Abstract
Urea-directed carbonylative insertion of Rh(I)-catalysts into one of the two proximal C–C bonds of aminocyclopropanes generates rhodacyclopentanone intermediates. These are trapped by N-tethered alkynes to provide a (3+1+2) cycloaddition protocol that accesses N-heterobicyclic enones. Stoichiometric studies on a series of model rhodacyclopentanone complexes outline key structural features and provide a rationale for the efficacy of urea directing groups. A comprehensive evaluation of cycloaddition scope and a ‘second generation’ cationic Rh(I)-system, which provides enhanced yields and reaction rates for challenging substrates, are presented.
Highlights
Flexible and modular entries to stereochemically rich N-heterocyclic scaffolds are of topical interest to the pharmaceutical sector.[1]
Pioneering studies by Wilkinson demonstrated Rh/CO insertion into cyclopropane to generate a dimeric rhodacyclopentanone.7a Subsequent work by McQuillin examined the regioselectivity of this process for substituted variants.7b An alternative approach was reported by Murakami and Ito, where rhodacyclopentanones were accessed by the insertion of Rh(I)-systems into the acyl-carbon bond of cyclobutanones.[8]
This process has served as the basis for a series of methodologies,9e11 carbonylative rhodacyclopentanone formation has not been as widely exploited in synthesis.3a,12 Notable processes that harness this approach include carbonylative rearrangements of spiropentanes, as reported by Murakami,12b and (3þ1þ2) cycloadditions involving alkynes to generate carbocyclic systems, as reported by Narasaka.3a In this latter process, the alkyne is invoked as a directing group
Summary
Flexible and modular entries to stereochemically rich N-heterocyclic scaffolds are of topical interest to the pharmaceutical sector.[1]. Trapping of 3 with N-tethered alkynes provided a (3þ1þ2) cycloaddition strategy to generate N-heterobicyclic enones (4/5).[3] These investigations provided proof-ofprinciple for an approach that has the potential to enable a wide range of carbonylative cycloadditions for accessing directly ‘sp3rich’ chiral scaffolds.[1,4] to date, the catalysis platform outlined in Scheme 1 has served as the basis for related (3þ1þ2) cycloadditions involving alkenes,[5] and a (7þ1) cycloadditionfragmentation approach to substituted azocanes.[6] In this article we disclose our full studies on the development of urea-directed (3þ1þ2) cycloadditions involving alkynes.
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