Sterically Controlled Late-Stage C–H Alkynylation of Arenes

Abstract

Phenylacetylenes are key structural motifs in organic chemistry, which find widespread applications in bioactive molecules, synthetic intermediates, functional materials, and reagents. These molecules are typically prepared from prefunctionalized starting materials, e.g. using the Sonogashira coupling, or using directing groupbased C−H activation strategies. While highly efficient, these approaches remain limited by their inherent selectivities for specific regioisomers. Herein we present a complementary approach based on an arene-limited nondirected C−H activation. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for latestage functionalization are demonstrated.

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium

“…For this purpose the deuterated benzoate substrate 1b-d5 was subjected to the catalyst system without adding the olefin reaction partner (note that a change of model substrate was required, since a background-H/D-exchange in known to occur for more electron-rich substrates). [11,28] We observed a substantial degree of H/D-exchange, thus proving the reversibility of the C-H activation step under the reaction conditions. Similarly, we subjected the same substrate to the reaction conditions in the presence of the olefin reaction partner and found that the H/D-exchange in the remaining substrate was strongly reduced.…”

“…[9,10] Recently our group has developed an arene-limited nondirected C-H alkynylation. [11] Furthermore, we could recently demonstrate that this design can also be applied to devise sterically controlled heteroarene functionalizations. [12] These studies hint at the tremendous synthetic potential of a broadly applicable generation of aryl-palladium species through nondirected C(sp 2 )-H activation.…”

“…Interestingly, while catalysts based on either one of these ligand types have been studied extensively, [13][14][15][16][17] so far only few mechanistic details are available on this dual ligand catalysis approach. [9,11] Herein we describe combined experimental and theoretical studies on the mechanism of the dual ligand-enabled nondirected olefination of arenes. The results illustrate the generality of dual ligand-enabled C-H activation and lead to a mechanistic model that serves to rationalize the role of each ligand in this process as well as the observed trends in reactivity and selectivity.…”

Palladiumkatalysierte C‐H‐Alkinylierung unaktivierter Alkene

“…Das Testen von Säure/Base‐Kombinationen ergab, dass 1‐Adamantancarbonsäure (AdCOOH) und Kaliumcarbonat effiziente Aktivatoren für die C‐H‐Alkinylierung sind (Eintrag 4). Die Zugabe eines Silbersalzes als Halogenidfänger, eine Voraussetzung bei mehreren ähnlichen Transformationen, war für das Reaktionsergebnis nicht vorteilhaft (AgOAc, 48 % Ausbeute, Eintrag 5). Weitere Optimierungen zeigten, dass eine geringere Katalysatormenge gut toleriert wurde und die Ausbeute sogar leicht auf 84 % verbesserte (Eintrag 6).…”

Dual Ligand-Enabled Late-Stage Fujiwara–Moritani Reactions

“…10 Furthermore, we described an analogous alkynylation later that year. 11 Importantly, all of these methods used the arene as the limiting reagent and can therefore, in principle, be used for late-stage functionalization. In our study on the Fujiwara-Moritani reaction, we hypothesized that this should be possible, but the suitability of our protocol for the late-stage olefination of arenes was not experimentally evaluated.…”