Abstract
We report a new method for a tandem Pd-catalyzed intramolecular addition of active methylene compounds to internal alkynes followed by coupling with aryl and heteroaryl bromides. Highly substituted vinylidenecyclopentanes were obtained with good yields, complete selectivity, and excellent functional group tolerance. A plausible mechanism, supported by DFT calculations, involves the oxidative addition of bromoarene to Pd(0), followed by cyclization and reductive elimination. The excellent regio- and stereoselectivity arises from the 5-exo-dig intramolecular addition of the enol form of the substrate to alkyne activated by the π-acidic Pd(II) center, postulated as the rate-determining step.
Highlights
Cyclization of alkynes and alkenes bearing a tethered nucleophilic group constitutes a direct and effective strategy for the construction of a range of carbo- and heterocyclic scaffolds [1,2,3,4,5,6,7,8,9,10]
One of the remaining challenges of both 5-exo-dig cycloisomerization and cyclization/coupling processes catalyzed by carbophilic Lewis acids is the low reactivity of substrates derived from internal alkynes
For challenging challenging substrates substrates bearing bearingan aninternal interalkyene motif, a benchmark reaction of dimethyl hex-4-yn-1-ylmalonate with bromobennal alkyene motif, a benchmark reaction of dimethyl hex-4-yn-1-ylmalonate 1 with brozene was evaluated over a range of Pd-catalysts and reaction conditions (Table 1) [39]
Summary
Cyclization of alkynes and alkenes bearing a tethered nucleophilic group constitutes a direct and effective strategy for the construction of a range of carbo- and heterocyclic scaffolds [1,2,3,4,5,6,7,8,9,10]. One of the most effective of such strategies relies on the use of transition metal complexes exhibiting carbophilic Lewis acidic character (e.g., Au, Pd, Pt, Cu, Ag), capable of coordination to the C-C multiple bond, and in consequence, its activation for nucleophilic attack [14,15,16,17,18,19,20,21,22] This approach offers another opportunity for harnessing the reactivity of the metal–vinyl intermediate for further functionalization via cross-coupling, generating higher molecular complexity in a single step [23,24,25,26,27,28]. Excellent functional group tolerance and selectivity towards a single of the cycoupling product.product
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