Stereodiversified Modular Synthesis of Non‐planar Five‐Membered Cyclic N‐Hydroxylamidines: Reactivity Study and Application to the Synthesis of Cyclic Amidines

• Published in: Advanced synthesis & catalysis 2018-11, Vol.360 (22), p.4362-4371
• Main Authors: Prieto‐Ramírez, Mary Cruz, Fernández, Israel, da Silva, Ivan, González‐Platas, Javier, de Armas, Pedro, García‐Tellado, Fernando
• Format: Article
• Language: English
• Subjects: amidines; amidinoxyl radical; Aromatic compounds; auto-oxidation; Hydroxylation; Manifolds; multicomponent; on water; Oxidation; Stereoselectivity; Synthesis
• ISSN: 1615-4150; 1615-4169
• DOI: 10.1002/adsc.201800749

A modular, stereodiversified and scalable synthesis of 5‐membered cyclic N‐hydroxylamidines endowed with three contiguous stereogenic centres is reported. The synthesis utilizes 2‐cyano‐3‐aryl‐4‐nitro‐alkynoates as key building blocks, which are provided by a novel 3‐component Knoevenagel ‐Michael addition manifold carried out as an aqueous emulsion (on water). The key building blocks are obtained as separable mixtures of two series of diastereomers: 2,3,4‐syn,syn and 2,3,4‐syn,anti. Both series were separately transformed into the corresponding 5‐membered 3,4,5‐trisubstituted N‐hydroxylamidines by a tandem hydrogenation cyclization reaction (stereodiversification phase). These N‐hydroxylamidines are functionalized at C3‐methinic position of the ring (alpha to the amidine function) by a robust and unprecedented N‐amidinoxyl radical‐mediated auto‐oxidation process (hydroxylation), or by a diastereoselective enamine‐based C−C bond forming manifold (creation of an all‐carbon quaternary centre). The outcome of the latter is biased by the relative disposition of substituents in the ring, affording C3‐quaternized 5‐membered cyclic N‐hydroxylamidines or 2,9‐diazabicyclo[4.3.0]non‐1‐en motives. Finally, the Ti(III)‐reduction of these quaternized N‐hydroxylamidines generates the corresponding amidines in excellent yields.