Asymmetric Synthesis of Polyfunctionalized Pyrrolidines via a Thiourea Catalyzed Domino Mannich/Aza‐Michael Reaction

The domino Mannich/aza‐Michael reaction of γ‐malonate‐substituted α,β‐unsaturated esters with N‐protected arylaldimines has been achieved. Catalyzed by bifunctional thioureas, 2,5‐cis‐configured polysubstituted pyrrolidines are obtained in good to excellent yields (76–99%), enantioselectivities (75–94%) and excellent diastereoselectivities (de >95%). The pure stereoisomers are available by crystallization and removal of the racemates.     

Niobium‐Catalyzed Highly Enantioselective Aza‐Diels–Alder Reactions

Niobium‐based chiral Lewis acid was found to be highly effective catalyst for aza‐Diels–Alder reactions of imines with Danishefsky‘s dienes. The reactions proceed in high yield with high enantioselectivity for both aromatic and aliphatic imines. The developed methodology was applied to total synthesis of (+)‐anabasine.     

Chiral Phosphoric Acid‐Catalyzed Asymmetric Aza‐Friedel–Crafts Reaction of Indoles with Cyclic N‐Acylketimines: Enantioselective Synthesis of Trifluoromethyldihydroquinazolines

An enantioselective aza‐Friedel–Crafts (F‐C) reaction of indoles with cyclic N‐acylketimines has been developed. By using chiral phosphoric acid catalysts, a wide range of enantioenriched trifluoromethyldihydroquinazolines was obtained in excellent yields (up to 98%) with good to high enantioselectivities (up to 99% ee).

     

Highly Enantioselective Zinc‐Catalyzed Friedel–Crafts Alkylation of Indoles with Ethyl Trifluoropyruvate

A highly enantioselective Friedel–Crafts alkylation of indoles with ethyl trifluoropyruvate has been developed using N,N′‐dioxide‐zinc(II) complexes. Both enantiomers of the desired adducts were obtained by the use of enantiomeric ligands in excellent results (up to 99% yield and 98% ee) within 0.5 h under mild conditions. On the basis of the experimental results, a proposed working model was proposed to explain the origin of the asymmetric induction.     

Metal Triflate‐Catalyzed Regio‐ and Stereoselective Friedel–Crafts Alkenylation of Arenes with Alkynes in an Ionic Liquid: Scope and Mechanism

In the metal triflate‐catalyzed hydroarylation of alkynes, employing an ionic liquid dramatically enhanced the catalytic activities, resulting in broadening the scope of substrates (arenes and alkynes). In some cases, even reactions that were not possible in conventional organic solvents proceeded smoothly in ionic liquids. Moreover, the ionic liquid phase containing catalyst could be readily recovered by simple decantation of the organic layer after reaction and reused for the following runs without any significant loss of activity. Mechanistic studies including ¹³C NMR analysis of reaction intermediates and isotope experiments confirmed for the first time that this type of reaction proceeds via vinyl cationic intermediates.     

Chiral Imidodiphosphoric Acids‐Catalyzed Friedel–Crafts Reactions of Indoles/Pyrroles with 3‐Hydroxy‐indolyloxindoles: Enantioselective Synthesis of 3,3‐Diaryloxindoles

The first enantioselective Friedel–Crafts alkylation of indoles and pyrroles with 3‐hydroxy‐3‐indolyloxindoles to access two novel types of 3,3‐diaryloxindoles catalyzed by chiral imidodiphosphoric acids has been reported. A range of quaternary carbon centered 3,3‐diaryloxindoles were synthesized in high yield (up to >99%) with excellent enantioselectivity (up to 98% ee) at low catalyst loadings (as low as 0.5 mol%). The Friedel–Crafts reaction between indoles and 3‐hydroxy‐3‐indolyloxindoles is amenable to gram scale syntheses.

     

Efficient Synthesis of 9‐Tosylaminofluorene Derivatives by Boron Trifluoride Etherate‐Catalyzed Aza‐Friedel–Crafts Reaction of in situ Generated N‐Tosylbenzaldimines

An efficient and expeditious boron trifluoride etherate (BF₃⋅Et₂O) catalyzed one‐pot reaction for the synthesis of N‐tosyl‐9‐aminofluorenes and anthracene derivatives from in situ generated N‐tosylbenzaldimines via an aza‐Friedal–Crafts reaction has been developed. The catalytic reaction shows high substrate tolerance with excellent yields.     

Chiral Phosphoric Acid‐Catalyzed Enantioselective Aza‐Friedel–Crafts Alkylation of Indoles with γ‐Hydroxy‐γ‐lactams

An enantioselective aza‐Friedel–Crafts reaction of indoles with γ‐hydroxy‐γ‐lactams using a chiral phosphoric acid catalyst is reported. The approach described herein provides an efficient access to 5‐indolylpyrrolidinones in good to quantitative yields and excellent enantioselectivities (up to >99% ee). The results suggest that the reaction may proceed via N‐acyliminium intermediates associated with the chiral phosphoric acid anion.     

Chiral Phosphoric Acid‐Catalyzed Enantioselective Three‐ Component Aza‐Diels–Alder Reactions of Aminopyrroles and Aminopyrazoles

A highly stereoselective three‐component Povarov reaction, catalyzed by (R)‐ and (S)‐BINOL hydrogen phosphate, was achieved for the first time with aminopyrroles and aminopyrazoles as 2‐azadiene precursors. A variety of aldehydes, enecarbamates, amino‐substituted azines participated in the reaction to afford the tetrahydropyrrolopyridines and tetrahydropyrazolopyridines in good yields with excellent diatereo‐ and enantioselectivities. A stereochemical model is proposed to account for the observed absolute stereochemistry.

     

Synthesis of carvacrol by Friedel–Crafts alkylation of o‐cresol with isopropanol using superacidic catalyst UDCaT‐5

BACKGROUND: Alkylation of o‐cresol with propylene or isopropyl alcohol (IPA) over solid acid catalysts results in the formation of carvacrol, which finds potential applications in the synthesis of fine chemicals, intermediates, specialty chemicals, flavours and fragrances. RESULTS: The present work covers evaluation of novel mesoporous superacidic catalysts namely UDCaT‐4, UDCaT‐5 and UDCaT‐6 in the greener synthesis of carvacrol. The catalysts are modified versions of zirconia showing high catalytic activity, stability and reusability. The catalytic activity increases in the following order: UDCaT‐5 > UDCaT‐4 > UDCaT‐6 > sulfated zirconia. The process was optimized and a mathematical model developed to describe the reaction pathway in liquid phase. Carvacrol could be efficiently obtained with a selectivity up to 82% at an isopropanol conversion of 98% after 2 h over UDCaT‐5 at 180 °C. CONCLUSION: The reaction is free from any external mass transfer as well as intraparticle diffusion limitations and is intrinsically kinetically controlled. An overall second‐order kinetic equation was used to fit the experimental data. The activation energy was found to be 19.2 kcal/mol. The reaction was carried out without any solvent in order to make the process cleaner and greener. Copyright © 2009 Society of Chemical Industry     

Palladium‐Catalyzed Intramolecular ipso‐Friedel–Crafts Allylic Alkylation of Phenols via Arylative Activation of Allenes

A novel and efficient synthetic method for functionalized spiro[4.5]cyclohexadienones was developed based on the palladium‐catalyzed sequential process: Heck insertion to an allene–intramolecular ipso‐Friedel–Crafts allylic alkylation cascade. Using 5 mol% of palladium catalyst, a wide variety of spirocycles was obtained in good to excellent yields. The developed cascade process was also applicable to the synthesis of tetrahydronaphthalene derivatives.

     

Chemoselective Cascade Synthesis of N‐Fused Heterocycles via Silver(I) Triflate‐Catalyzed Friedel–Crafts/N‐C Bond Formation Sequence

An efficient cascade methodology toward chemoselective synthesis of N‐fused heterocycles including 9H‐pyrrolo[1,2‐a]indole, 3H‐pyrrolo[1,2‐a]indole and 1H‐pyrrolo[1,2‐a]indole derivatives has been developed. This transformation proceeds via a silver(I) triflate‐catalyzed consecutive Friedel–Crafts reaction/N C bond formation sequence between readily available propargyl alcohols and 3‐substituted 1H‐indoles. Not only is excellent chemoselectivity observed according to the substitution patterns of propargyl alcohols, but also the Lewis acid‐catalyzed N C bond formation process can be carried out under base‐ and ligand‐free conditions.     

Chiral N,N′‐Dioxide‐Zinc(II) Complex‐Catalyzed Asymmetric Aza‐Friedel–Crafts Reaction of Isatin‐Derived Ketimines with Indoles

A highly efficient chiral N,N′‐dioxide‐zinc(II) complex catalytic system has been developed for the enantioselective aza‐Friedel–Crafts reaction of isatin‐derived ketimines with indoles. A series of enantiomerically enriched 3‐indolyl‐3‐aminooxindoles containing a tetrasubstituted stereocenter were obtained in up to 99% yield with up to 96% ee. Furthermore, control experiments provide a fundamental sight into the mechanism of the reaction.

     

A Coenzyme‐Independent Decarboxylase/Oxygenase Cascade for the Efficient Synthesis of Vanillin

Vanillin is one of the most widely used flavor compounds in the world as well as a promising versatile building block. The biotechnological production of vanillin from plant‐derived ferulic acid has attracted much attention as a new alternative to chemical synthesis. One limitation of the known metabolic pathway to vanillin is its requirement for expensive coenzymes. Here, we developed a novel route to vanillin from ferulic acid that does not require any coenzymes. This artificial pathway consists of a coenzyme‐independent decarboxylase and a coenzyme‐independent oxygenase. When Escherichia coli cells harboring the decarboxylase/oxygenase cascade were incubated with ferulic acid, the cells efficiently synthesized vanillin (8.0 mM , 1.2 g L ^?1) via 4‐vinylguaiacol in one pot, without the generation of any detectable aromatic by‐products. The efficient method described here might be applicable to the synthesis of other high‐value chemicals from plant‐derived aromatics.     

Iron‐Catalyzed Oxidative Cleavage of Olefins and Alkynes to Carboxylic Acids with Aqueous tert‐Butyl Hydroperoxide

A new method for the oxidation of aromatic olefins and alkynes has been developed using inexpensive iron(III) chloride hexahydrate (FeCl₃⋅6 H₂O, 5 mol%) catalyst in combination with commercially available aqueous 70% tert‐butyl hydroperoxide (TBHP) as oxidant. The present system works well for aromatic alkenes and alkynes with both electron‐donating and electron‐withdrawing substituents being tolerated. The protocol is free from chromatographic purification and the carboxylic acids are obtained in high yields by simple filtration.     

Iron(III) Chloride‐Catalyzed Tandem Aza‐Prins/Friedel–Crafts Cyclization of 2‐Arylethyl‐2,3‐butadienyl Tosylamides and Aldehydes‐An Efficient Synthesis of Benzo[f]isoquinolines

An efficient approach for the synthesis of 1,2,3,4,5,6‐hexahydrobenzo[f]isoquinolines via a tandem aza‐Prins/Friedel–Crafts cyclization from 2‐arylethyl‐2,3‐butadienyl tosylamides and aldehydes has been developed. This iron(III) chloride‐catalyzed cascade cyclization at the room temperature with different types of aldehydes, such as aromatic and heteroaromatic aldehydes, alkyl aldehydes, and α,β‐unsaturated aldehydes, affords the products in moderate to excellent yields (up to 97 %). In this reaction, chlorotrimethylsilane was applied to activate the aldehydes. The cheap catalyst, the mild reaction conditions, and the broad scope of the substrates make this method highly useful.

     

Asymmetric Brønsted Acid‐Catalyzed Friedel–Crafts Reactions of Indoles with Cyclic Imines ‐ Efficient Generation of Nitrogen‐Substituted Quaternary Carbon Centers

A new enantioselective Brønsted acid‐catalyzed Friedel–Crafts reaction of indole with cyclic imines has been develeoped. This organocatalytic reaction provides for the first time optically active indolindolinone derivatives in high yields and with excellent enantioselectivities (up to 91% ee) under mild reaction conditions.