A direct and sustainable synthesis of tertiary butyl esters enabled by flow microreactors

Abstract

Tertiary butyl esters find large applications in synthetic organic chemistry. A straightforward method for the direct introduction of the tert-butoxycarbonyl group into a variety of organic compounds has been developed using flow microreactor systems. The resultant flow process was more efficient, versatile and sustainable compared to the batch.

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org Concept stable hetero-substituted organolithiums generated in flow by deprotonation has been reported by Barker andc o-workers. [23] Ad ifferent approach, for the introduction of ad ihalomethylenic unit, was recently reported by Knochel, who developed a continuousf low tactic for homologation of esters using di-chloroacetic acid 13.T he reported strategy, was an unprecedented mild and scalable Claisen reactiont hat used an unstable chloroacetated ianion tamed using flow technology (Scheme 6).…”

“…Luisi and co-workers, recently developed ac ontinuous flow direct introductiono ft he carboxylic functionality,a st he tertbutyl ester unit. [32] The flow conditions allowed to control the chemoselectivity of the process, [33] avoiding the formation of the by-product tertiary alcohol( Scheme12a). The flow process could be efficiently appliedt oa ryllithiums,a lkenyllithiumsa s well as alkynyllithiums.…”

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org tion of an aldol reactioni nvolving an ester lithium enolate and an aldehydee nding up with adduct 29 (Scheme 14). [41] To comply with recommendations by pharmaceutical regulatory authorities, the process was designedt aking advantages from processa nalytical technology( PAT) that allow for an accurate processd evelopment.…”

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

“…Another nice example on the use of microreactor technology for the development of sustainable chemical processes, is represented by the direct introduction of the tert -butoxycarbonyl group into organometallic reagents [34]. The reaction between organolithium reagents and di- tert -butyl dicarbonate run under flow conditions, allowed a straightforward preparation of several tert -butyl esters.…”

Recent advancements on the use of 2-methyltetrahydrofuran in organometallic chemistry

“…Luisi et al performed a direct and sustainable synthesis of tertiary butyl esters by the addition of organolithiums to (Boc) 2 O under microfluidic conditions by employing 2-MeTHF as the solvent [60]. The reactions conducted under batch condition needed cryogenic temperatures, and considerable amounts of the corresponding tertiary alcohols were formed as a consequence of the predictable multiple addictions.…”