Reaction of 6,6-dimethylfulvene with aromatic imines in the presence of Lewis acids

Formal aza-Diels-Alder (Povarov) reaction of 6,6-dimethylfulvene with aromatic imines is described for the first time.     

Three-component one-pot synthesis of 1,2,3,4-tetrahydroquinoline derivatives in hexafluoroisopropanol

The one-pot aza-Diels-Alder reaction of substituted aromatic amines, ethyl glyoxylate and benzyl vinylcarbamate or N- benzyloxycarbonyl 2-pyrroline was conducted in hexafluoroisopropanol, providing the desired 1,2,3,4-tetrahydroquinline derivatives in moderate yields.     

Enzyme-catalyzed direct three-component aza-Diels–Alder reaction using lipase from Candida sp.99–125

The direct three-component aza-Diels–Alder reaction was conducted with lipase as a catalyst for the first time. Under the optimized conditions, the aza-Diels–Alder reaction catalyzed by lipase from Candida sp.99–125 provided the products in moderate to excellent yields. Meanwhile, the endo/exo ratio reached up to 88:12.     

Catalytic enantioselective aza-Diels-alder reactions of imines--an approach to optically active nonproteinogenic alpha-amino acids

A catalytic enantioselective aza-Diels-Alder reaction of imines has been developed. The reaction of N-tosyl alpha-imino ester with different dienes including activated, non-activated, cyclic, and acyclic dienes has been investigated in the presence of various chiral Lewis acids. A series of phosphino-oxazoline ligands have been synthesized and evaluated for the reaction. It was found that the combination of phosphino-oxazoline ligands with copper(I) salts gives the best results for the activated dienes, while BINAP-copper(I) complexes are good catalysts for all the dienes studied. In the case of activated acyclic dienes the aza-Diels-Alder products can be obtained in higher than 80% isolated yield and 96% ee, while for the unactivated cyclic dienes the exo diastereomer is formed as the major product in up to 95 % ee. For an activated cyclic conjugated diene, 2-trimethylsilyloxy-1,3-cyclohexadiene, the reaction proceeds as a Mannich-type addition reaction giving optically active gamma-oxo alpha-amino acid derivatives in good yields and up to 96% ee. The reaction of an unactivated acyclic diene, 2,3-dimethyl-1,3-butadiene, with the N-tosyl alpha-imino ester gives both the aza-Diels-Alder and aza-ene products, in a ratio of 9:1 favoring the aza-Diels-Alder product. Furthermore, a series of different imines have been synthesized and investigated as possible substrates for the present catalytic enantioselective aza-Diels-Alder reaction in order to obtain mechanistic insight. All imines studied gave moderate to high ee. Particularly, the reaction of the N-phenyl and N-p-methoxyphenyl substituted glyoxylate imines with Danishefsky's diene proceeded well affording the corresponding aza-Diels-Alder product in high yield with up to 91% ee at room temperature. The present catalytic enantioselective reaction of imines provided an effective route to optically active nonproteinogenic alpha-amino acids. The products of the catalytic enantioselective aza-Diels-Alder reaction of the cyclic dienes can be used for the preparation of key compounds such as natural products and compounds of pharmaceutical interest. The absolute configurations of five products have been solved by X-ray structural analysis, and it is found that the absolute configuration of the aza-Diels-Alder adduct is dependent on the substituent on the imine nitrogen atom. It turned out that the N-tosyl glyoxylate imine and N-p-methoxyphenyl glyoxylate imine give the aza-Diels-Alder adduct with opposite absolute configuration using the same enantiomer of the catalyst. On the basis of the results the mechanistic aspects for the reactions are discussed.     

Novel intramolecular aza-Diels-Alder reaction: a facile synthesis of trans-fused 5H-chromeno[2,3-c]acridine derivatives

A novel series of 5H-chromeno[2,3-c]acridine derivatives has been prepared through the intramolecular aza-Diels-Alder reaction of alkene-tethered chromene-3-carboxaldehyde with various aromatic amines. This is the first example of the preparation of pentacyclic poly aromatic compounds in a single-step operation at ambient temperature.     

Enantioselective aza-Diels-Alder reaction of Brassard’s diene with aldimines catalyzed by chiral N,N′-dioxide-Yb(OTf)3 complex

The chiral N,N′-dioxide-Yb(OTf)₃ complex-catalyzed enantioselective aza-Diels-Alder reaction of Brassard’s diene with aldimines has been developed, giving the corresponding α,β-unsaturated δ-lactam derivatives in moderate yields with good enantioselectivities (up to 81% ee and up to 99% ee by single recrystallization) under mild conditions. Isolation of the reaction intermediate indicates that this asymmetric aza-Diels-Alder reaction proceeds through a stepwise Mannich-type pathway.     

Enantioselective aza-Diels-Alder reaction of aldimines with "Danishefsky-type diene" catalyzed by chiral scandium(III)-N,N'-dioxide complexes

A new kind of complex prepared from scandium(III) triflate and l-proline-derived N,N'-dioxides has been developed to catalyze the enantioselective aza-Diels-Alder reaction between 1,3-butadiene (diene 1) and aldimines 2, affording the corresponding 2,5-disubstituted dihydropyridinones in moderate to high yields (up to 92%) with good enantioselectivities (up to 90% ee) at room temperature. A variety of aldimines including aromatic, heteroaromatic, conjugated, and aliphatic imines were found to be suitable substrates. Enantiopure samples (up to 99% ee) were obtained for some products by a single recrystallization. The absolute configuration of the products was determined by X-ray diffraction and CD analysis. On the basis of the investigation of 1H NMR spectra and the positive nonlinear effect, the catalyst structure was carefully discussed.     

Phosphomolybdic acid-catalyzed efficient one-pot three-component aza-Diels-Alder reactions under solvent-free conditions: a facile synthesis of trans-fused pyrano- and furanotetrahydroquinolines

trans-Fused pyrano- and furanotetrahydroquinoline derivatives have been synthesized via a one-pot three-component aza-Diels-Alder reaction of aryl imines formed in situ from aromatic amines and arylaldehydes with cyclic enol ethers,such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran,in the presence of 1 mol % of phosphomolybdic acid under solvent-free conditions at room temperature in good to excellent yields.     

Efficient three-component synthesis of tetrahydrothieno[3,2-f]quinolines

An efficient one-pot method for the synthesis of tetrahydrothieno[3,2-f]quinolines is described, using the imino Diels-Alder reaction between ethyl-5-aminobenzothiophene-2-carboxylate, aromatic aldehydes and cyclic enol ethers. Furthermore, hydroxyalkyl-substituted tetrahydrothieno[3,2-f]quinolines were synthesized in good yields, by performing the same imino Diels-Alder reaction in absence of aldehydes. The intramolecular aza-Diels-Alder reaction of 5-aminobenzothiophene with o-(allyloxy)benzaldehyde was also performed resulting in the fully oxidized thienoquinoline derivative.     

Mannich-Michael versus formal aza-Diels-Alder approaches to piperidine derivatives

A review into the aza-Diels-Alder reaction, mainly concentrating on literature examples that form piperidin-4-ones from the reaction of imines and electron rich dienes or enones, either through a Lewis acidic/Br?nsted acid approach or through the use of an organocatalyst. This review questions whether the mechanism of the aza-Diels-Alder reaction is step wise as opposed to concerted when using oxygenated dienes.     

Chiral phosphoric acid catalyzed inverse-electron-demand aza-Diels-Alder reaction of isoeugenol derivatives

Highly enantio- and diastereoselective three-component inverse electron-demand aza-Diels-Alder reaction of aldehydes, anilines, and isoeugenol derivatives catalyzed by a chiral phosphoric acid catalyst are reported. A wide variety of 2,3,4-trisubstituted tetrahydroquinolines containing an aryl group at the 4-position were obtained in a one-pot process with good to high yields and excellent stereoselectivities (>95:5 dr and up to >99% ee).     

A diastereoselective aza-Diels-Alder reaction of N-aryl-1-azadienes derived from α-amino acids with enamines

A diastereoselective inverse electron demand aza-Diels-Alder reaction of N-aryl-1-azadienes derived from α-amino acids is accomplished using enamine dienophiles. Activation with ytterbium triflate of these azadienes affords dimeric structures through aza-Diels-Alder reaction, where the alkene double bond of 1-azadienes also adopts the role of dienophile. An asymmetric synthesis of functionalised 1,4,5,6-tetrahydropyridine compounds derived from α-amino acids using an optically active enamine is reported.     

The Lewis acids catalyzed aza-Diels-Alder reaction of methylenecyclopropanes with imines

[reaction: see text] The methylenecyclopropanes can react with various imines to give the aza-Diels-Alder adducts in good yields in the presence of Lewis acids.     

Catalytic enantioselective approach to the stereodivergent synthesis of (+)-lasubines I and II

A concise and efficient approach to the stereodivergent synthesis of (+)-lasubines I and II is described. The key common intermediate is a chiral N-sulfonyl 2,3-dihydropyridone obtained by a novel Cu-catalyzed asymmetric formal aza-Diels-Alder reaction between N-tosyl aldimines and Danishefsky's diene.     

Acid-mediated three-component aza-Diels-Alder reactions of 2-aminophenols under controlled microwave heating for synthesis of highly functionalized tetrahydroquinolines. Part 9: Chemistry of aminophenols

The aza-Diels-Alder reactions of two 2-aminophenols in combination with six substituted benzaldehydes and two electron-rich cyclic alkenes were investigated under controlled microwave heating. The reactions were carried out in the presence of a catalytic amount of CF₃CO₂H in MeCN at 60 °C for 15 min, affording highly functionalized 8-hydroxy-1,2,3,4-tetrahydroquinolines in 39-59% isolated yields and in 36:64-16:84 diastereomer ratios in favor of the trans isomers. The microwave-heated three-component aza-Diels-Alder reactions completed in significantly reduced reaction time to give the same level of chemical yield and diastereomer ratio obtained from the room temperature reaction.     

Ketene dithioacetals in the aza-Diels-Alder reaction with N-arylimines: a versatile approach to tetrahydroquinolines, 2,3-dihydro-4-quinolones,and 4-quinolones

[reaction: see text] The first successful use of ketene dithioacetals as dienophiles in the aza-Diels-Alder reaction with N-arylimines is described. Among the ketene dithioacetals tested, 1,4-benzodithiafulvenes are most effective in assembling the tetrahydroquinoline core. Subsequent chemical manipulations provide a concise and divergent approach to the synthesis of 2,3-tetrahydroquinolines, 2,3-dihydro-4-quinolones, and 4-quinolones.     

Synthesis of substituted 8-aminoquinolines and phenanthrolines through a Povarov approach

The synthesis of 8-aminoquinolines and 1,10-phenanthrolines with substituents in α of the nitrogen has been performed through an inverse-demanding aza-Diels-Alder (Povarov reaction) in the fluoroalcohols TFE or HFIP. This path involves simple starting materials: 1,2-phenylenediamines, enol ethers and aldehydes.     

Aza-Diels-Alder reaction of α,β-unsaturated sulfinylimines derived from α-amino acids with enolethers and enamines

α,β-Unsaturated sulfinylimines derived from α-amino acids undergo aza-Diels-Alder reaction with electron rich dienophiles such as enolethers and enamines. Subsequent elimination of sulfinyl and amine or alkoxy moiety on the resulting cycloadducts affords pyridines derived from α-amino acids.     

Lithium heptadecafluorooctanesulfonate catalyzed Mannich-type and aza-Diels-Alder reactions in supercritical carbon dioxide

The Mannich-type reaction of imines with (1-methoxy-2-methylpropenyloxy)trimethylsilane and aza-Diels-Alder reaction of imines with Danishefsky's diene can be carried out in scCO₂ in the presence of lithium heptadecafluorooctanesulfonate which offer a way to synthesize β-amino carbonyl compounds and nitrogen-containing six-membered ring compounds under environmentally benign conditions.     

Useful dual Diels-Alder behavior of 2-azetidinone-tethered aryl imines as azadienophiles or azadienes: a beta-lactam-based stereocontrolled access to optically pure highly functionalized indolizidine systems

Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to be versatile Diels-Alder reagents in that they exhibit two reactivity patterns. 2-Azetidinone-tethered imines undergo diastereoselective reaction with Danishefsky's diene in the presence of different Lewis acids. The effect of the amount of catalyst on the conversion rate as well as on the product ratio has been studied. Under standard reaction conditions, indium(III) chloride and zinc(II) iodide provided the best yields, and indium(III) triflate the highest diastereoselectivity in the Lewis acid promoted aza-Diels-Alder cycloaddition. Treatment of the aforementioned imines with cyclopentadiene, 2,3-dimethyl-1,3-butadiene or 3,4-dihydro-2 H-pyran led to cycloadducts arising from inverse electron-demand condensation involving the beta-lactam-tethered aryl imine as the heterodiene component. In addition, the first methodology for preparing indolizidines from beta-lactams has been developed. This process involves amide bond cleavage of the beta-lactam ring in the aza-Diels-Alder cycloadducts with concomitant cyclization. Full chirality transfer occurs when the reaction is performed with an enantiomerically pure substrate.