Abstract
Density functional theory (DFT) calculations were performed to investigate the mechanism and the enantioselectivity of the aza-Henry reaction of isatin-derived ketimine catalyzed by chiral guanidine–amide catalysts at the M06-2X-D3/6-311+G(d,p)//M06-2X-D3/6-31G(d,p) (toluene, SMD) theoretical level. The catalytic reaction occurred via a three-step mechanism: (i) the deprotonation of nitromethane by a chiral guanidine–amide catalyst; (ii) formation of C–C bonds; (iii) H-transfer from guanidine to ketimine, accompanied with the regeneration of the catalyst. A dual activation model was proposed, in which the protonated guanidine activated the nitronate, and the amide moiety simultaneously interacted with the ketimine substrate by intermolecular hydrogen bonding. The repulsion of CPh3 group in guanidine as well as N-Boc group in ketimine raised the Pauli repulsion energy (∆EPauli) and the strain energy (∆Estrain) of reacting species in the unfavorable si-face pathway, contributing to a high level of stereoselectivity. A new catalyst with cyclopropenimine and 1,2-diphenylethylcarbamoyl as well as sulfonamide substituent was designed. The strong basicity of cyclopropenimine moiety accelerated the activation of CH3NO2 by decreasing the energy barrier in the deprotonation step. The repulsion between the N-Boc group in ketimine and cyclohexyl group as well as chiral backbone in the new catalyst raised the energy barrier in C–C bond formation along the si-face attack pathway, leading to the formation of R-configuration product. A possible synthetic route for the new catalyst is also suggested.
Highlights
The aza-Henry reaction is one of the most effective methods for the construction of carbon–carbon bonds with concomitant generation of two vicinal stereogenic centers bearing nitro and amino functional groups [1]
Since the first example of a catalytic enantioselective aza-Henry reaction was reported by Shibasaki [11], many metal-based [12,13,14,15] and organic catalysts [16,17] have been employed in the nucleophilic addition of aldimine, affording β-nitroamines in high yield and stereoselectivity [18]
The density functional theory (DFT) method was adopted to study the reaction mechanism and the origin of enantioselectivity of the aza-Henry reaction between isatin-derived N-Boc ketimine and nitromethane catalyzed by the guanidine–amide catalyst
Summary
The aza-Henry reaction (or nitro-Mannich reaction) is one of the most effective methods for the construction of carbon–carbon bonds with concomitant generation of two vicinal stereogenic centers bearing nitro and amino functional groups [1]. Chiral thiourea [30] and thiourea- [31] or sulphone-amide-modified cinchona derivatives [32] are applied into aza-Henry reactions of ketimine They serve to simultaneously activate the electrophile and nucleophile during C–C bond formation by hydrogen bonding, and are essential for reaction rate and selectivity. Our hope was that through the synergistic effects of the stronger Brønsted base and the hydrogen bonding donor as well as the modification of the chiral backbone, superior reactivity and selectivity could be obtained These results are expected to provide useful information for the synthesis of new chiral organocatalysts for aza-Henry reactions of ketimine. SMcheechmaen2is.mMeocfhaaznai-sHmeonfryazrae-aHcetinorny breeatwcteioenn bkeettwimeeinneke(Rti1mainaend(RR1a1ba)ndanRd1bn)itarnodmneitthraonmee(tRha2n),ecatalyzed by guanidine–a(Rm2i)d,ecactaatlaylyzestd(bGy1)g.uanidine–amide catalyst (G1)
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