The Scope and Limitations of Intramolecular Nicholas and Pauson−Khand Reactions for the Synthesis of Tricyclic Oxygen- and Nitrogen-Containing Heterocycles

Abstract

We studied the scope and limitations of a tandem intramolecular Nicholas/Pauson-Khand strategy for the synthesis of tricyclic oxygen- and nitrogen-containing heterocycles. This methodology enables conversion of simple acyclic starting materials into a series of previously unknown heterocyclic architectures. For the preparation of cyclic ethers (Z = O), tricyclic [5,6,5]- through [5,9,5]-systems (m = 1, n = 1-4) are available with the [5,7,5]- and [5,8,5]-systems amenable to quick and efficient synthesis. Tricyclic [5,7,5]- and [5,8,5]-amine-containing (Z = NTs) heterocycles can be successfully prepared. Attempts to make larger ring systems (Z = O, m = 2; Z = O, n = 5; or Z = NTs, n = 4-5) or prepare lactones via Nicholas reactions with carboxylic acid nucleophiles (available via oxidation of alcohol nucleophiles, Z = O) result in decomposition or dimerization. The latter process enables formation of 14-, 16-, and 18-membered ring diolides when using carboxylic acid nucleophiles. We also investigated the use of chiral amine promoters in the Pauson-Khand step but found no asymmetric induction.

A Decade of Advancements in Pauson–Khand‐Type Reactions

“…Shea and coworkers recently demonstrated the utility of intramolecular Nicholas and Pauson–Khand reactions in the synthesis of tricyclic heterocycles 122. The acyclic enynes 31 were first chelated onto dicobalt octacarbonyl complexes to form the cobalt‐alkyne complexes 32 , followed by a Nicholas reaction to provide the heterocycles 33 , and were then finally cyclized through intramolecular Pauson–Khand reactions to afford the desired tricyclic heterocycles 34 (Scheme ).…”

Cobalt-Catalysed Bond Formation Reactions; Part 2

“…Secondly, Shea reported the combination of an intramolecular Nicholas reaction with the PKR for the synthesis of [5,7,5]-tricyclic ring systems (Scheme 73). 253…”

Diastereoselective Pauson‐Khand Reaction using Chiral Pool Techniques (Chiral Substrates)

“…33 This methodology enables the conversion of simple acyclic starting materials, 112, into a series of previously unknown heterocycles, 114. Tricyclic ethers (Z = O) with [5,7,5]-and [5,8,5]-systems and tricyclic [5,7,5] Attempts to make larger ring systems or prepare lactones via Nicholas reactions with carboxylic acid nucleophiles resulted in decomposition or dimerization of the starting materials.…”