Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles

Abstract

An unusual reactivity of nitrostyrenes in phosphorous acid was discovered, which permits the employment of these readily available synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective (4+1)-cycloaddition of indoles to afford 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically pure form.

Preparation of Stereodefined 2-(3-Oxoindolin-2-yl)-2-Arylacetonitriles via One-Pot Reaction of Indoles with Nitroalkenes

“…It was previously proposed , that the key step of spirane formation involves an acid-promoted 5-endo-trig cyclization of hydroxylamine 6 to form spiro-2,5-dihydroisoxazole species 7 , which under the reaction conditions isomerizes into the thermodynamically more favored (3 R *,4′ S *)-4,5-dihydroisoxazole 8 (Scheme ). Naturally, for N -unsubstituted indoles ( R 4 = H), this intermediate exists in equilibrium with neutral species 3 , which can be isolated. , We suggest that iminium ion 8 in its carbocation resonance form 9 is susceptible to a pinacol-type rearrangement involving a stereoretentive 1,2-alkyl shift to provide dihydrooxazinium species 10 with a (4 R *,4a R *) configuration. Finally, deprotonation at C-3 accompanied by cleavage of the N–O bond furnished nitrile 5 (Scheme ).…”

“…Reaction progress and purity of isolated compounds were controlled by TLC on ALUGRAM Xtra SIL G/UV254 plates, eluting with hexanes/EtOAc mixture 4:1. Spirocyclic precursors 3 were synthesized according to our recently published protocols. , All other reagents and solvents were purchased from commercial vendors and used as received.…”

“…We have recently described a highly diastereoselective route toward 4′ H -spiro­[indole-3,5′-isoxazoles] ( 3 ) proceeding via unusual formal [4 + 1] cycloaddition reaction involving a nitroalkene ( 2 ) as a 1,4-CCNO dipole and the nucleophilic C-3 of an indole ( 1 ) as the dipolarophilic C 1 moiety (Scheme ). , In continuation of these studies, we intended to investigate possibilities of performing base-assisted cleavage − of the isoxazoline ring in spirocyclic product 3 , targeting 2-hydroxy-1 H -indole-3-acetonitriles 4 . To our great surprise, this reaction took an unexpected pathway involving a skeletal rearrangement accompanied by a 1,2-migration of the acetonitrile moiety and the formation of product 5 .…”

Electrophilically activated nitroalkanes in reaction with aliphatic diamines en route to imidazolines

“…As shown previously, both PPA and H 3 PO 3 enable this step, but diphosphite 15 is less sterically hindered and usually more reactive than diphosphate analog derived from PPA. 28 Nucleophilic attack by NH 2 -moiety of diamine 2 at C-1 of aci -form would first afford aminal 16, which after subsequent elimination of phosphorus acid molecule would be transformed into amidine species 17. The latter would experience 5- exo-trig nucleophilic attack by secondary amine moiety to produce intermediate triaminomethane 18.…”

Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence

“…We have recently reported a highly efficient and diastereoselective formal [4 + 1]-spirocyclization of indoles with nitroolens serving as unusual 1,4-CCNO dipoles (Scheme 1). [15][16][17] This reaction proceeded in the presence of phosphorous acid, affording very good yields of spiroindoles 3, hardly accessible by other means. For a series of these compounds promising antitumor activity against neuroblastoma cells was discovered.…”