Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid‐Catalyzed [3+2]‐Cycloadditions of Ketenes and Azomethine Imines

Abstract

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid-catalyzed formal [3 + 2]-and [3 + 2 + 2]-cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R = alkyl, OAc). The products were formed in good to excellent yields (71-99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (� 93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3 + 2 + 2]-cycloaddition to form structurally interesting bicyclic pyrazolo-oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.

Organocatalyzed cycloaddition reactions of azomethine imines—A lookback

“…AMI with aromatic rings having both electron-withdrawing and electron-donating substituents showed good enantioselectivity. They recently reported the asymmetric synthesis of bicyclic pyrazolidinones through (DHQ) 2 PHAL and (DHQD) 2 PHAL catalyzed [3+2+2] cycloaddition of ketenes with AMI (Scheme 14) [28].…”

“…Organocatalyzed cycloaddition of AMI has been widely used in the synthesis of many such biologically relevant molecules. For example, various groups have synthesized a class of molecules with proven anti-Alzheimer's properties by incorporating cycloaddition of AMI as the key step, as discussed in this review [27,28,51]. Some other compounds with similar structural motifs exhibit antibiotic, antidepressant, antiviral, anti-convulsant, and anti-inflammatory activities.…”

Synthesis of Pyrazolidinone-Fused Benzotriazines through C–H/N–H Bond Functionalization of 1-Phenylpyrazolidinones with Oxadiazolones

“…In addition, they have also found wide applications in the development of novel photoelectric materials, fluorescent brighteners, and dyes. , Meanwhile, the pyrazolidinone skeleton is prevalent in anti-inflammatory, analgesic, antipyretic, and anticonvulsant drugs (Figure ). Considering the importance of benzotriazine and pyrazolidinone, it is reasonable to infer that a hybrid skeleton combining these two privileged structural scaffolds might be bestowed with synergistic biological activities. While a number of methods for the respective synthesis of benzotriazines or pyrazolidinones have been developed so far, the synthetic protocol for the construction of such sophisticated hybrid molecular structure from simple starting materials without tedious prefunctionalization has not been reported.…”

“… Considering the importance of benzotriazine and pyrazolidinone, it is reasonable to infer that a hybrid skeleton combining these two privileged structural scaffolds might be bestowed with synergistic biological activities. While a number of methods for the respective synthesis of benzotriazines or pyrazolidinones have been developed so far, the synthetic protocol for the construction of such sophisticated hybrid molecular structure from simple starting materials without tedious prefunctionalization has not been reported.…”

N-Heterocyclic Carbene-Catalyzed Stereoselective [3 + 2] Cycloaddition of N,N′-Cyclic Azomethine Imines with Aryl Acetaldehydes

“…Consequently, the development of expedient strategies toward the concise and stereoselective construction of N , N ′-bicyclic pyrazolidinones has captivated extensive attention from the synthetic chemistry as well as medicinal chemistry communities. N , N ′-Cyclic azomethine imines, owing to their bench stability and synthetic versatility, have been broadly employed in diverse catalytic 1,3-dipolar cycloaddition reactions to prepare dinitrogen-fused heterocycles . In 2017, 2018, and 2022, Kerrigan, , our group, and Yang and Zhong successively reported three organocatalytic asymmetric [3 + 2] cycloaddition reactions of N , N ′-cyclic azomethine imines with carbonyl compounds to afford N , N ′-bicyclic pyrazolidinones (Scheme a).…”