Fulvenes as Effective Dipolarophiles in Copper(I)‐Catalyzed [6+3] Cycloaddition of Azomethine Ylides: Asymmetric Construction of Piperidine Derivatives

Abstract

Catalytic asymmetric [3+2] cycloaddition of azomethine ylides is one of the best methods for constructing enantioenriched heterocyclic pyrrolidines, [1] and extensive studies have been conducted on the use of various electron-deficient alkenes as the 2p synthons over the past decade. [2] However, although there are elegant and creative azomethine-ylideinvolved cycloaddition reactions toward the construction of five-membered pyrrolidine architectures, [1,2] the direct catalytic asymmetric approach to enantioenriched six-membered heterocyclic piperidines, which are prevalent scaffolds that serve as the core structures of natural alkaloids and bioactive molecules, [3] has met with little success, [4] and we believe this represents a considerable challenge.In 2003, Hong et al. [5] reported a [6+3] cycloaddition of azomethine ylides with fulvenes [6] , in which fulvenes served as 6p components, thus leading to the synthesis of racemic sixmembered piperidine derivatives. However, there is a lack of catalytic asymmetric [6+3] cycloadditions which tolerate variations in both the azomethine ylides and fulvenes. Stimulated by the biological significance of piperidine derivatives and the challenging synthetic difficulties associated with enantio-and diastereoselectivity control, we questioned whether fulvenes containing no electron-withdrawing groups could be employed as efficient 6p dipolarophiles and provide a straightforward and asymmetric approach to enantioenriched piperidines. Very recently, one example on the asymmetric cycloaddition of unsymmetrical fulvenes and azomethine ylides has been published concurrently with the preparation of the present manuscript. [7] Herein, we report the Cu I /TF-BiphamPhos-catalyzed asymmetric synthesis of highly substituted piperidines by the [6+3] cycloaddition of azomethine ylides with various fulvenes (Scheme 1, right), and subsequent transformations which allow facile access to enantioenriched fused polycyclic piperidine derivatives without loss in diastereoselectivity and enantioselectivity.For our initial studies, the readily available fulvene 2 a [8] was chosen as the model 6p component. Initially we began our investigations by examining the ability of Cu I /TF-BiphamPhos and Ag I /TF-BiphamPhos [9] complexes to probe the possibility of an asymmetric variant of this challenging [6+3] cycloaddition reaction employing the N-(4-chlorobenzylidene)glycine methyl ester 3 a as the dipole precursor (Table 1). To our delight, the reaction was completed in less than 24 hours with AgOAc/(S)-TF-BiphamPhos (1 a) as the catalyst and Et 3 N as the base in dichloromethane at room temperature, thus yielding the expected six-membered heterocyclic piperidine 4 a with excellent diastereoselectivity and 36 % ee (Table 1, entry 1). Neither [3+2] nor regioisomeric [6+3] cycloadducts were observed although the by-product [10] formed by self-cycloaddition of 3 a was isolated in 10 % yield. The cycloadduct 4 a is formed exclusively and no [1,5] Hshift [11] occurred, probably because most of the subst...

Cycloamination strategies for renewable N-heterocycles

“…Using imine esters 153 as three-atom units (Fig. 3), (a) five-membered heterocyclic compounds (e.g., pyrrolidines) can be acquired by [3 + 2]-cycloaddition with twoatom dipolarophiles (e.g., electron-deficient alkenes); 308 (b) fused and bridged six-membered piperidines can be acquired via [6 + 3]-cycloaddition reactions of 6-π dipolarophiles (e.g., fulvenes, 2-acyl cycloheptatrienes, tropone) with azomethine, [309][310][311] while six-membered heterocyclic frameworks can be acquired by cross 1,3-dipolar [3 + 3]-cycloaddition of azomethine with pyrazolidinium ylides; 312 and (c) seven-membered heterocyclic azepines can be acquired from methyl coumalate via tandam [4 + 3]-cycloaddition/decarboxylation/isomerization. 308 By changing the chain length of the employed substrates, other five, six, seven, and eight membered N-heterocycles are obtained using appropriate catalysts or catalytic systems.…”

An overview of the cycloaddition chemistry of fulvenes and emerging applications

“…Pentafulvenes can react as 2π components with moderately electron-deficient dienes and 4π components in reactions with dienophiles (Scheme 5), whereas pentafulvenes substituted with EDG (e.g., NMe 2 ) at the exocyclic C6 position possess an increased electron density about the fulvene π-system, increasing the stability and hence nucleophilicity of the fulvene [29,73,96–104]. This allows the fulvene to function as a 6π component in reactions with electron-deficient dienes (Scheme 5) and fulvenes acting as dipolarophiles have been reported for enantioselective [6 + 3] and [3 + 2] cycloadditions [83–84 105]. In general, reactions with electron-rich alkenes will take place preferentially at the exocyclic C6 position while other less electron-rich species interact most strongly with the fulvene HOMO resulting in only [4 + 2] cycloadditions [101,103].…”

General Enantioselective C−H Activation with Efficiently Tunable Cyclopentadienyl Ligands

“…Furthermore, investigations of the possible effect of R 3 on the ester group revealed that big groups such as ethyl resulted in lower reactivity for this specific reaction although the enantioselectivity remained comparable (Table S3, entry 10). The corresponding ligand in optically pure form can be prepared by using preparative HPLC on a chiral stationary phase for racemate separation on gram scale or by using a known enantioselective [6+3] cycloaddition . With this optically pure ligand in hand, we investigated the importance of the protective group on the secondary amine.…”