Synthesis of Bi(hetero)aryls via Sequential Oxidation and Decarboxylation of Benzylamines in a Batch/Fully Automated Continuous Flow Process

Abstract

Catalytic dehydrogenative cross‐coupling of two C–H bonds represents a green strategy in view of the atom‐ and step‐economy. However, the challenge is to discover a new innovative bond strategy, especially for the direct coupling between Csp2–H and benzylamines (BzAs). A series of biaryls and bi(hetero)aryls were prepared from commercially available substituted BzAs, AgNO3, cheap K2S2O8 as an oxidant, and benzene/pyridines as the coupling source in batch and flow processes. The batch reaction is somewhat problematic in terms of safety (peroxides, high temperature, high pressure, toxic pyridines), we have chosen an automated flow setup to perform the reaction in a controlled and safe manner in one pot for the synthesis of biaryls. The mechanistic studies revealed that the current protocol involves radical initiation, multi‐step BzA oxidation, and subsequent decarboxylative coupling for the generation of biaryls.

Sulphonated graphene oxide catalyzed continuous flow synthesis of pyrazolo pyrimidinones, sildenafil and other PDE-5 inhibitors

“…Batch process have a low surface to volume ratio and inefficient mixing, results in longer reaction times (4-24 h) to complete the reaction with off-quality product and are hence inappropriate for automation. [20][21][22] The existing batch process involves labour and costconsuming multiple operational processes that need to be absolutely avoided by the chemical industry. In recent years, to minimize the wastage in the chemical reaction, heterogeneous catalysis with packed bed systems is well explored.…”

“…Herein, we observed the sulphonated product 6 was obtained in 10 min, at ambient temperature with 88% yield (see the ESI, Table S3, † entry 4). As shown in (ESI Table S4 †), further to remove the excess amount of the chloro sulfonic acid which is present in the reaction medium and also to minimize the post-downstream purication process, we further appended continuous aqueous quenching, and dropletbased extraction strategy [32][33][34][35][36][37] (see the ESI; Fig. S8 and Table S4 †).…”

“…Batch process have a low surface to volume ratio and inefficient mixing, results in longer reaction times (4–24 h) to complete the reaction with off-quality product and are hence inappropriate for automation. 20–22 …”

Integrated Microfluidic Photo-Flow Process (μ-PFP) for Direct Upconversion of Exhaust Gas to Value-Added Chemicals

“…This autonomous separation was achieved by a simple norm that the hydrophobic liquid could preferentially wet and permeate through the hydrophobic PTFE membrane, while the nonwetting DMSO/water went to the waste without the penetration . Note that the dual channel type of the microseparator was fabricated by using a chemically resistant Teflon film and membrane, unlike previous reports where PDMS (swelling in organic solvent) or polyimide (Hofmann degradation under basic condition) was used ,,− (details in the Supporting Information). Further, a similar strategy was consecutively employed for product separation into 3a , 4a , and 5a by adding strong acid (HCl) and base (NaOH) via two more extraction and phase separation (details in the Supporting Information).…”

An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors

“…Ley’s group also reported the multistep continuous flow process system with an amine-redox cycle followed by hydrolysis of the hydrazine surrogate in an industrial unfavorable solvent and ensuing cyclo-condensation at high temperature (140 °C) with a moderate residence time (28 min) resulting in poor pyrazole (celecoxib) yield (48%). , The micro-total process system (μ-TPS) involves quenching, extraction, and a separation system that does not involve an extra work-up procedure. The system completely addresses the tedious problems related to the organic synthesis. ,,− ,− To understand and further improve the concept of a μ-TUFPS, herein we describe the integrated continuous flow process for pyrazole synthesis via cyclo-condensation of substituted diketone ( 2 ) and 4-hydrazinylbenzenesulfonamide hydrochloride ( 1 ) in a combination of methanol or industrially favorable isopropanol and water as the green solvents. The strategy was further extended to minimize the tedious work-up process of potential reaction intermediates by a way of continuous flow extraction and separation resulting in a short residence time with good yield.…”