2‐Cyanoazetidines and Azetidinium Ions: Scaffolds for Molecular Diversity

Abstract

Ring strain in azetidines and azetidinium ions can be efficiently used to promote ring‐expansion and ring‐opening reactions, and this renders these four‐membered heterocycles ideal scaffolds for diversity oriented synthesis. This microreview focuses on 2‐cyanoazetidines, which are easily prepared from β‐amino alcohols through a ring‐closing reaction involving C–C bond formation. The azetidines can be readily expanded to five‐ to eight‐membered nitrogen heterocycles after suitable functionalization and/or activation. Alternatively, N‐alkylated derivatives, namely, azetidinium ions, are easily prepared and displayed rich reactivity as new electrophilic building blocks and as sources of nitrogen ylides.

Cobalt-Catalyzed (Hetero)arylation of Saturated Cyclic Amines with Grignard Reagents

“…Among the saturated N -heterocycles, 4-arylpiperidines, 3-arylpiperidines, 3-arylpyrrolidines and 3-arylazetidines are attractive scaffolds in drug discovery, exhibiting a broad range of biological activities [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Due to these interesting properties, numerous methods have been developed to access these aryl substituted N -heterocycles, either through ring formation or arylation of cyclic compounds [ 9 , 10 , 11 , 12 , 13 ]. The latter approach could be considered more convergent when molecular diversity is targeted and, particularly, metal-catalyzed cross-couplings involving (pseudo)halogeno- N -heterocycles have emerged as a powerful strategy to generate libraries of arylated N -heterocycles.…”

Counterion‐Induced Asymmetric Control in Ring‐Opening of Azetidiniums: Facile Access to Chiral Amines

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Counterion-induced stereocontrol is apowerful tool in organic synthesis.However,such enantiocontrol on tetrahedral ammonium cations remains challenging.Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 %e e). [4, 5] They are susceptible to ring opening by nucleophiles because of the inherent ring strain. [2] In contrast, the direct use of quaternary ammonium salts as substrates for catalytic asymmetric synthesis is rare.

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“…[2] In contrast, the direct use of quaternary ammonium salts as substrates for catalytic asymmetric synthesis is rare. [4, 5] Consequently,c atalytic strategies that permit easy conversion of the readily available azetidinium species into enantioenriched amine products are particularly desirable.I ndeed, enantioselective desymmetrization of the prochiral 3-substituted azetidiniums has not been developed. [4, 5] They are susceptible to ring opening by nucleophiles because of the inherent ring strain.…”

Counterion‐Induced Asymmetric Control in Ring‐Opening of Azetidiniums: Facile Access to Chiral Amines

“…[3] Azetidiniums are versatile synthons for the preparation of bioactive and organic targets. [4,5] They are susceptible to ring opening by nucleophiles because of the inherent ring strain. Compared to neutral azetidines and oxetanes,their reactivity is much higher and may allow more mild reaction conditions and more compatible nucleophiles.E nantioenriched azetidiniums are typically employed to furnish b-chiral amines by ring-opening,b ut unfortunately,t he synthesis of these substrates is not straightforward.…”

“…Compared to neutral azetidines and oxetanes,their reactivity is much higher and may allow more mild reaction conditions and more compatible nucleophiles.E nantioenriched azetidiniums are typically employed to furnish b-chiral amines by ring-opening,b ut unfortunately,t he synthesis of these substrates is not straightforward. [4,5] Consequently,c atalytic strategies that permit easy conversion of the readily available azetidinium species into enantioenriched amine products are particularly desirable.I ndeed, enantioselective desymmetrization of the prochiral 3-substituted azetidiniums has not been developed. Such transformations would provide expedient access to b-chiral amines,afamily of privileged structures present in arange of bioactive molecules,including various notable drug molecules.…”