Development of a selective and scalable N1-indazole alkylation.

N1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish N1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of N1-alkyl indazoles. The procedure is highly selective for N1-alkylation, practical, and broad in scope, with no N2-alkyl products detected at completion. Mechanistic understandings were consistent with attributing the high selectivity to thermodynamic control. Additional data-driven process development led to this reaction being safely demonstrated on a 100 g scale, with potential for further scale up. This study highlights pragmatic principles followed to develop a necessitated methodology, suitable for large scale manufacture.

On the Use of Triarylsilanols as Catalysts for Direct Amidation of Carboxylic Acids.

Triarylsilanols have been reported as the first silicon-centered molecular catalysts for direct amidation of carboxylic acids with amines as identified after a screen of silanols, silanediols, disiloxanediols, and incompletely condensed silsesquioxanes as potential homogeneous catalysts. Subsequent synthesis and testing of various electronically differentiated triarylsilanols have identified tris(p-haloaryl)silanols as more active than the parent triarylsilanol, where the bromide congener is found to be the most active. Catalyst decomposition can be observed by NMR methods, but RPKA methods reveal that product inhibition is operative, where tertiary amides are more inhibitory than secondary amides. Studies using an authentically synthesized triaryl silylester as a putative intermediate in the catalytic system enable a plausible mechanism to be proposed as supported by computationals.

Tetramethyl Orthosilicate (TMOS) as a Reagent for Direct Amidation of Carboxylic Acids.

Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.