Diazonium salts are intermediates that are widely used in organic synthesis. Unlike extensively used aryl diazonium salts, alkyl diazonium intermediates are much less studied, due to their lower stability. They usually decompose into typical carbocation products. Despite the large range of reactivity of these intermediates, and the propension to activate strong C-N bonds, alkyl diazonium salts are generally under-used, mainly due to the lack of control of their reactivity. Continuous flow technology was recently used by our group to perform the esterification of carboxylic acids via the diazotisation of alkylamines. The reaction proceeds in 20 minutes and is compatible with a large range of functional groups. In order to broaden the use of aliphatic diazonium intermediates, we developped a procedure enabling the synthesis of hydroxyesters from carboxylic acid and aminoalcohols. Polyfonctiunnalyzed esters were obtained in continuous flow within a 30-60 min residence time. The procedure was also expended to batch, using a novel, more stable dinitrite reagent stemming from cheap neopentyl glycol. The reaction proceeded with excellent yields within a 6-16 h reaction time, and no products of intramolecular cyclisation of hydroxydiazonium intermediates were detected. Lactones were also abtained from an aminoacid. Diazotisation of alkyl amines was also performed with electronically defficient phenols, such as 4-nitrophenol. Aryl-alkylethers were obtained in good yield in 1 h. Finally the diazotisation reaction was expended to 1H-5-substituted tetrazole, leading to the preferential formation of 2,5-disubstituted tetrazoles. The procedure was used in a one-pot cycloaddition-diazotisation reaction, starting from widely available nitriles. Several parameters influencing the ratio of the isomers were studied. Ratio up to &gt;95:5 were obtained.

Batch and continuous flow functionalization of diazonium intermediates

ACS Fall 2021

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