Three-component Povarov Reaction Research Articles

Conjugate‐Base‐Stabilized Brønsted Acids as Asymmetric Catalysts: Enantioselective Povarov Reactions with Secondary Aromatic Amines

Caught in the act: A new concept for asymmetric Brønsted acid catalysis is presented. Compounds containing an acidic functionality in addition to an anion recognition site act as powerful conjugate-base-stabilized Brønsted acid catalysts. This strategy was applied to the first catalytic enantioselective three-component Povarov reaction of indoline and other secondary aromatic amines (see scheme; M.S.=molecular sieves).

Microwave-assisted expeditious and efficient synthesis of cyclopentene ring-fused tetrahydroquinoline derivatives using three-component Povarov reaction

We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction time (10–15min) with high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The optimization process is reported and the results from the microwave route are compared with those of the conventional synthetic route. In almost all cases, the microwave acceleration consistently provided improved yields favoring the cis-diastereomer.

Highly enantioselective three-component Povarov reaction catalyzed by SPINOL-phosphoric acids

Chiral SPINOL-phosphoric acids exhibited high activities and excellent diastereo- and enantioselectivities in the catalysis of the three-component Povarov reaction of benzyl N-vinylcarbamate, anilines and aldehydes with a catalyst loading of 5 mol%. The synthetic utility of this protocol was demonstrated by the asymmetric synthesis of enantioenriched benzo[e]indolizidine with excellent yield and excellent level of sterecontrol.

Organocatalysis in the three-component Povarov reaction and investigation by mass spectrometry

A diastereoselective three-component cascade reaction, catalyzed by p-sulfonic acid calix[4]arene, provides a unique method to access diverse julolidine derivatives in high yields. Additionally, the reaction was also monitored by mass spectrometry and the mechanistic pathway uncovered.

An Asymmetric Organocatalytic Povarov Reaction with 2-Hydroxystyrenes

An organocatalytic asymmetric three-component Povarov reaction involving 2-hydroxystyrenes has been established to provide an efficient method to access structurally diverse cis-disubstituted tetrahydroquinolines in high stereoselectivities of up to >99:1 dr and 97% ee. This protocol also provides an easy access to tetrahydroquinolines with chiral quaternary stereocenters upon using α-alkyl 2-hydroxystyrenes as substrates. The theoretical studies revealed that the Povarov reaction proceeded through a sequential vinylogous Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as bifunctional catalyst to activate 2-hydroxystyrene and aldimine simultaneously.

Phosphoric Acid Catalyzed Three-Component Povarov Reaction

Key words Brønsted acids - enethioureas - multicomponent reaction - Povarov reaction

ChemInform Abstract: Chiral Phosphoric Acid‐Catalyzed Enantioselective Three‐Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo‐ and Enantioselective Synthesis of Substituted 4‐Aminotetrahydroquinolines.

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF3, NO2) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction i...

Efficient synthesis and free-radical scavenging capacity of new 2,4-substituted tetrahydroquinolines prepared via BiCl3-catalyzed three-component Povarov reaction, using N-vinylamides

Efficient synthesis of new structurally different 2-(het)aryl-4-amidyl-substituted tetrahydroquinolines 8-29 is reported. The synthesis based on BiCl(3)-catalyzed three-component Povarov reaction between anilines, (het)aryl aldehydes and enamides offers a fast, safe, and cheap way for efficient tetrahydroquinoline libraries construction. Using N-vinylamides (N-vinylpyrrolidin-2-one and N-vinylacetamide) in this reaction, it was possible to obtain two series of different cis tetrahydroquinolines with antioxidant properties. Among 14 tested compounds, 7 tetrahydroquinolines revealed a prominent anti-radical capacity, equal or higher than that of the commercial antioxidants. Being the most active molecule, the N-[2-(α-furanyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-4-yl] acetamide 21 was ca. 2.2-fold more potent than the well-known antioxidant, vitamin E (α-tocopherol).

Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo- and Enantioselective Synthesis of Substituted 4-Aminotetrahydroquinolines

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF(3), NO(2)) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst-substrate interaction as well as a linear correlation between catalyst and product ee's were also documented.

Ferric sulfate [Fe 2(SO 4) 3· xH 2O]: an efficient heterogeneous catalyst for the synthesis of tetrahydroquinoline derivatives using Povarov reaction

Fe 2(SO 4) 3· xH 2O can be used as an efficient and reusable catalyst for the synthesis of pyrano- and furanotetrahydroquinolines via one-pot three-component Povarov reaction involving aromatic aldehydes, aromatic amines, and cyclic enol ethers. The catalyst is recyclable, economically viable, and environmentally benign. This protocol provides good yields and diastereoselectivity as well as applicability on a wide range of substrates.

Transformations of 2‐aryl‐4‐(2‐oxopyrrolidinyl‐1)‐1,2,3,4‐tetrahydroquinolines, cycloadducts of the BiCl3‐catalyzed three‐component Povarov reaction: Oxidation and reduction processes towards new potentially bioactive 2‐arylquinoline derivatives

Abstract magnified image Synthesis and spectral characterization of new series of 2‐aryl‐4‐(2‐oxopyrrolidinyl‐1)‐1,2,3,4‐tetrahydroquinolines and their aromatic analogs, 2‐arylquinolines are reported. It was found that substituted tetrahydroquinoline precursors are easily prepared using BiCl3‐catalyzed three‐component Povarov reaction between 4‐nitrobenzaldehyde or 2‐naphtylcarboxyaldehyde, anilines and N‐vinylpyrrolidin‐2‐one, and could be transformed via oxidation and reduction processes into potentially bioactive 2‐arylquinoline derivatives, unsubstituted at the C‐4 position. The all set of (tetrahydro)quinolines were characterized by IR, 1H and 13C‐NMR spectroscopy. J. Heterocyclic Chem., (2010).

Lewis Acid Catalyzed Three-Component Hetero-Diels−Alder (Povarov) Reaction of N-Arylimines with Strained Norbornene-Derived Dienophiles

Generally, the hetero-Diels-Alder reaction (Povarov reaction) of N-arylimine dienes are limited to reaction with activated, electron-rich alkenes. However, introduction of ring strain in the dienophile, as with moderately strained bicyclo[2.2.1]heptenes (norbornene), enables three-component Povarov reaction with in situ formed N-arylimines under Lewis acid catalyzed conditions (BF(3).OEt(2)). The reactions proceed efficiently with a diverse set of commercially available anilines and benzaldehydes, as well as a variety of substituted norbornenes. The corresponding tetrahydroquinolines are formed with high complexity in a multicomponent fashion and are obtained in good yield and high diastereoselectivity. In addition, more reactive ethyl glyoxylate derived imines were utilized to achieve faster, room temperature reactions with norbornene. In all cases, attack of the N-arylimine dienes occurred exclusively from the exo-face of the norbornene ring, but the relative stereochemistry of the substituent alpha to the tetrahydroquinoline nitrogen, as well as the regioselectivity of reaction, was shown to depend upon subtle substituent effects on the aniline precursors. In most cases, a preference for the formation of exo-exo diastereomeric adducts was observed, but for reactions of ortho- or meta-substituted anilines, the formation of exo-endo adducts was also observed. These observations may be rationalized by two competing mechanistic models, involving either a concerted asynchronous [4 + 2]-like mechanism or a stepwise mechanism.

A new process of multicomponent Povarov reaction–aerobic dehydrogenation: synthesis of polysubstituted quinolines

A new domino process of three-component Povarov reaction and aerobic dehydrogenation was developed toward the synthesis of polysubstituted quinolines. 2,4-Disubstituted-8-nitroquinolines, which are important precursors for the synthesis of antimalarial primaquine drug-like molecules, were prepared conveniently by this method in moderate to good yields. Brönsted acid (HClO 4)-modified montmorillonite was found to be a crucial catalyst in promoting the procedure.

Brønsted Acid Catalyzed Enantioselective Three-Component Povarov Reaction

An enantioselective three-component Povarov reaction of aldehydes, anilines, and an enecarbamate is reported. In the presence of chiral phosphoric acid catalyst 1, cis-2,4-disubstituted tetrahydroquinolines 4 are obtained in good yields with excellent enantioselectivity. Both aromatic and aliphatic aldehydes as well as anilines with different electronic properties are suitable substrates.

Solvent-Free Microwave-Assisted Synthesis of New 2-Aryl-Tetrahydroquinolines Using Three-Component Povarov Reaction

A new series of 2-aryl-1,2,3,4-tetrahydroquinolines has been synthesized in good yields through a BiCl3- catalyzed three-component Povarov reaction (imino Diels-Alder cycloaddition) between anilines, benzaldehydes and Nvinylpyrrolidin- 2-one in MeCN. The same series has been prepared without solvent using microwave radiation, which resulted in better yields, a considerable decrease in reaction times and simplified workup. Keywords: 2-Aryl-1,2,3,4-tetrahydroquinolines, microwave-heated three-component Povarov (imino Diels-Alder) reaction, dry media

Chiral Brønsted Acid-Catalyzed Enantioselective Three-Component Povarov Reaction

The three-component Povarov reaction of aldehydes (2), anilines (3), and benzyl N-vinylcarbamate 4 in the presence of 0.1 equiv of chiral phosphoric acid 5 afforded cis-2,4-disubstituted tetrahydroquinolines (1) in good yields and excellent enantiomeric excesses. The shortest synthesis of torcetrapib reported to date, which features this key three-component reaction, is documented.

Lanthanide(III)-catalyzed multi-component aza-Diels–Alder reaction of aliphatic N-arylaldimines with cyclopentadiene

Abstract The Ln(OTf) 3 -catalyzed formal aza-Diels–Alder (or Povarov) reaction of cyclopentadiene with in situ generated N -arylimines containing enolizable protons is described. This three-component Povarov reaction generates highly functionalized C-2 aliphatic substituted tetrahydroquinolines, heterocycles that were previously inaccessible using the Povarov reaction, because of the instability of the intermediate aliphatic N -arylaldimine.