Combined Experimental and Computational Study of Ruthenium N-Hydroxyphthalimidoyl Carbenes in Alkene Cyclopropanation Reactions

Abstract

A combined experimental–computational approach has been used to study the cyclopropanation reaction of N -hydroxyphthalimide diazoacetate (NHPI-DA) with various olefins, catalyzed by a ruthenium-phenyloxazoline (Ru-Pheox) complex. Kinetic studies show that the better selectivity of the employed redox-active NHPI diazoacetate is a result of a much slower dimerization reaction compared to aliphatic diazoacetates. Density functional theory calculations reveal that several reactions can take place with similar energy barriers, namely, dimerization of the NHPI diazoacetate, cyclopropanation (inner-sphere and outer-sphere), and a previously unrecognized migratory insertion of the carbene into the phenyloxazoline ligand. The calculations show that the migratory insertion reaction yields an unconsidered ruthenium complex that is catalytically competent for both the dimerization and cyclopropanation, and its relevance is assessed experimentally. The stereoselectivity of the reaction is argued to stem from an intricate balance between the various mechanistic scenarios.

Experimental and Computational Studies for the Synthesis of Functionalized Cyclopropanes from 2‐Substituted Allylic Derivatives with Ethyl Diazoacetate

“…The previous computational study has suggested their formation to be extremely closed in energies, [10b] except for position Eq cis , which was found to be disfavored kinetically. Nonetheless, it also suggests that the most probable pathway occurs through isomer Ap syn .…”

“…As recently studied by Mendoza, Himo and co‐workers, Ru(II)‐catalyzed cyclopropanations have multiple possible mechanistic manifolds (Scheme 6a, inner‐sphere vs outer‐sphere mechanisms) [10b] . They have investigated the cyclopropanation reaction of N ‐hydroxy phthalimide diazoacetate (NHPI‐DA) with propene and styrene, using catalyst I [10b] . Their calculations suggest that the reaction proceeds preferentially via an outer‐sphere mechanism, in which three acetonitrile (ACN) molecules remain bound as ligands.…”

“…As recently studied by Mendoza, Himo and co‐workers, Ru(II)‐catalyzed cyclopropanations have multiple possible mechanistic manifolds (Scheme 6a, inner‐sphere vs outer‐sphere mechanisms) [10b] . They have investigated the cyclopropanation reaction of N ‐hydroxy phthalimide diazoacetate (NHPI‐DA) with propene and styrene, using catalyst I [10b] .…”

“…Due the unique nature of alkenes 1 a‐h used in our study, we turned to computational chemistry to gain insight into the process and evaluate the influence of the haloalkene on the mechanistic outcome. Due to the good correlation between their calculations and experiments, we elected to use the same computational protocol as Mendoza, Himo and co‐workers (see SI for full computational details), [10b] but using methyl diazoacetate (MDA) as an ethyl diazoacetate (EDA) surrogate model. For the substrates, we elected to use the 2‐halopropenes (X=F, Cl, Br, Y=CH 3 ) as model alkenes.…”

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

“…The rhodium-catalyzed reactions of diazo compounds have broad applications in organic synthesis. − Previously, we showed that donor/acceptor carbenes offer new synthetic opportunities because of the attenuating influence of the donor group. , They can be used in several different types of enantioselective transformations, such as cyclopropanation, cyclopropenation, C–H and X–H insertions, as well as a variety of reactions involving ylide intermediates. ,− In the past, questions arose about the feasibility of running large-scale reactions with diazo compounds because they are highly energetic and potentially unstable. − These safety concerns have been greatly alleviated in recent years on account of the advances in generating diazo compounds in flow. − Considerable efforts have been made to replace the rhodium with cheaper metals, but the dirhodium catalysts have special properties that are difficult to replicate. ,− They are kinetically very active at decomposing diazo compounds, yet perfectly stable to air and moisture. Many of the designed chiral ligands self-assemble around the dirhodium core to generate elaborate high-symmetry chiral complexes capable of very high levels of asymmetric induction .…”