An expeditious and multikilogram-scale process for the Balz−Schiemann synthesis of o-difluorobenzene from ofluoroaniline via two separate continuous flow reactors in 90.0% yield has been set up. The main steps involved the generation of stable diazonium fluoborate intermediate in situ via continuous diazotization reactor at 20°C, and the choice of odifluorobenzene as cosolvent to achieve the continuous flow fluorodediazoniation system. Reaction time of both steps could be brought down to within 10 s and 2 min, respectively, by increasing the reaction temperature and thereby taking advantage of improved mass and heat transfer of a continuous flow system. ■ INTRODUCTIONThe Balz−Schiemann reaction is a classical method for replacing the diazonium group by fluorine (fluorodediazoniation) which involves heating ArN 2 + BF 4 − without solvent. 1 Interest in the Balz−Schiemann reaction and its variants has not diminished over time because regiospecific fluorination continuous to be a challenge and demand of aryl fluorides is increasing, although this reaction has disadvantages such as high energy consumption and unstable yields. 2 Diazotization of aromatic amines is usually exothermic and fast and usually performed on bulk scale in anhydrous conditions at low temperature; however, higher temperature can be achieved with the use of diazonium tetrafluoroborates or certain arenediazonium sulfonates or in the presence of complex anions, e.g. zinc chloride and hexafluorophosphate. 3 Diazotization of aromatic amines in continuous microreactors for iododeamination, 4 chlorodeamination, 5 azo dyes, 6 and chlorosulfonylation 7 has been established, although these contributions were only reported on laboratory-scale. The problems of a large-scale Balz−Schiemann reaction include the following: (i) the thermal instability of the diazonium intermediate, (ii) the difficulty raised by interaction between mixed and unmixed strata in large vessels, and (iii) nonuniform heating or water in the diazonium fluoroborate, leading to an uncontrollable thermal decomposition reaction and more byproduct 8 (see Scheme 1).The development of synthetic chemistry utilizing continuous flow synthesis has been of increasing interest in both academia and industry in recent years. Continuous flow reactors offer several advantages over the traditional batch vessels such as the following: (i) mass and heat transfer can be significantly improved by decreasing reactor size and increasing surface-tovolume ratio; (ii) fewer transport limitations can be offered by the feasibility and device flexibility of continuous flow synthesis; (iii) yield and selectivity can be improved due to the precise control of reaction variables such as temperature, pressure, residence time, and stoichiometry; (iv) scale-up of continuous flow synthesis is readily achieved by simply increasing the number of reactors or their sizes. 9 Motivated by these advantages, our group have been committing to the continuous flow synthesis technology and have reported a continuous kilogram-scale...

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A practical continuous nitration process for 2,5-difluoronitrobenzene via nitration of p-difluorobenzene with fuming nitric acid in 98% yield has been developed. The excellent yield of this liquid/liquid biphasic reaction resulted from the advantages of a continuous flow system. The 2.0 equiv sulfuric acid could be used three times directly with product yields in the range of 96–98%, and further recycling of waste acid could be partly achieved by adjusting the concentration of sulfuric acid. Reaction time could be brought down to 2 min by increasing the reaction temperature and thereby taking advantage of superior mass and heat transfer of this continuous flow system.

An expeditious and multikilogram-scale process for the synthesis of 7-ethyltryptophol via a continuous flow reactor from 2-ethylphenylhydrazine and 4-hydroxybutyraldehyde in higher and high yield was described. The main steps in this synthesis involved not only the generation of the hydrazone intermediate in situ but also the catalysis of the subsequent [3 + 3] sigmatropic rearrangement in the tandem loop reactor. Decomposition of the intermediate hydrazone was found to be a key factor resulting in low yield.

Aryl diazonium salts play an important role in the chemical transformation, however nature of explosiveness limits their applications in batch. Continuous flow technology allows safer operation for diazotization and application...

A fully continuous-flow diazotization−hydrolysis protocol has been developed for the preparation of p-cresol. This process started from the diazotization of p-toluidine to form diazonium intermediate. The reaction was then quenched by urea and subsequently followed by a hydrolysis to give the final product p-cresol. Three types of byproducts were initially found in this reaction sequence. After an optimization of reaction conditions (based on impurity analysis), side reactions were eminently inhibited, and a total yield up to 91% were ultimately obtained with a productivity of 388 g/h. The continuous-flow methodology was used to avoid accumulation of the highly energetic and potentially explosive diazonium salt to realize the safe preparation for p-cresol.

Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)­ethoxy)-2-nitropyridine (compound I) afforded the desired product (R)-3-[1-(2,6-dichloro-3-fluorophenyl)­ethoxy]­pyridin-2-amine (compound II) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II.

An expeditious process for synthesis of 2-ethylphenylhydrazine hydrochloride via a continuous flow reactor from 2-ethylaniline in 94% yield was described. The main steps in this synthesis involved not only the generation of diazonium salt intermediate in situ, but also the temperature-programmed reduction by sodium sulfite in the tandem loop reactor. Total residence time was reduced to less than 31 min by increasing reaction temperature and thereby taking advantage of improved mass and heat transfer of a continuous flow system. Purification process was simplified by extraction of impurities in situ.