TEMPO-Mediated Cross-Dehydrogenative Coupling of Indoles and Imidazo[1,2-a]pyridines with Fluorinated Alcohols

Abstract

A simple and highly efficient metal-free method has been developed for hydroxyfluoroalkylation of indoles and imidazo­[1,2-a]­pyridines via TEMPO-mediated C­(sp3)–H and C­(sp2)–H bond cross-dehydrogenative coupling of fluorinated alcohols and indoles. The protocol showed broad substrate scope, afforded good yields of hydroxyfluoroalkylated products, and was amenable for scale-up. Mechanistic investigation indicated involvement of the radical pathway.

TEMPO-Mediated Synthesis of Indolyl/Imidazo[1,2-a]pyridinyl-Substituted para-Quinone Methides from Butylated Hydroxytoluene

“…On the other hand, TEMPO (2,2,6,6-tetramethylpiperidine- N -oxyl), a stable organic nitroxyl radical, has been found as an efficient and effective catalyst in oxidative C–H functionalization reactions in recent years due to its versatile catalytic activity . In a study on mechanistic investigation of TEMPO-mediated hydroxyfluoroalkylation of indoles and imidazo­[1,2- a ]­pyridines in the presence of BHT, we observed the formation of the indole-substituted p -QM . This inspired us to further investigate this reaction of BHT in the presence of TEMPO.…”

“…Quinolin-8-ol (6) produced the corresponding 2,6-di-tert-butyl-4-((8-hydroxyquinolin-5-yl)methylene)cyclohexa-2,5-dien-1-one (10) in 63% yield (Table 2, entry 1). Bis(hetero)arylmethanes 11 and 12 were obtained from 4-hydroxycoumarin (7) and benzimidazole (8), while 4-phenylquinolin-2(1H)-one (9) failed to react under these conditions.…”

“…The compound was purified by column chromatography on silica gel using EtOAc/nhexane (1.5:8.5, v/v) as an eluent: red solid (71 mg, 65%); mp = 260−262 °C; 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.58 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 3H), 7.45 (d,J = 7.2 Hz,1H),7.42 (d,J = 5.2 Hz,2H),7.38 (d,J = 8.4 Hz,1H),7.20 (s,1H),7.06 (d,J = 8.4 Hz,1H),2.34 (s,3H), 1.24 (s, 9H), 1.10 (s, 9H); 13 C{ 1 H} NMR (100 MHz, DMSO-d 6 ) δ 185. 8,145.6,145.2,142.0,140.3,136.0,135.5,131.6,130.6,130.3,129.5,129.4,127.7,127.5,125.2,120.1,112.4,110.0,35.3,35.0,29.8,29.5,HRMS (ESI) m/z [M + H] + calcd for C 30 H 34 NO + 424.2635, found 424.2651.…”

“…7 In a study on mechanistic investigation of TEMPOmediated hydroxyfluoroalkylation of indoles and imidazo[1, 2a]pyridines in the presence of BHT, we observed the formation of the indole-substituted p-QM. 8 This inspired us to further investigate this reaction of BHT in the presence of TEMPO. Herein, we report a transition-metal-free TEMPOmediated method for the generation of p-QMs through the oxidative coupling of the C(sp 3 )−H bond of butylated hydroxytoluene (BHT) with the C(sp 2 )−H bond of indoles or imidazo[1,2-a]pyridines under neutral conditions (Scheme 1e).…”

An iron-catalyzed domino reaction of donor–acceptor cyclopropanes: a diastereoselective approach towards diversely functionalized pyrrolo-quinazolines

“…These observations indicate that the reaction proceeds through a radical pathway. 12 To confirm the role of DMSO as the oxidant, 13 the reaction between 1a and 2a with 20 mol% Fe(OTf) 3 and DMSO (3 equiv.) in the DCE solvent was performed and the reaction proceeded well to furnish 3a in 72% yield.…”