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.     

Synthesis of Halogenated α,β‐Unsaturated γ‐Butyrolactone Derivatives by Triphenylphosphine‐Catalyzed Cyclization of α‐Halogeno Ketones with Dialkyl Acetylenedicarboxylates (=Dialkyl But‐2‐ynedioates)

A Ph₃P‐catalyzed cyclization of α‐halogeno ketones 2 with dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates) 3 produced halogenated α,β‐unsaturated γ‐butyrolactone derivatives 4 in good yields (Scheme 1, Table). The presence of electron‐withdrawing groups such as halogen atoms at the α‐position of the ketones was necessary in this reaction. Cyclization of α‐chloro ketones resulted in higher yields than that of the corresponding α‐bromo ketones. Dihalogeno ketones similarly afforded the expected γ‐butyrolactone derivatives in high yields.     

Rhodium‐Catalyzed Ketone Methylation Using Methanol Under Mild Conditions: Formation of α‐Branched Products

The rhodium‐catalyzed methylation of ketones has been accomplished using methanol as the methylating agent and the hydrogen‐borrowing method. The sequence is notable for the relatively low temperatures that are required and for the ability of the reaction system to form α‐branched products with ease. Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one‐pot iridium‐ and rhodium‐catalyzed process.     

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.     

1,2‐Addition of α,α,α‐Trichlorotoluene to Ketones via a Mg Barbier Reaction in DMF: New Route to Cycloalk‐1‐en‐1‐yl and Alk‐1‐en‐1‐yl Phenyl Ketones

The reductive cyclocondensation of α,α,α‐trichlorotoluene to enolisable ketones enables the preparation of (cyclo)alken‐1‐en‐1‐yl phenyl ketones via the formation of an intermediate chlorooxirane.     

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.     

Synthesis,structure determination and chemoselective catalytic studies of amino acids complexes of osmium(II)

The two new half sandwich amino acids complexes of osmium, i.e. [Os(η6‐p‐cymene)(κ1‐N‐(rac)‐phenylglycine methylester)Cl₂] ( A ) and [Os(η6‐p‐cymene)(κ1‐N,N′‐(S)‐phenylalanineamido)Cl] ( B ) have been synthesized and employed for chemoselective reduction of ketones (nine α,β‐unsaturated ketones and three saturated ketones). The complexes were characterized by spectroscopic as well as analytical methods; their solid structures were confirmed by single‐crystal X‐ray analysis. Both of the osmium complexes catalyze the reduction of α,β‐unsaturated ketones to saturated ketones via isomerization of the initially produced allylic alcohols. The reducible substrates were studied to obtain information on the steric and electronic factors which may affect the interaction of the substrate with the metal center and, thus, control the selectivity of the hydrogen‐transfer reductions. Copyright © 2008 John Wiley & Sons, Ltd.     

Transformation of Aryl Acyloin O‐Alkyl and O‐Phenyl Derivatives to Ketones

The treatment of aryl acyloin (α‐hydroxyketone) O‐alkyl and O‐phenyl derivatives with 2–3 equiv of Zn and 1–2 equiv of NH₄Cl in ethanol, refluxing for 20–120 min, gave the corresponding ketones with excellent yields. Further, α,β‐epoxy ketones can be efficiently transformed to β‐hydroxy ketones, and 2,2‐dialkoxy‐1‐phenyl ketone also can be dealkoxylated to 1‐phenyl ketone.     

Photochemical Synthesis of Highly Functionalized Cyclopropyl Ketones

A series of di‐ and trisubstituted cyclopropyl ketones 11 were prepared by irradiation of ketones 3 and 5 , which bear a leaving group adjacent to the carbonyl C‐atom. The required ketones 3 could be easily synthesized either by functionalization of ketones 1 with a hypervalent iodine reagent, 2 , or by O‐sulfonylation of α‐hydroxy ketones 7 . The nitrates 5 were obtained by treatment of the corresponding α‐bromo ketones with AgNO₃. The irradiation of 3 and 5 must be performed in the presence of an acid scavenger (1‐methyl‐1H‐imidazole) to obtain the cyclopropanes 11 in good yields. The synthetic efficiency of the method was, among other things, demonstrated by the preparation of a highly strained bicyclo[2.1.0]pentane 11i in good yield. The mechanism of the photochemical cyclization was investigated by means of photokinetic measurements, as well as by quantum‐chemical calculations. It was shown that the presence of the leaving group substantially influences all steps of the photochemical reaction cascade. The X‐ray crystal structures of 11j and exo‐ 11k were also determined.     

Remarkable Differences in Reactivity between Benzothiazoline and Hantzsch Ester as a Hydrogen Donor in Chiral Phosphoric Acid Catalyzed Asymmetric Reductive Amination of Ketones

Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p‐anisidine. The asymmetric reductive amination of ketones with a Hantzsch ester as a hydrogen donor provided the corresponding chiral amines exclusively, regardless of the structures of the ketones, whereas a similar transformation with a benzothiazoline provided chiral amines and p‐methoxyphenyl‐protected primary amines in variable yields, depending on the structures of both the ketones and benzothiazolines. Because a benzothiazoline has an N,S‐acetal moiety that is vulnerable to p‐anisidine, the primary amine can be formed through transimination of the benzothiazoline with p‐anisidine followed by reduction of the resulting aldimine with remaining benzothiazoline.     

N‐Heterocyclic Carbene‐Catalyzed α‐Alkylation of Ketones with Primary Alcohols

Several N‐heterocyclic carbene precursors are synthesized and used in the α‐alkylations of ketones with primary alcohols. With the assistance of a base, these N‐heterocyclic carbenes can catalyze the reaction smoothly to furnish dialkylated ketones in good‐to‐excellent yields.     

L-脯氨酸催化下甲基酮和1-芳基-2,2,2-三氟乙酮的不对称Aldol反应

Direct asymmetric aldol addition of methyl ketones to 2,2,2-trifluoro-1-phenylethanone and its ring-substituted derivatives was achieved using L-proline as a chiral promoter. Various optically active β-trifluoromethyl-β-hydroxy ketones were obtained in almost quantitative yields with moderate enantioselectivities up to 64 % ee.     

Novel Route to 4‐(Adamantan‐1‐yl)quinoline Derivatives Based on the Friedländer Condensation

2,3,4‐Trisubstituted quinolines, substituted with adamantan‐1‐yl or (adamantan‐1‐yl)methyl in the 4‐position, were prepared from the corresponding admantan‐1‐yl 2‐aminophenyl ketones or admantan‐1‐ylmethyl 2‐aminophenyl ketones and ketones with an α‐CH₂ group. These reactions were carried out under neat conditions or in toluene, and the products were obtained in moderate‐to‐excellent yields. The scope and limitations of the examined procedures are discussed. All new compounds are fully characterized by IR and NMR spectroscopy and mass spectrometry. The molecular structures of five new quinolines, obtained via single‐crystal X‐ray diffraction analyses, are discussed.     

Nickel‐Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N‐Alkyl Pyridinium Salts with Activated Carboxylic Acids

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.     

Copper/Palladium‐Cocatalyzed Aerobic Synthesis of Bisaryl Ketones from Olefins via C‐C Double Bonds Cleavage

A novel palladium/copper‐catalyzed aerobic synthesis of bisaryl ketones from 1,2‐diarylalkenes via C‐C double bonds cleavage has been described. This reaction constitutes a new transformation from 1,2‐diarylalkenes into bisaryl ketones, providing a unifying, simple and environmentally friendly complement to the available methods.     

One‐Pot and Convenient Conversion of 5‐Azidopyrazole‐4‐carboxaldehyde to Pyrazolo[3,4‐b]pyridines

A one‐pot and convenient synthesis of multisubstituted pyrazolo[3,4‐b]pyridines in moderate to high yields has been achieved by a two‐step reaction: diazo‐transfer of 5‐azido‐1‐phenylpyrazole‐4‐carboxaldehydes to ketones in ethanolic KOH to give 5‐amino‐1‐phenylpyrazole‐4‐carboxaldehyde and subsequent Friedlaender reaction of 5‐amino‐1‐phenylpyrazole‐4‐carboxaldehyde with ketones.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).     

CuBr2‐Promoted Multicomponent Aerobic Reaction for the Synthesis of 1,2,3‐Triaroylindolizines

An efficient synthesis of 1,2,3‐triaroylindolizines has been developed via CuBr₂‐promoted reaction of three molecules of aromatic methyl ketones and one molecule of pyridine derivative. A wide range of methyl aryl ketones and methyl heteroaryl ketones took part in the reaction and generate 1,2,3‐triaroylindolizines in good yields. This protocol also features such advantages as mild reaction conditions and high atom economy and step economy.     

Expedient Synthesis of Ketones via N‐Heterocyclic Carbene/Nickel‐Catalyzed Redox‐Economical Coupling of Alcohols and Alkynes†

An N‐heterocyclic carbene/nickel‐catalyzed direct coupling of alcohols and internal alkynes to form α‐branched ketones has been developed. This methodology provides a new approach to afford branched ketones, which are difficult to access through the hydroacylation of simple internal alkenes with aldehydes. This redox‐neutral and redox‐economical coupling is free from any oxidative or reductive additives as well as stoichiometric byproducts. These reactions convert both benzylic and aliphatic alcohols and alkynes, two basic feedstock chemicals, into various α‐branched ketones in a single chemical step.     

Direct Asymmetric Alkylation of Ketones: Still Unconquered

The alkylation of ketones is taught at basic undergraduate level. In many cases this transformation leads to the formation of a new stereogenic center. However, the apparent simplicity of the transformation is belied by a number of problems. So much so, that a general method for the direct asymmetric alkylation of ketones remains an unmet target. Despite the advancement of organocatalysis and transition‐metal catalysis, neither field has provided an adequate solution. Indeed, even use of an efficient and general stoichiometric chiral reagent has yet to be reported. Herein we describe the state‐of‐the‐art in terms of direct alkylation reactions of some carbonyl groups. We outline the limited progress that has been made with ketones, and potential routes towards ultimately achieving a widely applicable methodology for the asymmetric alkylation of ketones.