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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.

[reaction: see text] Cobalt-mediated [2 + 2 + 2] cycloaddition of alpha,omega-diynes and isocyanates provides a direct approach to macrocyclic 2-oxopyridinophanes. This macrocyclization process, which proceeded most efficiently with aliphatic isocyanates, was conveniently performed at a moderate temperature (85 degrees C) without irradiation or syringe-pump addition.

High levels of diastereoselection were achieved in the PKR of 1,6- and 1,7-cyclopropylidenynes bearing a bulky propargylic C(2)-symmetric acetal.

Depending on the thermolytic conditions, dicobalthexacarbonyl-complexed enynes underwent cyclizations to provide different carbocyclic frameworks. Bicyclopentanones were formed from enyne-Co2(CO)6 complexes, or from enynes that were treated with Co2(CO)8, or more effectively, with Co4(CO)12 in an alcoholic solvent under a H2 or N2 atmosphere. This transformation proceeded via a sequential cyclocarbonylation and 1,4-reduction and is the first account using the cobalt carbonyl cluster. Under these conditions a cobalt hydride was presumably generated, which mediated reduction of the enone to the saturated ketone. In contrast, thermolysis of dicobalthexacarbonyl-complexed enynes under a hydrogen atmosphere in toluene resulted in their reductive cyclization to form monocyclic alkenes in moderate yields, in addition to the bicyclopentenone product. In some cases, addition of a hydrosilane to the reaction induced a complete suppression of the bicyclopentenone formation. While the former results demonstrate a reaction that occurs after the cycloaddition, the latter depicts another example of an interruption of the normal route in the Pauson-Khand reaction pathway.

In this report we have shown that the commercially available Co(2)(CO)(8) and Co(4)(CO)(12), and enyne--Co(2)(CO)(6) complexes, are sufficiently effective in catalyzing the Pauson--Khand reaction under one atmosphere of CO pressure. It was further demonstrated that the efficiencies of these cyclization protocols could be enhanced by the presence of cyclohexylamine. These procedures have also rendered more practical and highly convenient alternatives for the catalytic Pauson--Khand reaction. Most importantly, we have dispelled the common belief that Co(4)(CO)(12) is inactive in the Pauson--Khand reaction under one atmosphere of carbon monoxide. Of mechanistic importance is that these studies have also shown that the probable formation of Co(4)(CO)(12) is not necessarily a dead end pathway in the Co(2)(CO)(8)-catalyzed Pauson--Khand reaction. It is also of interest that substoichiometric amounts of Co(2)(CO)(8), in DME and in the presence of cyclohexylamine, are sufficient for the cyclocarbonylation of enynes under a nitrogen atmosphere. Our findings have provided more practical protocols for the Pauson-Khand reaction using catalytic amounts of cobalt carbonyl complexes and a better understanding of the influence of Lewis bases on their efficiency. These reports on the activity of Co(4)(CO)(12) are anticipated to develop into a convenient and practical alternative for Co(2)(CO)(8) catalysis.