Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Abstract

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Revisiting aromatic diazotization and aryl diazonium salts in continuous flow: highlighted research during 2001–2021

“…To prevent the production of this side product, a fully organic diazotization continuous flow system was introduced. Commonly used organic nitrosating reagents include tert-butyl nitrite, 53,[59][60][61][62][63][64][65][66][67][68] isobutyl nitrite, 69 and isoamyl nitrite (Scheme 1b). [70][71][72] To address the problem of diazonium salt precipitation in organic systems, organic solvents with higher polarities, such as acetonitrile, 53,[62][63][64][65] methanol, 60,61 tetrahydrofuran, 72 and N,N-dimethylformamide, [59][60][61] are often chosen or dilute conditions are adopted (Table 1).…”

“…Commonly used organic nitrosating reagents include tert-butyl nitrite, 53,[59][60][61][62][63][64][65][66][67][68] isobutyl nitrite, 69 and isoamyl nitrite (Scheme 1b). [70][71][72] To address the problem of diazonium salt precipitation in organic systems, organic solvents with higher polarities, such as acetonitrile, 53,[62][63][64][65] methanol, 60,61 tetrahydrofuran, 72 and N,N-dimethylformamide, [59][60][61] are often chosen or dilute conditions are adopted (Table 1). However, it cannot be ignored that some organic solvents can be used as hydrogen sources to promote hydro-dediazotization, so it is necessary to select suitable organic solvents in conjunction with subsequent reactions.…”

“…Bostyn et al investigated in detail the parameters of diazotization/chlorodiazotization in an anhydrous sequential continuous flow process. 64 The application of the Simplex method only requires 6 experiments to determine the optimal conditions (i.e., temperature, catalyst loading and residence time) of the chlorination reaction in a continuous flow system. The difference with Ley's system is that the continuous flow system can only be compatible with electron-deficient and electron-neutral aromatic anilines.…”