Iron‐Catalyzed Cycloisomerization and C−C Bond Activation to Access Non‐canonical Tricyclic Cyclobutanes

Kramm, Frederik; Ullwer, Franziska; Zheng, Min; Plietker, Bernd; Klinnert, Benedict

doi:10.1002/anie.202205169

“…An intriguing [3.2.0]‐bridged cycle 15 was also smoothly obtained in >20 : 1 dr via Ni‐catalyzed [2+2] cyclization [78] from 14 . All these enantioenriched rings are prevalent in biologically active molecules [79, 80] …”

Section: Resultsmentioning

confidence: 99%

Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Wang

¹

,

Xiao

²

,

Wang

³

et al. 2022

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Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5conjugate reaction, followed by inter-or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

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“…In such cases, the use of non-photocatalytic methods is a promising alternative (Figure b). However, such methods usually require the use of activated dienes or enynes . Exceptions are the iron- and cobalt-based pyridinediimine systems (type 1 , Chart ) developed by Chirik, which can effectively convert N-functionalized diallylamines to the corresponding azabicyclo[3.2.0]heptanes at low catalyst loadings .…”

Section: Introductionmentioning

confidence: 99%

Iron-Catalyzed Synthesis of Conformationally Restricted Bicyclic N-Heterocycles via [2+2]-Cycloaddition: Exploring Ring Expansion─Mechanistic Insights and Challenges

Hertwig

¹

,

Bender

²

,

Becker

³

et al. 2023

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We present an efficient iron-catalyzed method for synthesizing conformationally restricted cyclobutane-fused Nheterocycles from unactivated precursors. This method is orthogonal to the established photocatalytic methods, extends the range of substrates, and provides a single-step route to previously unattainable cyclobutane-fused piperidines and azepanes. Ring stereochemistry depends on size, with five-and sixmembered rings adopting a cis configuration and seven-membered rings preferring a trans configuration. A key aspect of this method is the use of a catalyst design based on an electron-deficient, redoxactive, pyrimidinediimine scaffold. Mechanistic investigations suggest that the π-acidic core significantly enhances catalyst stability against deleterious intramolecular C−H activation pathways, while the electron-rich flanking groups accelerate the reaction rate. Mechanistic insights were obtained by extracting kinetic profiles and establishing catalyst−activity relationships. Computational studies established that the oxidative cyclization step proceeds with the highest energy barrier, which is further confirmed by experimental Hammett analysis.

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“…An intriguing [3.2.0]‐bridged cycle 15 was also smoothly obtained in >20 : 1 dr via Ni‐catalyzed [2+2] cyclization [78] from 14 . All these enantioenriched rings are prevalent in biologically active molecules [79, 80] …”

Section: Resultsmentioning

confidence: 99%

“…All these enantioenriched rings are prevalent in biologically active molecules. [79,80] Because of their unique electronic and steric properties, especially their rigid three-dimensional conformations, small rings have been widely incorporated into drug molecules and also exist broadly in natural products. [80][81][82][83][84] However, the enantioselective construction of small rings has always been a formidable challenge due to their high ring strain, congested steric hindrance and unstability.…”

Section: Forschungsartikelmentioning

confidence: 99%

Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Wang

¹

,

Xiao

²

,

Wang

³

et al. 2022

Angewandte Chemie

4

0

View full text Add to dashboard Cite

Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5conjugate reaction, followed by inter-or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

show abstract

Iron‐Catalyzed Cycloisomerization and C−C Bond Activation to Access Non‐canonical Tricyclic Cyclobutanes

Cited by 7 publications

References 50 publications

Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Iron-Catalyzed Synthesis of Conformationally Restricted Bicyclic N-Heterocycles via [2+2]-Cycloaddition: Exploring Ring Expansion─Mechanistic Insights and Challenges

Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

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