In Situ Kinetic Studies of Rh(II)-Catalyzed C–H Functionalization to Achieve High Catalyst Turnover Numbers

Abstract

Detailed kinetic studies on the functionalization of unactivated hydrocarbon sp3 C–H bonds by dirhodium-catalyzed reaction of aryldiazoacetates revealed that the C–H functionalization step is rate determining. The efficiency of this step was increased by using the hydrocarbon as a solvent and using donor/acceptor carbenes with an electron-withdrawing substituent on the aryl donor group. The optimum catalyst for these reactions is the tetraphenylphthalimido derivative Rh2(R-TPPTTL)4, and a further beneficial refinement was obtained by using N,N′-dicyclohexylcarbodiimide as an additive. Under the optimum conditions with a catalyst loading of 0.001 mol %, effective enantioselective C–H functionalization (66–97% yield, 83–97% ee) of cycloalkanes was achieved with a range of aryldiazoacetates as long as the aryldiazoacetate was not sterically demanding. The reaction with cyclohexane using a catalyst loading of 0.0005 mol % could be recharged twice with additional aryldiazoacetate, resulting in an overall dirhodium catalyst turnover number of 580,000.

Stereoselective Synthesis of Either Exo- or Endo-3-Azabicyclo[3.1.0]hexane-6-carboxylates by Dirhodium(II)-Catalyzed Cyclopropanation with Ethyl Diazoacetate under Low Catalyst Loadings

“…26 (4) Elevated temperatures enhance overall efficiency. 25 (5) Bridged tetracarboxylate ligands confer greater stability to the catalysts. 28 Using these trends as guiding principles, we conducted an optimization study for the cyclopropanation of N-Boc-2,5dihydropyrrole 9.…”

“…In the case of the donor/acceptor carbenes, we found that the optimum temperature for high TON was 60− 70 °C. 25,26 When the reactions with 10 were conducted at 70 °C, the yields of the cyclopropanation were still relatively low Further optimization of the Rh 2 (esp) 2 -catalyzed reaction was conducted at 90 °C, and under these conditions, the yield of exo/endo-1 greatly improved to 76% (entry 8). In the case of aryldiazoacetates, the trihaloethyl esters often gave better performance, 26 but with diazoacetates, this was not the case as the trichloroethyl derivative actually gave lower yield (entry 11).…”

“…In recent years, great advances have been made in generating diazo compounds in flow, − so the main remaining challenge is to improve the efficiency of the rhodium-catalyzed reaction. The Davies group has had a long-standing interest in the chemistry of donor/acceptor carbenes and has shown that cyclopropanation with these carbenes can be routinely conducted with very low catalyst loadings (<0.001 mol %). − Therefore, we decided to embark on a collaborative study to determine whether the information gained about donor/acceptor carbenes could be applied to acceptor carbenes and, thus, achieve a practical entry to either diastereomer of the azabicyclic scaffold 1 (Scheme B). The results of this study are described herein.…”

“…(3) Dimethyl carbonate (DMC) is more effective and environmentally friendly than dichloromethane . (4) Elevated temperatures enhance overall efficiency . (5) Bridged tetracarboxylate ligands confer greater stability to the catalysts …”

“… 26 (4) Elevated temperatures enhance overall efficiency. 25 (5) Bridged tetracarboxylate ligands confer greater stability to the catalysts. 28 …”