Selective Synthesis of 1-Functionalized-alkyl-1H-indazoles

Abstract

An efficient method for the selective "N1" alkylation of indazoles is described. Use of alpha-halo esters, lactones, ketones, amides, and bromoacetonitrile provides good to excellent yield of the desired N1 products.

Direct Catalytic Functionalization of Indazole Derivatives

“…Uncatalyzed direct alkylation of indazoles is well known in the literature. [92][93][94][95] [96] Six years later in 2012, another phase transfer catalyzed direct method for alkylation of indazole was developed by Chandramouli et al In this process, 5cyano 1H-indazole (33 a) was alkylated by heating at 60°C with alkyl chloride in presence of K 2 CO 3 as a base and (Bmim)BF 4 as a phase transfer catalyst in ethyl acetate to achieve N-1 alkylated 1H-indazole derivative (33 b) as a major product (88%) and N-2 alkylated 2H-indazole derivative (33 c) as a minor product (12%) (Scheme 33). [97] Yu et al explored a new microwave-assisted, metal-free, green method for N-alkylation of indazoles with vinylpyridines in water.…”

Design and Synthesis of N‐Substituted Indazole‐3‐Carboxamides as Poly(ADP‐ribose)polymerase‐1 (PARP‐1) Inhibitors†

“…The selective alkylation of the N ‐1 position remains a challenge, specifically for C 3 ‐unsubstituted indazoles (16). It has been previously reported that use of potassium carbonate as a base yielded 92:1 ratio of N ‐1 versus N ‐2‐alkylated indazole derivatives (17). Moreover, the portion of N ‐2‐alkylated products is highly dependent on the bulkiness of the substituent at C 3 position as exemplified through N ‐1 versus N ‐2 ratio of 65:35 (when C 3 =‐H) as opposed to the corresponding ratio of 95:5 (when C 3 =4‐fluorophenyl) (18).…”

Synthesis of 2-Alkenyl-2H-indazoles from 2-(2-Carbonylmethyl)-2H-indazoles

“…A potentially more productive approach to 2-alkenyl-2 H -indazole targets begins with alkylation of indazole with α-bromocarbonyl compounds (path (c), Scheme 1). The major difficulty associated with this process is that N -1 thermodynamic alkylation products predominate in reactions run under most basic conditions [18]. Fortunately, the results of recent studies in this area show that 2 H -indazoles are generated through gallium/aluminium- and aluminium-mediated direct regioselective alkylation reactions of an indazole with α-bromocarbonyl compounds [19].…”