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.     

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.     

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.     

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.     

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.     

Asymmetric anti‐Selective Michael Reaction of Imidazole‐Modified Ketones with trans‐β‐Nitroalkenes

The successful application of imidazole‐modified ketones in asymmetric anti‐selective Michael reactions with trans‐β‐nitroalkenes is presented by employing a newly developed 3‐bromothiophene‐modified chiral diamine ligand. The corresponding conjugate adduct was submitted to further transformations with Grignard reagents to solve the problem of α‐site selectivity of simple linear ketones. Additionally, the syn‐selective product was obtained by treating the anti‐selective adduct with a simple base. In this way, the site‐specific products for both diastereomers in the asymmetric conjugate addition of simple ketones to nitroalkenes can be obtained.     

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.     

A Photochemical Organocatalytic Strategy for the α‐Alkylation of Ketones by using Radicals

Reported herein is a visible‐light‐mediated radical approach to the α‐alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon S_N2‐based activation of alkyl halides and blue light irradiation. The resulting open‐shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two‐electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox‐neutral nature of this process makes it compatible with a cinchona‐based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α‐alkylation of ketones.     

Retro‐Corey‐Chaykovsky Epoxidation: Converting Geminal Disubstituted Epoxides to Ketones

Corey‐Chaykovsky epoxidation has been widely applied in the conversion of aldehydes and ketones to epoxides with sulfonium and sulfoxonium ylides. The reverse transformation is realized for conversion of geminal disubstituted epoxides to ketones in the presence of DABCO in refluxing mesitylene. The method is a weak basic transformation from epoxides to ketones with loss of a methylene group and can be applied as an alternative strategy of the acid‐catalyzed Meinwald rearrangement or oxidation for conversion of epoxides to carbonyl compounds.     

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.     

From Alkyl Halides to Ketones: Nickel‐Catalyzed Reductive Carbonylation Utilizing Ethyl Chloroformate as the Carbonyl Source

Ketones are an important class of molecules in synthetic and medicinal chemistry. Rapid and modular synthesis of ketones remains in high demand. Described here is a nickel‐catalyzed three‐component reductive carbonylation method for the synthesis of dialkyl ketones. A wide range of both symmetric and asymmetric dialkyl ketones can be accessed from alkyl halides and a safe CO source, ethyl chloroformate. The approach offers complementary substrate scope to existing carbonylation methods while avoiding the use of either toxic CO or metal carbonyl reagents.     

Highly Enantioselective Copper(I)‐Catalyzed Conjugate Addition of Terminal Alkynes to 1,1‐Difluoro‐1‐(phenylsulfonyl)‐3‐en‐2‐ones: New Ester/Amide Surrogates in Asymmetric Catalysis

A highly enantioselective copper‐catalyzed conjugate alkynylation of monoactivated enones, namely 1,1‐difluoro‐1‐(phenylsulfonyl)‐3‐en‐2‐ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The β‐alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding β‐alkynylated difluoro‐ and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1‐difluoro‐1‐(phenylsulfonyl)‐3‐en‐2‐ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates.     

Gold‐Catalyzed Oxidation/C−H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones

An efficient strategy to construct salicyl ketones through gold‐catalyzed oxidation/C?H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non‐diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α‐oxo gold carbenes generated in situ through gold‐catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC‐3 prostate cancer cell line and SKOV‐3 human ovarian carcinoma cell line yield IC₅₀ were 0.81±0.05 and 0.87±0.15 μm , respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.     

Palladium(II)‐Catalyzed Dehydroboration via Generation of Boron Enolates

The Pd^II‐catalyzed dehydroboration of boron enolates generated from ketones and 9‐iodo‐9‐borabicyclo[3.3.1]nonane was achieved, providing a synthetically versatile protocol from ketones to α,β‐unsaturated ketones. The Pd^II compound employed in this reaction worked catalytically in the presence of Cu(OAc)₂. The high trans‐selectivity of the olefinic moiety was observed. Aryl halide moieties (‐Br and ‐Cl) remained intact for this reaction in spite of the presence of a Pd species. An ester substrate could also be applied when a stoichiometric amount of Pd^II was used. The crossover reactions using boron and silyl enolates revealed that the oxidation reaction is much faster than the Saegusa‐Ito reaction.     

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.     

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.     

Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

A broadly applicable, practical, scalable, efficient and highly α‐ and enantioselective method for addition of a silyl‐protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97 % yield and 98.5:1.5 enantiomeric ratio. Alkyl‐, alkenyl‐, alkynyl‐, aryl‐ or heteroaryl‐substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis.     

Computational insight into asymmetric uranyl‐salophen coordinated with α, β‐unsaturated aldehydes and ketones

The study of the catalytic activity and activation mechanism of asymmetric uranyl‐salophens with α, β‐unsaturated aldehydes or α, β‐unsaturated ketones, is a research hotspot. In this paper, the complexes of the uranyl–salophen(U‐S) modified by unilateral benzene, coordinated with cyclohexenone, cyclopentenone and acrolein, were investigated using density functional theory calculations at the level of B3LYP/6‐311G(d, p) basis set. The results showed that the uranyl‐salophen(U‐S) weakened the large π bond between C = C and C = O of the α, β‐unsaturated aldehydes and ketones, making the unsaturated aldehydes and ketones activated. In addition, the molecular‐recognition selectivity of the asymmetrical uranyl‐salophen for cyclohexenone and cyclopentenone were much higher than for acrolein.     

Ketones as Molecular Co‐catalysts for Boosting Exciton‐Based Photocatalytic Molecular Oxygen Activation

Excitonic processes in semiconductors open up the possibility for pursuing photocatalytic organic synthesis. However, the insufficient spin relaxation and robust nonradiative decays in semiconductors place restrictions on both quantum yield and selectivity of these reactions. Herein, by taking polymeric carbon nitride (PCN)/acetone as a prototypical system, we propose that extrinsic aliphatic ketones can serve as molecular co‐catalysts for promoting spin‐flip transition and suppressing non‐radiative energy losses. Spectroscopic investigations indicate that hot excitons in PCN can be transferred to ketones, while triplet excitons in ketones can be transferred to PCN. As such, the PCN/ketone systems exhibit considerable triplet‐exciton accumulation and extended visible‐light response, leading to excellent performance in exciton‐based photocatalysis, such as singlet oxygen generation. This work provides a fundamental understanding of energy harvesting in semiconductor/molecule systems, and paves the way for optimizing exciton‐based photocatalysis via molecular co‐catalyst design.