Synthesis of 1,4-Enamino Ketones by [3,3]-Rearrangements of Dialkenylhydroxylamines

Abstract

The synthesis of 1,4-enamino ketones has been achieved through the [3,3]-rearrangement of dialkenylhydroxylamines generated from the addition of N-alkenylnitrones to electron-deficient allenes. The mild conditions required for this reaction, and the simultaneous installation of a fluorenyl imine N-protecting group as a consequence of the rearrangement, avoid spontaneous cyclization of the 1,4-enamino ketones to form the corresponding pyrroles and allow for the isolation and controlled divergent functionalization of these reactive intermediates. The optimization, scope, and tolerance of the new method are discussed with demonstrations of the utility of the products for the synthesis of pyrroles, 1,4-diones, and furans.

De novo branching cascades for structural and functional diversity in small molecules

“…N-phenyl nitrones (1) undergo [3 þ 2] cycloadditions with allenic esters (2) and the corresponding isoxazolidines (3) follow a pericyclic rearrangement leading to azepinones (5, Fig. 2) [30][31][32][33][34] . Azepinone 5 beholds different reactive functionalities like a secondary amine and a bketoester that can be exploited in branching cascade approach to build distinct azaheterocyclic frameworks.…”

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. [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). [14] To construct three stereocenters in the nine-membered rings, we proposed that N-vinyl-α,β-unsaturated ketonitrones and methylenecyclopropanes (MCPs) would undergo cycloaddition and sequential [3,3]-rearrangement to afford formal [7 + 2] cycloaddition products containing three stereocenters (Scheme 1-B).…”

Synthesis of Spirofluorenyl-1,2,4-oxadiazinan-5-ones through Metal-Free [3+3] Cycloaddition of N-Vinyl Fluorenone Nitrones with Aza-oxyallyl Cations

“…For example, in 2014, Anderson and co-workers found that the addition of N-vinyl fluorenone nitrones to electron-deficient allenes and sequential [3,3]-rearrangement afforded various 1,4-enamino ketones (Scheme 1, B). 7 They proposed a simple addition reaction mechanism rather than a [3+2] cycloaddition, due to the sterically hindered and electronically deactivated fluorenyl imine.…”

“…oxadiazinan]-5′-one (3na)Yield: 0.078 g (98%); white solid; mp 94-95 °C.IR (thin film): 3063, 2964, 1741, 1677, 1364, 1014, 949 cm -1 1. H NMR (400 MHz, CDCl 3 ):  = 7.77 (d, J = 7.6 Hz, 1 H), 7.65-7.63 (m, 2 H),7.52 (d, J = 7.6 Hz, 1 H), 7.44-7.40 (m, 2 H), 7.30-7.26 (m, 2 H), 7.12-7.04 (m, 3 H), 6.77 (q, J = 7.2 Hz, 2 H), 4.66 (d, J = 9.2 Hz, 1 H), 4.52 (d, J = 9.2 Hz, 1 H), 2.09 (s, 3 H), 1.82 (s, 3 H), 1.62 (s, 3 H). 13 C NMR (100 MHz, CDCl 3 ):  = 170.9, 141.1, 140.7, 140.3, 140.1, 134.4, 130.6, 130.2, 129.0, 128.2, 128.1, 128.0, 127.9, 126.7, 125.1, 120.1, 120.0, 92.0, 82.3, 78.2, 37.7, 24.6, 23.5.…”