Application of the heck reaction for the synthesis of 1-alkoxyisoquinoline- 3-carboxylic acids esters

Abstract

It has been shown that the cyclization of the methyl 2-(2,2,2-trifluoroacetylamino)acrylate arylation product using methyl 4,6-dichloro-2-iodobenzoate gives the corresponding 1-methoxyisoquinoline-3-carboxylic acid ester through loss of water rather than methanol. This feature of the condensation has been used for the synthesis of methyl 1-(tert-butoxycarbonylmethoxy)isoquinoline-3-carboxylate.The isoquinoline-3-carboxylic acid structure has attracted the attention of chemists to this time due to the many variants of its modification at different isoquinoline positions and also the possibility of converting the carboxyl group into esters, amides, and heterocycles. For instance, esters of 2,4,6-substituted isoquinoline-3-carboxylic acids have been used in the development of novel protein kinase inhibitors [1]. Selective inhibition of phosphodiesterase type 5 has been found in a series of 1,4,6,7-substituted isoquinoline-3-carboxylic acids [2]. 1-Arylisoquinoline-3-carboxylic acid dialkylamide PK11195 (ligand of peripheral benzodiazepine receptors) is a known chemical biomarker of neurodegeneration [3]. A recent synthesis of 1-aryl-substituted isoquinolines involves the use of the Suzuki reaction [4] and is now used for the preparation of PK11195 [5] and its analogs [6]. The most suitable starting materials for the Suzuki reaction are 1-halo-substituted isoquinoline-3-carboxylic acid esters which are readily prepared from the corresponding 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid esters. The main methods for the synthesis of such compounds are condensation of 1-isochromenones with ammonia or with amines [7,8] or the reaction of o-formylbenzoic acids with derivatives of glycine or its cyclic analogs [9][10][11] or with nitrogen-containing Horner-Wadsworth-Emmons reagents [12,13].A more attractive method for the synthesis of 1-oxo-1,2-dihydroisoquinolines has recently appeared, i.e. the tandem Heck reaction [14] of 2-(acetylamino)acrylates with o-iodobenzoic acid esters and their subsequent cyclization [15]. This route has already been used in the preparation of compound PK11195 [5] and also for development of solid-phase synthetic methods [16]. The indicated method allows the preparation of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid esters unsubstituted in the benzene ring in 60-65% yields.

Dehydroamino acids: chemical multi-tools for late-stage diversification

“…A number of examples have been reported in the literature, often providing, selectively, the Z-product with the new substituent trans to the dhAA carbonyl group. 53 The Heck chemistry can be performed in tandem with heteroannulation to allow access to isoquinolines, 129,130,161 pyrroles, 162,163 and oxazoles. 164 Due to the solubility needs of the catalyst and elevated reaction temperatures, these reactions have mostly been limited to small molecule dhAAs being modified in typically organic solvents.…”