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.

Transition metals in organic synthesis: Highlights for the year 2005

“…Cobalt mediated [2 + 2 + 2]cycloadditions were used to prepare aryl-containing macrocycles [1290], [7]helicenelike molecules [1291] and the deoxygenated pancrastistatin core [1292]. Benzolactones and lactams were prepared via a cobalt-catalyzed [2 + 2 + 2]cycloadditions of (2-4)-yne-1-ols and 2-yne-1-amines with propynoic acid esters [1293].…”

CHAPTER 5. Cobalt-Catalyzed Heterocycle Synthesis

“…Maryanoff and co-workers investigated the formation of macrocycles from a,p-diynes in cobalt-mediated co-cyclotrimerization reactions. 70,71 Longchain a,p-diynes underwent metal-mediated [2 þ 2 þ 2] cycloadditions with nitriles, cyanamides or isocyanates in the presence of CpCo(CO) 2 to yield pyridine-containing macrocycles, i.e. m-and p-pyridinophanes.…”

Recent Advances in the Synthesis of Pyridines by Transition-Metal-Catalyzed [2+2+2] Cycloaddition

“…Thus, meta-25 and 27 and parapyridinophanes 24 and 26 have been synthesized (Scheme 8); 19 the regioselectivity of the reaction is dependent on the length and type of tether.…”