Steric Parameterization Delivers a Reciprocally Predictive Model for Substrate Reactivity and Catalyst Turnover in Rh-Catalyzed Diyne-Alkyne [2 + 2 + 2] Cycloadditions

Abstract

The Rh-catalyzed [2 + 2 + 2] cycloaddition of diynes and alkynes is a synthetically useful transformation that rapidly constructs complex scaffolds and has been used extensively for >70 years. Despite this utility, substrate reactivity issues persist, which are not mechanistically defined. Here, we provide a general predictive model for reactivity and turnover for this reaction. Contrary to the proposed electronic model, this is a predominately sterically driven process where productive turnover is proportional to alkyne steric parameters. This model allows for a priori prediction of catalyst loading, turnover, and reaction yield based on a simple assessment of the steric parameter (e.g., A-value) of the alkyne. The relationship is reciprocal, allowing A-values to be calculated from observed turnover.

Synthesis of complex aryl MIDA boronates by Rh-catalyzed [2+2+2] cycloaddition

“…This is directly related to the steric footprint of the BMIDA unit, which restricts catalytic turnover as previously described ( vide infra ). 32 BINAP was the optimal ligand, with other ligands significantly less effective ( e.g. , entries 2 and 3).…”

“…A key limitation of this strategy is associated with a long-standing problem in semi-intermolecular [2+2+2] cycloaddition where internal alkynes are not tolerated unless they have coordinating groups. 32–34 With borylated internal alkynes, there are very few examples. Aubert has shown that dicobalt hexacarbonyl complexes undergo cycloaddition to deliver the expected products (Scheme 1b), 24,25 and Yamamoto has used borylated internal alkynes as the diene component through a tethering approach (Scheme 1c).…”

“…Finally, slow addition of the diyne was necessary to control competing reaction kinetics (entry 7): diyne reactivity is significantly greater than the internal alkyne leading to dimer- and trimerisation pathways. 32 Slow addition effectuates control allowing productive engagement of the less reactive internal alkyne. Reactions stop upon consumption of the diyne, which is fully consumed.…”

“…Since BMIDA has a relatively high steric component, this therefore necessitates higher catalyst loading for effective product formation. 32…”

“…coordinating groups. [32][33][34] With borylated internal alkynes, there are very few examples. Aubert has shown that dicobalt hexacarbonyl complexes undergo cycloaddition to deliver the expected products (Scheme 1b), 24,25 and Yamamoto has used borylated internal alkynes as the diene component through a tethering approach (Scheme 1c).…”