Radical Deoxygenation of 3-Azatricyclo[2.2.1.0^2,6]heptan-5-ols to 1,2-Dihydropyridines

Abstract

Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0 2,6 ]heptan-5-ols 9 (R = alkyl) give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes 10, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0 2,6 ]heptan-5-ols 9 (R = aryl) give 2-aryl-5-tosyl-1,2-dihydropyridines 12.Radical cyclisations and rearrangements constitute powerful methodology for the synthesis of ring systems. 1 Radical rearrangements in nortricyclyl (tricyclo[2.2.1.0 2,6 ]heptanyl) and norbornenyl (bicyclo[2.2.1]heptenyl) systems are well-known, usually leading to mixtures of tricyclic and bicyclic products. For example, radical-induced reductions of nortricyclyl bromide 1 and norbornenyl bromide 2 are known to give the same mixture of nortricyclene 3 and norbornene 4 (3:4, ca. 40:60; Scheme 1). 2 Scheme 1Recently, during the development of novel analgesics related to epibatidine, we showed that radical deoxygenation of 7-azanortricyclanols 5 selectively gave 6-substituted 2-azabicyclo[2.2.1]hept-5-enes 7, even when R is potentially radical stabilising (e.g. aryl, Scheme 2). 3 The origin of the selectivity in this rearrangement is probably the stabilisation afforded to the intermediate radical 6 by the a-nitrogen. 4 In the present communication we report on studies originally designed to broaden the scope of the above strategy to give differently substituted 2-azabicyclo[2.2.1]hept-5-enes, but which have also led to an extended radical rearrangement process to give 1,2-dihydropyridines.Epoxide 8 (readily available in two steps from N-Boc pyrrole) 5 underwent exo-selective attack at the a,b-unsaturated sulfone functionality with a variety of Grignard reagents, organolithiums, and MeOLi 6 to give the corresponding substituted 7-azanortricyclanols 9 in good yields (72-96%, Scheme 3). In the case of 7-azanortricyclanol 9 (R = 4-MeOC 6 H 4 ) the structural assignment was supported by X-ray crystallographic analysis. 7 Subsequent radical deoxygenation 8 of alkyl-substituted 7-azanortricyclanols 9 (R = Me, i-Pr) using Bu 3 SnH (2 equiv) gave the anticipated 2-azabicyclo[2.2.1]heptenes 10. 9

Selective Carbon–Carbon Bond Cleavage of Cyclopropylamine Derivatives

“…Alternatively, dihydropyridines 326 can be accessed via further rearrangement before the trapping event (Scheme 79A). 246 This methodology has been used to transform 327 to 328, which is a precursor en route to epibatidine analogue 329 (Scheme 79B). 247,248 A related rearrangement strategy was developed for the synthesis of kainoid amino acids.…”

“…β-Scission of 323 to 324 is promoted by relief of ring strain, and the resulting radical 324 can be trapped directly by n -Bu 3 SnH to provide 325 . Alternatively, dihydropyridines 326 can be accessed via further rearrangement before the trapping event (Scheme A) . This methodology has been used to transform 327 to 328 , which is a precursor en route to epibatidine analogue 329 (Scheme B). , A related rearrangement strategy was developed for the synthesis of kainoid amino acids .…”

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

“…Cyclopropane ringopening takes place under typical radical deoxygenation conditions to generate the radical 76, stabilised by the nitrogen atom. Two main types of reactivity are eventually observed: either direct trapping by Bu 3 SnH to produce 2-azabicyclo[2.2.1]hept-5-enes or a further β-fragmentation to produce the radical 77, which finally abstracts a hydrogen atom from Bu 3 SnH to give a dihydropyridine compound(Scheme 50, top) 152,153,154,155,156. The latter reaction pathway operates only when the starting radical precursor bears a radical-stabilising group R 1 (e.g.…”

Stereocontrolled Syntheses of Kainoid Amino Acids from 7-Azabicyclo[2.2.1]heptadienes Using Tandem Radical Addition-Homoallylic Radical Rearrangement

“…To investigate the origins of the selectivity for the isomeric azabicycles in the radical addition reaction, xanthate 29 was synthesized for radical deoxygenation (Scheme ). Treatment of epoxide 27 (available via regio- and stereoselective epoxidation of dienyl sulfone 16 ) with t -BuMgCl (3 equiv) led to the formation of tricyclic alcohol 28 (92%) . Attempted radical deoxygenation of the derived xanthate 29 at room temperature using Et 3 B and Bu 3 SnH led only to recovery of the xanthate 29 .…”