Acceleration of metallacycle-mediated alkyne–alkyne cross-coupling with TMSCl

Abstract

Investigation of titanium-centered metallacycle-mediated cross-coupling between unsymmetrical internal alkynes has led to the discovery that TMSCl significantly accelerates the C–C bond forming event. We report a collection of results that compare the efficiency of this reaction employing Ti(Oi-Pr)4/2n-BuLi in PhMe with and without TMSCl, demonstrating in every case that the presence of TMSCl has a profound impact on efficiency. While relevant in the context of developing this fundamental bond-forming process as an entry to more complex organometallic transformations, these modified reaction conditions allow coupling processes to be run at > 10 times the concentrations previously possible [in 2.4M n-BuLi (hexanes)], without the requirement of additional solvent. Finally, we demonstrate the effectiveness of these modified reaction conditions for the annulative cross-coupling between TMS-alkynes and 1,6-enynes leading to the formation of angularly substituted hydrindanes with, now well appreciated, high levels of regio- and stereoselection.

From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling

“…While useful here, it is important to appreciate that metallacycle-mediated coupling reactions of internal alkynes are often plagued by challenges associated with regioselection, and herein the coupling reactions proceeded with a regioselectivity (rs) of 3–4:1. Due to the modest levels of regioselectivity, careful purification was required to enrich samples to be used in subsequent profiling experiments …”

“…Due to the modest levels of regioselectivity, careful purification was required to enrich samples to be used in subsequent profiling experiments. 23 The panel of oleic acid mimetics that was prepared is depicted in Figure 5 and includes six different compounds for each mimetic class (1A−F, 2A−F, 3A−F, and 4A−F). For Class I compounds, the first chiral conformational constraint appears at C3 of the fatty acid backbone.…”

Synthesis of Angularly Substituted trans‐Fused Decalins through a Metallacycle‐Mediated Annulative Cross‐Coupling Cascade

“…As illustrated in Figure 3C,t he addition of TMSCl had ap rofound impact on selectivity. [10] With this simple experimental modification, coupling of TMS-alkyne 6 with enyne 7 delivered the angularly substituted trans-fused decalin 10 in 69 %i solated yield, with no evidence being found for the production of ar egio-or stereoisomeric product.…”

The Development of Alkoxide‐Directed Metallacycle‐Mediated Annulative Cross‐Coupling Chemistry

“…To perturb its propensity to engage in such a coordination event, we pursued silylation of the alkoxide prior to protic quench. Delightfully, when we intervened with the addition of TMSCl prior to the protic quench, a substantial shift in selectivity was observed . As illustrated in Figure B, this modification to the reaction procedure produced the trans ‐fused product containing a benzylic TMS‐ether ( 58 ) in 69 % yield.…”