Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes: synthesis of 4-cyclopentylbenzo[e][1,2,3]oxathiazine 2,2-dioxides

The palladium-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes and 1-azadienes has been developed under mild reaction conditions, giving the multisubstituted cyclopentane derivatives in good to excellent yields with moderate to good diastereoselectivities. The relative configuration of both diastereomers of the products have been determined through X-ray crystallographic diffraction.

The cyclopentane framework is ubiquitous in nature and it is also an important structural moiety in many pharmaceuticals, agrochemicals, and materials. 1 The development of simple, fast and efficient synthetic methods for highly substituted cyclopentanes has attracted much attention. Among various methods for synthesis of cyclopentane structure, the cycloaddition reaction is a very attractive one. 2 Under palladium catalysis conditions, vinylcyclopropane derivatives underwent a ring-opening reaction to generate the zwitterionic allylpalladium intermediate, which reacted with carbon-carbon, carbon-oxygen, carbon-nitrogen double bonds and diazo compounds to provide a variety of ve-membered cyclic compounds. 3 In the past decades, this type of annulation reactions has emerged as a powerful tool for the synthesis of carbocyclic and heterocyclic compounds. 2 Diverse substrates including isocyanates, 4 aldehydes, 5 isatins, 6 3-diazooxindoles, 7 electron-decient alkenes such as para-quinone methides, 8 a,bunsaturated aldehydes, 9 b,g-unsaturated a-keto esters, 10 nitro-olens, 11 azlactone-and Meldrum's acid alkylidenes, 12 and anucleobase substituted acrylates, 13 have been exploited in palladium-catalyzed [3 + 2] cycloadditions of vinyl cyclopropane, delivering biologically interesting functionalized heterocyclic compounds and cyclopentane derivatives. In 2015, Liu and He reported a palladium-catalyzed [3 + 2] cycloaddition of vinyl cyclopropane and a,b-unsaturated imines generated in situ from aryl sulfonyl indoles, providing the optically enriched spirocyclopentane-1,3 0 -indolenines with high diastereoselectivity. 14 This is the only example where a,b-unsaturated imines were employed in Pd-catalyzed [3 + 2] cycloaddition reaction of vinyl cyclopropane.
As a type of a,b-unsaturated imines, cyclic 1-azadienes such as (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxides 2 are easily accessible and stable (Scheme 1). In particular, they contain the sulfonate-moiety, which is an interesting biologically important motif, and has a great potential in the synthesis of bioactive molecules. 15 The cyclic 1-azadienes have been used in a series of annulation reactions such as [2 + n], 16-18 [3 + n], 19 and [4 + n] 20 annulation reactions. Based on the electron-decient nature of the carbon-carbon double bond in these cyclic 1-azadienes, in 2016, Chen and Ouyang developed cinchona-derived tertiary amine-catalyzed asymmetric [3 + 2] annulation of isatin-derived Morita-Baylis-Hillman (MBH) carbonates with cyclic 1-azadienes to form spirooxindole. 17 In the same year, our group demonstrated a phosphine-catalyzed [3 + 2] annulation of MBH carbonates with cyclic 1-azadienes. 18 Considering that the 1azadiene 2 is an electron-decient alkene with good reactivity, its reaction with a zwitterionic p-allyl Pd complex formed via ring-opening of vinylcyclopropane may be feasible. However, this type of cyclic 1-azadienes have never been used in Pdcatalyzed annulation reactions involving vinylcyclopropanes. As our continuing interest on cycloaddition reactions, 21 herein we disclose a [3 + 2] cycloaddition of palladium-catalyzed vinyl cyclopropane with cyclic 1-azadienes to afford the multisubstituted cyclopentane derivatives (Scheme 1).
To further demonstrate the reaction to be a practical tool for the synthesis of polysubstituted cyclopentane derivatives, the reaction was carried out on the gram scale. We were satised to found that when decreasing the loading of palladium/ligand to 0.5%/1.0%, the reaction still worked very efficiently and completed in one hour to provide the product 3aa in 92% yield with 7 : 1 dr (Scheme 2).

Conclusions
In conclusion, we have developed a new method to access the functionalized polysubstituted cyclopentane derivatives in good to excellent yields, employing palladium-catalyzed [3 + 2] cycloaddition between vinylcyclopropanes and 1-azadienes under mild reaction conditions. The reaction tolerated a wide range of substrates and could be performed on the gram scale, showing that it is a practical tool for synthesis of biologically interesting cyclopentane derivatives.

General methods
All reactions were performed under argon atmosphere. Infrared spectra were recorded using an FT-IR spectrophotometer. 1 H and 13 C NMR spectra were recorded using a 300 MHz NMR instrument. Accurate mass measurements were performed on an electrospray ionization (ESI) apparatus using time-of-ight (TOF) mass spectrometry. Melting points were determined on Scheme 1 [3 + 2] Cycloaddition of 1,3-zwitterions with cyclic 1azadienes.