Asymmetric Aza‐Henry Reaction of Indolenines Mediated by a Cinchona‐Alkaloid‐Thiourea Organocatalyst

Shao, Yan; He, Xiu‐Yan; Han, Dandan; Yang, Xin‐Ru; Yao, Hai‐Bin; Cheng, Dao‐Juan

doi:10.1002/ajoc.201900504

Cited by 9 publications

(6 citation statements)

References 41 publications

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“…Asymmetric organocatalysis is a very attractive methodology for the synthesis of organic compounds with high enantiomeric purity [1–6] . Important applications of organocatalysis in organic synthesis have been reported in recent years, especially thiourea bifunctional organocatalysts [2,7–9] . Although organocatalysis is usually considered an environmentally friendly and low‐cost catalytic approach, high concentrations of catalysts are generally used [10] , making the search for more efficient catalysts a fundamental problem in this kind of catalysis.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5][6] Important applications of organocatalysis in organic synthesis have been reported in recent years, especially thiourea bifunctional organocatalysts. [2,[7][8][9] Although organocatalysis is usually considered an environmentally friendly and low-cost catalytic approach, high concentrations of catalysts are generally used [10] , making the search for more efficient catalysts a fundamental problem in this kind of catalysis. Thus, a detailed understanding of the mechanism involved in the reaction can be useful in the development of low-loading catalysts.…”

Section: Introductionmentioning

confidence: 99%

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Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

Rufino

Pliego

2021

Asian J Org Chem

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Primary-amine thioureas are preeminent organocatalysts used in challenging asymmetric Michael-type reactions, such as in the addition of nitromethane to enones. However, the complete reaction mechanism of this reaction has not yet been fully elucidated. Considering that the primary-amine group could act via both base and iminium ion catalysis, both mechanisms were investigated in this work using theoretical methods. The calculations have indicated that the base catalysis is kinetically unfeasible, with very high overall ΔG � . An imine-iminium ion catalysis is a viable route. This mechanism requires the participation of an acid as a cocatalyst (additive) in several steps, including the formation of the imine. The rate-determining step corresponds to the proton transfer from the nitromethane to the imine, forming the nitronate-iminium ion-pair intermediate. This complex reacts via nucleophilic attack of the nitronate ion to the electrophilic carbon of the iminium ion, forming a new CÀ C bond that determines the enantioselectivity of the reaction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

Rufino

Pliego

2021

Asian J Org Chem

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“…Apart from this, they have various applications such as utilization in chiral ligands in the preparation of metal complexes, in NMR as chiral agents, resolving agents, chiral stationary phase in HPLC, electrolytic additives, and chiral solvating agents. They have been successfully used in various important asymmetric transformations such as the Mannich reaction [91][92][93], Michael addition [94][95][96], aza-Henry reactions [97,98], and epoxidation [99,100], in order to promote a highly enantio-and diastereoselective outcome.…”

Section: Cinchona Alkaloidsmentioning

confidence: 99%

Regiodivergent Organocatalytic Reactions

et al. 2021

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Organocatalysts are abundantly used for various transformations, particularly to obtain highly enantio- and diastereomeric pure products by controlling the stereochemistry. These applications of organocatalysts have been the topic of several reviews. Organocatalysts have emerged as one of the very essential areas of research due to their mild reaction conditions, cost-effective nature, non-toxicity, and environmentally benign approach that obviates the need for transition metal catalysts and other toxic reagents. Various types of organocatalysts including amine catalysts, Brønsted acids, and Lewis bases such as N-heterocyclic carbene (NHC) catalysts, cinchona alkaloids, 4-dimethylaminopyridine (DMAP), and hydrogen bond-donating catalysts, have gained renewed interest because of their regioselectivity. In this review, we present recent advances in regiodivergent reactions that are governed by organocatalysts. Additionally, we briefly discuss the reaction pathways of achieving regiodivergent products by changes in conditions such as solvents, additives, or the temperature.

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“…In 2019 Cinchona-alkaloid-based thiourea bifunctional organocatalyst Cat-18, was used by Cheng and coworkers to catalyze an aza-Henry reaction and in this way obtain a series of structurally novel and optically active 2-nitromethyl indolines (125) from racemic 3,3-disubstituted 3H-indoles (124) (Figure 8D; Shao et al, 2019a). The products, which are useful synthetic intermediates, were obtained in useful yields (up to 91%) and good to high enantioselectivities (up to 94% ee).…”

Section: Oxindoles and Indoleninesmentioning

confidence: 99%

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds

2020

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The nitro-Mannich (aza-Henry) reaction, in which a nitroalkane and an imine react to form a β-nitroamine, is a versatile tool for target-oriented synthesis. Although the first stereoselective reaction was developed only 20 years ago, and enantioselective and diastereoselective versions for the synthesis of non-racemic compounds soon after, there are nowadays a variety of reliable methods which can be used for the synthesis of APIs and other biologically active substances. Hence many anticancer drugs, antivirals, antimicrobials, enzyme inhibitors and many more substances, containing C-N bonds, have been synthesized using this reaction. Several transition metal complexes and organocatalysts were shown to be compatible with the presence of a wide range of functional groups in these molecules, and very high levels of asymmetric induction have been achieved in some cases. The reaction has also been applied in cascade processes. The structural diversity of the products, ranging from simple heterocycles or azabicycles to complex alkaloids, iminosugars, amino acids or diamino acids and phosphonates, shows the versatility of the nitro-Mannich reaction and its potential for future developments.

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Asymmetric Aza‐Henry Reaction of Indolenines Mediated by a Cinchona‐Alkaloid‐Thiourea Organocatalyst

Cited by 9 publications

References 41 publications

Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

Regiodivergent Organocatalytic Reactions

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds

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