Flow Chemistry under Extreme Conditions: Synthesis of Macrocycles with Musklike Olfactoric Properties

Abstract

Starting from small cyclic ketones, continuous flow synthesis is used to produce medium-sized rings and macrocycles that are relevant for the fragrance industry. Triperoxides are important intermediates in this process and are pyrolyzed at temperatures above 250 °C. The synthesis is carried out in two continuously operated flow reactors connected by a membrane-operated separator. The practicality of flow chemistry is impressively demonstrated in this work by the use of hazardous reagent mixtures (30% H2O2, 65% HNO3) and the pyrolysis of no less problematic peroxides. All new macrocycles were tested for their olfactory properties in relation to musk.

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

“…An illustrative multistep protocol with practical relevance to the fragrance and flavor industry is a three-step flow-through protocol leading to macrocycles with musk-like olfactoric properties, which was realized under extreme conditions. These include the use of safety-hazardous reaction mixtures, the handling of explosive intermediates, and their pyrolysis at high temperatures ( Scheme 17 ) [ 93 ]. Cyclohexanone ( 25 ) was mixed with conc.…”

Synthesis of odorants in flow and their applications in perfumery

“…Despite the elegance of this access, the safety of this process is questionable complicating the large-scale production in batch. Very recently, Kirschning and co-workers developed a flow protocol to overcome these limitations and prepared various macrolactones from triperoxides by pyrolysis in an inductively heated flow reactor ( Scheme 13 ) [ 50 – 51 ]. Due to the commercial relevance of juniper lactone ( 56 ), they designed a flow setup for a scalable and safe two-step synthesis of 56 from cyclohexanone.…”

Enabling Technology for Supramolecular Chemistry

“…Recently, flow chemistry has been used to optimize the yield, selectivity, and limited scale-up, of both macrocyclic ( Bogdan and James, 2010 ; Bogdan and James, 2011 ; Bedard et al, 2013 ; Bédard et al, 2015 ; Lucke et al, 2016 ; Morin et al, 2019 ; Jones et al, 2021 ; Seemann et al, 2021 ) and cage ( Briggs et al, 2015 ; Kitchin et al, 2015 ) supramolecular structures. For example, Bédard et al synthesized medicinally relevant ( Marsault and Peterson, 2011 ) macrocyclic lipids under continuous flow, with yields of up to 97% in short reaction times ( Bedard et al, 2013 ).…”