Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

A Ru‐catalyzed direct asymmetric reductive amination of ortho‐OH‐substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible ‐OH group.     

Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2‐Dioxides Catalyzed by Cinchona Alkaloid‐based Primary Amines

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2‐dioxides could be successfully carried out utilizing a combination of cinchona alkaloid‐derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89–97 % ee and with various aryl methyl ketones in 85–98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.     

Facile Access to Sterically Hindered Aryl Ketones via Carbonylative Cross-Coupling: Application to the Total Synthesis of Luteolin

A general and mild protocol for achieving the carbonylative cross-coupling of sterically hindered, ortho-disubstituted aryl ketones is reported. The commercially available PEPPSI-IPr catalyst is shown to efficiently promote the carbonylative cross-coupling of hindered ortho-disubstituted aryl iodides to give diaryl ketones; traditional phosphine catalysts are less effective. Carbonylative Suzuki-Miyaura cross-couplings provide a diverse array of biaryl ketones in good to excellent yields. The same catalyst is also shown to catalyze a carbonylative Negishi cross-coupling reaction, utilizing a variety of alkynyl-zinc reagents to give the corresponding alkynyl aryl ketones. Application of this new methodology to the synthesis of the natural product luteolin is reported.     

Practical preparation of methyl vinyl ethers through the direct coupling of ketones with CHCl2OMe promoted by Mg/TiCl4/THF

Herein we utilized a new methylene carbenoid as an extremely simple and highly practical reagent for the preparation of vinyl ether with good to excellent yield. This method efficiently effects methoxymethylenation or vinyl ether formation of enolizable, nonenolizable, and sterically hindered ketones. The complexation of Ti–Mg–CHOMe was facilitated, presumably, by THF dramatically increasing the feasibility; and scope of this protocol is to produce vinyl ethers which can be used as convenient building blocks for the preparation of biologically useful molecules.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Asymmetric dihydroxylation of disubstituted allenes

Asymmetric dihydroxylation of 1,1-disubstituted and 1,3-disubstituted allenes can be used to synthesize chiral α-hydroxy ketones. We have also obtained α,α′-dihydroxy ketones with high enantioselectivity from 1,3-disubstituted allenes. Low conversion of the dihydroxylation of chiral allenes can be used as a kinetic resolution of sterically hindered allenes.     

Comparative Study of Bifunctional Mononuclear and Dinuclear Amidoiridium Complexes with Chiral C−N Chelating Ligands for the Asymmetric Transfer Hydrogenation of Ketones

A series of new bifunctional C?N chelating Ir complexes possessing a metal/NH group was synthesized by cyclometalation of optically active primary benzylic amines such as O‐silylated (S)‐2‐amino‐2‐phenylethanols ( 1 a and 1 a’ ), (R)‐5‐amino‐6,7,8,9‐tetrahydro‐5H‐benzocycloheptene ( 1 b ), and (R)‐1‐phenyl‐2,2‐dimethylpropylamine ( 1 c ). Although treatment of KOtBu with the amine complexes originating from 1 a and 1 a’ afforded amido‐bridged dinuclear complexes ( 3 a and 3 a’ ), more sterically hindered complexes were solely transformed into the coordinatively unsaturated mononuclear amido complexes ( 3 b and 3 c ), which can serve as real catalyst species in the asymmetric transfer hydrogenation. The structural difference in the C?N chelate framework markedly affected the catalytic performance. Among them, amido complex 3 c showed a pronounced ability to catalyze the transfer hydrogenation of acetophenone in 2‐propanol, even at a low temperature of ?30 °C. A hydridoiridium complex ( 4 c ) was also identified in the reaction of 3 c in 2‐propanol, which provides mechanistic insights into the enantiodiscriminating step in the hydrogen transfer to prochiral ketones.     

Three-step synthesis of chiral and sterically hindered amino alcohols based on cyclic enol phosphates

The new synthesis of chiral and sterically hindered 1,2-amino alcohols derivatives of 2-methyl-indane and 1,2,3,4-tethrahydrophenanthrene based on cyclic enol phosphates were investigated. The desired products were obtained using three step procedure: oxidation of accessible enol phosphates, transformation α-hydroxy ketones into corresponding oximes and finally reduction of the last one to 1,2-amino alcohols. The optimal conditions of all stages to obtain products with high enantioselectivity or diastereomeric ratio were found and elaborated. The structures and absolute configurations of (3R)-2,3-dihydro-3-hydroxy-1H-phenanthren-4-one and corresponding oxime were confirmed by X-ray analysis.     

The 1,3 O→C silyl rearrangement of silyl enol ether anions - synthesis of α-silyl ketones

Silyl enol ethers with sterically hindered silyl groups are transformed into the corresponding α-silyl ketones by treatment with n-butyllithium/potassium tert-butylate.     

Interactions of aliphatic β-amino-β-trifluoromethylvinyl ketones with ethylenediamine

The reactions of aliphatic β-amino-β-trifluoromethylvinyl ketones with an excess of ethylenediamine at room temperature afforded the corresponding 2,3-dihydro-1H-1,4-diazepines or substituted 2-acetonyl-2-trifluoromethylimidazolidines (the latter were obtained when the approach to the carbonyl group was sterically hindered). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2305–2308, November, 1998.     

Synthesis of sterically hindered ketones from aldehydes via O-silyl oximes

A mild and efficient method to synthesize sterically hindered ketones from aldehydes via O-silyl oximes was developed. Treatment of O-triphenylsilylated oximes with alkyl iodides in the presence of triethyl borane afforded the corresponding ketones.     

Dichloromethane activation. Direct methylenation of ketones and aldehydes with CH2Cl2 promoted by Mg/TiCl4/THF

[reaction: see text] This Mg-TiCl4-promoted CH2-transfer reaction of CH2Cl2 represents an extremely simple, practical, and efficient methylenation of a variety of ketones and aldehydes, especially in enolizable or sterically hindered ketones such as 2,2-dimethylcyclohexanone, camphor, and fenchone.     

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

A Ru-catalyzed direct asymmetric reductive amination of ortho-OH-substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible -OH group.     

Practical and Efficient Acylation and Tosylation of Sterically Hindered Alcohols Catalyzed with 1-Methylimidazole

Acylation of sterically hindered alcohols is frequently encountered in synthetic chemistry. An efficient and mild procedure for tosylation and esterification of sterically hindered hydroxyl groups with p-TsCl, Ac2O and Bz2O in the presence of 1-methylimidazole is described. It was observed that auxiliary base, triethylamine, accelerates the acylation reaction.     

Quenching of aromatic ketone phosphorescence by sterically hindered alkenes

The deactivation of the excited states of triplet ketones by sterically hindered alkenes results in lower rate constants (usually due to increased activation energies) than by relatively unhindered alkenes.     

Carbene adduct of cyclopalladated ferrocenylimine catalyzed α-arylation of ketones with aryl chlorides or bromides

Carbene adduct of cyclopalladated ferrocenylimine exhibited highly catalytic activity for the α-arylation of ketones with aryl halides. The corresponding products were obtained in moderate to excellent yields. Such protocol was applied to various ketones and a broad scope of aryl halides including aryl chlorides, bromides as well as unactivated and sterically hindered aryl halides.     

Mukaiyama Aldol Reactions Catalyzed by a Trimeric Organo Aluminum(III) Alkoxide

Abstract

Mukaiyama aldol reactions of enol ethers with a variety of aldehydes and ketones are efficiently catalyzed at 0–25 °C by the sterically bulky trimeric organo aluminum(III) alkoxide 1 synthesized via the reaction of 3 equiv of AlMe₃ with tripodal tris(2-hydroxy-3-tert-butyl-5-methylphenyl) methane and the elimination of 3 equiv of methane. Comparisons of its catalytic properties with the less sterically hindered analogue 2, the more sterically hindered analogue 3, a monomeric aluminum near-analogue 4, and a dimeric alumatrane 5 revealed that 1 possesses superior activity.     

Ligand-Controlled Site- and Enantioselective Carbene Insertion into Carbon-Silicon Bonds of Benzosilacyclobutanes

We report herein a highly efficient palladium-catalyzed carbene insertion into strained Si−C bonds of benzosilacyclobutanes, which provides an efficient method to access α-chiral silanes. With a sterically hindered ligand, carbene insertion into the C(sp³)−Si bond of benzosilacyclobutanes occurred in excellent site- and enantioselectivity, while C(sp²)−Si bond insertion occurred selectively with less sterically hindered ligands. Reaction mechanism, in particular the roles of the chiral ligands in controlling the site-selectivity of the insertion reactions, are elucidated by using hybrid density functional theory.     

A Well‐Defined Monomeric Aluminum Complex as an Efficient and General Catalyst in the Meerwein–Ponndorf–Verley Reduction

The metal‐catalyzed Meerwein–Ponndorf–Verley (MPV) reduction allows for the mild and sustainable reduction of aldehydes and ketones but has not found widespread application in organic synthesis due to the high catalyst loading often required to obtain satisfactory yields of the reduced product. We report here on the synthesis and structure of a sterically extremely overloaded siloxide‐supported aluminum isopropoxide capable of catalytically reducing a wide range of aldehydes and ketones (52 examples) in excellent yields under mild conditions and with low catalyst loadings. The unseen activity of the developed catalyst system in MPV reductions is due to its unique monomeric nature and the neutral donor isopropanol weakly coordinating to the aluminum center. The present work implies that monomeric aluminum alkoxide catalysts may be attractive alternatives to transition‐metal‐based systems for the selective reduction of aldehydes and ketones to primary and secondary alcohols.     

Ammounium acetate as a catalyst of the condensation of sterically hindered functionalized hydroxylamines with ketones

Ammonium acetate was found to be a catalyst of the condensation of α-hydroxylamino oximes and α-hydroxylamino alcohols with ketones. This condensation leads to sterically hindered heterocyclic hydroxylamines, which are precursors of stable nitroxides.