Asymmetric aza-Henry Reaction Research Articles

Asymmetric aza-Henry reaction toward trifluoromethyl β-nitroamines and biological investigation of their adamantane-type derivatives.

Amino acid-derived quaternary ammonium salts were successfully applied in the asymmetric aza-Henry reaction of nitromethane to N-Boc trifluoromethyl ketimines. α-Trifluoromethyl β-nitroamines were synthesized in good to excellent yields with moderate to good enantioselectivities. This reaction is distinguished by its mild conditions, low catalyst loading (1mol%), and catalytic base. It also proceeded on a gram scale without loss of enantioselectivity. The products were transformed to a series of adamantane-type compounds containing chiral trifluoromethylamine fragments. The potent anticancer activities of these compounds against liver cancer HepG2 and melanoma B16F10 were evaluated. Six promising compounds with notable efficacy have potential for further development.

Asymmetric aza-Henry reaction of BOC-protected imines with zinc-FAM catalyst

Derivatives of ferrocenyl-substituted aziridinyl methanol (FAM) ligands were used with zinc metal for asymmetric aza-Henry (nitro-aldol) reaction of N-Boc protected imines with nitroalkanes. At optimized reaction conditions Zn-PFAM1 catalyst system with a variety of aromatic imines provided products in up to 77% ee and 88% yield. In addition, the reaction of N-Boc substituted imines with nitroethane also proceeded smoothly with moderate enantioselectivities and diastereoselectivities.

L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%) and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%) with high enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).

Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol % dinuclear zinc-AzePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and high diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

Asymmetric aza-Henry reaction of fluoromethylated imines catalyzed by cinchona-derived bifunctional thiourea

The asymmetric aza-Henry reaction of fluoromethyl imines derived from 4-methoxyaniline with nitromethane was achieved under mild conditions using cinchona-derived bifunctional thiourea as catalyst. A series of chiral fluoromethylated β-nitroamines were synthesized and their transformation to optically pure 4-fluoromethyl-2-imidazolidones was illustrated.

Isatin N-protected ketimines with nitromethane catalyzed by chiral binol linked monomeric macrocyclic Cu(II)–salen complex

Chiral Cu-1B generated in situ was used as an efficient catalyst for the synthesis of β-nitroamines in high yield (88%) with excellent enantioselectivity (ee up to 99%) at RT in absence of co-catalyst via asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane. This catalytic system did not work well with other nitroalkanes under the above optimized reaction conditions. To examine this catalytic behaviour, quantum chemical DFT calculations were performed with the nucleophiles (CH2NO2− and CH3CHNO2−) for the conversion of 1a to 2a using macrocyclic Cu-1B complex. The DFT calculated results have shown that the reaction with CH2NO2− is more favourable than the corresponding CH3CHNO2−. The calculated activation barriers suggest that the reaction with CH2NO2− is ∼8.0 kcal/mol energetically favoured than CH3CHNO2−. This catalytic protocol was further used to obtain chiral β-diamines (a building block for pharmaceuticals) at gram scale. In order to elucidate the reaction mechanism of asymmetric aza Henry reaction kinetic experiments were performed with different concentrations of the catalyst Cu-1B, nitromethane and 1g as the representative substrate. The reaction of isatin N-Boc ketimine was first order with respect to the concentration of the catalyst and the nitromethane but did not depend on the initial concentration of the substrate. A possible mechanism for the aza Henry reaction was proposed.

Chiral Cu(II)-N4 Complex Catalyzed Asymmetric Aza-Henry Reaction and Its Application in the Synthesis of β -Diamine

Chiral Cu(II)-N₄ Complex Catalyzed Asymmetric Aza-Henry Reaction and Its Application in the Synthesis of <i>β</i> -Diamine

ChemInform Abstract: Recent Advances on the Organocatalytic Asymmetric Aza‐Henry Reaction

ChemInformVolume 47, Issue 45 Reviews ChemInform Abstract: Recent Advances on the Organocatalytic Asymmetric Aza-Henry Reaction Ana M. F. Phillips, Ana M. F. Phillips Cent. Quim. Estrut., Inst. Super. Tec., P-1049 Lisboa, Port.Search for more papers by this author Ana M. F. Phillips, Ana M. F. Phillips Cent. Quim. Estrut., Inst. Super. Tec., P-1049 Lisboa, Port.Search for more papers by this author First published: 20 October 2016 https://doi.org/10.1002/chin.201645211AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue45October, 2016 RelatedInformation

Total Synthesis of Anti-Influenza Agents Zanamivir and Zanaphosphor via Asymmetric Aza-Henry Reaction.

The potent anti-influenza agents, zanamivir and its phosphonate congener, are synthesized by using a nitro group as the latent amino group at C4 for asymmetric aza-Henry reaction with a chiral sulfinylimine, which is derived from inexpensive d-glucono-δ-lactone to establish the essential nitrogen-containing substituent at C5. This method provides an efficient way to construct the densely substituted dihydropyran core of zanamivir and zanaphosphor without using the hazardous azide reagent.

Recent Advances on the Organocatalytic Asymmetric Aza-Henry Reaction

Recent Advances on the Organocatalytic Asymmetric Aza-Henry Reaction

Recyclable chiral Cu(II) macrocyclic salen complex catalyzed enantioselective aza-Henry reaction of isatin derived N-Boc ketimines and its application for the synthesis of β-diamine

Recyclable chiral Cu(II) macrocyclic salen complex Cu(II)-7 generated in situ efficiently catalyzed asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane as nucleophile at RT to give a high yield (88%) of β-nitro amines with excellent chiral induction (ee, up to 99%) with the added advantage of six times catalyst recyclability. This catalytic system also worked well with nitroethane and nitropentane to furnish the corresponding products in moderate yields with high enantioselectivities for major diastereomers. This protocol is also used for the synthesis of enantiomerically pure (S)-β-diamines via asymmetric aza-Henry reaction of N-Boc ketimine (1b) in two steps in good yield with high enantioselectivity.

ChemInform Abstract: Chiral Bifunctional Guanidine‐Catalyzed Enantioselective Aza‐Henry Reaction of Isatin‐Derived Ketimines.

An efficient asymmetric aza-Henry reaction of isatin-derived ketimines has been achieved by using a chiral guanidine–amide organocatalyst. A series of 3-substituted 3-amino-2-oxindoles was obtained with excellent results (up to 99% yield, 94% ee). Other functionalized derivatives were also conveniently transformed. This metal-free system was convenient, practical, and insensitive to air and moisture. On the basis of the crystal structure of the catalyst and NMR spectra analysis, a bifunctional catalytic model was suggested to explain the origin of the asymmetric process.

Chiral bifunctional guanidine-catalyzed enantioselective Aza-Henry reaction of isatin-derived ketimines.

An efficient asymmetric aza-Henry reaction of isatin-derived ketimines has been achieved by using a chiral guanidine-amide organocatalyst. A series of 3-substituted 3-amino-2-oxindoles was obtained with excellent results (up to 99% yield, 94% ee). Other functionalized derivatives were also conveniently transformed. This metal-free system was convenient, practical, and insensitive to air and moisture. On the basis of the crystal structure of the catalyst and NMR spectra analysis, a bifunctional catalytic model was suggested to explain the origin of the asymmetric process.

Asymmetric aza-Henry reaction to provide oxindoles with quaternary carbon stereocenter catalyzed by a metal-templated chiral Brønsted base

An inert octahedral chiral-at-metal iridium(iii) complex serves as a highly effective chiral Brønsted base catalyst for implementing a quaternary carbon stereocenter.

ChemInform Abstract: Organocatalytic Enantioselective aza‐Henry Reaction of Ketimines Derived from Isatins: Access to Optically Active 3‐Amino‐2‐oxindoles.

An organocatalytic asymmetric aza-Henry reaction of ketimines derived from isatins with nitroalkanes has been achieved using Cinchona alkaloid organocatalysts. This method works efficiently with several ketimines to produce a good (up to 82%) yield of the corresponding 3-substituted 3-amino-2-oxindoles with a good (up to 89%) enantiomeric excess.

New sugar-derived bifunctional chiral ureas as highly effective organocatalysts in asymmetric aza-Henry reaction

A simple synthesis of series of new catalysts derived from chiral bifunctional ureas is described. The aza-Henry reaction of imines with nitromethane was promoted by sugar derived bifunctional organocatalysts to give optically active β-nitroamines. The aza-Henry reaction products were obtained in good yields (35–98%) and ee up to 99%.

Asymmetric aza-Henry Reaction Catalyzed by Copper

Asymmetric aza-Henry Reaction Catalyzed by Copper

Synthesis and characterization of new chiral Cu(ii)-N4 complexes and their application in the asymmetric aza-Henry reaction.

Cu(ii) Schiff base complexes Cu(ii)- and Cu(ii)- based on 2-acetyl pyridine with both (1R,2R)-1,2-diaminocyclohexane and (1S,2S)-1,2-diaminocyclohexane were synthesized in a single step. Subsequent reduction of ligands and with NaBH4 followed by complexation with Cu(OTf)2 resulted in generation of two more additional chiral centers in complexes Cu(ii)- and Cu(ii)-. The ligands and their corresponding complexes were well characterized by several spectral techniques like (1)H-NMR, (13)C-NMR, LC-MS, CD, UV-Vis spectroscopy and microanalysis. The respective Cu(ii) complexes derived from ligands and were investigated using both the solution and solid state EPR spectra. The particular orientation of the reduced complex with Cu(OTf)2 was confirmed by the X-ray crystal structure of the corresponding complex. All the catalytic protocols were applied in the asymmetric aza-Henry reaction to evaluate the catalytic properties of the Cu(ii) complexes in the present study.

Organocatalytic enantioselective aza-Henry reaction of ketimines derived from isatins: access to optically active 3-amino-2-oxindoles

An organocatalytic asymmetric aza-Henry reaction of ketimines derived from isatins with nitroalkanes has been achieved using Cinchona alkaloid organocatalysts.

Chiral Cu(ii)-amino alcohol based complexes for asymmetric aza-Henry reaction of N-Ts imines

A series of chiral dimeric ligands 1A–C, 2A–B, 3A–B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(−)-2-aminodiphenylethanol, (1S,2R)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were synthesized. In situ generated complexes 1A–C–, 2A–B–, 3A–B–, 4A–Cu(II)/Cu(I) of dimeric chiral ligands with different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products (80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(II) complex 1A–Cu(II) retained its performance at the gram level and was expediently recycled for a number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole (an anthelminthic agent) in good yield and ee in three steps.