Three-component aza-Diels Alder Reaction Research Articles

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.

A diastereoselective synthesis of tetrahydro- and dihydro-pyrido[2,3-c]coumarin derivatives via a one-pot three-component Povarov reaction catalyzed by bismuth(III) chloride

A diastereoselective synthesis of tetrahydro- and dihydro-pyrido[2,3-c]coumarin derivatives has been achieved via a one-pot three-component aza-Diels–Alder reaction of aromatic aldehydes, 3-aminocoumarin and dienophiles catalyzed by BiCl3. NOE studies proved that exo-isomers were obtained in all cases with high selectivity. The reaction proceeded at room temperature providing good yields of products as well as applicability on a wide range of substrates. Among all the synthesized derivatives, compounds 4i and 4k showed promising DPPH radical scavenging activity as compared to other tested derivatives.

ChemInform Abstract: Chiral Bimetallic Catalysts Derived from Chiral Metal Phosphates: Enantioselective Three‐Component Asymmetric Aza‐Diels—Alder Reactions of Cyclic Ketones.

A new type of chiral bimetallic catalyst is disclosed. These chiral bimetallic catalysts are easily formed through mixing a metal Lewis acid and a metal binaphthyl phosphate (MLA/M[P]3) in solution. 1H and 31P NMR spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, and X-ray crystallographic analysis reveal a bimetallic structure of the Y(Yb)III/Y[P]3 complexes with bridging binaphthyl phosphate ligands. The Lewis acidity of these chiral bimetallic catalysts is readily tuned by changing either the metal Lewis acid or the chiral metal phosphate. Through cooperative metal Lewis acid–enamine catalysis, asymmetric three-component aza-Diels–Alder reactions of 5-, 6-, and 7-membered cyclic ketones, unsaturated ketoesters, and arylamines were successfully achieved to afford fused bicyclic dihydropyridines in high yields (up to 94%) with high enantioselectivity (up to 99% enantiomeric excess) and excellent chem...

Heteropoly acid-catalyzed three-component aza-Diels–Alder reaction in a continuous micro-flow system

The first direct aza-Diels–Alder reaction catalyzed using phosphotungstic acid combined with a water absorption device in a micro-flow system was reported.

Three-component aza-Diels–Alder reactions using Yb(OTf)3 catalyst under conventional/ultrasonic techniques

The Yb(OTf)3 catalyzed formal aza-Diels–Alder (or Povarov) reaction of cyclopentadiene and 1,3-cyclohexadiene with in situ-generated N-arylimines under conventional/ultrasonic techniques is herein described. This kind of three-component Povarov reaction results in quinoline and phenanthridine derivatives, which are important biological compounds.

ChemInform Abstract: Microwave‐Assisted Efficient Synthesis of Spiroquinoline Derivatives via a Catalyst‐ and Solvent‐Free Aza‐Diels—Alder Reaction.

Abstract A microwave-assisted, one-pot three-component aza-Diels–Alder reaction strategy has been developed for the synthesis of some complex spiroquinoline derivatives from 1-aminonaphthalene, aromatic aldehyde, and 5-benzylidene-1,3-dimethyl pyrimidine-2,4,6-trione under catalyst- and solvent-free conditions.

Arylamine‐Catalyzed Enamine Formation: Cooperative Catalysis with Arylamines and Acids

The explosive growth of organocatalysis has had a huge impact on asymmetric catalysis in the past decade. Transition-metal catalysis, on the other hand, has been established for a long time as one of the most powerful methods in organic synthesis. Aminocatalysis is a major field in organocatalysis. The combination of organocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to achieve organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently. Although it promises huge potential, this research area has grown only slowly. The major challenge lies in the incompatibility of the catalysts, in particular, the combination of enamine catalysis with harder metal Lewis acid is very difficult. The circumvention of this problem would represent an important breakthrough, given the huge number of substrates that can be activated by the large variety of metal Lewis acids. Herein, we present the solution to this longstanding problem by using arylamines as the catalysts in enamine catalysis. Very importantly, we demonstrate that arylamines can serve as efficient amine catalysts in direct asymmetric aldol reactions. Furthermore, we have developed a highly chemoand enantioselective three-component azaDiels–Alder reaction by combining arylamines with metal Lewis acids. The combination of enamine catalysis with metal Lewis acid catalysis was first reported by Ibrahem and Codava in 2006. Since then, considerable progress has been made in this area, leading to a series of exciting discoveries. However, these combinations were limited to soft metals, such as Cu, Ag, Au, Ir, and Pd or Pd, activating either p-allyl electrophiles or alkynes (Scheme 1,A and B). Combining enamine catalysis with harder metal Lewis acid (Scheme 1, C) turned out to be very challenging because of acid–base self-quenching reactions, which render the catalysts inactive. In asymmetric aminocatalysis involving either an enamine or an iminium intermediate, a chiral aliphatic secondary or primary amine serves as the catalyst. Aliphatic amines are hard bases, and thus likely to be compatible with softer metals based on the soft/hard approach, but less likely to be compatible with harder metals. We hoped to find an amine catalyst that is compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine/ metal Lewis acid catalysis, and to facilitate the development of a new research area of iminium/metal Lewis acid catalysis. We considered to use arylamines, such as aniline, because they have a much lower pKa value (4–6) than aliphatic amines (9–11), and should be much softer because of the delocalization of the lone pair to the aromatic p system. It appeared to us that arylamines are ideal candidates for combination with harder metal Lewis acids. Despite their ubiquity in organic chemistry, arylamines have never been used in enamine catalysis. This may be mainly due to the general understanding that the nucleophilicity of arylamines is much lower compared to aliphatic amines. However, List and co-workers suggested the formation of enamine intermediates from arylamines as a step in organocatalytic cascade reactions. In a recent report, Gong and co-workers also suggested that an achiral arylamine played a crucial role in controlling the stereochemistry of a Friedl nder condensation by forming an enamine intermediate. We speculate that arylamines might be suitable to serve as an efficient amine catalyst in enamine catalysis in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid. The asymmetric aza-Diels–Alder reaction (ADAR) is the most convenient and powerful method to form nitrogencontaining heterocycles, which are one of the most important structural motifs in natural products, pharmaceuticals, and biosystems. While the recent progress on normal-electrondemand ADARs based on dienamines and imine dienophiles Scheme 1. Combination of enamine catalysis with metal catalysis.

Efficient synthesis of dihydropyrido[4,3-d]pyrimidines by microwave-promoted three-component aza-Diels–Alder reaction

A microwave-promoted solvent- and catalyst-free aza-Diels–Alder reaction is described. 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil reacts with aldehyde and amine inside a microwave reactor to produce dihydropyrido[4,3-d]pyrimidine derivatives in excellent yield and within a very short time.

Microwave-assisted efficient synthesis of spiroquinoline derivatives via a catalyst- and solvent-free aza-Diels–Alder reaction

A microwave-assisted, one-pot three-component aza-Diels–Alder reaction strategy has been developed for the synthesis of some complex spiroquinoline derivatives from 1-aminonaphthalene, aromatic aldehyde, and 5-benzylidene-1,3-dimethyl pyrimidine-2,4,6-trione under catalyst- and solvent-free conditions.

L-Proline catalyzed efficient one-pot three-component aza-Diels–Alder reactions on nitrostyrylisoxazoles: a facile synthesis of new isoxazolyl tetrahydroquinolines and isoxazolo[2,3-a]pyrimidines

l-Proline acts as an efficient organocatalyst and found to promote one-pot three-component aza-Diels–Alder reaction of aryl or isoxazole imines formed in situ from aromatic or isoxazoleamines and aromatic aldehydes with nitrostyrylisoxazoles to afford the isoxazolyl tetrahydroquinolines or isoxazolo[2,3-a]pyrimidines, respectively, in excellent yields at ambient temperature under neutral conditions.

Enzyme-Catalyzed Direct Three-Component Aza-Diels–Alder Reaction Using Hen Egg White Lysozyme

The direct three-component aza-Diels-Alder reaction of aromatic aldehyde, aromatic amine, and 2-cyclohexen-1-one was catalyzed by hen egg white lysozyme for the first time. Under the optimized conditions investigated in this paper, the enzyme-catalyzed aza-Diels-Alder reaction gave yields up to 98% and stereoselectivity of endo/exo ratios up to 90:10.

One-pot synthesis of pyrrolidino- and piperidinoquinolinones by three-component aza-Diels–Alder reactions of in situ generated N-arylimines and cyclic enamides

An efficient synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and hexahydropyridino[3,2-c]quinolin-2-ones has been developed in moderate to high yields by one-pot two-step aza-Diels–Alder reactions of N-arylimines, formed in situ from anilines and benzaldehydes, with cyclic enamides, formed in situ from 5-hydroxypyrrolidin-2-ones and 6-hydroxypiperidin-2-ones by BF3·OEt2-promoted dehydration in dichloromethane at room temperature. The hexahydropyrrolo[3,2-c]quinolin-2-ones were formed as a single exo-stereoisomer in most cases and hexahydropyridino[3,2-c]quinolin-2-ones were formed as a mixture of exo- and endo-isomers favoring the endo-diastereomer.

Ionic Liquid Phase Synthesis of Tetrahydropyrano- and Tetrahydrofuranoquinolines under Microwave Irradiation

In this paper, a microwave assisted one-pot three-component aza-Diels–Alder reaction to synthesis 1-[2-(4-benzoyloxy)ethyl]-3-methylimidazolium tetrafluoroborate-bound tetrahydro- quinolines was developed by using 1-[2-(4-benzoyloxy)ethyl]-3- methylimidazolium tetrafluoro- borate bound aldehyde as soluble support. After cleavage, the target compounds were obtained in good yields and purity, and the ionic liquid might be recovered and used in next cycle. Under the microwave irradiation, the two steps of cyclocondensation and cleavage completed in only about 15 min.

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 CF 3CO 2H 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.

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-2 H-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.

Montmorillonite KSF‐Catalyzed One‐Pot, Three‐Component, Aza‐Diels—Alder Reactions of Methylenecyclopropanes with Arenecarbaldehydes and Arylamines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Liquid-phase synthesis of 2,3-dihydro-4-pyridones: one-pot three-component aza Diels–Alder reaction of Danishefsky's diene with aldehydes and PEG-supported amine

An efficient liquid-phase synthesis technique for the construction of 2,3-dihydro-4-pyridones on soluble polymer support has been developed, which utilized one-pot reaction of Danishefsky's diene with aldehydes and polymer-supported amine.

Brønsted acid-catalyzed aza Diels-Alder reaction of Danishefsky's diene with aldimine generated in situ from aldehyde and amine in aqueous media

Three-component aza Diels-Alder reaction, starting from aldehyde, aniline, and Danishefsky's diene, took place smoothly under the influence of HBF 4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields.