Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

Abstract

Possible mechanisms and origins of stereoselectivity of N‐heterocyclic carbene (NHC) promoted spirobenzazepinone formation from the annulation of an isatin‐derived enal and N‐(ortho‐chloromethyl)aryl amide have been investigated computationally. DFT results (M06–2X) suggest that the preferred mechanism consists of six steps: The nucleophilic coupling of the NHC catalyst and isatin‐derived enal was considered as the first reaction step (step I), followed by generation of the Breslow intermediate through a HCO3– assisted proton transfer event (step II). The next step is the addition of Breslow intermediate to N‐(ortho‐chloromethyl)aryl amide generating the acyl azolium intermediate (step III). Then the reaction proceeds through successive intramolecular cycloaddition (step IV), H2O‐mediated 1,3‐proton transfer (step V) and catalyst elimination (step VI) affording the [3+4] cycloaddition product. Step V plays a pivotal role in determining the stereoselectivity of the reaction and leads to the experimentally observed S‐configuration product. The DFT results account for the experimental observations. Global reactivity index analysis has also been conducted to identify the role of NHC catalyst.

Theoretical Insights into Enantioselective [3 + 2] Cycloaddition between Cinnamaldehyde and Cyclic N-Sulfonyl Trifluoromethylated Ketimine Catalyzed by N-Heterocyclic Carbene

“…There are two possible proton transfer processes, including direct proton transfer and alkali-assisted proton transfer. According to the above DFT results, the most favorable reaction mechanism includes the following five steps: the catalytic cycle starts from the nucleophilic addition of olefinic aldehyde reactant R1 to produce a zwitterionic intermediate, DIPEA-assisted [1,2]proton transfer process to produce a Breslow intermediate, the intermediate attacked by cyclic imine to form the C−C bond, the intermediate tautomerization from the alcohol form to ketone form, and ring closing with the departure of the catalyst to yield the final cycloaddition product. The results show that DIPEA plays an important role in the proton transfer process and reduces its activation free energy.…”

“…Nitrogen-containing heterocycles are important intermediates in many organic synthesis reactions and are also substructures in medicines and natural products, especially in bioactive molecules. , In recent years, it has been one of the hottest research topics in chemical synthesis to find a more effective method that uses N -heterocyclic carbene (NHC) as a catalyst to form these products. , NHCs as efficient and convenient tools also have a wide range of applications and great potential for the synthesis of various asymmetric products except metal and enzyme catalysts. − NHCs have considerable versatility and selectivity in promoting the conversion and organic synthesis of many organic compounds, such as the Breslow intermediates, , α–β unsaturated acyl heterocycles, acyl heterocycles, alkenes, and so on. − It is because of their unique property of polarity reversal that they can react with aldehydes or ketones to produce homoenolates and acyl compounds in a variety of organic transformations, which leads to the diversification of reaction pathways. More importantly, NHCs have been successfully applied in the formation of a C–C or C–heteroatom bond in various reactions, such as the homoenoic acid reaction, Stetter reaction, Claisen rearrangement, Michael addition, C–H bond activation, C–C bond activation, cycloaddition, and other types of cyclization reactions …”

“…Nitrogen-containing heterocycles are important intermediates in many organic synthesis reactions and are also substructures in medicines and natural products, especially in bioactive molecules. 1,2 In recent years, it has been one of the hottest research topics in chemical synthesis to find a more effective method that uses N-heterocyclic carbene (NHC) as a catalyst to form these products. 3,4 NHCs as efficient and convenient tools also have a wide range of applications and great potential for the synthesis of various asymmetric products except metal and enzyme catalysts.…”

“…In this study, we choose cinnamaldehyde (R1) and cyclic Nsulfonyl trifluoromethylated ketimine (R2) as the computational reactant models and use the calculational results of the density functional theory (DFT) method to explore the mechanism and origin of stereoselectivity in the NHCcatalyzed [3 + 2] cycloaddition of R1 with R2, shown in Scheme 1. We will solve three problems: (1) what is the mechanism detail of the catalytic cycle? (2) Which step is the key factor to determine the stereoselectivity?…”