A General One‐Pot Synthesis of 2H‐Indazoles Using an Organophosphorus–Silane System

Abstract

A simple and direct approach for the regioselective construction of the privileged 2H-indazole scaffold is described. The developed one-pot strategy involves phospholene-mediated N-N bond formation to access 2H-indazoles. The amount of organophosphorus reagent was minimized by recycling the phospholene oxide with organosilane reductants. Starting from functionalized 2-nitrobenzaldehydes and primary amines, a mild reductive cyclization, involving the use of commercially available phospholene oxide and silanes, delivered a wide variety of substituted 2H-indazoles in good to excellent yields.

Probing 2H‐Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors

“…While unsubstituted 1 H ‐indazoles and N1‐substituted‐1 H ‐indazoles are well represented in the chemical space and in particular populating the kinase ligand space, the 2 H ‐indazole framework is only rarely described. This is mainly attributed to the fact that until very recently, only a few direct methods allowed regioselective access to N2‐substituted 2 H ‐indazoles …”

“…A variety of substituents at the meta and para position with respect to the nitro group were generated following this strategy. The amine derivatives 2 a – r were then reacted with commercially available 3‐nitroisonicotinaldehyde ( 3 ) in a one‐step–one‐pot Cadogan reaction to regioselectively afford the final 6‐aza‐2 H ‐indazoles 4 a – r .…”

“…For construction of the 5‐methoxy‐substituted 6‐aza‐2 H ‐indazoles 8 a – r and the corresponding 5‐hydroxy derivatives 9 a – p , 2‐methoxy‐5‐nitroisonicotinaldehyde ( 5 ) and mono‐ tert ‐butyloxy‐protected meta ‐ or para ‐phenylenediamine 6 were used for the respective one‐step–one‐pot Cadogan reaction . This was followed by cleavage of the Boc group from amino intermediate 7 using hydrochloric acid in dioxane.…”

“…A persistent issue hampering the introduction of new scaffolds and their qualification as privileged structures is the lack of a short, robust, and facile synthetic route to the corresponding chemotype. In this context, we recently described a regioselective, robust, and simple one‐pot synthesis to access the 2 H ‐indazole backbone . In this study, we applied this methodology to synthesize the rarely described 6‐aza‐2 H ‐ indazoles to probe the suitability of this framework to target the challenging AGC kinase family—which is far less explored and chemically addressed—with a focus on SGK kinase, while also investigating the potential of binding to TK kinases such as SRC and Tie2, as suggested by our initial profiling.…”

“…Schoene access the 2H-indazole backbone. [10] In this study,w ea pplied this methodology to synthesize the rarely described 6-aza-2Hindazoles to probe the suitability of this framework to target the challenging AGC kinase family-which is far less explored and chemically addressed-with af ocus on SGK kinase, while also investigating the potential of binding to TK kinases such as SRC and Tie2, as suggested by our initial profiling. Guided by rational in silicod esign and ak nowledge-based selection approach, we aimed to furtheru ncover and qualify the N-sub-stituted2 H-indazole framework as as caffold for selective kinase inhibitors (Figure1).…”