Synthesis of Spiropyrrolidines via Five‐Component 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Olefinic Dipolarophiles Generated In Situ Simultaneously

An efficient and straightforward five‐component cascade protocol has been developed to synthesize the highly substituted dispiroindenoquinoxaline pyrrolidine derivatives from ninhydrin, 1,2‐phenylenediamine, sarcosine, 1,3‐indanedione, and aldehydes via cascade reactions under mild conditions, in which 1,3‐dipole azomethine ylide and the dipolarophile were simultaneously generated in situ. This novel method is complementary to the classical Huisgen cycloaddition in that it is well‐suited to the preparation of dispiroindenoquinoxaline pyrrolidine derivatives.     

Organocatalysed asymmetric beta-amination and multicomponent syn-selective diamination of alpha,beta-unsaturated aldehydes

An easy and affordable route for obtaining chiral beta-aminated- and alpha,beta-diaminated aldehydes, 1,3-aminoalcohols, and related compounds by using organocatalysis is presented. The chiral secondary amine (S)-2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine is used as the catalyst to activate alpha,beta-unsaturated aldehydes, which allows succinimide to add in a 1,4-regio- and stereoselective fashion thereby forming N-protected 1,3-aminoaldehydes in good yields and enantioselectivities. This is followed by two easy transformations giving rise to optically active 1,3-aminoalcohols, a common motif in many biologically active compounds, for example, fibrinogen receptor antagonists. Furthermore, optically active alpha,beta-syn-diaminated aldehydes were obtained by the addition of diethyl azodicarboxylate in a one-pot reaction.     

Synthesis of Functionalized Thiophenes by Four‐component Reactions of 1,3‐Thiazolidinedione,Aromatic Aldehydes,Cyanoacetamide and Cyclic Secondary Amines

The polysubstituted thiophene derivatives were conveniently prepared by the four‐component reactions of 1,3‐thiazolidinedione, aromatic aldehydes, cyanoacetamide and cyclic secondary amines such as pyrrolidine, morpholine and piperidine. The reaction mechanism is believed to involve domino reactions of Knoevenagel condensation, Michael addition, ring‐opening and recyclization of 1,3‐thiazolidinedione.     

Microwave-Assisted Method for Synthesis of 1,3-Disubstituted Pyrroles

1,3-Disubstituted pyrroles were prepared by a microwave-assisted reaction of pyrrolidine and aldehydes in toluene as well as in solvent-free conditions. Reactions were completed in a few minutes in the solvent-free condition but a long time (up to 30 min) was necessary to complete reactions in toluene. Yields of products depended considerably on the aldehyde used.     

Condensation of 2-acylcyclohexane-1,3-diones with aromatic aldehydes

Condensation of 2-propanoyl-, 2-butanoyl-, and 2-pentanoylcyclohexane-1,3-diones with aromatic aldehydes in the presence of secondary amines (diethylamine, pyrrolidine, morpholine, piperidine, and hexamethyleneimine) leads to the formation of the corresponding 2-[1-(dialkylamino)-2-alkyl-3-aryl-2-propylidene]cyclohexane-1,3-diones and derivatives of 4H-chromen-4,5(6H)-dione. A primary screening of some of the resulting enamino derivatives for fungicidal activity has been performed.     

Expeditious synthesis of bicyclic pyrrolidine/pyrrolizidine/thiazolidine grafted macrocycles through intramolecular 1,3-dipolar cycloaddition of azomethine ylides

Stereoselective synthesis of bicyclic pyrrolidine and pyrrolizidine grafted macrocycles has been accomplished through intramolecular 1,3-dipolar cycloaddition (1,3-DC) reaction. Alkenyl aldehydes 4a–b derived from salicylaldehyde have been reacted with secondary aminoacids to generate azomethine ylides which in turn were trapped intramolecularly by suitably placed dipolarophiles to give the corresponding macrocycle in moderate yield. The structures were assigned by 2D NMR spectra and the regio- and stereochemical outcome of the cycloadducts was established by a single crystal X-ray analysis of one of the products.     

One-pot,five-component 1,3-dipolar cycloaddition: A facile synthesis of spiropyrrolidine and spiropyrrolizidine derivatives

A one-pot, five-component strategy toward the synthesis of new indole substituted pyrrolidine and pyrrolizidine heterocycles through 1,3-dipolar cycloaddition reactions using ninhydrin, 1,2-phenylenediamine, amino acids, 3-cyanoacetyl indoles and aryl aldehydes is described. The features of this procedure were characterized by the mild reaction conditions, high yields, one-pot procedure, and operational simplicity.     

Synthesis of exo- and endocyclic enamino derivatives of 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones

Condensation of 2-acetylcyclohexane-1,3-diones with aromatic aldehydes in the presence of piperidine, pyrrolidine, hexamethyleneimine, or morpholine gave the corresponding 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones as the major products and 2-[3-aryl-1-cycloalkylaminoprop-2-en-1-ylidene]cyclohexane-1,3-diones as minor ones. Endocyclic enamino derivatives were synthesized in two steps through enol methyl ethers which reacted with amines. Endocyclic enamino derivatives of 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones containing an aryl group on the nitrogen atom readily underwent cyclization to 1,2,3,4,5,6,7,8-octahydroquinoline-4,5-dione derivatives.     

Reactions of 6-(Dimethylamino)fulvene with diazoazoles and arene- and azolediazonium salts

6-(Dimethylamino)fulvene reacted with 3- and 4-substituted 5-diazoazoles, as well as with 4-substituted benzene- and pyrazole-5-diazonium salts, in an aprotic solvent with high regioselectivity at an extremely high rate to give acyclic coupling products at the α-carbon atom of the cyclopenta-1,3-diene fragment. The nature of the diazo component did not affect the reaction direction, rate, or yield. Hydrolysis of the azo compounds obtained from arenediazonium salts involved elimination of the dimethylamino group with formation of aldehydes, and their reaction with pyrrolidine resulted in replacement of the dimethylamino group by pyrrolidine ring.     

Organocatalytic asymmetric multi-component [C+NC+CC] synthesis of highly functionalized pyrrolidine derivatives

The highly chemo- and enantioselective organocatalytic [C+NC+CC] coupling process between aldehydes, dialkyl 2-aminomalonates and α,β-unsaturated aldehydes is presented. The reaction gives access to highly functionalized pyrrolidine derivatives in good yields with >10:1 dr and 90-98% ee.     

Direct, pyrrolidine sulfonamide promoted enantioselective aldol reactions of α,α-dialkyl aldehydes: synthesis of quaternary carbon-containing β-hydroxy carbonyl compounds

A procedure has been developed for direct, asymmetric aldol reactions of α,α-dialkyl aldehydes with aromatic aldehydes, which produces quaternary carbon-containing β-hydroxy carbonyl compounds. The processes, promoted by the organocatalyst (S) pyrrolidine sulfonamide, take place in high yields with exceptionally high levels of enantioselectivities.     

Tandem Michael addition of amines to maleic anhydride and 1,3-prototropic shift: experimental and theoretical results

Amines, namely diethylamine, diphenylamine, benzylamine, and pyrrolidine react with maleic anhydride to form Michael adducts. The Michael adducts formed with the first three amines undergo tandem 1,3-prototropic shift to give the final products. Computational calculations at the DFT (B3LYP/6-31+G*) level reveal that a reactant-complex formed between the initially formed Michael adduct and the respective amine plays a crucial role in the 1,3-prototropic shift. In the reaction of pyrrolidine with maleic anhydride, Michael addition is not followed by 1,3-prototropic shift. The theoretical studies of the latter reaction show that a reactant-complex is not formed in this case. Dimethyl maleate and dimethyl fumarate react with pyrrolidine to give the same Michael addition product.     

Self-assembled proline-amino thioureas as efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins

A small co-catalyst library of amino thioureas has been established from chiral 1,3-diamines. These bifunctional thioureas can form assemblies with proline to cooperatively catalyze the asymmetric Michael addition of aldehydes to nitroolefins. Both the reaction rate (up to 98% yield for 18 h) and the enantioselectivity (up to 94% ee) were significantly improved upon in less polar solvents.     

Pyrrolidine and iodine catalyzed domino aldol-Michael-dehydrogenative synthesis of flavones

A one pot synthesis of flavones is established from 2′-hydroxyacetophenones and substituted aromatic aldehydes. The method uses domino aldol-Michael-oxidation reaction catalyzed by pyrrolidine as a base and iodine as an oxidant in dimethyl sulfoxide.     

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.     

Electron deficiency of aldehydes controls the pyrrolidine catalyzed direct cross-aldol reaction of aromatic/heterocyclic aldehydes and ketones in water

A synthetically useful pyrrolidine catalyzed direct cross-aldol reaction of aromatic/heterocyclic aldehydes with ketones in water affords the aldol addition product in up to 93% yield. Electrophilicity of the aldehydes controls the course of the reaction.     

TiO2-Mediated,One-Pot,Four-Component 1,3-Dipolar Cycloaddition Reaction: A Facile Synthesis of Dispiro-pyrrolidine Ring Systems

An expedient regioselective synthesis of dispiroindenoquinoxaline pyrrolidine derivatives mediated by TiO₂ in a one-pot, four-component 1,3-dipolar cycloaddition reaction is described.     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

Direct organocatalytic asymmetric heterodomino reactions: the Knoevenagel/Diels-Alder/epimerization sequence for the highly diastereoselective synthesis of symmetrical and nonsymmetrical synthons of benzoannelated centropolyquinanes

Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/Diels-Alder/epimerization reactions of readily available various precursor enones (1a-l), aldehydes (2a-p), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted, symmetrical and nonsymmetrical spiro[cyclohexane-1,2'-indan]-1',3',4-triones (5) in a highly diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation of arylaldehydes (2a-p) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3-indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine-catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellent starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields. Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retro-Michael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5ab in moderate yield from enone 1a and 1,3-indandione 3.     

The formation of novel 1,3-dioxolanes: atypical Baylis-Hillman reaction of a sesquiterpene lactone parthenin

The Baylis-Hillman reaction of a sesquiterpene lactone parthenin with various aldehydes gave unexpected products containing a 1,3-dioxolane moiety. Both small aliphatic and aromatic aldehydes produced 1,3-dioxolanes, whereas higher aliphatic aldehydes produced normal Baylis-Hillman products.