A Simple Tool to Benchmark Reactivity in Asymmetric Catalysis

Dedicated to the memory of our dear friend and colleague Keith Fagnou

Abstract

Herein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.

Key words

relative rates - kinetics - N-heterocyclic carbenes - Rh(I) cycloaddition

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• 28 Typical Procedure: Stock solutions of 10 (1.0 M in toluene), C-1 (0.1 M in toluene), C-5 (0.1 M in toluene), and KHMDS (0.1 M in toluene) were freshly prepared inside a glovebox under N₂ atmosphere. From these stock solutions, C-1 (3.45 mL, 2.5 mol%) and C-5 (3.45 mL, 2.5 mol%) were dosed inside a scrupulously dried 1-dram vial, into which 600 mL of degassed and anhydrous toluene (0.023 M) was added. KHMDS (6.9 mL from 0.1 M stock solution, 5 mol%) was added and the reaction was stirred for 5 minutes. Substrate 10 was then dosed (13.8 mL from 0.1 M stock solution, 5 mol%) and the reaction was stirred for 1 hour. The reaction mixture was then concentrated to dryness in vacuo. The crude reaction mixture was filtered over a Celite plug with DCM and then subject to analysis by chiral-phase HPLC.