Multistep Continuous-Flow Synthesis of Condensed Benzothiazoles

Abstract

In medicinal chemistry, the development of synthetic procedures for the access of new heterocyclic systems as potential scaffolds is elementary. Herein, we report our results on the formation of small drug-like heterocycles, utilizing flow chemistry. This approach enables the extension of the reaction parameter window, including high-pressure/high-temperature or hazardous chemistry. In our work, various novel condensed tricyclic benzothiazoles fused with furo-and thieno-rings were synthesized applying a multistep continuous-flow protocol. The process includes two ring closure steps and a nitro group reduction step. Batch and telescoped continuous-flow syntheses were also designed and performed.

Unsymmetrical Benzothieno-Fused BODIPYs as Efficient NIR Heavy-Atom-Free Photosensitizers

“…The synthesis of the key precursor thieno­[3,2- g ]­indole has been described in our previous work, while the reported method suffers from inconvenient and expensive starting material 2-chloro-3-nitrobenzaldehyde. In this work, we provide an improved method as shown in Scheme , commercially available 1-(2-hydroxy-3-nitrophenyl)­ethenone 1 , or can be readily produced from 2′-hydroxy acetophenone by nitration, was transformed to benzothiophene 2 via tandem processes including sulfonylation to give a good leaving group TsO-, nucleophilic aromatic substitution, and finally cyclization with ethyl thioglycolate (90%). After Fe/AcOH reduction (92%), the amino compound 3 was transformed to thieno­[3,2- g ]­indoles 4a – c (62–78%) with various 6-substituents successfully following our reported procedure …”

“…The structure of compound 2 has been reported previously. 17 Our method to prepare compound 2 is as follows: Compound 1 (9.06 g, 50.00 mmol) and TEA (10 mL) were dissolved in dichloromethane (DCM) (200 mL) and stirred for 10 min at 10 °C before adding TsCl (14.30 g, 75.00 mmol) in portions. The mixture was warmed to room temperature and stirred for 1 h to complete the reaction.…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…9 The C-N coupling step involved in the synthesis of Imatinib was conducted in aqueous-organic biphasic system to prevent precipitation of inorganic byproducts, while N, N-dimethyloctanamide cosolvent ensured efficient mass transfer and high reaction rates. Additionally, solubility problems were prevented, as each of the reagents could be dissolved in either aqueous or organic phase.…”

“…Hydrogen is commonly used in flow synthesis, 99,100 usually in excess amounts. When hydrogenation is followed by other steps, 9,26,29,33,101,102 a simple buffer flask allows the outgassing of hydrogen, after the pressure is reduced. However, in some cases the applied chemistry did not tolerate this method.…”

“…Our ongoing efforts in this field 9 inspired us to summarize the difficulties concerning the integration of individually optimized chemical reactions into multistep systems, as well as common problems and their innovative solutions described in the recent literature [6][7][8][10][11][12][13][14][15][16][17][18] of API continuous flow synthesis, including analytics and purification methods.…”