Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

Abstract

A continuous‐flow homogeneous photocatalytic method has been devised for the direct arylation of 2H‐indazoles. This visible‐light‐promoted approach directly accesses a wide range of structurally diverse C3‐arylated scaffolds of biological interest in a fast (1 min), single‐step reaction by using eosin Y as an organophotocatalyst. Furthermore, a microreactor technology is also employed for the fast synthesis of liver X receptor inhibitor drugs with very good yields under metal‐free conditions, whereas the reported methods required multiple steps and much longer reaction times (18–24 h).

Aryldiazonium Salts in Photoredox Catalysis – Recent Trends

“…Dong-Pyo Kim and co-workers demonstrated direct CÀ H arylation of 2H-indazoles at C-3 position with aryldiazonium salts using eosin Y as the photocatalyst at room temperature. [48] By using a continuous flow process, the reaction time was reduced to 1 min. N-2phenyl-substituted 2H-indazoles afforded good yields, whereas N-2-alkyl, benzyl, heteroaryl substituents didn't furnish the desired products.…”

“…Dong‐Pyo Kim and co‐workers demonstrated direct C−H arylation of 2H‐indazoles at C‐3 position with aryldiazonium salts using eosin Y as the photocatalyst at room temperature [48] . By using a continuous flow process, the reaction time was reduced to 1 min.…”

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

“…The key aryl radical was trapped with heteroarenes, such as 11.2, to give the arylation products 11.3. Recently, similar methodologies for aryl radical generations have been developed exploiting flow techniques [74] and different organophotocatalysts, such as a metal-free porphyrin [75] and rhodamine 6G (OD14) [76].…”

Direct Catalytic Functionalization of Indazole Derivatives

“…In the bath reactor, 2-phenyl-2H-indazole (31 a) reacted with aryl diazonium tetrafluoroborate in DMSO in presence of 3 mol% eosin Y as a photocatalyst and DIPEA as a base under green light irradiation producing up to 65% of desired C-3 arylated product 31 b within 18 to 24 h (Scheme 31). [59] But by using continuous-flow microfluidic reactor (which is a highly transparent perfluoroalkoxy alkane coil capillary (ID: 0.25 mm, L: 2 m) with LED light) the reaction time dramatically decreased to 1 min under the standard condition with higher % of yields. This was due to the high surfacearea-to-volume ratio of the microfluidic reactor, which provided high spatial illumination homogeneity, excellent light penetration and intrinsic mixing efficiency throughout the micro-scale reaction space.…”

“…[51][52][53][54][55][56][57] A very recent breakthrough in this field is visible-lightinduced direct organophotocatalytic functionalization strategies. [58][59][60][61] In spite of a broad spectrum of uses and various protocols for the synthesis, only a few review articles related to synthesis, functionalization and medicinal uses of indazoles are published in the literature. [1,[3][4][5][6]62] But from the best of our knowledge, no such review article is published on the direct functionalization of indazoles.…”