Regioselective synthesis of 2H-indazoles through Ga/Al- and Al-mediated direct alkylation reactions of indazoles

Abstract

A procedure has been developed for the regioselective, high yielding synthesis of 2H-indazoles that involves direct alkylation of indazoles with various allyl and benzyl bromides, and α-bromocarbonyl compounds.

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

“…[19] Results and Discussion Synthesis The first strategy started from 4-ethylaniline (19). Reductive aminationo f19 afforded 20,a nd was followed by condensation with 1H-indazole-5-sulfonyl chloride to afford 21.A se xpected from the literature, [20] the alkylation of indazoles (e.g., 21)w as generallyn ot selectiveb ut in nearly all cases,t he isomers, for example, 4a and 5a,w ere easily separated by preparative LC-MS. If the alkyl halidesw eren ot commerciallya vailable, Mitsunobu-Ts unoda alkylationc onditions [21] were directly appliedw ith the corresponding alcohols (e.g., 4e and 4g)a f-fording the final compounds in generally acceptable yields (Scheme 1).…”

“…Indazolone analogue 10 c was preparedb ymethanolysis of 39 to afford ester 40,w hich was cyclizedt oi ndazolone 41 and N-alkylated with 4-(bromomethyl)tetrahydro-2H-pyran, albeit in poor yield. 3-Aminoindazole analogue 10 d was prepared by first transformationo fa cid chloride 39 to the primary carboxamide that was dehydrated to the corresponding nitrile 44.T he sequence Scheme6.Synthesis of indoline derivative 10 a:a)trifluoroacetic anhydride, CH 2 Cl 2 ,08C, 1h(quantitative); b) chlorosulfonic acid, 70 8C, 3h(76 %);c )oxalyl chloride, CH 2 Cl 2 ,DMF,reflux, 20 h( quantitative);d )4-ethyl-N-isobutylaniline (20), THF,pyridine RT,16h(67 %);e)NaOH( 1m), THF,RT, 16 h( 99 %);f)tetrahydro-2H-pyran-4-carbaldehyde, NaBH(OAc) 3 ,dichloroethane, AcOH,R T, 72 h, (46 %). was completed by cyclization with hydrazinea nd N-alkylation to afford 10 d.T he synthesis of tetrahydroquinoline analogue 11 g was inspired by Bunce et al [23] First, transformation of 40 to aldehyde 42 was achieved by ar eduction-oxidations equence.…”

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

“…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]. Below, we describe observations made in an investigation in which this new alkylation procedure was applied to the synthesis of a variety of 2-alkenyl-2 H -indazoles.…”

Selective N2-Alkylation of 1H-Indazoles and 1H-Azaindazoles

“…7b Bandichhor and co-workers reported an elegant method for the selective N2-methylation of various indazoles, under acidic reaction conditions, using methyl 2,2,2-trichloroacetimidate, which was employed in the synthesis of Pazopanib. 7c Procedures for the N2-allylation 8 and N2-protection 9 of indazoles have also been described. To our knowledge, no general method has been reported for the selective N2-alkylation of indazoles that combines both a diverse indazole and alkylating partner scope.…”