Acid Catalyzed Cascade Reaction Research Articles

A Novel C3/C4-Fused Indole Scaffold through Acid-Catalyzed Cascade Reaction.

3,4-bridged indoles are underrepresented among the vast number of indoles described in the literature. Attempts to access 3,4-macrocyclized indoles led to the unexpected formation of a novel tetracyclic indole through intramolecular acid-catalyzed ring contraction. The herein-established one-step synthetic route provides an excellent medicinal chemistry platform for the construction of screening libraries covering a unique chemical space of indoles.

Brønsted Acid-Catalyzed Synthesis of 4-Functionalized Tetrahydrocarbazol-1-ones from 1,4-Dicarbonylindole Derivatives.

A p-toluenesulfonic acid-catalyzed cascade reaction is reported for the synthesis of 4-functionalized tetrahydrocarbazolones via the reaction of 4-(indol-2-yl)-4-oxobutanal derivatives with a variety of nucleophiles in acetonitrile or hexafluoroisopropanol. After the initial intramolecular Friedel-Crafts hydroxyalkylation, the 3-indolylmethanol intermediate is subsequently activated and reacted with the external nucleophile. The reaction conditions are crucial to avoid alternative reaction pathways, allowing direct substitution reaction with thiols, (hetero)arenes, alkenes, or sulfinates. The procedure features high overall yields to access a diverse family of compounds bearing the tetrahydrocarbazole core.

Solid acid-catalyzed one-pot multi-step cascade reaction: Multicomponent synthesis of indol-3-yl acetates and indol-3-yl acetamides in water

A solid acid-catalyzed cascade reaction of condensation/intermolecular nucleophilic addition/intramolecular cyclization, esterification and amination has been developed to rapidly construct complex polysubstituted indole compounds. This one-pot, three-step five-component cascade reaction affords a series of 2-(4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl) acetamide derivatives with good yield under mild conditions. The present procedure exhibited some attractive features, including inexpensive and easy available reagents, large substrate scope, separable intermediate products, recyclable solid acid catalyst, and more importantly, it can be conveniently performed by simple one-pot three-step procedure, involving the sequential mixture of 3-(arylamino)cyclohex-2-en-1-ones, 2,2-dihydroxy-1-arylethan-1-ones, meldrum acid, and alcohols, anilines in the of solid acid at 80 °C. Significantly, this strategy not only expands the application range of solid acid, but also provides a series of 2-(4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)acetate/acetamide derivatives.

Electronic effect control of regioselectivity in the Michael-Addition inspired cascade reaction of 1,3-dimethyl-6-amino-uracil and 2-hydroxychalcones

An unexpected Brosnted acid-catalyzed cascade reaction of 1,3-dimethyl-6-aminouracil with 2-hydroxychalcone has been developed to afford pyrido[2,3–d]pyrimidine-2,4-diones derivatives and 2,8-dioxabicyclo[3.3.1]nonane derivatives in moderate to good yields. This method not only establishes a new transformation of 1,3-dimethyl-6-amino-uracil and 2-hydroxychalcone but also provides an efficient method for the synthesis of pyrido[2,3–d]pyrimidine-2,4-diones and 2,8-dioxabicyclo[3.3.1]nonane derivatives.

Acid-Catalyzed Cascade Reaction of 2-Alkylfurans with α,β-Unsaturated Ketones: A Shortcut to 2,3,5-Trisubstituted Furans.

The convergent one-pot method toward trisubstituted furans has been developed. The key transformation behind the synthetic protocol comprises the cascade acid-catalyzed conjugated addition of furans to commercially available or easily accessible α,β-unsaturated ketones followed by the rearrangement of the intermediate Michael adducts into isomeric furans. The prospect of utilizing the target products as building blocks for the preparation of potential functional molecules for organic electronics has been demonstrated.

Direct synthesis of quinazolinones via the carbon-supported acid-catalyzed cascade reaction of isatoic anhydrides with amides and aldehydes

A novel catalytic system is reported for the construction of quinazolinones via the carbon-supported acid-catalyzed cascade coupling of isatoic anhydrides with amides and aldehydes. Subsequent selective hydrosilylation of the quinazolinones using a hydrogen-transfer strategy was also explored to provide dihydroquinazolines with structural diversity. The developed methodology proceeds with a broad substrate scope, excellent functional group tolerance, and utilizes a reusable catalyst and air as a green oxidant.

Cut and sew: benzofuran-ring-opening enabled cyclopentenone ring formation.

A facile approach to the fully substituted cyclopentenones involving an unprecedented benzofuran-ring-opening is described. The cleavage of a benzofuran endocyclic C2-O bond proceeded smoothly in the absence of any transition metal catalyst or highly reactive organometallic reagent. Such benzofuran-ring-opening is delicately incorporated into an acid-catalyzed cascade process, orchestrating a novel synthetic strategy for complex cyclopentenones with excellent yields and diastereoselectivities.

Trifluoroacetic Acid Catalyzed Cascade Reactions of 2,3‐Diketoesters with Cyclohexane‐1,3‐diones: Strategy Towards 4‐Hydroxybenzofuran Derivatives

AbstractAn efficient trifluoroacetic acid catalyzed cascade reaction of 2,3‐diketoesters with cyclohexane‐1,3‐diones is described for the synthesis of a series of 4‐hydroxybenzofurans. This simple protocol has the advantages of easy operation, readily available starting materials, good functional group tolerance, and easily scale‐up. Subsequent derivatization of the 4‐hydroxybenzofurans provides a reasonable route to access highly functionalized benzofurans.magnified image

Diversity-oriented one-pot synthesis of furan based densely substituted biheteroaryls via isocyanide insertion

A facile and efficient acid-catalyzed cascade reaction for the synthesis of novel biheteroaryl structural motifs containing densely functionalized furans has been developed. The reaction sequence involves a Knoevenagel condensation of arylglyoxals with aroyl or heteroaroylacetonitrile and subsequently an isocyanide insertion via formal [4+1] cycloaddition followed by rapid [1,3]-H shift to afford uniquely decorated novel biheterocycles. Furthermore, the scope of the methodology was extended to diverse biheteroaryls by employing 3-(2-furyl)-3-oxopropanenitrile, 3-cyanoacetyl-1-methylindole, 3-oxo-3-(1H-pyrrol-2-yl)propanenitrile, 3-(1H-indol-3-yl)-3-oxopropanenitrile, 3-Oxo-3-(2-thienyl)propionitrile and benzoylacetonitriles.

Revised Theoretical Model on Enantiocontrol in Phosphoric Acid Catalyzed H-Transfer Hydrogenation of Quinoline

The enantioselective H-transfer hydrogenation of quinoline by Hantzsch ester is a relevant example of Brønsted acid catalyzed cascade reactions, with phosphoric acid being a privileged catalyst. The generally accepted mechanism points out the hydride transfer step as the rate- and stereodetermining step, however computations based on these models do not totally fit with experimental observations. We hereby present a computational study that enlightens the stereochemical outcome and quantitatively reproduces the experimental enantiomeric excesses in a series of H-transfer hydrogenations. Our calculations suggest that the high stereocontrol usually attained with BINOL-derived phosphoric acids results mostly from the steric constraints generated by an aryl substituent of the catalyst, which hinders the access of the Hantzsch ester to the catalytic site and enforces approach through a specific way. It relies on a new model involving the preferential assembly of one of the stereomeric complexes formed by the chiral phosphoric acid and the two reaction partners. The stereodetermining step thus occurs prior to the H-transfer step.

Cascade Synthesis of 2‐Cyanoacrylamides through Deacetalization and/or Knoevenagel Condensation followed by Selective Monohydration of Acetals and Aldehydes over Solid Acid Ferrites

AbstractA new protocol of cascade synthesis for biologically active 2‐cyanoacrylamides (1) was developed. The reaction proceeds over a novel magnetically retrievable solid‐acid composite of iron oxide, poly(vinylpyrrolidone) and phosphotungstic acid (Fe3O4/PVP–PWA) in AcOH–H2O medium under reflux conditions. This transformation is facilitated through single‐site Brønsted acid catalyzed cascade reactions involving deacetalization and/or Knoevenagel condensation followed by selective monohydration of nitriles starting from acetals (5) and aldehydes (2) with malononitrile (3). A series of aldehydes, dimethyl and diethyl acetals, along with some heterocyclic aldehydes were successfully transformed to 2‐cyanoacrylamides with >95 % yields. TEM images confirmed the coating of the PVP over nanosized Fe3O4. Stereoselective monohydration of 2‐benzylidenemalononitriles (4) to E isomers was demonstrated by NOESY experiments. The catalyst could be efficiently recycled seven times on employment of both acetals and aldehydes as substrates, as a result of its magnetic nature.

ChemInform Abstract: Synthesis of Functionalized Tryptamines by Broensted Acid Catalyzed Cascade Reactions.

AbstractSolvent‐free PTSA‐catalyzed reaction between 2‐hydroxycyclobutanone and N‐alkylanilines gives tryptamine derivatives in low to good yields.

ChemInform Abstract: Asymmetric Catalytic Cascade Reactions for Constructing Diverse Scaffolds and Complex Molecules

AbstractReview: 53 refs.

Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules.

With the increasing concerns about chemical pollution and sustainability of resources, among the significant challenges facing synthetic chemists are the development and application of elegant and efficient methods that enable the concise synthesis of natural products, drugs, and related compounds in a step-, atom- and redox-economic manner. One of the most effective ways to reach this goal is to implement reaction cascades that allow multiple bond-forming events to occur in a single vessel. This Account documents our progress on the rational design and strategic application of asymmetric catalytic cascade reactions in constructing diverse scaffolds and synthesizing complex chiral molecules. Our research is aimed at developing robust cascade reactions for the systematic synthesis of a range of interesting molecules that contain structural motifs prevalent in natural products, pharmaceuticals, and biological probes. The strategies employed to achieve this goal can be classified into three categories: bifunctional base/Brønsted acid catalysis, covalent aminocatalysis/N-heterocyclic carbene catalysis, and asymmetric organocatalytic relay cascades. By the use of rationally designed substrates with properly reactive sites, chiral oxindole, chroman, tetrahydroquinoline, tetrahydrothiophene, and cyclohexane scaffolds were successfully assembled under bifunctional base/Brønsted acid catalysis from simple and readily available substances such as imines and nitroolefins. We found that some of these reactions are highly efficient since catalyst loadings as low as 1 mol % can promote the multistep sequences affording complex architectures with high stereoselectivities and yields. Furthermore, one of the bifunctional base/Brønsted acid-catalyzed cascade reactions for the synthesis of chiral cyclohexanes has been used as a key step in the construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of α-lycorane. Guided by the principles of covalent aminocatalysis and N-heterocyclic carbene catalysis, we synthesized chiral piperidine, indole, and cyclobutane derivatives. The synthesis of chiral cyclobutanes and pyrroloindolones showed unprecedented reactivity of substrates and catalysts. The development of the strategy of asymmetric organocatalytic relay cascades has provided a useful tool for the controlled synthesis of specific diastereomers in complex molecules. This Account gives a panoramic view and the logic of our research on the design, development, and applications of asymmetric catalytic cascade reactions that will potentially provide useful insights into exploring new reactions.

ChemInform Abstract: Lewis Acid Catalyzed Cascade Reaction to Carbazoles and Naphthalenes via Dehydrative [3 + 3]‐Annulation.

AbstractThis novel reaction proceeds through a cascade process involving the cleavage and formation of multiple chemical bonds in a single operation releasing water as the only by‐product with readily available electron‐rich benzylic alcohols and propargylic alcohols as starting materials.

ChemInform Abstract: Broensted Acid Catalyzed Cascade Reactions of 2‐[(2‐Aminophenyl)ethynyl]phenylamine Derivatives with Aldehydes: A New Approach to the Synthesis of 2,2′‐Disubstituted 1H,1′H‐3,3′‐Biindoles.

ChemInform Abstract: Broensted Acid Catalyzed Cascade Reactions of 2‐[(2‐Aminophenyl)ethynyl]phenylamine Derivatives with Aldehydes: A New Approach to the Synthesis of 2,2′‐Disubstituted 1H,1′H‐3,3′‐Biindoles.

ChemInform Abstract: Recent Advances on the Lewis Acid‐Catalyzed Cascade Rearrangements of Propargylic Alcohols and Their Derivatives

AbstractReview: 71 refs.

Lewis acid catalyzed cascade reaction to carbazoles and naphthalenes via dehydrative [3 + 3]-annulation.

A novel Lewis acid catalyzed dehydrative [3 + 3]-annulation of readily available benzylic alcohols and propargylic alcohols was developed to give polysubstituted carbazoles and naphthalenes in moderate to good yields with water as the only byproduct. The reaction was presumed to proceed via a cascade process involving Friedel-Crafts-type allenylation, 1,5-hydride shift, 6π-eletrocyclization, and Wagner-Meerwein rearrangement.

Recent Advances on the Lewis Acid-Catalyzed Cascade Rearrangements of Propargylic Alcohols and Their Derivatives

Propargylic alcohols and their derivatives are important classes of organic compounds that can be easily accessible from terminal alkynes and aldehydes or ketones. They are attractive and have been extensively applied as synthetic intermediates in modern organic synthesis. Recent investigations on the chemistry of propargylic alcohols and their derivatives disclosed a variety of highly efficient Lewis acid-catalyzed cascade reactions based on Meyer–Schuster rearrangement of propargylic alcohols and [3,3] rearrangement of propargylic esters and propargyl vinyl ethers. A tremendous number of structurally versatile enones, carbocycles, and heterocycles have been constructed through these methodologies. These advances, including our recent researches in this field, are summarized in this review.

Brønsted Acid Catalyzed Cascade Reactions of 2-[(2-Aminophenyl)ethynyl]phenylamine Derivatives with Aldehydes: A New Approach to the Synthesis of 2,2′-Disubstituted 1H,1′H-3,3′-Biindoles

An unusual Brønsted acid catalyzed cascade reaction of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aryl(heteroaryl)aldehydes to afford an efficient alternative entry into 2,2'-disubstituted-1H,1'H-3,3'-biindoles under metal-free conditions is reported.