title: A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration.
abstract: This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.
authors.affiliation: Department of Chemistry, Gunning-Lemieux Chemistry Centre University of Alberta, Edmonton, AB T6G 2G2, Canada.
authors.forename: Barry B
authors.initials: BB
authors.lastname: Touré
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Hoveyda
authors.forename: Jyoti
authors.initials: J
authors.lastname: Tailor
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ulaczyk-Lesanko
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Hall