Dual-activation protocol for tandem cross-aldol condensation: An easy and highly efficient synthesis of α,α′-bis(aryl/alkylmethylidene)ketones

Commercially available lithium hydroxide monohydrate (LiOH·H₂O) was found to be a novel ‘dual activation’ catalyst for tandem cross-aldol condensation between cyclic/acyclic ketones and aromatic/heteroaromatic/styryl/alkyl aldehydes leading to an efficient and easy synthesis of α,α′-bis(aryl/alkylmethylidene)ketones at r.t. in short times. The reaction of aryl, heteroaryl, styryl and alkyl aldehydes with acyclic and five/six-membered cyclic ketones afforded excellent yields after 2 min to 1.25 h. The reaction conditions were compatible with various electron withdrawing and electron donating substituents, e.g. Cl, F, NO₂, OMe and NMe₂. The rate of the cross-aldol condensation was influenced by the nature of the ketone and electronic and steric factors associated with the aldehyde. The reaction took place at a faster rate for acyclic ketone (e.g., acetone) than that for cyclic ketone (e.g., cyclohexanone). In case of cycloalkanones, the rate of the reaction was dependent on the size of the ring of the cycloalkanone. The cross-aldol condensation of cyclopentanone was faster than that of cyclohexanone for a common aldehyde. In case of reactions involving aliphatic aldehyde having α-hydrogen atom no self-aldol condensation of the aldehyde took place.     

Microwave‐Assisted,Rhodium(III)‐Catalyzed N‐Annulation Reactions of Aryl and α,β‐Unsaturated Ketones with Alkynes

New Rh^III‐catalyzed, one‐pot N‐annulation reactions of aryl and α,β‐unsaturated ketones with alkynes in the presence of ammonium acetate have been developed. Under microwave irradiation conditions, the processes lead to rapid formation of the respective isoquinoline and pyridine derivatives with efficiencies that are strongly dependent on the steric nature of the aryl ring and enone substituents. By employing this protocol, a variety of isoquinoline and pyridine derivatives were prepared in high yields. In addition, a new one‐pot approach to the synthesis of pyridines, involving four‐component reactions of ketones, formaldehyde, NH₄OAc, and alkynes, has been uncovered. This process takes place through a route involving initial aldol condensation of the ketone with formaldehyde to generate a branched α,β‐unsaturated ketone that then undergoes Rh^III‐catalyzed N‐annulation with NH₄OAc and the alkyne.     

Perchloric Acid Supported on Silica Catalyzed Efficient Synthesis of 1,5‐Benzodiazepines

Perchloric acid adsorbed on silica gel efficiently catalyzed the condensation of o‐phenylenediamines (OPDA) with cyclic and acyclic ketones at ambient temperature to afford 1,5‐benzodiazepines in good yields under solvent‐free conditions.     

Solid‐Phase Synthesis of Structurally Diverse Heterocycles by an Amide–Ketone Condensation/N‐Acyliminium Pictet–Spengler Sequence

An efficient approach for the solid‐phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone–amide condensation reactions to form cyclic N‐acyliminium intermediates. In the presence of a tethered nucleophile, a second cyclization reaction results in the formation of a fused bicyclic ring system. The scope of the methodology was demonstrated by several combinations of substituted ketones and nucleophiles, the latter conveniently originating from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. The cyclization sequence provides diastereomerically pure products in high yields. In one extension of the methodology, the resulting relative stereochemistry of the products enables the formation of bridged ring systems by a unique cyclative release mechanism.     

Chiral Primary‐Amine‐Catalyzed Conjugate Addition to α‐Substituted Vinyl Ketones/Aldehydes: Divergent Stereocontrol Modes on Enamine Protonation

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α‐chiral carbonyls. We describe herein chiral primary‐amine‐catalyzed conjugate additions of indoles to both α‐substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate‐limiting in iminium formation and they all involve a uniform H₂O/acid‐bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α‐branched acroleins, facial selections on H₂O‐bridged protonation determine the enantioselectivity, which is enhanced by an OH???π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the C? C bond‐formation step, which precedes a highly stereospecific enamine protonation.     

ZrCl4 as an Efficient Catalyst for Crossed‐Aldol Condensation of Cyclic Ketones with Aromatic Aldehydes in Refluxing Ethanol

The aldol condensation reaction of cyclic ketones with aromatic aldehydes in ethanol under reflux conditions using ZrCl₄ as a catalyst to afford the corresponding α,α′‐bis(substituted benzylidene and cinnamylidene)cycloalkanones in excellent yields has been described. No self‐condensation product was produced.     

Palladium‐mediated polymerization of cyclic diazoketones

Palladium‐mediated polymerization of cyclic diazoketones was investigated. Although cyclic diazoketones 1a,b derived from cyclohexanone and 1‐tetralone did not homopolymerize, they can be used as a comonomer for copolymerization with polymerizable acyclic diazoketones. On the other hand, an α,β‐unsaturated cyclic diazoketone 2a prepared from 2‐cyclohexen‐1‐one polymerized to give a polymer poly 2a ′ with M_n = 1400 in a 23.8% yield. Addition of some nucleophiles to C?C bond in poly 2a ′ was carried out. Copolymerization of 2a and its dimethyl‐substituted analogues 2b,c with acyclic diazoketones was also investigated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1638–1648, 2008     

Multicomponent, solvent-free synthesis of β-aryl-β-mercapto ketones using zirconium chloride as a catalyst

Zirconium chloride efficiently catalyzes the one-pot, three-component reaction of an aryl aldehyde, cyclic or acyclic enolizable ketones, and thiols under solvent-free conditions at room temperature to afford the corresponding β-aryl-β-mercaptoketones via aldol-Michael addition reactions. This methodology affords a large number of β-aryl-β-mercapto ketone derivatives in high yields and in short reaction times.     

An efficient synthesis of ferrocenyl substituted 1,5-diketone and cyclic α,β-unsaturated ketones under ultrasound irradiation

Michael reactions of deoxybenzoin or dibenzyl ketone with ferrocenyl substituted chalcones catalyzed by sodium hydroxide under ultrasound irradiation can afford the corresponding Michael adducts with excellent yields. It presents a convenient, efficient and simple method for the preparation of ferrocenyl substituted 1,5-diketone compounds in the presence of ultrasound irradiation. In addition, the formation of cyclic, α,β-unsaturated ketones via the reactions of dibenzyl ketone with ferrocenyl substituted chalcones were found, and characterized by X-ray crystal structure analysis.     

Dibromomethane as one-carbon source in organic synthesis: microwave-accelerated α-methylenation of ketones with dibromomethane and diethylamine

The reactivity of aryl alkyl ketone with a preheated mixture of dibromomethane and diethylamine is poor and gives an α-methylenation product in very low yield even under refluxing condition. It can be accelerated dramatically by microwave irradiation. Under microwave condition, the cyclic 1,3-dicarbonyls, aryl alkyl ketones, heteroaryl alkyl ketones and acyclic benzyl ketone give α-methylenation products in modest to good yields.     

Catalytic Asymmetric Intramolecular Homologation of Ketones with α‐Diazoesters: Synthesis of Cyclic α‐Aryl/Alkyl β‐Ketoesters

A catalytic asymmetric intramolecular homologation of simple ketones with α‐diazoesters was firstly accomplished with a chiral N,N′‐dioxide–Sc(OTf)₃ complex. This method provides an efficient access to chiral cyclic α‐aryl/alkyl β‐ketoesters containing an all‐carbon quaternary stereocenter. Under mild conditions, a variety of aryl‐ and alkyl‐substituted ketone groups reacted with α‐diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β‐ketoesters in high yield and enantiomeric excess.     

Novel Mg-organic reagents in organic synthesis. Cp2TiCl2 catalyzed intermolecular cyclomagnesiation of cyclic and acyclic 1,2-dienes using Grignard reagents

High-yield (>80%) catalytic intermolecular cyclomagnesiation of cyclic and acyclic allenes with the aid of Grignard reagents has been realized in the presence of Cp₂TiCl₂. The synthesized unsaturated bi- and tricyclic organomagnesium compounds (OMC) have been successfully converted in situ into thiophenes, unsaturated ketones, cyclic and acyclic hydrocarbons with high regio- and stereoselectivity.     

Highly enantioselective aldol reactions using a tropos dibenz[c,e]azepine organocatalyst

The four-step synthesis of a chiral primary tertiary diamine salt, possessing a tropos dibenz[c,e]azepine ring is described. It is shown that 3.5-5 mol % of this salt is capable of promoting highly enantioselective crossed-aldol reactions between cyclohexanone and a series of aromatic aldehydes. In all cases, the aldol reactions proceed with high diastereoselectivity for the anti-aldol product. The outcome of crossed-aldol reactions involving other cyclic ketones and acyclic ketones are also described. All examples involving cyclic ketones result in selectivity for the anti-aldol products, whereas acyclic ketones were found to favour the syn-aldol products. A discussion on the role of the chiral primary tertiary diamine salt in the catalysis of the aldol reactions is also presented.     

Oxidative iodination of carbonyl compounds using ammonium iodide and oxone®

A simple, efficient, mild, and regioselective method for oxyiodination of carbonyl compounds has been reported by using NH₄I as the source of iodine and Oxone® as an oxidant. Various carbonyl compounds such as aralkyl ketones, aliphatic ketones (acyclic and cyclic), and β-keto esters proceeded to the respective α-monoiodinated products in moderate to excellent yields. Unsymmetrical aliphatic ketones reacted smoothly yielding a mixture of 1-iodo and 3-iodo ketones with the predominant formation of 1-iodoproduct.     

Palladium-catalysed intramolecular enolate O-arylation and thio-enolate S-arylation: synthesis of benzo[b]furans and benzo[b]thiophenes

Enolates derived from α-(ortho-haloaryl)-substituted ketones undergo palladium-catalysed C-O bond formation to deliver benzofuran products in good yield. A catalyst generated from Pd₂(dba)₃ and the ligand DPEphos effects the key bond formation to deliver a variety of substituted products from both cyclic and acyclic precursors. The analogous thio-ketones undergo C-S bond formation using identical reaction conditions and are converted to benzothiophene products. A cascade sequence that produces the required α-aryl ketones in situ has also been developed, although the substrate scope is more restricted.     

LiBr‐Catalyzed Simple and Efficient Synthesis of Some Novel Substituted Quinolines via Friedlander Heteroannulation Reaction

A simple and efficient method has been developed for the condensation of o‐aminoaryl ketones with α‐methylene ketones in the presence of catalytic amounts of LiBr to afford the corresponding fused cyclic quinolines in high yield using the Friedlander heteroannulation reaction. The reaction works at ambient temperature to give the products within 1.5–2 h.     

General Synthesis of 1‐Substituted 2‐Methylbenzimidazoles from Ketones and 2‐Aminoacetanilide

A novel method for preparation of 1‐substituted benzimidazoles via reductive amination of ketones with N‐differentiated 1,2‐diaminobenzenes is described. The method appears to be general in application to acyclic and cyclic ketones, as well as heteroatom‐substituted cyclic ketones.     

A novel aromatic alkylation of anilines with cyclic and acyclic ketones under hydrothermal conditions

A novel aromatic ring-alkylation was achieved by condensation between aniline·HCl salts and cyclic or acyclic ketones under hydrothermal conditions.     

Phosphine‐Catalyzed [4+2] Cycloadditions of Allenic Ketones: Enantioselective Synthesis of Functionalized Tetrahydropyridines

Amino‐acid‐derived phosphine catalyzed [4+2] cycloaddition leading to chiral tetrahydropyridines, making use of α‐substituted allenic ketones as “C4 synthons” and N‐sulfonyl cyclic ketimines, has been developed. This asymmetric cycloaddition tolerates a wide range of α‐substituted allenic ketones. A series of chiral sultam‐fused tetrahydropyridines bearing a quaternary stereocenter were obtained in high yields with good enantioselectivities.     

Sulfamic acid: an efficient, cost-effective and recyclable solid acid catalyst for the Friedlander quinoline synthesis

o-Aminoaryl ketones undergo smooth condensation with α-methylene ketones in the presence of sulfamic acid (NH₂SO₃H) (SA) under mild reaction conditions to afford the corresponding polysubstituted quinolines in excellent yields. The catalyst can be recovered by simple filtration and can be recycled in subsequent reactions. The method is simple, cost-effective and environmentally benign.