Imino Aldol Reaction Research Articles

Domino imino-aldol-aza-Michael and imino-aldol-aza-Michael-imino-aldol reactions: Diastereoselective synthesis of highly functionalized 2,6-disubstituted piperidines

Enolate mediated domino imino-aldol-aza-Michael and domino imino-aldol-aza-Michael-imino-aldol reactions of α-(aryl/alkyl)methylidene-β-diketones with activated N-aryl aldimines (1.0 and 2.0 equiv., respectively) have been developed for the diastereoselective (de >99%) synthesis of two sets of highly functionalized 2,6-disubstituted piperidines. The reaction course follows an intermolecular imino-aldol reaction followed by an intramolecular aza-Michael reaction with 1.0 equiv. of imine; whereas another intermolecular imino-aldol reaction takes place when 2.0 equiv. of imine is present in the reaction medium. The formation of the piperidine derivatives has been explained by plausible reaction mechanisms.

Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines.

Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that unactivated imines will react with difluoroenolates under exceedingly mild conditions when using magnesium salts and organic bases. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.

A Two-Directional Synthesis of (+)-β-Isosparteine.

A two-directional synthesis of (+)-β-isosparteine is described in five steps from glutaric acid, where the entire carbon and nitrogen backbone of the alkaloid, possessing the requisite relative and absolute stereochemistry at its four stereogenic centers, is assembled using a double imino-aldol reaction.

Stereoselective synthesis of activated 2-arylazetidines via imino-aldol reaction.

A simple and efficient synthetic route to substituted N-sulfinyl and N-sulfonyl azetidines is described involving imino-aldol reaction of ester enolates with racemic and non-racemic aldimines for obtaining β-amino esters as a key step. These β-amino esters on subsequent reduction followed by TsCl/KOH mediated cyclization produced the corresponding racemic and non-racemic azetidines with high yield and stereoselectivity.

ChemInform Abstract: Total Synthesis of the Tetracyclic Lupin Alkaloid (+)‐Allomatrine.

(+)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N-acyliminium cyclization as key steps. Strategically, use of the tert-butylsulfinimine derivative of (E)-4-(trimethylsily...

Total Synthesis of the Tetracyclic Lupin Alkaloid (+)-Allomatrine

(+)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N-acyliminium cyclization as key steps. Strategically, use of the tert-butylsulfinimine derivative of (E)-4-(trimethylsilyl)but-2-enal enabled the staged formation of three C-C bonds, a C-N bond, and the four stereogenic centers within the target.

Memory of Chirality (MOC) Concept in Imino-Aldol Reaction: Enantioselective Synthesis of α,β-Diamino Esters and Aziridines

A simple strategy for the synthesis of chiral α,β-diamino- and α-amino,β-hydroxy ester derivatives in high yields with moderate to high ee has been developed via asymmetric imino-aldol and aldol reactions, respectively, starting from protected aminoesters employing memory of chirality concept for chiral induction. This strategy has been extended for the enantioselective synthesis of aziridines (ee up to 92%). The absolute configuration of the imino-aldol adducts has been determined. The stereochemical outcome of the products has been explained by a suitable mechanism and supported by computational studies.

Total Syntheses of (−) Epilupinine and (−)-Tashiromine Using Imino-Aldol Reactions

Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ∼13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.

Enantioselective synthesis of α,β-diamino ester derivatives: memory of chirality in imino-aldol reactions

A simple strategy for the synthesis of chiral α,β-diamino ester derivatives in good yields and ee (up to 92%) utilizing the ‘memory of chirality’ concept is reported. This methodology has been extended for the enantioselective synthesis of substituted aziridines with excellent ee (92%).

A new synthesis of pyrrolidines via imino-aldol reaction of (2-trimethylsilylmethyl)cyclopropyl ketones with imines

A new synthesis of 2,3,5-trisubstituted pyrrolidines from the imino-aldols formed from Lewis acid-mediated reactions of (2-trimethylsilylmethyl)cyclopropyl ketones with benzylimines is described. The ring closure of the imino-aldols formed from the benzylimines of 2-chloro-, 2-fluoro-, and 2-trifluoromethylbenzaldehydes proceeds with predominantly 2,5- anti selectivity to generate the corresponding pyrrolidines in moderate yields.

Lewis Base Catalyzed Aza-Diels-Alder Type Reactions between Danishefsky’s Dienes in the Presence of Lewis Base Catalysts. An Efficient Method for the Synthesis of Substituted 2,3-Dihydropyridin-4-ones

Aza-Diels-Alder type reactions of various imines with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky's diene) derivatives catalyzed by Lewis bases such as lithium methoxide are described. The reaction proceeds via a stepwise pathway, i.e. first by an imino-aldol reaction followed by the acid mediated annulation to afford the corresponding 2,3-dihydropyridin-4-ones in high yields. An appropriate choice of the substituents on nitrogen plays important roles both in addition of the silyl enolates and in the subsequent annulation to form the desired cycloadducts.

Synthesis of 1,2‐Dihydropyridines Using Vinyloxiranes as Masked Dienolates in Imino‐Aldol Reactions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of 1,2-Dihydropyridines Using Vinyloxiranes as Masked Dienolates in Imino-Aldol Reactions

[reaction: see text] The application of vinyloxiranes, substituted with an electron-withdrawing group, as masked dienolates in vinylogous imino-aldol reactions was achieved. Under the reaction conditions highly substituted 1,2-dihydropyridines were obtained in moderate to good yields. Mechanistic studies indicate that the reaction proceeds via the formation of an (E)-amino-alpha,beta-unsaturated aldehyde, followed by isomerization to the (Z)-isomer, cyclization, and elimination of a water molecule, leading to the formation of the 1,2-dihydropyridine.

A Cation-Exchange Resin Promoted Imino Aldol Reaction of Chiral Alkoxyketene Silyl Acetals with α,β-Unsaturated Imines, Leading to a Facile Synthesis of β-Lactams.

Imino aldol reaction of chiral ketene silyl acetals derived from 3-hydroxybutanoates with α,β-unsaturated imines proceeds smoothly to give β-amino esters in good yields with high syn-selectivity under the influence of a cation-exchange resin. Subsequent treatment with tert-butylmagnesium chloride gave β-lactams in a highly stereoselective manner.

Mixed Organofluorine—Organosilicon Chemistry. Part 14. Mild Synthesis of β‐Amino‐α,α‐difluoro Ketones from Acylsilanes and Trifluoromethyltrimethylsilane in a One‐Pot Imino Aldol Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Mild Synthesis of β‐Amino‐α,α‐difluoro Ketones from Acylsilanes and Trifluoromethyltrimethylsilane in a One‐Pot Imino Aldol Reaction

Abstractβ‐Amino‐α,α‐difluoro ketones have been very conveniently prepared in a one‐pot procedure from acylsilanes, trifluoromethyltrimethylsilane and imines. The key intermediate in this reaction is a difluoroenoxysilane. The Lewis acid promoted imino aldol reaction was performed with BF3·OEt2 or under very mild conditions using a catalytic amount of Yb(OTf)3. The reaction with chiral benzylimines occurred in good yield with 52–78 % de. Palladium‐catalyzed hydrogenolysis furnished an unprotected β‐amino‐α,α‐difluoro ketone or a β‐amino‐α,α‐difluoro alcohol. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A Cation‐Exchange Resin Promoted Imino Aldol Reaction, Leading to the Synthesis of 2‐Isocephem and 2‐Oxa‐isocephem.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Cation-Exchange Resin Promoted Imino Aldol Reaction of Chiral Alkoxyketene Silyl Acetals with α,β-Unsaturated Imines, Leading to a Facile Synthesis of β-Lactams

Imino aldol reaction of chiral ketene silyl acetals derived from 3-hydroxybutanoates with α,β-unsaturated imines proceeds smoothly to give β-amino esters in good yields with high syn-selectivity under the influence of a cation-exchange resin. Subsequent treatment with tert-butylmagnesium chloride gave β-lactams in a highly stereoselective manner.

Diastereoselective reductive imino-aldol reaction of α-imino esters promoted by titanium tetraiodide: synthesis of α,β-diamino esters

Under the influence of titanium tetraiodide reductive imino-aldol reaction of the N-tosylimine derived from ethyl glyoxylate proceeded with aldimines to give alpha,beta-diamino esters in good yields in a highly diastereoselective manner.

A Cation-exchange Resin Promoted Imino Aldol Reaction, Leading to the Synthesis of 2-Isocephem and 2-Oxa-isocephem

Abstract Imino aldol reaction of ketene silyl acetals with the chiral imine 1 proceeds smoothly to giveβ-amino esters in good yields with high diasetereoselectivity under the influence of a cation-exchange resin, and the subsequent functional group transformations provide a formal synthesis of 2-isocephem and 2-oxa-isocephem β-lactam antibiotics.