Process for the preparation of arylamides of heteroaromatic carboxylic acids

A process for the preparation of an amide of the formula:

• wherein:
• A1 is nitrogen or CR1,
• A2 is nitrogen or CR2,
• A3 is nitrogen or CR3,
• A4 is nitrogen or CR4 and
• A5 is nitrogen or CR5,
• with the proviso that at least one of the ring members A1 to A5 is nitrogen and that two nitrogen atoms are not bonded directly to one another;
• R1 to R5, if present, independently of one another are hydrogen, C1-4-alkyl or aryl, but one of the substituents R1 to R5 is a group of the formula —OR, wherein R is an optionally substituted aromatic or heteroaromatic radical;
• R6 is hydrogen or C1-4-alkyl;
• and
• R7 is an optionally substituted aromatic or heteroaromatic radical, said optional substituents being ones which will not undergo alkylation, comprising, in a first step, reacting a dihalide of the general formula:
• wherein A1 to A5 are as defined above, X is chlorine, bromine, or iodine, one of the radicals R1 to R5 on a carbon atom adjacent to a ring nitrogen atom is Z, Z being chlorine, bromine, or iodine, and the remaining radicals R1 to R5, if present, are as defined above, with an aromatic or heteroaromatic hydroxyl compound of the formula:
• R—OH VI
• wherein R is as defined above, to give a (hetero)aryloxy halogen compound of the formula:
• wherein A1 to A5 are as defined above, and, in a second step, reacting said product of formula II with carbon monoxide and a primary or secondary amine of the formula:
• R6—NH—R7 III
• wherein R6 and R7 are as defined above, in the presence of a complex of palladium with a triphenylphosphine of the formula:
• wherein R8 to R10 independently of one another are C1-4-alkyl, or fluorine, and with a base other than a primary or secondary or tertiary amine.

A process for the preparation of an amide of the formula

• wherein:
• A1 is nitrogen or CR1,
• A2 is nitrogen or CR2,
• A3 is nitrogen or CR3,
• A4 is nitrogen or CR4 and
• A5 is nitrogen or CR5,
• with the proviso that at least one of the ring members A1 to A5 is nitrogen and that two nitrogen atoms are not bonded directly to one another;
• R1 to R5, if present, independently of one another are hydrogen, C1-4-alkyl or aryl, but one of the substituents R1 to R5 is a group of the formula —OR, wherein R is an optionally substituted aromatic or heteroaromatic radical;
• R6 is hydrogen or C1-4-alkyl;
• and
• R7 is an optionally substituted aromatic or heteroaromatic radical, said optional substituents being ones which will not undergo alkylation, comprising reacting a halogen compound of the formula:
• wherein A1 to A5 are as defined above and X is chlorine, bromine, or iodine, directly with carbon monoxide and a primary or secondary amine of the formula:
• R6—NH—R7 III
• wherein R6 and R7 are as defined above, in the presence of a complex of palladium with a triphenylphosphine of the formula:
• wherein R8 to R10 independently of one another are C1-4-alkyl, C1-4-alkoxy, fluoro, or benzyloxy, provided at least one of R8, R9, and R10 is benzyloxy, and with a base other than k primary or secondary or tertiary amine.

A process for the preparation of an amide of the formula:

• wherein:
• A1 is nitrogen or CR1,
• A2 is nitrogen or CR2,
• A3 is nitrogen or CR3,
• A4 is nitrogen or CR4 and
• A5 is nitrogen or CR5,
• with the proviso that at least one of the ring members A1 to A5 is nitrogen and that two nitrogen atoms are not bonded directly to one another;
• R1 to R5, if present, independently of one another are hydrogen, C1-4-alkyl or aryl, but one of the substituents R1 to R5 is a group of the formula —OR, wherein R is an optionally substituted aromatic or heteroaromatic radical;
• R6 is hydrogen or C1-4-alkyl;
• and
• R7 is an optionally substituted aromatic or heteroaromatic radical, said optional substituents being ones which will not undergo alkylation, comprising, in a first step, reacting a dihalide of the general formula:
• wherein A1 to A5 are as defined above, X is chlorine, bromine, or iodine, one of the radicals R1 to R5 on a carbon atom adjacent to a ring nitrogen atom is Z, Z being chlorine, bromine, or iodine, and the remaining radicals R1 to R5, if present, are as defined above, with an aromatic or heteroaromatic hydroxyl compound of the formula:
• R—OH VI
• where R is as defined above, to give a (hetero)aryloxy halogen compound of the formula:
• wherein A1 to A5, R and X are as defined above, and, in a second step reacting said product of formula II with carbon monoxide and a primary or secondary amine of the formula:
• R6—NH—R7 III
• wherein R6 and R7 are as defined above, in the presence of a complex of palladium with a triphenylphosphine of the formula:
• wherein R8 to R10 independently of one another are C1-4-alkyl, C1-4-alkoxy, fluoro, or benzyloxy, provided at least one of R8, R9, and R10 is benzyloxy, and with a base other than said primary or secondary or tertiary amine. —