Neber Reaction Research Articles

Organocatalysts for the Asymmetric Neber reaction: Synthesis of Chiral 2‐(Tetrazol‐5‐yl)‐2H‐Azirines

Abstract‐ Several novel organocatalysts derived from β‐ and γ‐lactam‐fused thiazolidines and L‐phenylalanine‐based thiazolidines were efficiently synthetized. These organocatalysts, as well as other previously developed thiazolidine‐derived thioureas, were tested in the asymmetric one‐pot Neber reaction of β‐ketoxime‐1H‐tetrazoles towards chiral 2‐(tetrazol‐5‐yl)‐2H‐azirines. The results obtained when using thioureas only differing in the lactam ring size demonstrate that the presence of the 6β‐lactam ring in the catalysts is a requirement to achieve high enantioselectivity in the studied transformation. The new 6β‐aminopenicillanic acid‐derived thiourea afforded the R enantiomer of 3‐phenyl‐2‐(tetrazol‐5‐yl)‐2H‐azirine with >99 % ee.

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

A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.

Facile construction of trifluoromethyl-azirines via one-pot metal-free Neber reaction

A Et3N-mediated Neber reaction of aryl/alkyl-2,2,2-trifluoroethylketoximes has been developed. This one-pot metal-free protocol enables the facile construction of an array of trifluoromethyl-substituted azirines in moderate to high yields under mild reaction conditions. Further transformations of azirines to CF3-containing pyrrole and amino-alcohol derivatives are also demonstrated.

ChemInform Abstract: A Neber Approach for the Synthesis of Spiro‐Fused 2H‐Azirine‐Pyrazolone.

AbstractA base‐mediated Neber reaction of enaminopyrazolones (I) and tosyl chloride affording title compounds (II) is reported.

A Neber approach for the synthesis of spiro-fused 2H-azirine-pyrazolone.

A base-mediated Neber reaction of enaminopyrazolones, which are the tautomers of 4-acyloxime-2-pyrazolin-5-ones, with sulfonyl chlorides was achieved. With this developed approach, a range of spiro-fused 2H-azirine-pyrazolones were obtained in good yields under mild conditions. A preliminary trial of a catalytic asymmetric version of the Neber reaction was conducted and gave promising enantioselectivity.

The organocatalytic asymmetric Neber reaction for the enantioselective synthesis of spirooxindole 2H-azirines.

The asymmetric Neber reaction of 3-O-sulfonyl ketoxime, in situ generated from isatin ketoxime and sulfonyl chloride, for the synthesis of chiral spirocyclic oxindole compounds is reported. With the developed protocol, a range of chiral spirooxindole 2H-azirines could be obtained in good to excellent yields and up to a 92 : 8 enantiomeric ratio by using (DHQD)2PHAL as the catalyst. This methodology is the only example of the catalytic asymmetric construction of spirooxindole 2H-azirine compounds.

Total synthesis of motualevic acids A–F, (E) and (Z)-antazirines

Total synthesis of motualevic acids A–F and (E) & (Z) geometrical isomers of antazirines has been achieved from a commercially available starting material, 1,10-decanediol. The synthesis of motualevic acid E served as a common key intermediate for the synthesis of most of these natural products. The key steps involved in this synthesis were Wittig olefination, Corey–Fuchs reaction, Neber reaction, amide coupling.

ChemInform Abstract: Neber Approach to 2‐(Tetrazol‐5‐yl)‐2H‐azirines.

AbstractThe synthesis of novel tetrazolylaziridines bearing a phenyl or various heteroaryl‐substituents at C‐3 via the Neber reaction of β‐ketoxime tetrazole derivatives is reported.

The Neber Approach to 2-(Tetrazol-5-yl)-2H-Azirines

The synthesis of 2-(tetrazol-5-yl)-2H-azirines is reported for the first time. Using the Neber approach, β-ketoxime-1H-tetrazoles were converted into the target 2H-azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl substituents at C-3. It was demonstrated that the alkaloid-mediated Neber reaction allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines.

ChemInform Abstract: Organocatalytic Asymmetric Neber Reaction for the Synthesis of 2H‐Azirine Carboxylic Esters.

AbstractThe reaction of β‐ketoxime sulfonates is catalyzed by a bifunctional thiourea catalyst to afford the enantioenriched target products with good yields and high enantioselectivities.

Organocatalytic Asymmetric Neber Reaction for the Synthesis of 2H-Azirine Carboxylic Esters

The first enantioselective Neber reaction of β-ketoxime sulfonates catalyzed by a bifunctional thiourea has been developed. The reaction proceeds stereoselectively with 5 mol % of the catalyst to give the 2H-azirine carboxylic esters in good yields with up to 93% ee. In addition, the resulting azirines can be successfully employed in the stereoselective synthesis of di- and trisubstituted aziridines.

Lipase-Catalyzed Resolution of (2R*,3S*)- and (2R*,3R*)-3-Methyl-3-phenyl-2-aziridinemethanol at Low Temperatures and Determination of the Absolute Configurations of the Four Stereoisomers

[reaction: see text] Lipase-catalyzed resolution of (2R*,3S*)-3-methyl-3-phenyl-2-aziridinemethanol, (+/-)-2, at low temperatures gave synthetically useful (2R,3S)-2 and its acetate (2S,3R)-2a with (2S)-selectivity (E = 55 at -40 degrees C), while a similar reaction of (2R*,3R*)-3-methyl-3-phenyl-2-aziridinemethanol, (+/-)-3, gave (2S,3S)-3 and its acetate (2R,3R)-3a with (2R)-selectivity (E = 73 at -20 degrees C). Compound (+/-)-2 was prepared conveniently via diastereoselective addition of MeMgBr to tert-butyl 3-phenyl-2H-azirine-2-carboxylate, (+/-)-1a, which was successfully prepared by the Neber reaction of oxime tosylate of tert-butyl benzoyl acetate 7a. The tert-butyl ester was requisite to promote this reaction. For determination of the absolute configuration of (2S,3R)-2a, enantiopure (2S,3R)-2 was independently prepared in three steps involving diastereoselective methylation of 3-phenyl-2H-azirine-2-methanol, (S)-10, with MeMgBr. The absolute configuration of (2S,3S)-3 was determined by X-ray analysis of the corresponding N-(S)-2-(6-methoxy-2-naphthyl)propanoyl derivative (S,S,S)-13.

Asymmetric Synthesis of 2H‐Aziridine Phosphonates, and α‐ or β‐Aminophosphonates from Enantiomerically Enriched 2H‐Azirines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric synthesis of 2 H-aziridine phosphonates, and α- or β-aminophosphonates from enantiomerically enriched 2 H-azirines

A simple and efficient method for asymmetric synthesis of 2 H-azirine-2-phosphonates 6 is described. The key step is a base-mediated Neber reaction of p-toluenesulfonyloximes 4 derived from phosphonates. Triethylamine 5, alkaloids 7 and solid-phase bound achiral 8 or chiral amines 9 are used. Reduction of 2 H-azirines 6 with sodium borohydride in ethanol gives cis-aziridine-phosphonates 10. Ring opening of aziridines 10 and 11 leads to the formation of enantiomerically enriched β- 12 and 14 and α-aminophosphonates 13 and 15.

Asymmetric synthesis of 2H-azirines derived from phosphine oxides using solid-supported amines. Ring opening of azirines with carboxylic acids.

A simple and efficient asymmetric synthesis of 2H-azirine-2-phosphine oxides 3 is described. The key step is a solid-phase bound achiral or chiral amine-mediated Neber reaction of beta-ketoxime tosylates derived from phosphine oxides 1. Reaction of 2H-azirines 3 and 11 with carboxylic acids 4 gives phosphorylated ketamides 5 and 12. Ring closure of ketamides 5 and 12 with triphenylphosphine and hexachloroethane in the presence of triethylamine leads to the formation of phosphorylated oxazoles 8 and 13.

ChemInform Abstract: Easy and Efficient Synthesis of Enantiomerically Enriched 2H-Azirines Derived from Phosphonates.

Abstract An efficient synthesis of 2 H -azirines substituted with a phosphonate group is described. The key step is an alkaloid-mediated Neber reaction of β-ketoxime tosylates. Reduction of 2 H -azirines with sodium borohydride in ethanol gives 2-phosphorylated cis -aziridines.

Easy and efficient synthesis of enantiomerically enriched 2 H-azirines derived from phosphonates

An efficient synthesis of 2 H-azirines substituted with a phosphonate group is described. The key step is an alkaloid-mediated Neber reaction of β-ketoxime tosylates. Reduction of 2 H-azirines with sodium borohydride in ethanol gives 2-phosphorylated cis-aziridines.

ChemInform Abstract: Asymmetric Synthesis of 2H‐Azirine Carboxylic Esters by an Alkaloid‐ Mediated Neber Reaction.

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Synthesis of 10β-(1′-azirinyl)estr-4-en-3,17-dione as an aromatase inhibitor

The novel 10β-(1′-azirinyl)estr-4-en-3,17-dione ( 10 ) has been synthesized from 19-methyl-19-methiodide salt intermediates 15 and 16 by a modified Neber reaction. Four other hitherto undescribed 10β-1′-azirinyl steroids 9, 12, 17 , and 18 were also synthesized. Compound 10 inhibited human placental aromatase in vitro (IC 50 value = 5.5 μM) but was not as potent as the related (19 R)-10β-aziridine ( 1 ).

Asymmetric Synthesis of 2H-Azirine Carboxylic Esters by an Alkaloid-Mediated Neber Reaction

Asymmetric Synthesis of 2<i>H</i>-Azirine Carboxylic Esters by an Alkaloid-Mediated Neber Reaction