Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Alves, Cláudia; Grosso, Carla; Barrulas, Pedro; Paixão, J. A.; Cardoso, António J. Marques; Burke, Anthony J.; Lemos, Américo; Melo, Teresa M. V. D. Pinho e

doi:10.1055/s-0039-1691533

Cited by 13 publications

(11 citation statements)

References 19 publications

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“…The oxime tosylates of cyclic ketones are common starting materials of the Neber rearrangement reaction, in which NaOEt or KOEt is generally used as a base in dry EtOH or benzene, followed by acidic hydrolysis to produce the hydrochloric salt of the α-aminoketone [ 2 ]. In enantioselective organocatalytic Neber rearrangements, in which the isolation of the optically active 2 H -azirine derivative is needed, reactive oxime tosylates were reacted with thiourea [ 7 , 9 ] or cinchona organocatalysts [ 30 ] in the presence of an inorganic base and there was no subsequent acidic hydrolysis. In our experiments, we treated the oxime tosylates 5a - g with NaOEt base in dry toluene for one day at room temperature and performed the acidic hydrolysis with 3N HCl solution for two hours on the CH 2 Cl 2 solution of the concentrated filtrate.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in this work the diastereoselectivity and side-products of the Neber reaction in the presence of an inherent C-2 chirality center of flavanones were studied further by modifying the reaction conditions and isolation of the diastereomeric products. Asymmetric organocatalytic Neber reactions of oxime tosylates producing optically active 2 H -azirine derivatives have been recently reported, in which the reaction conditions are adjusted to stop the transformation at the stage of the 2 H -azirine intermediates [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones

et al. 2020

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Racemic chiral O,N-heterocycles containing 2-arylchroman or 2-aryl-2H-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of cis- or trans-3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the trans diastereomer as the major product and enabled the isolation of both the cis- and trans-diastereomers. The cis- and trans-aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,4]oxazines. Antiproliferative activity of the condensed heterocycles and precursors was evaluated against A2780 and WM35 cancer cell lines. For a 3-(N-chloroacetylamino)-flavan-4-ol derivative, showing structural analogy with acyclic acid ceramidase inhibitors, 0.15 μM, 3.50 μM, and 6.06 μM IC50 values were measured against A2780, WM35, and HaCat cell lines, and apoptotic mechanism was confirmed. Low micromolar IC50 values down to 2.14 μM were identified for the thiazole- and pyrrole-condensed 2H-chromene derivatives. Enantiomers of the condensed heterocycles were separated by HPLC using chiral stationary phase, HPLC-ECD spectra were recorded and TDDFT-ECD calculations were performed to determine the absolute configuration and solution conformation. Characteristic ECD transitions of the separated enantiomers were correlated with the absolute configuration and effect of substitution pattern on the HPLC elution order was determined.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones

et al. 2020

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“…Several methods have been established for the Neber rearrangement by using bases like K 2 CO 3 [28,29] and Na 2 CO 3 [30–32]. Holzer and his group established a Neber rearrangement using K 2 CO 3 that tolerates an oxime activating group O ‐(trichloroacetate), which has been used in the preparation of spirocyclic 2 H ‐azirines (Scheme 15) [28].…”

Section: Neber Rearrangementmentioning

confidence: 99%

“…However, a successful one‐pot method was developed by Pinho e Melo et al for the synthesis of chiral 2‐tetrazolyl‐2 H ‐azirine in 92% ee , followed by Neber reaction. This reaction occurred in the presence of chiral thiourea organocatalysts derived from 6β‐aminopenicillanic acid afforded excellent enantioselectivities (Scheme 23) [29].…”

Section: Neber Rearrangementmentioning

confidence: 99%

Synthesis of various functionalized 2H‐azirines: An updated library

Majee

2021

Journal of Heterocyclic Chem

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In the current extensive review, we pay special attention to the progress in the synthesis of 2H‐azirine. Content is organized by several main approaches for the synthesis of 2H‐azirines such as‐ Neber rearrangement, decomposition of vinyl azides, oxidative cyclization of enamines, ring contraction of isoxazoles or oxazaphospholes, radical addition/cyclization of alkynes, Swern oxidation or elimination reactions of aziridine derivatives, catalytic decomposition of α‐oximino diazo compounds, addition of silyldibromomethyllithium compounds to nitriles, addition of carbenes to nitriles and via azirine‐azirine transformations. Some of these approaches open up access to new 2H‐azirine derivatives and make the already established compounds more convenient. A description of these methods and the progress of using well‐known reactions leading to the aziridine system are presented in this section. This review surveys the progress of various functionalized 2H‐azirine formation reactions from the exploration period to the present.

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“…8 Pinho e Melo and co-workers (University of Coimbra, Portugal) reported on a one-pot synthetic methodology for accessing chiral 2-(tetrazol-5-yl)-2H-azirines, involving an in situ ketoxime tosylation followed by a rare organocatalyzed asymmetric Neber reaction. 9 Carreiro and co-workers (University of Evora, Portugal) reported a sequential coppercatalyzed alkyne-azide cycloaddition (CuAAC)-multicomponent Biginelli reaction for the synthesis of novel 1,2,3-triazole-dihydropyrimidinone products that showed good antitumor activity. 10 Sticking with the theme of 1,2,3-triazole synthesis, Roux and Cisnetti (University of Clermont Auvergne, France) reported on a sequential Sonogashira-CuAAC process leading to suitably substituted triazoles.…”

Section: Cluster Syn Lettmentioning

confidence: 99%

Cluster Preface: Special Edition Dedicated to ISySyCat2019

Burke¹

2020

Synlett

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obtained his B.Sc. (joint honors in chemistry & biology, 1988) from NUI-Maynooth and his Ph.D. from University College Dublin, Ireland (1993, supervisor: W. Ivo. O’Sullivan). After postdoctoral studies with Steve Davies (Oxford, 1993–1996) and Chris Maycock (ITQB Portugal, 1996–1999) and working for a year as a lecturer in analytical chemistry at Instituto Piaget: Instituto Superior de Estudos Interculturais e Transdisciplinares, Almada, Portugal, he accepted a position as assistant professor in organic chemistry, at the University Évora. He obtained the title of aggregation (‘habilitation’) in organic chemistry from the University of Évora in 2012 and was recently appointed to the position of associate professor at the same department. He was chairman for of 1st, 2nd and 3rd editions of the International Symposium on Synthesis and Catalysis (ISySyCat), and is actively planning the 4th edition for 31 Aug to 3 September, 2021. He was appointed a Fellow of ChemPubSoc Europe in Feb 2020.

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Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Cited by 13 publications

References 19 publications

Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones

Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones

Synthesis of various functionalized 2H‐azirines: An updated library

Cluster Preface: Special Edition Dedicated to ISySyCat2019

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