The mechanism of the full catalytic cycle for Fe-chiral-bisphosphine-catalyzed cross-coupling reaction between alkyl halides and Grignard reagents (Nakamura and co-workers, J. Am. Chem. Soc. 2015, 137, 7128) was rationalized by using density functional theory (DFT) and multicomponent artificial force-induced reaction (MC-AFIR) methods. The computed mechanism consists of (a) C-Cl activation, (b) transmetalation, (c) C-Fe bond formation, and (d) C-C bond formation through reductive elimination. Our survey on the prereactant complexes suggested that formation of Fe(BenzP*)Ph and Fe(BenzP*)Ph complexes are thermodynamically feasible. Fe(BenzP*)Cl complex is the active intermediate for C-Cl activation. Fe(BenzP*)Ph complex can be formed if the concentration of Grignard reagent is high. However, it leads to biphenyl (byproduct) instead of the cross-coupling product. This explains why slow addition of Grignard reagent is critical for the cross-coupling reaction. The MC-AFIR method was used for systematic determination of transition states for C-Fe bond formation and C-C bond formation starting from the key intermediate Fe(BenzP*)PhCl. According to our detailed analysis, C-C bond formation is the selectivity-determining step. The computed enantiomeric ratio of 95:5 is in good agreement with the experimental ratio (90:10). Energy decomposition analysis suggested that the origin of the enantioselectivity is the deformation of Ph-ligand in Fe-complex, which is induced by the bulky tert-butyl group of BenzP* ligand. Our study provides important mechanistic insights for the cross-coupling reaction between alkyl halides and Grignard reagents and guides the design of efficient Fe-based catalysts for cross-coupling reactions.
Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.
Take the right path: Comparison of the oxazolidinone and enamine pathways in enantioselective aldol reactions by using density functional and ab initio transition states reveals that the oxazolidinone route does not provide the correct stereochemical outcome (see picture), whereas the enamine pathway predicts the correct stereoselectivity.
The transition state models in two mechanistically distinct pathways, involving (i) an enamine carboxylic acid (path-A, 4) and (ii) an enamine carboxylate (path-B, 8), in the proline-catalyzed asymmetric α-amination have been examined using DFT methods. The path-A predicts the correct product stereochemistry under base-free conditions while path-B accounts for reversal of configuration in the presence of a base.
The stereocontrolling transition state (TS) models for C-C bond formation relying on hydrogen bonding have generally been successful in proline-catalyzed aldol, Mannich, α-amination, and α-aminoxylation reactions. However, the suitability of the hydrogen-bonding model in protic and aprotic conditions as well as under basic and base-free conditions has not been well established for Michael reactions. Through a comprehensive density functional theory investigation, we herein analyze different TS models for the stereocontrolling C-C bond formation, both in the presence and absence of a base in an aprotic solvent (THF). A refined stereocontrolling TS for the Michael reaction between cyclohexanone and nitrostyrene is proposed. The new TS devoid of hydrogen bonding between the nitro group of nitrostyrene and carboxylic acid of proline, under base-free conditions, is found to be more preferred over the conventional hydrogen-bonding model besides being able to reproduce the experimentally observed stereochemical outcome. A DBU-bound TS is identified as more suitable for rationalizing the origin of asymmetric induction under basic reaction conditions. In both cases, the most preferred approach of nitrostyrene is identified as occurring from the face anti to the carboxylic acid of proline-enamine. The predicted enantio- and diastereoselectivities are in very good agreement with the experimental observations.
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