C-C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides.

A new approach for the preparation of amides was developed using C-C bond cleavage that initiates C- to N-acyl transfer, employing activated ketones as acylation reagents and amine nucleophiles. The reaction was operational under the coupling reagent system that is commonly utilized for peptide bond formations. The method enables practical preparation of amides using linear and cyclic ketone substrates under mild conditions.

Methyl Pyruvate Oxime as a Carbonyl Synthon: Synthesis of Ureas, Carbamates, Thiocarbamates, and Anilides.

A new strategy for the synthesis of unsymmetrical ureas, carbamates, thiocarbamates, and anilides was developed with methyl pyruvate oxime as the carbonyl synthon. The intrinsic reactivity of the reagent enabled consecutive disubstitution involving direct amidation and one-pot deoximative substitution with various nucleophiles. The utility of the method was demonstrated with the synthesis of bioactive molecules.

A deconstruction-reconstruction strategy to access 1-naphthol derivatives: application to the synthesis of aristolactam scaffolds.

A deconstruction-reconstruction strategy for the synthesis of multisubstituted polycyclic aromatic hydrocarbons (PAHs) is delineated herein. The deconstruction step enables the synthesis of o-cyanomethylaroyl fluorides that are bifunctional substrates holding both a pro-nucleophile and an electrophile. The construction step involves a formal [4 + 2] benzannulation using o-cyanomethylaroyl fluorides and active methylenes. The utility of this synthetic method is also demonstrated by the synthesis of a tetracyclic aristolactam derivative.

A Strategic Synthesis of Fluoroethers via Ring-Opening Fluorinative Beckmann Fragmentation.

An SN1-type fluorination method for monofluoroethers is developed. The key to this reaction is fluorinative C-C bond cleavage that is driven by oxygen-assisted Beckmann fragmentation. To enable this transformation, cyclic α-aryloxyoximes derived from 3-coumaranone and 1-indanones were investigated as substrates, using N,N-diethylaminosulfur trifluoride (DAST) as a dual-role reagent of an oxime activator and fluoride donor. This method features the synthesis of an underdeveloped chemical motif with simple and mild operating conditions.

Synthesis of Carbamoyl Fluorides via a Selective Fluorinative Beckmann Fragmentation.

A fluorinative Beckmann fragmentation of α-oximinoamides was devised to provide synthetically useful carbamoyl fluorides. High selectivity for fragmentation over a potentially competing Beckmann rearrangement was observed. This protocol has a distinct mechanism and thus a different substrate scope compared with other synthetic methods. α-Oximinoamides derived from the readily available secondary amines, lactams, or isatins were converted into structurally diverse carbamoyl fluorides.

Recent Advances in One-Pot Modular Synthesis of 2-Quinolones.

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.

Synthesis of Acyl Fluorides via DAST-Mediated Fluorinative C-C Bond Cleavage of Activated Ketones.

A new protocol for preparation of acyl fluorides was developed by recognizing activated ketones as starting materials. The method provides a different scope compared with previously reported methods that employ carboxylic acids as substrates. A working hypothesis of pull-and-push-driven fluorinative C-C bond cleavage was successfully demonstrated by the simple addition of diethylaminosulfur trifluoride (DAST) derivatives to α-oximinoketones. The designed reaction system led to a highly efficient and chemoselective reaction. The wide availability of the ketones allowed for a range of synthetically useful aryloyl and aliphatic acyl fluorides including those containing chiral skeletons. The method is mild, fast, scalable, and potentially one-pot operative.

One-pot copper-catalyzed three-component reaction: a modular approach to functionalized 2-quinolones.

A copper-catalyzed three-component annulation for the synthesis of functionalized 2-quinolones was developed. Three reactions including an SN2, a Knoevenagel, and finally C-N bond formation are involved in the designed cascade reaction using 2-bromoacylarenes, 2-iodoacetamide, and nucleophiles as the three components. A new catalytic system was discovered during the study and this modular approach is highly efficient to access functionalized 2-quinolone derivatives, compatible with a broad range of functional groups, scalable, and step-economic. Further derivatization of the obtained product demonstrates the synthetic utility of this method.

Step-economical synthesis of 3-amido-2-quinolones by dendritic copper powder-mediated one-pot reaction.

The one-pot protocol by the dendritic copper powder-mediated Knoevenagel condensation/annelation is delineated here for the synthesis of 3-amido-2-quinolones. It is practical with moisture tolerance and easy setup, and is compatible with many functional groups under mild conditions. This method was applied for the preparation of the key intermediates of biologically relevant 3-amido-2-quinolones.

Intramolecular Acetyl Transfer to Olefins by Catalytic C-C Bond Activation of Unstrained Ketones.

A rhodium-catalyzed intramolecular acetyl-group transfer has been achieved through a "cut and sew" process. The challenge arises from the existence of different competitive pathways. Preliminary success has been achieved with unstrained enones that contain a biaryl linker. The use of an electron-rich N-heterocycilc carbene (NHC) ligand is effective to inhibit undesired ß-hydrogen elimination. Various 9,10-dihydrophenanthrene derivatives can be prepared with excellent functional-group compatibility. The 13 C-labelling study suggests that the reaction begins with cleavage of the unstrained C-C bond, followed by migratory insertion and reductive elimination.

Catalytic Cage Formation via Controlled Dimerization of Norbornadienes: An Entry to Functionalized HCTDs (Heptacyclo[6.6.0.0(2,6).0(3,13).0(4,11).0(5,9).0(10,14)]tetradecanes).

A general and practical catalytic method has been developed for the rapid synthesis of HCTD (heptacyclo[6.6.0.0(2,6).0(3,13).0(4,11).0(5,9).0(10,14)]tetradecanes) and various new 7,12-disubstituted HCTDs from norbornadienes. Compared to the known approaches, this new protocol avoids stoichiometric metals, utilizes commercially available reagents as catalysts, and affords higher yields and significantly improved selectivity. In addition, quadracyclane was discovered for the first time to undergo a similar endo,cis,endo cycloaddition to give HCTD in a good yield. Derivatization of HCTDs led to efficient preparation of a range of novel homo- and heterobifunctional scaffolds that hold potentials for biological and material applications.

Bifunctional Ligand-Assisted Catalytic Ketone α-Alkenylation with Internal Alkynes: Controlled Synthesis of Enones and Mechanistic Studies.

Here, we describe a detailed study of the rhodium(I)-catalyzed, bifunctional ligand-assisted ketone α-C-H alkenylation using internal alkynes. Through controlling the reaction conditions, conjugated enamines, α,ß- or ß,γ-unsaturated ketones, can be selectively accessed. Both aromatic and aliphatic alkynes can be employed as coupling partners. The reaction conditions also tolerate a broad range of functional groups, including carboxylic esters, malonates, secondary amides, thioethers, and free alcohols. In addition, excellent E-selectivity was observed for the tetra-substituted alkene when forming the α,ß-unsaturated ketone products. The mechanism of this transformation was explored through control experiments, kinetic monitoring, synthesizing the rhodium-hydride intermediates and their reactions with alkynes, deuterium-labeling experiments, and identification of the resting states of the catalyst.

Catalytic Intramolecular Ketone Alkylation with Olefins by Dual Activation.

Two complementary methods for catalytic intramolecular ketone alkylation reactions with unactivated olefins, resulting in Conia-ene-type reactions, are reported. The transformations are enabled by dual activation of both the ketone and the olefin and are atom-economical as stoichiometric oxidants or reductants are not required. Assisted by Kool's aniline catalyst, the reaction conditions can be both pH- and redox-neutral. A broad range of functional groups are thus tolerated. Whereas the rhodium catalysts are effective for the formation of five-membered rings, a ruthenium-based system that affords the six-membered ring products was also developed.

Transition metal-catalyzed ketone-directed or mediated C-H functionalization.

Transition metal-catalyzed C-H functionalization has evolved into a prominent and indispensable tool in organic synthesis. While nitrogen, phosphorus and sulfur-based functional groups (FGs) are widely employed as effective directing groups (DGs) to control the site-selectivity of C-H activation, the use of common FGs (e.g. ketone, alcohol and amine) as DGs has been continuously pursued. Ketones are an especially attractive choice of DGs and substrates due to their prevalence in various molecules and versatile reactivity as synthetic intermediates. Over the last two decades, transition metal-catalyzed C-H functionalization that is directed or mediated by ketones has experienced vigorous growth. This review summarizes these advancements into three major categories: use of ketone carbonyls as DGs, direct ß-functionalization, and α-alkylation/alkenylation with unactivated olefins and alkynes. Each of these subsections is discussed from the perspective of strategic design and reaction discovery.

Intermolecular radical cation Diels-Alder (RCDA) reaction of bicyclooctadienes: biomimetic formal total synthesis of kingianin A and total syntheses of kingianins D, F, H, and J.

Three endo bicyclooctadienol dimers corresponding to kingianins A and H, D, and F and J were obtained by the intermolecular radical cation Diels-Alder (RCDA) reaction. Each isomer was cleanly isolated without the aid of preparative HPLC. Kingianins D, F, H, and J were prepared by way of these intermediates from commercially available materials in 10, 13, 9, and 17 steps, respectively. Kingianin A has already been prepared from one of these compounds. Completion of the synthesis of kingianin H relied on Manchand's one-step, three-carbon homologation.

Total synthesis of kingianin A.

A 12-step synthesis of kingianin A, an inhibitor of the antiapoptotic protein Bcl-xL, is based on a radical cation Diels-Alder reaction (RCDA). This approach is thought to be biomimetic. The use of a tether in the key RCDA step controls the regiochemistry of the cycloaddition, leading to the desired core structure and a separable diastereomer.

Total synthesis of the potent androgen receptor antagonist (-)-arabilin: a strategic, biomimetic [1,7]-hydrogen shift.

The first total synthesis of (-)-arabilin, a Streptomyces metabolite that inhibits hormone activation of the androgen receptor, has been completed. The key step, a [1,7]-hydrogen shift, establishes the enol ether-containing skipped-tetraene substructure. This nonenzymatic pericyclic reaction is considered to be biomimetic.