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The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studi...
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N-type organic cathode materials containing carbonyl and imine groups have emerged as promising candidates for zinc-ion batteries due to their excellent charge storage capability, which arise from the synergic storage of both Zn²⁺ and H⁺. However, an increase in active sites also complicates the synthesis, introduces complex multi-electron reaction...
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The title compound, C21H17NS, was synthesized via the reaction of 5-(2-phenyleth-1-ynyl)thiophene-2-carbaldehyde and 3,4-dimethylaniline using ammonium bifluoride (NH4HF2) as an acid catalyst in methanol. The molecule has three aryl rings: a phenyl (A), a thiophene (B), and a dimethylbenzene ring (C). The dihedral angles between the mean p...
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Citations
... In 2017, our group [16] and the Suresh group [17] independently reported an NHC-catalyzed imine umpolung, followed by an interception of the aza-Breslow intermediates with activated CÀ C double bonds for the synthesis of indoles ( Figure 1B). Later, Lupton's [18] and our group [19] independently disclosed enantioselective variants of NHC-catalyzed imine umpolung, where the aza-Breslow intermediate was trapped with Michael acceptors and aldimines, respectively. Very recently, the trapping of aza-Breslow intermediates by carbonyl electrophiles has also been reported. ...
The umpolung of aldimines using N‐heterocyclic carbenes (NHCs) is less explored compared to the established polarity reversal of aldehydes. Described herein is an NHC‐catalyzed imine umpolung /6π‐electrocyclization cascade, which leads to the atom‐ and pot‐economic synthesis of biologically important dihydrochromeno indoles. For the first time, the nucleophilic aza‐Breslow intermediates have been intercepted with unactivated alkynes. Preliminary mechanistic and DFT studies shed light on the role of the phenolic −OH moiety in promoting the addition of the aza‐Breslow intermediate to the unactivated alkyne via an intramolecular proton transfer in a stepwise manner. DFT studies also support the regioselectivity preference for the 5‐exo‐dig cyclization pathway, leading to the exclusive formation of the indole products. Moreover, a comparison of Gibbs free energies provides insight into a thermodynamically preferred 6π‐electrocyclization over a competing oxa‐Michael pathway. Further, this strategy is applied to the formal synthesis of a Hepatitis C Virus (HCV) NS5A inhibitor in a step‐economical method.
... Our general synthetic protocol offers a reliable solution for the synthesis of 3-methylenchroman-2-one derivatives in a fourstep sequence starting from the available phenol derivatives (Scheme 1). Initially, we envisaged to perform alkylation of phenol derivatives with commercially available methyl 2-(bromomethyl)acrylate. [8] The reaction was effective albeit we noticed that acrylate suffers from slow polymerization and should be purified by distillation before use to achieve higher yields. ...
We aimed to design and synthesize 3‐methylenechroman‐2‐one derivatives and test their potency as TrxR1 inhibitors. A convenient and easy‐to‐handle synthetic approach to 3‐methylenechroman‐2‐ones was developed. The in vitro inhibitory activity towards recombinant TrxR1 was determined for the obtained compounds. The most potent representatives exhibited submicromolar TrxR1 inhibition activity (IC50 varied from 0.29 μM to 10.2 μM). Structure‐activity relationship analysis indicates the beneficial role of the substituent at the position C‐6 of the core of chroman‐2‐one, where the derivatives containing halogen are the most active among the scope of compounds obtained. The most potent TrxR1 inhibitor of the series was further examined in in vitro cell‐based assays to assess cytotoxic effects on various cancer cell lines, and to evaluate their influence on cell apoptosis.
... In these two examples, umpolung of the aldimine to attack the Michael acceptor is the key step. Two years later, Lupton and coworkers [132] demonstrated an enantioselective intermolecular aza-Stetter reaction by utilizing a morpholine-based NHC catalyst 76, giving the desired dihydrocoumarins 78 with excellent levels of stereocontrol (Scheme 17a). Almost at the same time, Biju et al. [133] disclosed an NHC catalyzed highly enantioselective cycloaddition of bisimine 79, providing an approach to access dihydroquinoxalines 81 (Scheme 17b). ...
Enzymes are the core for biological transformations in nature. Their structures and functions have drawn enormous attention from biologists as well as chemists since last century. The large demand of bioactive molecules and the pursuit of efficiency and greenness of synthesis have spurred the rapid development of biomimetic chemistry in the past several decades. Biomimetic asymmetric catalysis, mimicking the structures and functions of enzymes, has been recognized as one of the most promising synthetic strategies for the synthesis of valuable chiral compounds. This review summarizes the evolution of asymmetric catalysis inspired by aldolases, vitamin B1/B6-dependent enzymes, NAD(P)H, flavin, hydrogenases, heme oxygenases, non-heme oxygenases, and dinuclear/multinuclear metalloenzymes in aspects of biomimetic design, catalyst development and related catalytic transformations. Those well-established synthetic approaches originating from biological reactions have demonstrated the unique prowess of biomimetic asymmetric catalysis in bridging the gap between bio-catalysis and chemical synthesis.
... The acyl anion equivalent (Breslow intermediate) generated from aldehyde after the addition of NHC can react with various α,β-unsaturated compounds, called Michael acceptors, to form 1,4-dicarbonyl compounds or other derivatives such as ketophosphonates [209], nitroketones [210], or ketonitriles [211]. Other approaches involved the generation of aza-Breslow intermediate via imine umpolung (aza-Stetter) [212] [214]. In total, 2.3 equivalents of the thiazolium salt were used in this reaction to obtain a product with a good yield. ...
Giving reactions the names of their discoverers is an extraordinary tradition of organic chemistry. Nowadays, this phenomenon is much rarer, although already named historical reactions are still often developed. This is also true in the case of a broad branch of N‑heterocyclic carbenes catalysis. NHCs allow many unique synthetic paths, including commonly known name reactions. This article aims to gather this extensive knowledge and compare historical reactions with current developed processes. Furthermore, this review is a great opportunity to highlight some of the unique applications of these procedures in the total synthesis of biologically active compounds. Hence, this concise article may also be a source of knowledge for scientists just starting their adventure with N‑heterocyclic carbene chemistry.
We summarize in this review the recent key progresses in the NHC-catalyzed electrophilic activation of carbonyl compounds for the regioselective functionalization of saccharides, enantioselective construction of heterocycles, and asymmetric synthesis...
Imidazolium‐dithiocarboxylate zwitterions (NHC ⋅ CS2), a novel organocatalyst that derived from N‐heterocyclic carbene (NHC), was used to activate cyclopropenones. Under the catalysis of 10 mol% NHC ⋅ CS2, a range of phenols, alcohols, primary and secondary amines react with cyclopropenones to produce trisubstituted α, β‐unsaturated esters and amides in 46–95% yield. More than 68 products, including 7 natural product derivatives have been synthesized through this method. Mechanism study showed NHC ⋅ CS2 act as a Lewis base to activate the C=C double bond of cyclopropenones and trigger the ring‐opening reaction. HRMS analysis indicated the formation of the key adduct of NHC ⋅ CS2 and cyclopropenone. More importantly, this study demonstrated completely different catalytic activity of NHC ⋅ CS2 and NHC catalysts, the latter one cannot catalyse these reactions.
N-Heterocyclic carbenes (NHCs) have been used as organocatalysts for a multitude of C-C and C-heteroatom bond-forming reactions. They enable diverse modalities of activating a wide range of structurally distinct substrate classes and allow access to electronically distinct intermediates. The easy tunability of the NHC scaffold contributes to its versatility. Recent years have witnessed a surge of interest in various organocatalytic reactions of NHCs, leading to the forays of NHC catalysis into the relatively newer domains such as reactions involving radical intermediates, atroposelective synthesis, umpolung of electrophiles other than aldehydes, and the use of NHCs as non-covalent templates for enantioinduction. This tutorial review provides an overview of various important structural features and reactivity modes of NHCs and delves deep into some frontiers of NHC-organocatalysis.
The umpolung of aldimines using N‐heterocyclic carbenes (NHCs) is less explored compared to the established polarity reversal of aldehydes. Described herein is an NHC‐catalyzed imine umpolung /6π‐electrocyclization cascade, which leads to the atom‐ and pot‐economic synthesis of biologically important dihydrochromeno indoles. For the first time, the nucleophilic aza‐Breslow intermediates have been intercepted with unactivated alkynes. Preliminary mechanistic and DFT studies shed light on the role of the phenolic −OH moiety in promoting the addition of the aza‐Breslow intermediate to the unactivated alkyne via an intramolecular proton transfer in a stepwise manner. DFT studies also support the regioselectivity preference for the 5‐ exo‐dig cyclization pathway, leading to the exclusive formation of the indole products. Moreover, a comparison of Gibbs free energies provides insight into a thermodynamically preferred 6π‐electrocyclization over a competing oxa‐Michael pathway. Further, this strategy is applied to the formal synthesis of a Hepatitis C Virus (HCV) NS5A inhibitor in a step‐economical method.
