Solvent-free mechanochemical route for green synthesis of pharmaceutically attractive phenol-hydrazones

Abstract

A series of hydrazones, as potential therapeutic agents, were successfully synthesized in a vibratory ball-mill from various substituted organic hydrazines and phenol aldehydes. The degree of conversion was increased by high electronic density on the amino group of the hydrazine reactant, as well as low steric hindrance around both reactive sites. In this particular case, the flexibility of the chain bearing the amino reactive site of hydrazine was highlighted as a factor influencing the reaction rate. The results showed that hydrazones could be obtained with more than a 99% transformation, without concurring by-products. This is highly adapted to the synthesis of active pharmaceutical ingredients, requiring a high level of purity. Owing to the fact that neither an environmentally unadvisable reagent nor additives or catalysts were added to achieve the transformation, this synthesis provides a good example and a prefiguration of an efficient green pharmaceutical process.

Comprehensive experimental investigation of mechanically induced 1,4-diazines synthesis in solid state

“…7e9 Mechanochemistry has been highlighted as an efficient route to prepare different classes of chemicals. 10e14 Organic mechanosyntheses often proceed rapidly, in solvent-free conditions with high yields 10, 15,16 and selectivity 17,18 and can originate unexpected reaction pathways. 19 Neat or liquid-assisted grinding of powders showed also to afford either known or novel products that cannot be prepared otherwise.…”

“…The solid properties are also responsible to promote or hamper product formation. 16,34 The reaction between o-phenylenediamine (1) and 9,10phenanthrenequinone (2a) under ball milling conditions yielding dibenzo[a,c]phenazine (3a) (Scheme 1) was previously investigated by the group. 8 The experimental results indicated the reaction continuation after the milling and a possible push-pull stepwise mechanism was proposed for this post-grinding period.…”

Mechanochemistry for “no solvent, no base” preparation of hydantoin-based active pharmaceutical ingredients: nitrofurantoin and dantrolene

“…In the case of dantrolene, the condensation reaction leading to the hydrazone occurs in the presence of 5-(4-nitrophenyl)-2-furfural, in similar reaction conditions (DMF/HCl 35% 20 or in acetonitrile 21 at room temperature up to 8 hours), with yields in the range 41-96% after purification by precipitation in hexane 22 or water, 20,[23][24] or by colum chromatography. 21 To our surprise, despite the simplicity of the preparation of arylhydrazones in solventfree conditions by mechanochemistry, grinding in a mortar 25 or ball-milling (vibrating [26][27][28][29] or planetary [30][31][32] ) from aryl diazonium salts in the presence of active methylene compounds 29 or more likely, by a condensation reaction, 25,[27][28][30][31] those methodologies were never applied to the preparation of nitrofurantoin 7 or dantrolene 8.…”

Alternative conditions for the synthesis of novel spiro[1,3-N,N-heterocyclic-adamantanes]

“…21 Inspired by the excellent results of the mechanochemical synthesis (e.g., 3a, Table 1, conversion ~ 99%), we decided to extend the ring closure of 1 with the reactions of a number of amides and hydrazides under either aqueous or ball-milling conditions. The idea for our initial mechanochemical experiment stemmed from the study by Oliveira et al, 22 in which a series of hydrazones was synthetized by the ball-milling of aldehydes with hydrazines in the solid state at rt. Conversions of 85-99% were obtained, depending on the aldehyde/hydrazide used.…”