A Study of Vinyl Radical Cyclization Using N-Alkenyl-7-bromo-Substituted Hexahydroindolinones

Abstract

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.

Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives

“…As a donor-acceptor cyclopropane, the intermediate 101 opens up and the nitrogen-containing tricycle 103 is obtained after reduction by sodium borohydride (Scheme 66) 183. It is worth of mention that 2,2-dichloroaminocyclopropane derivatives more typically undergo cleavage of the C1−C3 bond and departure of a chloride ion (see paragraph 3.5.2).…”

Sequential Vinyl Radical Cyclization/Fixation of Carbon Dioxide through Electrochemical Reduction of Vinyl Bromide in the Presence of an Electron‐Transfer Mediator

“…On the other hand, vinyl bromide and iodide are good and straightforward precursors for vinyl radicals. Reaction with Bu 3 SnH/AIBN generates a vinyl radical at the carbon with the bromine or iodine atom, which can also undergo efficient radical cyclization to afford unsaturated carbo‐ and heterocycles . As organotin reagents such as Bu 3 SnH are known to be hazardous, an environmentally benign alternative method for generating vinyl radicals without the use of hazardous reagents is desirable.…”

“…Reaction with Bu 3 SnH/AIBN generates av inyl radicala tt he carbon with the bromine or iodine atom, which can also undergo efficient radicalc yclization to afford unsaturated carbo-and heterocycles. [3][4][5][6][7][18][19][20] As organotin reagents such as Bu 3 SnH are known to be hazardous,a ne nvironmentally benign alternative method for generating vinyl radicals without the use of hazardous reagentsi sd esirable. Samarium diiodide is au seful reducinga gent for generation of av inyl radical by one-electronr eduction of vinyl bromide.…”

Novel Diastereoselective Synthesis of Bicyclic β-Lactams through Radical Cyclization and Their Reduction toward 2-(1-Alkoxy-2-hydroxyethyl)piperidines and 2-(1-Alkoxy-2-hydroxyethyl)azepanes

“…7 Furthermore, the 6-endo-trig cyclization of an N-allyl-7-bromo-3a-methylhexahydroindolinone system has been described under high dilution conditions with tributyltin hydride and a catalytic amount of AIBN toward a tricyclic γ-lactam, whereas also 5-exo-trig cyclization was observed as a minor reaction pathway if the radical reaction was executed with only tributyltin hydride and no AIBN. 8 In continuation of our interest in the synthesis of novel bicyclic -lactams, 9 an efficient and straightforward radical approach toward 1-azabicyclo[4.2.0]octan-8-ones and 1-azabicyclo[5.2.0]nonan-9-ones with excellent diastereocontrol is described in the present paper. The bicyclic azetidin-2-ones obtained in this work were subsequently transformed into functionalized 2-(1-alkoxy-2-hydroxyethyl)piperidine and -azepane derivatives as single diastereomers via a reductive ring opening.…”