Organocatalytic and Stereoselective [3 + 2] Cycloadditions of Azomethine Imines with α,β‐Unsaturated Aldehydes

Abstract

Bipyrazolidin-3-one derivatives are biologically significant compounds and their importance has increased in the past decades. In this paper, the first stereoselective [3 + 2] dipolar cycloadditions of azomethine imines with a,b-unsaturated aldehydes catalyzed by readily available a,adiarylprolinol salts are reported, providing a facile route to the synthesis of various chiral bipyrazolidin-3-one derivatives under mild conditions. The organocatalyst 1 g with strongly electron-withdrawing groups exhibited the best stereoselectivity (exo:endo up to 98:2, for exo product up to 97 % ee), in the combination with trifluoroacetic acid.Keywords: azomethine imines; bipyrazolidin-3-one; diarylprolinols; dipolar cycloaddition; organocatalysis; unsaturated aldehydes Recently, small organic molecules-catalyzed enantioselective transformations have attracted increasing attention.[1] Particularly, asymmetric amine catalysis has been the subject of intensive research since the discovery of the proline-catalyzed direct asymmetric intermolecular aldol reaction. Numerous 1,2-or 1,4-addition reactions with excellent enantioselectivities have been reported in the last five years.[2] On the other hand, asymmetric cycloaddition reactions have also been actively explored in the amine catalysis. The generation of active iminium ions, which are thought to lower the energy of the dienophile LUMO, generally plays a key role in the successful cycloaddition reactions. Nevertheless, the current examples are mostly limited to the common DielsAlder reactions.[3]The catalytic asymmetric [3 + 2] dipolar cycloaddition reaction provides one of the most powerful strategies for the enantioselective construction of fivemembered heterocycles. While considerable progress has been made in the metal-catalyzed asymmetric synthesis over the past decades, [4] the application of chiral organocatalysts in [3 + 2] cycloaddition reactions remains in its infancy since MacMillan's pioneering works in 2000.[5] Furthermore, only nitrones have been tested as the successful dipoles to date.[6] Based on our successful experience on the asymmetric vinylogous Michael addition of a,a-dicyanoolefins to a,bunsaturated aldehydes catalyzed by chiral a,a-diarylprolinol salts, [7] here we present the first asymmetric [3 + 2] cycloaddition reaction of azomethine imines with a,b-unsaturated aldehydes.Azomethine imines such as 2, prepared by the condensation of pyrazolidin-3-one with aldehydes, are stable and easily handled compounds. Their potential application as dipoles in cycloadditions with alkenes or alkynes has been established a long time ago. [8] Several pyrazolidin-3-one derivatives exhibit biological activities, and the importance of this type of compounds has risen significantly in the last two decades. One of the examples is the cycloaddition product LY 186826, which exhibits high anti-bacterial activity. [9] On the other hand, although a variety of asymmetric cycloadditions of chiral azomethine imines have been reported, [10] the catalytic enantioselective [...

1,3-Dipolar cycloadditions of azomethine imines

“…The enal activation takes place by iminium formation giving the corresponding fused pyrazolidinones 238 mainly with exo-selectivity and high enantioselectivities (Scheme 92). 140 The possible reaction models for this 1,3-DC is illustrated in Scheme 92: both transition states A and B with s-cis and s-trans conformations, respectively, would afford the exo-cycloadducts. 64 Scheme 93 NHC-catalyzed [3+2] cycloaddition of azomethine imines 166 with enals.…”

Asymmetric Organocatalysis

“…Various chiral bipyrazolin-3-one derivatives have been obtained with moderate to high enantiomerical excesses [78]. When cyclic enones were used, the combined catalyst system of 58b and 2,4,6-triisopropylbenzenesulfonic acid (TIPBA) offered a highly enantioselective transformation (Scheme 21) [79].…”

N‐Imide Ylide‐Based Reactions: CH Functionalization, Nucleophilic Addition and Cycloaddition

“…One example was the metalfree 1,3-dipolar cycloaddition of N,N-cyclic azomethine imines 56 with a,b-unsaturated aldehydes 163 catalyzed by a,a-diarylprolinol L 11 , yielding the bipyrazolin-3-one derivatives 164 enantioselectively. [64] Cyclic a,b-unsaturated enones 165 were also compatible in the stereoselective [3+2] cyclization of N,Ncyclic azomethine imines when the organocatalyst was switched to Cinchona alkaloid L 12 with a multi-functional primary amino group. [65] According to the result developed by Chen and co-workers, the additional and synergistic hydrogen-bond interaction of the catalyst and 1,3-dipole was beneficial for the outcome with excellent stereoselectivities.…”