Phosphine‐Catalyzed Annulations of 4,4‐Dicyano‐2‐Methylenebut‐3‐enoates with Maleimides and Maleic Anhydride

Abstract

A novel phosphine-catalyzed [4+1] annulation of maleimides with 4,4-dicyano-2-methylenebut-3-enoates has been developed to afford spirocyclic products, and the maleimides serves as C 1 synthons. Moreover, a phosphinecatalyzed formal [3+2] annulation between 4,4-dicyano-2methylenebut-3-enoates and maleic anhydride has been also achieved, and maleic anhydride behaved as a C 3 synthon in the reaction, thus efficiently affording the functionalized cyclopentenones. A stable phosphinium-containing zwitterionic compound is the key reactive intermediate in both annulations and was successfully isolated. Plausible mechanisms have been proposed on the basis of control experiments and deuteriumlabeling experiments.Functionalized five-membered carbocycles as structural motifs have drawn tremendous interest in the area of synthetic organic chemistry and medicinal chemistry since they are the ubiquitous substructures in a variety of natural products and biologically active molecules. [1] Recently, remarkable progress has been made in the development of nucleophilic phosphine organocatalysis, [2] and now phosphine-mediated/catalyzed reactions have emerged as a powerful tool for the synthesis of a wide variety of novel compounds. [3] Among them, phosphine-catalyzed [3+2] annulations of activated allenes or Morita-Baylis-Hillman (MBH) carbonates have become powerful approaches to synthesize functionalized carbo-and heterocycles. [4] Apart from phosphine-catalyzed [3+2] annulations, phosphine-catalyzed [4+1] annulations [5] are also an efficient methodology to construct functionalized five-membered carbo-and heterocycles.Maleimides as electron-deficient olefins have been widely used in annulations to give functionalized carbocyclic compounds. [6] More recently, several phosphine-catalyzed [3+2] annulations of maleimides have been developed by Lu, Shi, and co-workers to construct the corresponding functionalized cyclopentene derivatives (Scheme 1 a). [7] In all these reactions, maleimides were used as a C 2 synthon in annulations. However, to the best of our knowledge, there is no report that maleimides are used as a C 1 synthon to participate in phosphine-catalyzed annulations. Herein we report a novel phosphine-catalyzed [4+1] annulation of maleimides with 4,4dicyano-2-methylenebut-3-enoates, a reaction wherein maleimides were used as a C 1 synthon, for the first time, in phosphine-catalyzed annulations (Scheme 1 b). Moreover, among the phosphine-catalyzed annulations, electron-deficient olefins are important reagents and often used as C 2 synthons. [4] Maleic anhydride as an electron-deficient olefin is also a useful reagent. [8] However, phosphine-mediated/catalyzed reactions of maleic anhydride are very scarce. [9] As far as we know, there is no report about phosphine-catalyzed annulations of maleic anhydride. Herein, we also disclose a novel phosphine-catalyzed formal [3+2] annulation of maleic anhydride with 4,4-dicyano-2methylenebut-3-enoates to construct functionalized cyclopentenones. The maleic anhydride behaves as a ...

Phosphine Organocatalysis

“…It was not until 2014 that the Shi group disclosed the interesting reactivities of maleimides and maleic anhydrides behaving as one- and three-carbon synthons, respectively. 158 With maleimide and 1,3-butadiene as reaction partners, they synthesized a collection of functionalized spirocyclopentenes through a phosphine-catalyzed [4 + 1] annulation pathway (Scheme 86). Starting from the 1,3-butadiene, the zwitterion 48 is formed readily in the presence of triphenylphosphine.…”

“…In addition to the [4 + 1] annulation pathway, an unusual [3 + 2] annulation was also disclosed in the same Communication. 158 Through this pathway, maleic anhydride reacted to provide a three-carbon synthon for the annulation (Scheme 88). The initially formed zwitterion 51 undergoes addition to maleic anhydride to generate the intermediate 52 .…”

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

“…In addition to the MBH carbonates, Shi’s group recently revealed that maleimides 315 can serve as the C1 synthon to undergo an interesting formal [4+1] annulation with 4,4-dicyano-2-methylenebut-3-enoates 314 by nucleophilic phosphine catalysis (Scheme ) . Using 10 mol % of PPh 3 as the organocatalyst in toluene at 60 °C, the reaction with various aryl and heteroaryl-substituted 4,4-dicyano-2-methylenebut-3-enoates 314 and aryl or alkyl-bearing maleimides 315 smoothly proceeded to furnish the corresponding highly functionalized spirocyclic compounds 316 in generally acceptable yields.…”

“…214 In addition to the MBH carbonates, Shi's group recently revealed that maleimides 315 can serve as the C1 synthon to undergo an interesting formal [4+1] annulation with 4,4dicyano-2-methylenebut-3-enoates 314 by nucleophilic phosphine catalysis (Scheme 114). 215 Using 10 mol % of PPh 3 as the organocatalyst in toluene at 60 °C, the reaction with various aryl and heteroaryl-substituted 4,4-dicyano-2-methylenebut-3enoates 314 and aryl or alkyl-bearing maleimides 315 smoothly proceeded to furnish the corresponding highly functionalized spirocyclic compounds 316 in generally acceptable yields. The deuterium-labeling experiments and successful isolation of the stable zwitterions 314A and 314A′ (R 1 = 4-MeC 6 H 4 , R 2 = Me), which were initially formed from tertiary phosphine and 314, implied that these species are possible intermediates for this [4+1] annulation.…”