Regioselective Synthesis of 2H-Indazoles Using a Mild, One-Pot Condensation–Cadogan Reductive Cyclization

Abstract

An operationally simple and efficient one-pot synthesis of 2H-indazoles from commercially available reagents is reported. Ortho-imino-nitrobenzene substrates, generated via condensation, undergo reductive cyclization promoted by tri-n-butylphosophine to afford substituted 2H-indazoles under mild reaction conditions. A variety of electronically diverse ortho-nitrobenzaldehydes and anilines were examined. To further extend the scope of the transformation, aliphatic amines were also employed to form N2-alkyl indazoles selectively under the optimized reaction conditions.

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

“…In stark contrast, substituents at the 7‐position of the 2‐nitrobenzaldehydes in the vicinity of the reacting center were apparently detrimental for efficient conversion, as 44 was obtained in only a low yield. This finding is in line with all described reductive cyclizations of 3‐substituted 2‐nitrobenzaldimines to 2 H ‐indazoles and shows that proximal substituents severely affect Cadogan‐type organophosphorus‐mediated cyclizations . Nonetheless, our procedure also reliably generated more complex 2 H ‐indazoles bearing base‐ or acid‐sensitive substituents on the benzene ring, such as N 2‐(1 H ‐indol‐1‐yl)‐2 H ‐indazole heterocycle 46 with two acetoxy groups and derivative 45 with an ester group, which were obtained in moderate yields (44–46 %), as well as terminal alkyne 47 (51 %).…”

“…One of the most effective and general methods for the regioselective construction of 2 H ‐indazoles is Cadogan‐type N−N bond formation through reductive cyclization of 2‐nitrobenzaldimine derivatives by organophosphorus reagents at elevated temperatures. Until very recent reports by Genung et al . and Radosevich et al., however, who preformed 2‐nitrobenzaldimines, neat conditions or at least large excess amounts of the phosphines or phosphites were required.…”

Modern advances in heterocyclic chemistry in drug discovery

“…28 Direct alkylation of unsubstituted 1H-indazoles typically generates a mixture of 1-and 2-substituted products. 30 The newly established method uses a nucleophilic alkyl phosphine (tri-n-butylphosphine) and lower reaction temperatures to access 2H-indazoles selectively from commercially available reagents under milder reaction conditions. 29 Unfortunately the utility of this two-step approach is limited due to the exposure of high energy intermediates to elevated temperatures (typically 150°C with microwave radiation).…”

Crystal structure of 3-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde, a rare Z′ = 3 structure, C20H17N5O

“…Compounds containing a pyrazole ring system [6][7][8][9][10] exhibit a wide range of biological applications. Hence, it has been shown that many derivatives show antimicrobial, fungicidal, anticancer and antioxidant activities [11][12][13][14].…”