Radical trifluoromethylation of titanium ate enolate

The radical trifluoromethylation of ketone titanium ate enolates gave alpha-CF3 ketones in good yields. The use of excess amount of LDA and Ti(OiPr)4 in the preparation of titanium ate enolates is the key to the efficient radical trifluoromethylation. [reaction: see text]     

Efficient Lewis Acids Catalyzed Aza-Michael Reactions of Enones with Carbamates

The β-amino carbonyl functionality is not only a segment of biologically important natural products but also a versatile intermediate for the synthesis of nitrogen-containing compounds.1 The development of novel synthetic methods leading to β-amino ketone, β-amino acids or their derivatives has attracted much attention in organic synthesis.2 Among the traditional methods for generating β-amino carbonyl compounds, Mannich-type reaction is one of the classical and powerful methods.3 However,…     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

New oxidative pathways for the synthesis of α-hydroxy ketones—the α-hydroxylation and ketohydroxylation

α-Hydroxy ketones serve as versatile intermediates in organic chemistry. Although this functional group combination allows a variety of synthetic manipulation, catalytic methods for the selective generation of this structural motif, via oxidation of carbonyl compounds (α-hydroxylation) or olefins (ketohydroxylation), have recently been developed. The present review gives a brief overview of the recent developments in the field of catalytic α-hydroxylations and ketohydroxylations, with a focus on the latter reaction.     

Intramolecular Michael reactions of aliphatic aldehyde enolates generated by imidazolium carbenes

Due to the high reactivity of the formyl group under either basic or acidic reaction conditions required for the direct generation of aldehyde enolates, intramolecular Michael additions of aldehyde enolates to α,β-unsaturated carbonyl compounds have been underexplored for the stereoselective synthesis of carbocyclic compounds. The intramolecular Michael reaction of aldehyde enolates generated by imidazolium carbenes was explored for the synthesis of cyclopentane aldehydes. The imidazolium carbenes were used as Brønsted bases to directly generate the aldehydes enolates.     

Tandem nucleophilic addition/fragmentation reactions and synthetic versatility of vinylogous acyl triflates

A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the sigma-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 --> 6 or 8), is also illustrated.     

Synthesis, reactions, and applications of fluorine-containing multifunctional carbon compounds

The chemistry of compounds containing a carbon atom bearing three or four different labile functional groups has received little attention. These compounds should be of considerable significance in theoretical and synthetic organic chemistry. Among the compounds with multifunctional structures, those having both carbonyl and halogen groups in addition to other heteroatom groups seem especially valuable from a synthetic viewpoint. Their potential use as probes in pure and applied synthetic chemistry has not been exploited, presumably because of structural instability and a paucity of synthetic approaches. Keeping this background in mind, we focused on the synthesis of a new class of multifunctional carbon compounds in which ester carbonyl, halogen, and other heteroatom-derived functional groups are directly attached to the central carbon atom. Fluorine was chosen as the halogen because of the inherent stability of the CF bond and because of the fundamental chemical and biological interest in fluorine-containing compounds. The synthesis, reactions, and some applications of various fluorine-containing multifunctional carbon compounds are described.     

Conversion of Carbonyl Compounds to Olefins via Enolate Intermediate

A general and efficient protocol to synthesize substituted olefins from carbonyl compounds via nickel catalyzed C—O activation of enolates was developed. Besides ketones, aldehydes were also suitable substrates for the presented catalytic system to produce di‐ or tri‐ substituted olefins. It is worth noting that this approach exhibited good tolerance to highly reactive tertiary alcohols, which could not survive in other reported routes for converting carbonyl compounds to olefins. This method also showed good regio‐ and stereo‐selectivity for olefin products. Preliminary mechanistic studies indicated that the reaction was accomplished through nickel catalyzed C—O activation of enolates, thus offering helpful contribution to current enol chemistry.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Enolonium Species—Umpoled Enolates

Enolonium species/iodo(III)enolates of carbonyl compounds have been suggested to be intermediates in a wide variety of hypervalent iodine induced chemical transformations of ketones, including α‐C−O, α‐C−N, α‐C−C, and α‐carbon–halide bond formation, but they have never been characterized. We report that these elusive umpoled enolates may be made as discrete species that are stable for several minutes at −78 °C, and report the first spectroscopic identification of such species. It is shown that enolonium species are direct intermediates in C−O, C−N, C−Cl, and C−C bond forming reactions. Our results open up chemical space for designing a variety of new transformations. We showcase the ability of enolonium species to react with prenyl, crotyl, cinnamyl, and allyl silanes with absolute regioselectivity in up to 92 % yield.     

Intramolecular cross-dehydrogenative coupling of benzaldehyde derivatives: A novel and efficient route to benzocyclic ketones

Benzocyclic ketones are not only found throughout many natural products and synthetic pharmaceutically active compounds but also used as versatile building blocks in organic synthesis. In view of their importance, many researchers have been working to explore novel and efficient synthetic routes for this class of carbonyl compounds. Recently, cross-dehydrogenative coupling reactions have emerged as one of the most versatile and powerful synthetic strategies to construct various carbon-carbon and carbon-heteroatom bonds. In this regard, direct acylation of (hetero)arenes with aldehydes through C(sp²)-H activation opened up a new page on the synthesis of the titled compounds. In this focus-review, we discuss the most representative and important reports on the synthesis of cyclic diaryl ketones through intramolecular cross-dehydrogenative coupling reactions of corresponding benzaldehydes with emphasis on the mechanistic aspects of the reactions.     

Mercury,a Structural Building Block and Source of Localized Reactivity in Extended Metal–Metal Bonded Systems

Transition metal–mercury complexes were among the first compounds of study for the concept of direct metal–metal bonding which was established more than three decades ago. Since then, a large number of such systems have been synthesized and studied. The fact that mercury is readily attached to a large variety of main group or transition metals has stimulated its use as a general building block in the systematic synthesis of mixed-metal clusters. The past decade has witnessed a rapid expansion of bimetallic cluster chemistry in which species containing mercury have played a prominent role, and which has led to the discovery of many unprecedented cluster structures and reactions. In particular, the ability of mercury to form multicenter metal–metal bonds with polynuclear cluster fragments has substantially extended its coordination chemistry which was thus far dominated by simple linear structural arrangements. Although certain structural motifs are found to be common to many of the transition metal–mercury clusters investigated to date and thus enable a relatively systematic synthetic approach, the multitude of surprising discoveries has kept the interest in the chemistry of the element itself alive. The recent discovery of the redox and photochemical reactivity of some of these systems has opened up an exciting and promising area of cluster research. Its significance for the synthetic methodology lies in the fact that the increasing redox activity of molecular carbonyl clusters on going to higher nuclearities appears to set a limit on the size of metal frameworks attainable by the standard preparative methods. On the other hand, their potential use as photochromes or redox mediaters in coupled electron-transfer reactions provides an additional stimulus for future studies in this field.     

Homogeneously catalysed isomerisation of allylic alcohols to carbonyl compounds

Isomerisation of allylic alcohols forms an elegant shortcut to carbonyl compounds in a completely atom-economical process that offers several useful applications in natural-product synthesis and in bulk chemical processes. This review focuses on the heart of isomerisation catalysis: the catalyst. Combinations of transition metals (from Group 4 to 10), ligands and reaction conditions are compared with respect to yield, turnovers, rate and selectivity. A selected number of clever solutions to synthetic problems are highlighted, such as the synthesis of enols and enolates, chiral carbonyl compounds and silyl substituted ketones. Furthermore, a general overview of the mechanisms proposed for the isomerisation of allylic alcohols is given while some catalyst systems are singled out to discuss mechanistic research.     

A Focused Review of Synthetic Applications of Lawesson’s Reagent in Organic Synthesis

Lawesson’s reagent (LR) is a well-known classic example of a compound with unique construction and unusual chemical behavior, with a wide range of applications in synthetic organic chemistry. Its main functions were rounded for the thionation of various carbonyl groups in the early days, with exemplary results. However, the role of Lawesson’s reagent in synthesis has changed drastically, and now its use can help the chemistry community to understand innovative ideas. These include constructing biologically valuable heterocycles, coupling reactions, and the thionation of natural compounds. The ease of availability and the convenient usage of LR as a thionating agent made us compile a review on the new diverse applications on some common functional groups, such as ketones, esters, amides, alcohols, and carboxylic acids, with biological applications. Since the applications of LR are now diverse, we have also included some new classes of heterocycles such as thiazepines, phosphine sulfides, thiophenes, and organothiophosphorus compounds. Thionation of some biologically essential steroids and terpenoids has also been compiled. This review discusses the recent insights into and synthetic applications of this famous reagent from 2009 to January 2021.     

Synthesis of (E)-alpha-hydroxy-beta,gamma-unsaturated amides with high selectivity from alpha,beta-epoxyamides by using catalytic samarium diiodide or triiodide

The highly stereoselective synthesis of (E)-alpha-hydroxy-beta,gamma-unsaturated amides starting from alpha,beta-epoxyamides, by using catalytic SmI2 or SmI3, was achieved. This transformation can also be carried out by using SmI2 generated in situ from samarium powder and diiodomethane. The starting compounds 1 are easily prepared by the reaction of enolates derived from alpha-chloroamides with ketones at -78 degrees C. A mechanism to explain this transformation has been proposed. Cyclopropanation of (E)-alpha-hydroxy-beta,gamma-unsaturated amides has been performed to demonstrate their synthetic applications.     

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.     

Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapalindole indole alkaloid family has been achieved from carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi-fischerindole U isothiocyanate are reported. The absolute stereochemistry of the latter natural product has also been determined.     

Coupling reaction of alkyl chlorides with silyl enolates catalyzed by indium trihalide

Indium(III) halide catalyzed not only the coupling of alkyl chlorides with silyl enolates derived from esters, ketones, and aldehydes to give a variety of alpha-alkylated carbonyl compounds but also one-pot, three-component reactions of aldehyde enolate, alkyl chloride, and allylsilane or alkynylsilane.     

Cross-coupling reaction of alpha-chloroketones and organotin enolates catalyzed by zinc halides for synthesis of gamma-diketones

The reaction of tin enolates 1 with alpha-chloro- or bromoketones 2 gave gamma-diketones (1,4-diketones) 3 catalyzed by zinc halides. In contrast to the exclusive formation of 1,4-diketones 3 under catalytic conditions, uncatalyzed reaction of 1 with 2 gave aldol-type products 4 through carbonyl attack. NMR study indicates that the catalyzed reaction includes precondensation between tin enolates and alpha-haloketones providing an aldol-type species and their rearrangement of the oxoalkyl group with leaving halogen to produce 1,4-diketones. The catalyst, zinc halides, plays an important role in each step. The carbonyl attack for precondensation is accelerated by the catalyst as Lewis acid and the intermediate zincate promotes the rearrangement by releasing oxygen and bonding with halogen. Various types of tin enolates and alpha-chloro- and bromoketones were applied to the zinc-catalyzed cross-coupling. On the other hand, the allylic halides, which have no carbonyl moiety, were inert to the zinc-catalyzed coupling with tin enolates. The copper halides showed high catalytic activity for the coupling between tin enolates 1 and organic halides 7 to give gamma,delta-unsaturated ketones 8 and/or 9. The reaction with even chlorides proceeded effectively by the catalytic system.     

Metal‐Free Oxidative Radical Addition of Carbonyl Compounds to α,α‐Diaryl Allylic Alcohols: Synthesis of Highly Functionalized Ketones

A metal‐free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α‐diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2‐aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.