Aza‐Henry Reaction with Nitrones, an Under‐Explored Transformation

Messire, Gatien; Massicot, Fabien; Vallée, Alexis; Vasse, Jean‐Luc; Behr, Jean‐Bernard

doi:10.1002/ejoc.201801823

Cited by 8 publications

(9 citation statements)

References 77 publications

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“…Finally, this synthetic methodology enabled the fluorination in moderate to excellent yields of heterocyclic scaffolds relevant in medicinal chemistry and drug discovery such as pyridazines (e.g. 75, 172), pyrazines (74,173), indole (176), pyrimidines (122,(174)(175)(176)(177)(178), purines (76, 184-187), and the 1,8-naphthyridine-containing antibiotic 154.…”

Section: Recent S N Ar Fluorination Methodologies With Tmafmentioning

confidence: 99%

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

2022

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Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations.

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Section: Recent S N Ar Fluorination Methodologies With Tmafmentioning

confidence: 99%

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

2022

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“…These substances have a highly polarized double bond, and hence they are electrophilic in nature and susceptible to nucleophilic addition reactions. They have been used in the past as key substrates for the synthesis of iminosugars (Messire et al, 2019). In 2019 Behr and coworkers reported new studies involving nitrones (Figure 4D).…”

Section: Imino Sugars and Other Carbohydrate Derivativesmentioning

confidence: 99%

“…In 2019 Behr and coworkers reported new studies involving nitrones (Figure 4D). A nitromethylation of nitrones with CH 3 NO 2 was performed in the presence of tetramethylammonium fluoride or triazabicyclodecene, which were added as promoters (Messire et al, 2019). Phase transfer catalysts could also be used, which suggests that enantioselective transformations may become possible with further research.…”

Section: Imino Sugars and Other Carbohydrate Derivativesmentioning

confidence: 99%

“…During their studies with nitrones, described in the previous section, Behr and coworkers developed a method for the synthesis of (+)-Praziquantel (PZQ) (94), as mentioned above (Messire et al, 2019). Starting from nitrone 88, generated from 3,4-dihydroisoquinoline, the aza-Mannich reaction with nitromethane led to hydroxylamine 89 in high yield (Figure 6B).…”

Section: Piperazinones Quinazolines and Related Substancesmentioning

confidence: 99%

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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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“…Though the remaining two steps, N-acetylation and deprotection both can go smoothly to The d-xylose-derived nitrone A is a convenient starting material for the synthesis of 1-amino-2,5-imino-1,2,5-trideoxy-l-mannitol hydrochloride (A-11) and its 1-N-acetylamino derivative (A-10) [16]. Nucleophilic additions with trimethylsilyl cyanide (TMSCN) [16] and nitromethane [52] were studied as agents for the introduction of aminomethyl substituents. Reaction of nitrone A with TMSCN at room temperature provide hydroxylamine A-2 in 96% yield as the sole product, and its C-2 configuration was determined as S-configuration through NOESY experiments since a strong interaction of H-2 and H-4 was observed; in contrast, the aza-Henry reaction gave a pair of inseparable epimers (A-2 a and A-2 b) in a 1:1 ratio.…”

Section: Synthesis Of 1-n-mentioning

confidence: 99%

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

et al. 2020

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Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.

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Aza‐Henry Reaction with Nitrones, an Under‐Explored Transformation

Cited by 8 publications

References 77 publications

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

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

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

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