Diverse Applications of Nitrones for the Synthesis of Heterocyclic Compounds

Abstract

Although best known for their [3+ +2]-dipolar cycloaddition reactivity and use in the preparationo fi soxazolines and isoxazolidines,n itrones are versatile reagents that undergo av ariety of transformationsf or the synthesis of ad iverse array of heterocyclic compounds. Theb readth of heterocycle synthesis using nitrone reagentsi ncludes: 1) stepwise [3+ +3]-cycloaddition reactions of nitrones with vinyl diazoacetates, transition-metal-coordinated cycloisomerization intermediates, trimethylenem ethanes, and cyclopropane diesters to form dihydro-a nd tetrahydro-1,2-oxazines;2 )internal redox cyclization reactions of alkyne-tetheredn itrones to provide access to azabicyclooctanes,i soindoles, aminoindanones, and isoquinolones;3 )electrocyclizationso fi ns itu generated N-allenylnitrones to form pyridines and azetidine-N-oxides, as well as metal-catalyzed cyclizationsa nd rearrangements of nitrones to form azepine-N-oxides, spirocyclic isoxazolines, and a,b-epoxyimines;a nd 4) the use of [3+ +2]cycloaddition reactions of nitrones to trigger cascade reactions for the formationo ft etrahydrooxazepines, dihydrocarbazoles, and benzoindolizines. This Focus Review aims to highlight these diverse applicationso fn itrones for the synthesis of heterocyclest oe mphasize the broad utility of these reactive intermediates andt oi nspire their furtherd evelopment as important synthons beyond the scope of traditional [3+ +2]-dipolar cycloaddition reactions. Scheme1.[3+ +2]-Dipolar cycloadditions of nitrones and their application to the synthesis of naturalproducts and biologically active compounds:Diverse applicationsofn itrones for the synthesis of heterocyclic compounds.[a] Prof. Dr.L.L.A nderson 2. Formal [3+ +3]-Cycloadditions of Nitrones and [4+ +2]-Cycloadditions of N-Alkenylnitrones.Formal [3+ +3]-cycloadditions of nitrones have been investigated as alternative methods for the synthesis of dihydro-and tetrahydro-1,2-oxazines and offer new routes to these heterocycles that are unique from traditional [4+ +2]-cycloadditions of dienes and nitrosobenzenes. [8] The nitrone cycloaddition partners discussed below include vinyldiazoacetates, alkenyl gold complexes,m etal carbenoids generated through cycloisomerization processes, trimethylene methanes, and cyclopropane diesters (Scheme 3A). The synthesiso fN-alkenylnitrones has also prompted an investigation of these electron-deficient azadienesa si nverse-demand cycloaddition partners for the synthesis of six-membered-ring nitrones that are poised to undergo furtherf unctionalization (Scheme 3B). Prof. Laura L. Anderson receivedh er B.A. from Knox College in 2000 and moved to the University of California, Berkeley,f or her graduate studies where she worked with Prof. John Arnold and Prof. Robert G. Bergman developing new hydroamination catalystsa nd studying the reactivity of transition metal imido complexes. After obtaining her Ph.D. in 2005, Prof. Anderson movedt ot he Universityo f California, Irvine, wheres he completed aR uth L. Kirschstein NIH postdoctoral fellowship with Pr...

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

“…[4] Thec atalytic asymmetric 1,3-dipolar cycloaddition of nitrones [5] and prochiral fluoroalkylated olefins affords ready access to chiral isoxazolidines (Scheme 1), which is the key study in this report. [4] Thec atalytic asymmetric 1,3-dipolar cycloaddition of nitrones [5] and prochiral fluoroalkylated olefins affords ready access to chiral isoxazolidines (Scheme 1), which is the key study in this report.…”

“…Fort he challenging aliphatic nitrone substrates 2v, 2w,a nd 2x with aP ho rb enzyl (Bn) N-protecting group,g ood results were obtained by performing the reaction at À20, À10, and 0 8 8Cr espectively (entries [22][23][24]. When bromodifluoromethylated and monofluoromethylated vinyl sulfones 1d and 1e were used, the desired cycloadducts 3da-ea were obtained with good results by extending the reaction time (entries [4][5]. Next, the scope of b-fluoroalkylated a,b-unsaturated sulfones was examined by reaction with 2aunder the standard conditions (Table 3).…”

Yb(OTf)3‐Catalyzed Cycloaddition/[3,3]‐Rearrangement of N‐Vinyl‐α,β‐Unsaturated Ketonitrones with Methylenecycloprop‐anes: Stereoselective Synthesis of Nine‐Membered Nitrogen Heterocycles

“…In particular, adding Cu (OTf) 2 afforded 3 aa in 50% yield with a 15:1 dr ( Table 1, entries 2-3). Other solvents, such as MeCN, DCM, and toluene delivered 3 aa in low yields but with excellent cis/trans ratios in DCM and toluene ( Table 1, entries [10][11][12]. Pleasingly, Yb(OTf) 3 and Sc (OTf) 3 delivered 3 aa in 78% and 69% yields, respectively, with a 15:1 cis/trans ratio (Table 1, entries 6-7).…”

“…[11] N-Vinyl nitrones, a distinct type of nitrone, have been shown to be powerful synthons because the double bond at the nitrone N-atom can be introduced into target molecules through various transformations. [11] N-Vinyl nitrones, a distinct type of nitrone, have been shown to be powerful synthons because the double bond at the nitrone N-atom can be introduced into target molecules through various transformations.…”

“…As efficient 1,3-dipoles for cycloaddition, nitrones have attracted much attention in the synthesis of Nheterocycles. [11] N-Vinyl nitrones, a distinct type of nitrone, have been shown to be powerful synthons because the double bond at the nitrone N-atom can be introduced into target molecules through various transformations. [12] During studies on nitrones and their cycloadditions, [13] we recently developed a novel strategy for the highly diastereoselective synthesis of nine-membered ring scaffolds though a [3 + 2] cycloaddition and sequential [3,3]-rearrangement cascade strategy from N-vinyl-α,β-unsaturated ketonitrones and various electrophiles, including arynes, isocyanates, and activated alkynes (Scheme 1-A).…”