Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

Abstract

A multistep sequential flow synthesis of isopropyl phenol is demonstrated, involving 4-step exothermic, endothermic, and temperature sensitive reactions such as nitration, reduction, diazotization, and high temperature hydrolysis. Nitration of cumene with fuming nitric acid produces 2- and 4-nitrocumene which are converted into respective cumidines by the hydrogenation using Pd/Ni catalyst in H-cube with gravity separation. Hydrolysis of in situ generated diazonium salts in the boiling acidic conditions is carried out using integration of flow and microwave-assisted synthesis. 58% of 4-isopropyl phenol was obtained. The sequential flow synthesis can be applied to synthesize other organic compounds involving this specific sequence of reactions.

Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals

“…S14). 28) The HPLC retention time of 3′ was consistent with that of the by-product in Step b of the 100 mmol scale synthesis using CPME. Although the safety of the solvent has not been evaluated yet, 14) MTHP gave the highest yield and could be of interest.…”

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

“…Thus, Kulkarnia nd co-workers demonstrated the telescoped four-step flow synthesis of isopropyl phenol. [12] This flow method involved temperature-sensitive nitration,r eduction, diazotization, and hydrolysis, yielding 4-isopropyl phenol 38 with 61.7 %o verall yield and 58.4 %r egioselectivity ( Figure 10). It shouldb en oted that the system realized in-line separation by using al iquid-liquid separator at the end of each reaction module.…”

“…Diazotization of anilines can also be used to prepare phenols. Thus, Kulkarni and co‐workers demonstrated the telescoped four‐step flow synthesis of isopropyl phenol [12] . This flow method involved temperature‐sensitive nitration, reduction, diazotization, and hydrolysis, yielding 4‐isopropyl phenol 38 with 61.7 % overall yield and 58.4 % regioselectivity (Figure 10).…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…The implementation of flow technology allows for the rapid saturation of reaction media by making use of biphasic in-line mixing or gas-permeable membranes, leading to improved reaction kinetics. Devices such as the ThalesNano H-Cube ® [118,[224][225][226][227][228][229][230][231][232][233] (Figure 7) are used to effect highly efficient in-line mixing of hydrogen on a laboratory scale. Hydrogen is generated from electrolysis of water giving oxygen (or ozone) as a byproduct.…”