Construction of Fused Heterocyclic Architectures by Formal [4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins

Abstract

Over the last 50 years, seminal research from the groups of Franzen, [1] Corey, [2] Trost, [3] Aggarwal, [4] and Dai [5] have established sulfur ylides [6] as valuable and versatile intermediates in synthetic chemistry. As a consequence, sulfur ylides are widely utilized for the construction of epoxide, aziridine, and cyclopropane architectures. Recently, studies by Tang and co-workers [7] and others [8] have significantly extended the scope of the ylide-initiated reactions and outlined the first examples of tandem reactions initiated by sulfur ylides to furnish a range of functionalized cyclic compounds beyond three-membered rings. Despite the advances, the search for unprecedented ylide-based multiple cascade reactions continues, with the goal of increasing the diversity of possible substrates and the architectural complexity of products in a step-economical fashion.[9] Recently, our laboratory implemented a new reaction of sulfur ylides with nitroolefins to afford diverse and structurally complex oxazolidin-2-ones, wherein a transiently generated cyclic nitronate was involved.[10] On this basis, we became interested in the possibility of using the above mentioned cyclic nitronate as a suitable 1,3-dipole to react with electron-deficient components in situ, and in doing so create multiple bonds, rings, and stereocenters in a single transformation. Herein, we report a successful execution of this idea and describe the first intermolecular [4+1]/intramolecular [3+2] cycloaddition cascade of sulfur ylides and alkene-tethered nitroolefins.[11] This novel and catalyst-free strategy allows rapid access to functionalized 2,3,5-trioxa-2a-azapentaleno[1,6-ab]naphthalenes, 2,3-dioxa-5-thia-2a-azapentaleno[1,6-ab]naphthalenes, and isoxazolo[4,3,2-hi][2,1]benzisoxazoles in a highly concise fashion (Scheme 1); and these products are versatile synthons for the construction of densely functionalized chromans, thiochromans, amino acids, amino alcohols, and other important heterocycles. [12] We initially studied the reaction of dimethyl (2-oxo-2-phenylethyl)sulfonium ylide (1 a) with (E)-ethyl 3-(2-((E)-2-nitrovinyl)phenoxy)acrylate (2 a) in acetonitrile at 0 8C for 12 hours, at which point the reaction mixture was warmed to room temperature and stirred for an additional eight hours. To our delight, the proposed cycloaddition cascade was indeed facile and afforded ethyl 1-(phenylcarbonyl)-4,4a,9b,9c-tetrahydro-1H-2,3,5-trioxa-2a-azapent-aleno[1,6-ab]naphthalene-4-carboxylate (4 a) as a major isolable product in 43 % yield with great diastereocontrol (Table 1, d.r.[c]

Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and Heterocyclic Systems

“…On the basis of the mechanistic studies of the sulfur ylide-based cyclization reactions, Xiao and his co-workers fine-tuned a formal [4+1]/[3+2] cycloaddition cascade reaction between alkene-tethered β-nitroolefins 365 and stable sulfur ylides 282 without the addition of any catalyst (Scheme ) . The reaction enabled the efficient construction of various highly functionalized and fused heterocyclic systems 366 with excellent yields (75–99%) and stereoselectivities (>95/5 dr).…”

Construction of Saturated Oxazolo[3,2-b][1,2]oxazines via Tandem [3+2]-Cycloaddition/[1,3]-Rearrangement of Cyclic Nitronates and Ketenes

“…The power of this methodology was demonstrated by the asymmetric total synthesis of several stereochemically complex alkaloids developed by Denmark et al , Moreover, this strategy provides access to a polysubstituted 1,2-oxazine ring, which occurs in some bioactive natural molecules and is being explored in the design of pharmaceuticals . Recently, tandem cycloaddition sequences involving nitroalkenes were extended to [4+1]/[3+2] and [4+2]/[3+3] processes.…”

C2-Selective C–H Methylation of Heterocyclic N-Oxides with Sulfonium Ylides

“…Mechanistically, the nucleophilic addition of sulfur ylides into π-unsaturated compounds such as carbonyl, imine, and α,β-unsaturated moieties leads to the formation of betaine intermediates, which are decomposed by O, N, and C anions via intramolecular nucleophilic substitution. Recent advances have been made in the asymmetric synthesis of oxiranes, aziridines, and cyclopropanes via organocatalysis, photocatalysis, Lewis acid catalysis, or transition-metal catalysis . Asymmetric [2,3]-sigmatropic rearrangements of sulfur ylides (Doyle–Kirmse reaction) have been also explored .…”