Mechanism and Origins of Stereoinduction in an Asymmetric Friedel–Crafts Alkylation Reaction of Chalcone Catalyzed by Chiral N,N′-Dioxide–Sc(III) Complex

Abstract

The mechanism and selectivity of the asymmetric Friedel-Crafts (F-C) alkylation reaction between indole and chalcone catalyzed by chiral N, N'-dioxide-Sc(III) complexes were investigated at the M06/6-311+G(d,p)//M06/[LANL2DZ,6-31G(d)](SMD,CHCl) level. The reaction occurred via a three-step mechanism: (i) the C-C bond formation by interacting the most mucleophilic C center of indole with the most electrophilic C center of chalcone; (ii) the abstraction of the proton at the C atom of indole by counterion OTf; (iii) proton transfer from HOTf to the C atom of chalcone, generating the F-C alkylation product. The reaction preferred to occur along the favorable re-face attack pathway, producing the dominant R-product. The turnover frequency (TOF) of catalysis was predicted to be 1.59 × 10 s, with a rate constant of K( T) = 1.58 × 10 exp(-29057/ RT) dm·mol·s over the temperature range of 248-368 K. Activation strain model (ASM) and energy decomposition analysis (EDA), as well as noncovalent interaction (NCI) analysis, for the stereocontrolling transition state revealed that the substituent attached to the N atom of the amide subunits as well as the amino acid backbone of ligand played important roles in chiral inductivity. The benzyl group with structural flexibility tended to form strong π-π stacking with substrate as well as the terminal phenyl group of chalcone, stabilizing re-face attack transition state.

Mechanism of the Alkylation of Indoles with Nitrostyrenes Catalyzed by Chiral-at-Metal Complexes

“…Nevertheless, the direct 1,3-prototropy in the aci -nitro derivatives B X ( X = I – VI ) is not kinetically affordable (Δ G act > 40 kcal mol –1 ) and the assistance of a proton shuttle has to be invoked. As a matter of fact, similarly to related processes, affordable barriers have been calculated for the water-assisted prototropy in the aci -nitro derivatives B IV_ Re / Si ( Re , 21.8 kcal mol –1 ; Si , 18.0 kcal mol –1 ) and B V_ Re / Si ( Re , 16.2 kcal mol –1 (Figure , top); Si , 20.8 kcal mol –1 ). On the other hand, the steric hindrance at the H–O–NC moiety of the aci -nitro derivatives B X_Re/Si ( X = I – III , VI ) prevents the approach of one water molecule to this moiety.…”

Recent Advances in Selected Asymmetric Reactions Promoted by Chiral Catalysts: Cyclopropanations, Friedel–Crafts, Mannich, Michael and Other Zinc-Mediated Processes—An Update

“…The processes were catalyzed by PyBox [43] or iPrBox [44], respectively (Scheme 16). The asymmetric reaction of indoles with α,β-unsaturated carbonyl compounds 45 (enones) was carried out using three similar catalytic systems (Scheme 17) [45][46][47]. In the first contribution, reaction was promoted by imidazoline-oxazoline 46 complex with Cu(OTf) 2 (acetonitrile, room temperature), leading to indole derivatives acting as novel α-glucosidase inhibitors in vitro [45].…”

“…In the first contribution, reaction was promoted by imidazoline-oxazoline 46 complex with Cu(OTf) 2 (acetonitrile, room temperature), leading to indole derivatives acting as novel α-glucosidase inhibitors in vitro [45]. The second approach comprises a utilization of chiral N,N-dioxide 47-scandium(III) complexes in dichloromethane at 35 • C [46], and finally, the third work relies on the application of cationic aqua complex of 2,2 -bypiridine 48 with palladium(II) in water at room temperature [47]. Similar dinuclear zinc catalytic systems were also used in the synthesis of 2,5-pyrrolidinyl dispirooxindoles [51] and tetrahydrofuran spirooxindoles [52] via cascade reactions, where one of the steps is a Friedel-Crafts process.…”

Theoretical Study on Asymmetric [2 + 2] Cycloaddition of an Alkynone with a Cyclic Enol Silyl Ether Catalyzed by a Chiral N,N′-Dioxide-Zn(II) Complex

“…Our previous studies indicated that a counterion could coordinate to the metal center of a chiral N,N′-dioxide-metal complex, stabilizing the active species, 38 adjusting the Lewis acidity of the metal center, 39 and even taking part in reactions. 43 The positive effect of the counterion NTf 2 − in alkenylsilylation reactions was also studied by Xia and co-workers. 44,45 To understand the role of the counterion NTf 2 − in [2 + 2] cycloaddition reactions, we also optimized the geometry of a pentacoordinate Zn(II) complex without an NTf 2 − anion (L2-COM-P).…”