First aromatic amine organocatalysed activation of α,β-unsaturated ketones

Sonsona, Isaac G.; Marqués‐López, Eugenia; Gimeno, M. Concepción; Herrera, Raquel P.

doi:10.1039/c9nj02392e

Cited by 6 publications

(5 citation statements)

References 53 publications

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“…The previously reported iminium-catalyzed reactions have been reported mostly using tetrahydrofuran (THF) as the solvent. 14,15,17,19,23 However, since THF is considered an FDA class 2 solvent 33 and rated as problematic by CHEM21, 34 this solvent was not considered for our experiments. Instead, preliminary batch test reactions of different amine catalysts using either isopropanol or ethyl acetate as solvents were used.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Among the reported iminium-catalyzed reactions for the synthesis of 1 , acetic acid (FDA class 3) was one of the most frequent cocatalysts used, ,,, which led us to evaluate the addition of acetic acid as a potential cocatalyst. The previously reported iminium-catalyzed reactions have been reported mostly using tetrahydrofuran (THF) as the solvent. ,,,, However, since THF is considered an FDA class 2 solvent and rated as problematic by CHEM21, this solvent was not considered for our experiments. Instead, preliminary batch test reactions of different amine catalysts using either isopropanol or ethyl acetate as solvents were used.…”

Section: Resultsmentioning

confidence: 99%

“…Although the enantioselectivity was initially ascribed to the formation of an aminal intermediate, it was later shown that the imidazolidine catalyst decomposes to a diamine under those reaction conditions, and instead, the reaction was proposed to proceed through imine catalysis . A variety of amines have since been reported to catalyze the enantioselective formation of warfarin, such as derivatives obtained from cinchona amines, amino acids (e.g., phenylalanine and phenylglycine), , 1,2-diphenyl-1,2-ethylenediamine (DPEN), ,− squaramides, and 2,2′-diamino-1,1′-binaphthalene (DABN) (Figure ). Several of these catalysts were able to produce warfarin with good to excellent enantiomeric excess (80–90% ee) in moderate to good yields (63–99%).…”

Section: Introductionmentioning

confidence: 99%

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Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

Silva-Brenes,

Reyes-Vargas,

Duconge

et al. 2023

Org. Process Res. Dev.

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While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization's list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a single Michael addition reaction. However, the reaction is notoriously slow, with reflux times on the scale of days frequently affording the product in little more than 40% yield. Herein we report a highly intensified synthesis of warfarin exploiting the assets of flow chemistry and organocatalysis. The selection of a suitable catalyst to increase the rate of the reaction was crucial to obtain high conversion and selectivity, resulting in the development of a continuous flow protocol that affords warfarin in 85% isolated yield within 15 min of residence time. The product can be obtained with >97% purity by simple precipitation in acid. The achieved throughput of 9.4 g h −1 with a space-time yield (STY) of 1570.67 g h −1 L −1 is orders of magnitude higher than those of previously published flow protocols. Not only is this protocol more environmentally favorable, but also the estimated cost of 0.07 cents per dose hints that the novel process may be more economically favorable than the patented industrial synthesis.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

Silva-Brenes,

Reyes-Vargas,

Duconge

et al. 2023

Org. Process Res. Dev.

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“…Regarding this chapter, Peng, Li and co-workers have reported an incredible a crucial work comprehensively covering all the applications of asymmetric organocatalysis in medicinal chemistry since the early 2000s [90]. Returning to our chemistry, we have also developed some active compounds using organocatalysis as a key step in their synthesis, such as antimicrobial β-nitrohidrazydes [91,92], Warfarin and derivatives [93], iridodials [94,95], or the key intermediate to the analgesic Funapide [96] (Figure 3). Selected biologically active compounds synthesized using organocatalytic key steps: Serriconin [83], Convolutamydine A [84], (-)-Botryodiplodin [85], (-)-Oseltamivir [86], DPC 083 [87], Telcagepant [88] and Leucomidine B [89].…”

Section: Figurementioning

confidence: 99%

Horizons in Asymmetric Organocatalysis: En Route to the Sustainability and New Applications

2022

Self Cite

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Nowadays, the development of new enantioselective processes is highly relevant in chemistry due to the relevance of chiral compounds in biomedicine (mainly drugs) and in other fields, such as agrochemistry, animal feed, and flavorings. Among them, organocatalytic methods have become an efficient and sustainable alternative since List and MacMillan pioneering contributions were published in 2000. These works established the term asymmetric organocatalysis to label this area of research, which has grown exponentially over the last two decades. Since then, the scientific community has attended to the discovery of a plethora of organic reactions and transformations carried out with excellent results in terms of both reactivity and enantioselectivity. Looking back to earlier times, we can find in the literature a few examples where small organic molecules and some natural products could act as effective catalysts. However, with the birth of this type of catalysis, new chemical architectures based on amines, thioureas, squaramides, cinchona alkaloids, quaternary ammonium salts, carbenes, guanidines and phosphoric acids, among many others, have been developed. These organocatalysts have provided a broad range of activation modes that allow privileged interactions between catalysts and substrates for the preparation of compounds with high added value in an enantioselective way. Here, we briefly cover the history of this chemistry, from our point of view, including our beginnings, how the field has evolved during these years of research, and the road ahead.

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“…The synthesis of ( R) -warfarin ( 3a ) was described by Herrera et al for the first time using primary aromatic diamines 31 as organocatalysts. The application of this class of catalysts for the Michael asymmetric addition of 4-hydroxycoumarins 1 to enones 2 is interesting from the point of view of organocatalysis, since the presence of two primary amines enables both the formation of an imine ion with the enone and activation of the hydroxycoumarin by hydrogen bonding [ 41 ]. Despite the long reaction time (3 days), the desired products 3 were obtained with good to excellent yields and moderate enantiomeric excesses ( Scheme 9 ).…”

Section: Reviewmentioning

confidence: 99%

Asymmetric organocatalyzed synthesis of coumarin derivatives

Moreira¹,

Martelli²,

Corrêa³

2021

Beilstein J. Org. Chem.

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Coumarin derivatives are essential scaffolds in medicinal and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context, the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst.

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First aromatic amine organocatalysed activation of α,β-unsaturated ketones

Abstract: The first example of a chiral aromatic amine used to activate α,β-unsaturated ketones in aminocatalysis.

Cited by 6 publications

References 53 publications

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

Horizons in Asymmetric Organocatalysis: En Route to the Sustainability and New Applications

Asymmetric organocatalyzed synthesis of coumarin derivatives

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