title: Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions.
abstract: We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical, Research & Development, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Llorente V R
authors.initials: LV
authors.lastname: Boñaga
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Alessandro F
authors.initials: AF
authors.lastname: Moretto
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Diane A
authors.initials: DA
authors.lastname: Gauthier
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Leo
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff