foregoing substituents include one or more of the following: halogen, C O alkyl, C 2 .ιo alkenyl, C 2 . 10 alkynyl, Ci-io alkoxy, C 2 .ιo alkenyloxy, C 2 .ιo alkynyloxy, halo(Cι-ι 0 )alkyl, halo(Cι-ιo)- alkoxy, Cι-ι 0 alkylthio, Ci-io alkoxy(Cι. 10 )alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkyl(C 1 -ιo)alkyl, alkanoyloxy, benzoyloxy, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONRR", -CONR'R", -COOR, -SO 2 R, -OSO 2 R, -COR, -CR*=NR" or -N=CR'R" in which R and R" have the meanings given above. Alkyl groups and alkyl moieties have straight or branched chains and are, for example, methyl, ethyl, n-propyl, jso-propyl or tert-butyl. Alkynyl groups have straight or branched chains and preferably contain one or more (preferably 1 or 2) triple bonds. Alkynyl is, for example, propargyl. Halogen includes bromine and iodine but is preferably chlorine or fluorine. Cycloalkyl is, for example, cyclohexyl. Cycloalkyl groups are optionally substituted by halogen or Ci-β alkyl. Aryl includes fused benzene ring systems (such as naphthyl) but is preferably phenyl. Heteroaryl rings are preferably 5 or 6-membered ring systems comprising 1, 2 or 3 oxygen, sulphur or nitrogen atoms. Heteroaryl is, for example, furan, thiophene, pyridine, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, 1,2,4-triazole, imidazole, a triazine (1,2,3-, 1,2,4- or 1,3,5-), oxadiazole, thiadiazole, oxazole, thiazole or isoxazole. Non-aromatic heterocycle includes azetidine, pyrrolidine, piperidine or morpholine; and such rings are optionally substituted with C O alkyl. In one particular aspect the present invention provides a process for preparing a carboxylic acid of formula R x CO 2 H as hereinbefore defined, the process comprising reacting an alcohol of formula R 1 CH 2 OH, with oxygen in the presence of 0.8-1.5 (especially 1-1.2, preferably about 1) equivalents of a base, a catalytic amount of a copper (I) salt and a suitable ligand; the process being conducted in a solvent. The process of the present invention is optionally carried out in the presence of an additive. Suitable additives include hydrazine or a derivative thereof (such as a l,2-dicarb(Cι- ιo)alkoxyhydrazine (for example 1,2-dicarbethoxyhydrazine, 1,2-dicarbmethoxyhydrazine or 1,2-dicarb-tert-butoxyhydrazine), (2,4-dinitrophenyl)hydrazine, p-tosylhydrazine or a mono- or di- C MO alkylhydrazine (for example 1,2-dimethylhydrazine)), or a compound comprising the group -N=N- (such as a di(Cι-ιo alkyl) azodicarboxylate, for example diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate or di(2,4- dimethylpent-3 -yl) azodicarboxylate) . It is preferred that the molar ratio of suitable additive: copper salt is in the range l:(0.5-4.0), especially l :(0.9-2.5), for example about 1:1 or about 1:2. In another aspect the present invention provides a process for preparing a carboxylic acid of formula R ! CO 2 H as hereinbefore defined, the process comprising reacting an alcohol of formula R'CH^H or an aldehyde of formula R^HO, with oxygen, a base (such as potassium tert-butoxide. sodium hydroxide or potassium hydroxide), a catalytic amount of a copper (I) salt (such as copper (I) chloride), a suitable ligand (such as 1,10-phenanthroline) and optionally an additive (such as 1,2-dicarbethoxyhydrazine or di-tert-butyl azodicarboxylate). The process of the present invention is preferably conducted by mixing a base and an organic solvent and adding to this sequentially: i. a catalytic amount of a copper salt; ii. a suitable ligand; iii. an additive; and then iv. an alcohol of formula R'CH^H or an aldehyde of formula R'CHO. Oxygen or air is then bubbled into the reaction mixture and the reaction mixture is heated. Once the process has gone to completion the product can be separated by either: a) adjusting the pH (for example neutralising) of the reaction mixture with an acid (preferably a strong mineral acid such as hydrochloric acid), and separating the organic phase which contains the product; or, b) filtrating the reaction mixture and washing the residue to leave the filtrate which contains the product. The following Examples illustrate the process of the invention. EXAMPLE 1 This Example illustrates the preparation of p-chlorobenzoic acid. Sodium hydride (90mg, 80% in oil, 3.00mmol) was washed with hexane and suspended in dry toluene (10ml). Copper (I) chloride (lOmg, O.lOmmol) and 1,10- phenanthroline (18mg, 0. lOmmol) were added and the mixture was stirred at room temperature for 10 minutes. p-Chlorobenzyl alcohol (0.285g, 2.00mmol) was added and the reaction mixture was then heated at 90°C while oxygen was bubbled in. Analysis indicated that p-chlorobenzoic acid was formed in 99% yield after 2 hours. EXAMPLE 2 This Example illustrates the preparation of p-chlorobenzoic acid. Copper (I) chloride (10mg, O. lOmmol) and 1,10-phenanthroline (18mg, O.lOmmol) were mixed in toluene (10ml) and the mixture stirred for 10 minutes at room temperature. Potassium tert-butoxide (269mg, 2.4mmol) and p-chlorobenzyl alcohol (0.285g, 2.00mmol) were added successively and the mixture was heated at 90°C while oxygen was bubbled in. The reaction was monitored by X H NMR spectroscopy, which indicated that p-chlorobenzoic acid was formed in 80% yield after 2 hours. EXAMPLES 3-10 These Examples illustrate the preparation of p-chlorobenzoic acid. A copper (I) salt (amount shown in the table below) and 1,10-phenanthroline (one equivalent with respect to the copper (I) salt) were mixed in toluene (10ml) and the mixture stirred for 10 minutes at room temperature. A base and p-chlorobenzyl alcohol (1 equivalent) were added successively and the mixture was maintained at a temperature while oxygen was bubbled in. The reaction was monitored by 1H NMR spectroscopy, which indicated that p-chlorobenzoic acid was formed after 2 hours. Details for these Examples are provided in the table below. KOBu 1 = potassium tert-butoxide * = Sodium hydride reacts in situ with p-chlorobenzyl alcohol to provide sodium p- chlorobenzyl alkoxide. Λ = Molecular sieves used to remove some water produced during process.

Claims: CLAIMS 1. A process for preparing a carboxylic acid of formula R 1 CO 2 H, wherein R 1 is optionally substituted aryl, optionally substituted heteroaryl or alkenyl optionally substituted by aryl; the process comprising reacting an alcohol of formula R^H^H or an aldehyde of formula R^HO with oxygen in the presence of a base, a catalytic amount of a copper salt and a suitable ligand. 2. A process as claimed in claim 1 wherein the copper salt is a copper (I) salt. 3. A process for preparing a carboxylic acid of formula R'CO^ as claimed in claim 1, the process comprising reacting an alcohol of formula R'CHςiOH, with oxygen in the presence of 0.8-1.5 equivalents of a base, a catalytic amount of a copper (I) salt and a suitable ligand; the process being conducted in a solvent. 4. A process for preparing a carboxylic acid of formula R x CO 2 H as claimed in claim 1, wherein the molar ratio of alcohol of formula R'CH ∑ OH or aldehyde of formula R^HO opper sal ligand is in the range 1:(0.01-0.10):(0.01-0.10). 5. A process as claimed in claim 1, 2, 3 or 4 wherein the process is conducted in the presence of a suitable additive. 6. A process as claimed in claim 5 wherein the additive is hydrazine or a derivative thereof. 7. A process as claimed in claim 5 or 6 wherein the additive is a l,2-dicarb(Cι- 10 )- alkoxyhydrazine, (2,4-dinitrophenyl)hydrazine, p-tosylhydrazine, a mono- or di- C M O alkylhydrazine or a di(CMo alkyl) azodicarboxylate. 8. A process as claimed in claim 5, 6 or 7 wherein the molar ratio of suitable additivexopper salt is in the range 1:(0.5-4.0).

Inventors: BROWN STEPHEN MARTIN, GILES PAUL RICHARD, MARKO ISTVAN ETTIENNE, TUSKAZAKI MASAO, URCH CHRISTOPHER JOHN, BROWN, STEPHEN, MARTIN, GILES, PAUL, RICHARD, MARKO, ISTVAN, ETTIENNE, TUSKAZAKI, MASAO, URCH, CHRISTOPHER, JOHN
Applicants: BROWN STEPHEN MARTIN, GILES PAUL RICHARD, MARKO ISTVAN ETTIENNE, TUSKAZAKI MASAO, URCH CHRISTOPHER JOHN, ZENECA LTD, BROWN, STEPHEN, MARTIN, GILES, PAUL, RICHARD, MARKO, ISTVAN, ETTIENNE, TUSKAZAKI, MASAO, URCH, CHRISTOPHER, JOHN, ZENECA LIMITED
Application year: 1997
Main classification: C07C51
IPC codes: C07B33, C07B61, C07C51, C07C63