An Efficient Tetrabutylammonium Fluoride (TBAF)‐Catalyzed Three‐Component Synthesis of 3‐Substituted Indole Derivatives under Solvent‐Free Conditions

An expedient and efficient one‐pot three‐component synthesis of 3‐substituted indoles has been developed by the reaction of indoles, active methylene compounds and aldehydes using a catalytic amount of tetrabutylammonium fluoride under solvent‐free conditions.     

Highly Diastereo‐ and Enantioselective Vinylogous Mannich Reactions of Fluorinated Aldimines with Siloxyfurans

A highly regio‐ and enantioselective asymmetric vinylogous Mannich reaction of readily available fluorinated aldimines bearing a chiral auxiliary [(S)‐1‐phenylethyl group] with siloxyfurans to afford chiral fluorine‐containing γ‐butenolide or γ‐lactone derivatives has been developed in the presence of silver acetate (10 mol%) and axially chiral phosphine‐oxazoline ligand L1 (11 mol%). In most cases, the corresponding fluorinated adducts were obtained in high yields, good to excellent enantiomeric excesses and up to>20:1 dr.     

Suzuki–Miyaura Cross‐Coupling under Solvent‐Free Conditions

A solvent‐free reaction protocol for Suzuki–Miyaura cross‐couplings was developed. (Hetero)aryl bromides and chlorides are coupled with pinacol arylboronates in high yields. The reaction is catalyzed by conventional bis(triphenylphosphine)palladium(II) chloride [(PPh₃)₂PdCl₂] and/or palladium(II) acetate/SPhos [Pd(OAc)₂/SPhos] under air.

     

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.

     

Hafnium Chloride Tetrahydrofuran Complex‐Catalyzed Diels–Alder Cycloadditions of 3‐Ethoxycarbonylcoumarins with 1,3‐Dienes under Solvent‐Free Conditions

Hafnium chloride tetrahydrofuran complex (HfCl₄⋅2 THF) is an efficient catalyst for the Diels–Alder cycloadditions of 3‐ethoxycarbonylcoumarins 1a – c and 1,3‐butadienes 2x – z under solvent‐free conditions furnishing the corresponding cycloadducts in excellent yields. This salt is an air stable Lewis acid and therefore the reactions can be performed in air atmosphere making the procedure simple to be carried out.     

The First Catalytic Mannich‐Type Reaction of N‐Alkoxycarbonylamino Sulfones with Silyl Enolates

Bismuth triflate was found to be an efficient catalyst in the Mannich‐type reaction of silyl enolates with N‐alkoxycarbonylamino sulfones. The reaction proceeded smoothly with a low catalyst loading of bismuth triflate (0.5–1.0 mol %) to afford the corresponding protected β‐aminocarbonyl compound in very good yields (up to 96 %).     

Microwave‐Promoted Copper‐Free Sonogashira–Hagihara Couplings of Aryl Imidazolylsulfonates in Water

Aryl imidazol‐1‐ylsulfonates have been efficiently cross‐coupled with aryl‐, alkyl‐, and silylacetylenes in neat water under copper‐free conditions at 110 °C assisted by microwave irradiation. Using 0.5 mol% of an oxime palladacycle as precatalyst, 2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl (SPhos, 2 mol%) as ligand, hexadecyltrimethylammonium bromide (CTAB) as additive, and triethylamine (TEA) as base, a wide array of disubstituted alkynes has been prepared in good to high yields in only 30 min.     

Diastereo‐ and Enantioselective Direct Aldol Reactions in Aqueous Medium: A New Highly Efficient Proline‐Sugar Chimeric Catalyst

A new synthetic catalyst, capable of acting like an enzyme in the accomplishment of direct aldol reactions, is presented. Excellent results, in terms of chemical yields and diastereo‐/enantiomeric ratios, are reported for the catalyzed additions of cyclohexanone to variously substituted benzaldehydes.     

Improved Synthesis of Pyrroles and Indoles via Lewis Acid‐Catalyzed Mukaiyama–Michael‐Type Addition/Heterocyclization of Enolsilyl Derivatives on 1,2‐Diaza‐1,3‐Butadienes. Role of the Catalyst in the Reaction Mechanism

The Mukaiyama–Michael‐type addition of various silyl ketene acetals or silyl enol ethers on some 1,2‐diaza‐1,3‐butadienes proceeds at room temperature in the presence of catalytic amounts of Lewis acid affording by heterocyclization 1‐aminopyrrol‐2‐ones and 1‐aminopyrroles, respectively. 1‐Aminoindoles have been also obtained by the same addition of 2‐(trimethylsilyloxy)‐1,3‐cyclohexadiene on some 1,2‐diaza‐1,3‐butadienes and subsequent aromatization. Mechanistic investigations indicate the coordination by Lewis acid of the enolsilyl derivative and its 1,4‐addition on the azo‐ene system of 1,2‐diaza‐1,3‐butadienes. The migration of the silyl group from a hydrazonic to an amidic nitrogen, its acidic cleavage and the final internal heterocyclization give the final products. Based on NMR studies and ab initio calculations, a plausible explanation for the migration of the silyl protecting group is presented.     

Prolinamides versus Prolinethioamides as Recyclable Catalysts in the Enantioselective Solvent‐Free Inter‐ and Intramolecular Aldol Reactions

A solvent‐free asymmetric and direct anti‐aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by recyclable L ‐prolineamides and L ‐prolinethioamides 3 is studied. The L ‐prolinethioamide 3d (5 mol%), derived from L ‐Pro and (R)‐1‐aminoindane, is the most efficient catalyst for this process affording the anti‐aldol adducts in high yields with excellent diastereo‐ and enantioselectivities (up to >98/2 dr, up to 98% ee) at 0 °C or room temperature. Prolinethioamide 3d is an effective organocatalyst for the first asymmetric, solvent‐free, intramolecular Hajos–Parrish–Eder–Sauer–Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to reported catalysts in organic solvents. Moreover, organocatalyst 3d can be easily recovered and reused by a simple acid/base extraction.     

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

A series of novel quinoline derivatives having a spirocyclopropyl ring can be synthesized by one‐pot, three‐component aza‐Diels–Alder reactions of arenecarbaldehydes, arylamines, and methylenecyclopropanes (MCPs) using a heterogeneous solid acid catalyst, montmorillonite KSF, under mild reaction conditions in good to excellent yields.     

Catalysis by β‐Cyclodextrin Hydrate – Synthesis of 2,2‐Disubstituted 2H‐Chromenes in Aqueous Medium

A cost‐effective, operationally simple and eco‐compatible protocol for the one‐pot synthesis of photochromic pyrans by the reaction of propargyl alcohols as well as propargyl ethers with differently substituted phenols under ambient atmosphere in aqueous medium has been developed using β‐cyclodextrin hydrate as an efficient, recyclable and stable catalyst. This is the first report where β‐cyclodextrin hydrate acted as a catalyst for an organic transformation but β‐cyclodextrin alone failed.

     

Sulfonated N‐Heterocyclic Carbenes for Pd‐Catalyzed Sonogashira and Suzuki–Miyaura Coupling in Aqueous Solvents

The reactions of the N,N′‐diarylimidazolium and N,N′‐diarylimidazolinium salts with chlorosulfonic acid result in the formation of the respective disulfonated N‐heterocyclic carbene (NHC) precursors in reasonable yields (46–77%). Water‐soluble palladium catalyst complexes, in situ obtained from the respective sulfonated imidazolinium salt, sodium tetrachloropalladate (Na₂PdCl₄) and potassium hydroxide (KOH) in water, were successfully applied in the copper‐free Sonogashira coupling reaction in isopropyl alcohol/water mixtures using 0.2 mol% catalyst loading. The preformed (disulfonatedNHC)PdCl(cinnamyl) complex was used in aqueous Suzuki–Miyaura reactions at 0.1 mol% catalyst loading. The coupling protocol reported here is very useful for Sonogashira reactions of N‐ and S‐heterocyclic aryl bromides and chlorides with aryl‐ and alkylacetylenes.     

A Practical Recycle of a Ligand‐Free Palladium Catalyst for Heck Reactions

Ligand‐free palladium can be recovered almost quantitatively from Heck reaction mixtures by filtration after its deposition on a carrier such as silica or celite. Subsequently, it is re‐activated to its original activity by adding a small amount of iodine or bromine prior to the next reaction cycle. The catalyst results in excellent yields and selectivities, even for the less reactive aryl bromides. A catalytic cycle based on anionic palladium intermediates is proposed.     

Recoverable Palladium Catalysts for Suzuki–Miyaura Cross‐ Coupling Reactions Based on Organic‐Inorganic Hybrid Silica Materials Containing Imidazolium and Dihydroimidazolium Salts

The systems formed by palladium acetate [Pd(OAc)₂] and hybrid silica materials prepared by sol‐gel from monosilylated imidazolium and disilylated dihydroimidazolium salts show catalytic activity in Suzuki–Miyaura cross‐couplings with challenging aryl bromides and chlorides. They are very efficient as recoverable catalysts with aryl bromides. Recycling is also possible with aryl chlorides, although with lower conversions. In situ formation of palladium nanoparticles has been observed in recycling experiments.     

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.     

Bioinspired,Base‐ and Metal‐Free,Mild Decarboxylative Aldol Activation of Malonic Acid Half Thioesters Under Phase‐Transfer Reaction Conditions

Utilizing ‘off the shelf’ commercially available, cheap, small synthetic molecules that mimic the efficient mediation of important bioreactions utilized by Nature is not only highly sought after but also currently highly topical. This paper details our preliminary efforts at developing a unique base‐ and metal‐free phase‐transfer‐mediated malonic acid thioester (MAHT) ‘activation protocol’ that efficiently generates (±)‐β‐thioesters. Our bioinspired aldol process is exceptionally mild, conducted under near neutral pH reaction conditions, does not require an inert, oxygen‐free atmosphere or anhydrous reaction conditions and is highly atom‐economic. Exemplifying the utility of our protocol, the synthesis of an array of structurally and functionally diverse (±)‐β‐hydroxy thioesters equipped with highly prized functionality, i.e., chlorine, bromine, fluorine, nitrile and nitro groups, is reported, as is the diastereoselective potential of this important reaction.

     

Efficient and General Synthesis of 3‐Aminoindolines and 3‐Aminoindoles via Copper‐Catalyzed Three‐Component Coupling Reaction

An efficient three‐component coupling (TCC) reaction toward a variety of 3‐aminoindoline and 3‐aminoindole derivatives has been developed. This cascade transformation proceeds via the copper‐catalyzed coupling reaction between 2‐aminobenzaldehyde, a secondary amine, and an alkyne leading to a propargylamine intermediate which, under the reaction conditions, undergoes cyclization into the indoline core. The latter, upon treatment with a base, smoothly isomerizes into the indole. Alternatively, the indole can directly be synthesized in a one‐pot sequential reaction.     

Organocatalytic Asymmetric Mannich Reactions of 5H‐Oxazol‐4‐ones: Highly Enantio‐ and Diastereoselective Synthesis of Chiral α‐Alkylisoserine Derivatives

The first organocatalytic Mannich reaction of 5H‐oxazol‐4‐ones with various readily prepared aryl‐ and alkylsulfonimides has been developed. Two commercially available pseudoenantiomeric Cinchona alkaloids‐derived tertiary amine/ureas have been demonstrated as the most efficient catalysts to access the opposite enantiomers of the Mannich products with equally excellent enantio‐ and diastereoselectivities. From the Mannich adducts, important α‐methyl‐α‐hydroxy‐β‐amino acid derivatives, such as the α‐methylated C‐13 side chain of taxol and taxotere, can be conveniently prepared.     

Polystyryl‐BEMP as an Efficient Recyclable Catalyst for the Nucleophilic Addition of Nitroalkanes to α,β‐Unsaturated Carbonyl Compounds under Solvent‐Free Conditions

2‐tert‐Butylimino‐2‐diethylamino‐1,3‐dimethylperhydro‐1,3,2‐diazaphosphorine supported on polystyrene (PS‐BEMP) is an efficient catalyst for the addition of nitroalkanes (1–1.5 equiv.) to α,β‐unsaturated carbonyl compounds (1.0 equiv.) in the absence of a reaction medium (solvent‐free conditions). The corresponding γ‐nitro carbonyl compounds have been isolated in excellent yields but the catalyst can be satisfactorily recovered and used for only 3 times due to the magnetic stirring which caused crunching of the catalyst beads thus hampering its complete recovery. To optimize the catalyst’s reuse and improve the environmental efficacy of solvent‐free conditions, the first solvent‐free cyclic continuous‐flow reactor has been set up. This reactor has allowed the product to be isolated in an almost quantitative yield by using a very small amount of organic solvent, making the recovery and reuse of the catalyst efficient and reproducible.