Showing papers in "Journal of Organic Chemistry in 2016"
TL;DR: This Perspective highlights the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds.
Abstract: In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon–carbon and carbon–heteroatom bonds.
1,808 citations
455 citations
TL;DR: It is demonstrated that the continuous variation method use in supramolecular chemistry often provides false results, and an alternative, general method relying on the analysis of residual distribution in titration data fitting is proposed.
Abstract: Continuous variation method, known as Job plot, is the most commonly applied method for the determination of stoichiometry of complex chemical entities for over 100 years. Although, the method was proven successful in the analysis of very stable metal–ligand complexes, we demonstrate that its use in supramolecular chemistry often provides false results. We support this statement with multiple simulations as well as cases studies of several real host–guest systems. We propose an alternative, general method relying on the analysis of residual distribution in titration data fitting. The latter method is more convenient compared to the Job plot and unlike it gives correct results in all real cases studied.
257 citations
TL;DR: Two new strategies to accessortho-Quinone methides in situ that are compatible with simultaneous nucleophile generation and a suite of innovative and selective transformations accessing heterocycles for use in organic synthesis are presented.
Abstract: ortho-Quinone methides have emerged recently as useful electrophiles in metal-free catalysis. New strategies to access these species in situ that are compatible with simultaneous nucleophile generation have provided a suite of innovative and selective transformations accessing heterocycles for use in organic synthesis.
223 citations
TL;DR: A series of novel acridinium salts are reported as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).
Abstract: The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth’s crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).
220 citations
TL;DR: This synopsis focuses on visible-light catalysis, a recent and very promising technological refinement of this class of transformations, which allows for the use of a variety of (metallic or nonmetallic) systems to efficiently create some of the most commonly looked for types of bonds.
Abstract: Radical difunctionalizations of alkenes constitute an efficient method for the construction of complex organic molecules. This synopsis focuses on visible-light catalysis, a recent and very promising technological refinement of this class of transformations. Examples taken from the literature illustrate the use of a variety of (metallic or nonmetallic) systems, which allow us to leverage the energy of readily available visible-light radiation to efficiently create some of the most commonly looked for types of bonds (C–X, C–O, C–N, and C–C) under mild conditions and starting from unsaturated substrates.
219 citations
TL;DR: A photocatalytic decarboxylative/defluorinative reaction of α-trifluoromethyl alkenes with α-keto acids and α-amino acids has been developed, affording various γ,γ-difluoroallylic ketones and 1,1-dIFluorohomoallyl amines in good yields.
Abstract: A photocatalytic decarboxylative/defluorinative reaction of α-trifluoromethyl alkenes with α-keto acids and α-amino acids has been developed. The reaction occurs at room temperature under visible light irradiation, affording various γ,γ-difluoroallylic ketones and 1,1-difluorohomoallyl amines in good yields. The synthetic applications of the resulting functionalized gem-difluoroalkenes were also described.
166 citations
TL;DR: This synopsis surveys the diverse recent approaches to amide synthesis from nonactivated carboxylic acids and derivatives as well as noncar boxylic compounds, highlighting the most innovative methodologies and those that are more eco-friendly compared to traditional methods while focusing on recent developments during the past two years.
Abstract: Amides are unquestionably one of the most important functional groups in organic chemistry because of their presence in numerous interesting molecules such as peptides, pharmaceutical agents, naturally occurring molecules, proteins and alkaloids, among others. This synopsis surveys the diverse recent approaches to amide synthesis from nonactivated carboxylic acids and derivatives as well as noncarboxylic compounds, highlighting the most innovative methodologies and those that are more eco-friendly compared to traditional methods while focusing on recent developments during the past two years.
164 citations
TL;DR: This synopsis sets out to highlight recent advances in the field of amide activation, focused on the use of triflic anhydride, and the myriad of transformations that can ensue upon addition of several classes of electrophiles to the intermittently generated high energy intermediates.
Abstract: The electrophilic activation of amides, especially by the action of trifluoromethanesulfonic (triflic) anhydride, enables the formation of highly electrophilic and reactive intermediates, lending themselves to diverse reaction pathways. This synopsis sets out to highlight recent advances in the field of amide activation, focused on the use of triflic anhydride, and the myriad of transformations that can ensue upon addition of several classes of electrophiles to the intermittently generated high energy intermediates.
158 citations
TL;DR: The super electrophilicity of a shelf-stable, easily prepared trifluoromethylthio-dibenzenesulfonimide 7 was demonstrated and exhibits reactivity remarkably higher than that of other known electrophilic trifLUorometHylthiolating reagents.
Abstract: The super electrophilicity of a shelf-stable, easily prepared trifluoromethylthiolating reagent N-trifluoromethylthio-dibenzenesulfonimide 7 was demonstrated. Consistent with the theoretical prediction, 7 exhibits reactivity remarkably higher than that of other known electrophilic trifluoromethylthiolating reagents. In the absence of any additive, 7 reacted with a wide range of electron-rich arenes and activated heteroarenes under mild conditions. Likewise, reactions of 7 with styrene derivatives can be fine-tuned by simply changing the reaction solvents to generate trifluoromethylthiolated styrenes or oxo-trifluoromethylthio or amino-trifluoromethylthio difunctionalized compounds in high yields.
143 citations
TL;DR: Some recent advances in the construction of heterocycles are discussed, focusing on catalytic methodology, which has contributed in a major way to developments of green and sustainable chemistry.
Abstract: The synthesis of heterocycles is arguably one of the oldest and at the same time one of the youngest disciplines of organic chemistry. Groundbreaking principles to form heterocycles, mainly by condensation reactions, were recognized in the beginning of the 19th century, and many of the classical reactions discovered at that time are still of great value today. In the 21st century, the wealth of synthetic methodology toward heterocycles is overwhelming, and catalysis, in particular, as one of the cornerstones of green and sustainable chemistry has contributed in a major way to these developments. This perspective tries the impossible by discussing some recent advances in the construction of heterocycles, focusing on catalytic methodology. We are aware that we do not come close to giving adequate credit to the great creativity of chemists in the field.
TL;DR: It is demonstrated that N-acyl-tert-butyl-carbamates and N-ACYl-tosylamides, two classes of acyclic amides that have recently enabled the development of elusive amide bond N-C cross-coupling reactions with organometallic reagents, are intrinsically twisted around the N-O(O) axis.
Abstract: Amide N–C(O) bonds are generally unreactive in cross-coupling reactions employing low-valent transition metals due to nN → π*C═O resonance. Herein we demonstrate that N-acyl-tert-butyl-carbamates (Boc) and N-acyl-tosylamides (Ts), two classes of acyclic amides that have recently enabled the development of elusive amide bond N–C cross-coupling reactions with organometallic reagents, are intrinsically twisted around the N–C(O) axis. The data have important implications for the design of new amide cross-coupling reactions with the N–C(O) amide bond cleavage as a key step.
TL;DR: A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade, which provides a mild and effective method for the assembly of synthetically and structurally interesting spIROcyclopropanyl para-dienones.
Abstract: A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.
TL;DR: By developing a mild Ni-catalyzed system, a method for direct borylation of sp(2) and sp(3) C-N bonds has been established and shows good functional group compatibility and can serve as a powerful synthetic tool for gram-scale synthesis and late-stage Borylative cleavage of complex compounds.
Abstract: By developing a mild Ni-catalyzed system, a method for direct borylation of sp2 and sp3 C–N bonds has been established. The key to this hightly efficient C–N bond borylative cleavage depends on the appropriate choice of the nickel catalyst Ni(COD)2, ICy·HCl as a ligand, and the use of 2-ethoxyethanol as the cosolvent. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for gram-scale synthesis and late-stage C–N borylation of complex compounds.
TL;DR: The rhodium(III)-catalyzed intermolecular C7-thiolation and selenation of indolines with disulfides and diselenides were developed and relies on the use of a removable pyrimidyl directing group to access valuable C-7 functionalized indoline scaffolds with ample substrate scope and broad functional group tolerance.
Abstract: The rhodium(III)-catalyzed intermolecular C7-thiolation and selenation of indolines with disulfides and diselenides were developed. This protocol relies on the use of a removable pyrimidyl directing group to access valuable C-7 functionalized indoline scaffolds with ample substrate scope and broad functional group tolerance.
TL;DR: The utility of the copper-catalyzed C3 aryl- and heteroarylselenation of indoles employing selenium powder has been demonstrated in an efficient gram-scale synthesis and an application to the synthesis of tubulin polymerization inhibitor.
Abstract: A new and efficient copper-catalyzed C3 aryl- and heteroarylselenation of indoles employing selenium powder has been developed. The advantages of this chemistry involve the use of cheap selenating reagents, tolerance of a variety of functional groups, and practicality. In addition, this protocol has been further elaborated in an intramolecular phenylselenation of a (hetero) aryl C–H bond to construct an important motif of benzoselenopheno[3,2-b]indole. A preliminary mechanism study suggests that the reaction starts with a Ullman-type selenation between aryl iodides and selenium, followed by an oxidative cross-coupling with indole. The utility of this method has been demonstrated in an efficient gram-scale synthesis and an application to the synthesis of tubulin polymerization inhibitor.
TL;DR: A mixed MeCN/EtOH solvent system was found to enable effective C-N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amine.
Abstract: The Chan–Evans–Lam reaction is a valuable C–N bond forming process. However, aryl boronic acid pinacol (BPin) ester reagents can be difficult coupling partners that often deliver low yields, in particular in reactions with aryl amines. Herein, we report effective reaction conditions for the Chan–Evans–Lam amination of aryl BPin with alkyl and aryl amines. A mixed MeCN/EtOH solvent system was found to enable effective C–N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amines.
TL;DR: This protocol employs the readily prepared difluoromethyltriphenylphosphonium bromide as the diffluoromethylating reagent and alcohols/water as the nucleophiles, affording dif fluorometHyl(CF2H)-containing alcohols and ethers in moderate to excellent yields.
Abstract: A convenient, visible light induced oxidifluoromethylation of styrenes was developed. This protocol employs the readily prepared difluoromethyltriphenylphosphonium bromide as the difluoromethylating reagent and alcohols/water as the nucleophiles, affording difluoromethyl(CF2H)-containing alcohols and ethers in moderate to excellent yields.
TL;DR: A key enabling advance in this work was achieved by implementing visible light photoredox catalysis that proved to be applicable to many classes of heteroarenes and tolerant of diverse functional groups found in druglike molecules.
Abstract: We report the development of a method for room-temperature C–H hydroxymethylation of heteroarenes. A key enabling advance in this work was achieved by implementing visible light photoredox catalysis that proved to be applicable to many classes of heteroarenes and tolerant of diverse functional groups found in druglike molecules.
TL;DR: The mechanistic approach was extended using tosyl cyanide as a radical trap, enabling the conversion of alkyltrifluoroborates to nitriles via a Fukuzumi acridinium-catalyzed process, forming Allylic and homoallylic amines in moderate yields with high E/Z selectivity.
Abstract: Iridium- and ruthenium-free approaches to protected allylic amines and alkyl nitriles under photoredox conditions are reported. An inexpensive organic dye, eosin Y, catalyzes coupling of Boc-protected potassium α-aminomethyltrifluoroborates with a variety of substituted alkenyl sulfones through an α-aminomethyl radical addition–elimination pathway. Allylic and homoallylic amines were formed in moderate yields with high E/Z selectivity. The mechanistic approach was extended using tosyl cyanide as a radical trap, enabling the conversion of alkyltrifluoroborates to nitriles via a Fukuzumi acridinium-catalyzed process.
TL;DR: The ability to tune the reduction potential of metal-free phenothiazine-based photoredox catalysts is reported and the application of these catalysts for chemoselective carbon-halogen bond activation to achieve C-C cross-coupling reactions as well as reductive dehalogenations is demonstrated.
Abstract: Despite the number of methods available for dehalogenation and carbon-carbon bond formation using aryl halides, strategies that provide chemoselectivity for systems bearing multiple carbon-halogen bonds are still needed. Herein, we report the ability to tune the reduction potential of metal-free phenothiazine-based photoredox catalysts and demonstrate the application of these catalysts for chemoselective carbon-halogen bond activation to achieve C-C cross-coupling reactions as well as reductive dehalogenations. This procedure works both for conjugated polyhalides as well as unconjugated substrates. We further illustrate the usefulness of this protocol by intramolecular cyclization of a pyrrole substrate, an advanced building block for a family of natural products known to exhibit biological activity.
TL;DR: Density functional theory calculations are performed to determine why thiol additions to Michael acceptors are reversible and explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.
Abstract: Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of cova...
TL;DR: Consecutive intramolecular 1,3-hydride transfers from the ruthenium center to coordinated nitrile and boronate imine ligands, leading to the reduction and resulting in the formation of diboronates amines, are proposed as a plausible reaction mechanism.
Abstract: Ruthenium-catalyzed hydroboration of nitriles and imines is attained using pinacolborane with unprecedented catalytic efficiency. Chemoselective hydroboration of nitriles over esters is also demonstrated. A simple [Ru(p-cymene)Cl2]2 complex (1) is used as a catalyst precursor, which upon reaction with pinacolborane in situ generates the monohydrido-bridged complex [{(η6-p-cymene)RuCl}2(μ-H-μ-Cl)] 2. Further oxidative addition of pinacolborane to intermediate 2 leading to the formation of mononuclear ruthenium hydride species is suggested. Mass spectral analysis of the reaction mixture and independent experiments with phosphine-ligated ruthenium complexes indicated the involvement of mononuclear ruthenium intermediates in the catalytic cycle. Consecutive intramolecular 1,3-hydride transfers from the ruthenium center to coordinated nitrile and boronate imine ligands, leading to the reduction and resulting in the formation of diboronate amines, are proposed as a plausible reaction mechanism.
TL;DR: This approach has not only realized the successful application of o-hydroxylstyrenes as oxa-diene precursors in catalytic asymmetric cycloadditions but also established a new cooperative catalytic system of chiral phosphoric acid and chiral guanidine.
Abstract: An enantioselective [4 + 2] cycloaddition of o-hydroxylstyrenes with azlactones has been established by merging chiral Bronsted acid (chiral phosphoric acid) and base (chiral guanidine) catalysis, which constructed a biologically important dihydrocoumarin scaffold in an efficient and enantioselective style (up to 99% yield, 96:4 er). This approach has not only realized the successful application of o-hydroxylstyrenes as oxa-diene precursors in catalytic asymmetric cycloadditions but also established a new cooperative catalytic system of chiral phosphoric acid and chiral guanidine.
TL;DR: Formal regiodivergent C-H alkynylation of 2-pyridones bearing different N-substituents has been realized under Au(I) and Rh(III) catalysis using a hypervalent iodine alkyne reagent.
Abstract: Formal regiodivergent C–H alkynylation of 2-pyridones bearing different N-substituents has been realized under Au(I) and Rh(III) catalysis using a hypervalent iodine alkyne reagent. When catalyzed by Au(I), the alkynylation occurred at the most electron-rich 5-position via an electrophilic alkynylation pathway. The selectivity was switched to the 6-position under assistance of an N-chelation group when a Rh(III) catalyst was employed. A rhodacylic complex has been isolated as a key intermediate.
TL;DR: A variety of (E)-vinyl sulfones were constructed directly from cinnamic acids and sodium sulfinates with high regioselectivity at room temperature by virtue of an electrocatalytic oxidation.
Abstract: A variety of (E)-vinyl sulfones were constructed directly from cinnamic acids and sodium sulfinates with high regioselectivity at room temperature by virtue of an electrocatalytic oxidation A radical intermediate was detected, and the corresponding mechanism was investigated
TL;DR: Experimental and theoretical investigation implicated that a single-electron-transfer process is involved in this sulfonylation transformation of quinolines via bidentate-chelation assistance.
Abstract: Copper(I)-catalyzed 5-sulfonation of quinolines via bidentate-chelation assistance has been developed. The reaction is compatible with a wide range of quinoline substrates and arylsulfonyl chlorides. Experimental and theoretical (DFT) investigation implicated that a single-electron-transfer process is involved in this sulfonylation transformation.
TL;DR: An efficient and convenient palladium-catalyzed C-H bond oxidative sulfenylation of indoles and related electron-rich heteroarenes with aryl boronic acids and elemental sulfur has been described.
Abstract: An efficient and convenient palladium-catalyzed C–H bond oxidative sulfenylation of indoles and related electron-rich heteroarenes with aryl boronic acids and elemental sulfur has been described. This procedure provides a useful and direct approach for the assembly of a wide range of structurally diverse 3-sulfenylheteroarenes with moderate to excellent yields from simple and readily available starting materials. Moreover, this synthetic protocol is suitable for N-protected and unprotected indoles. Notably, the construction of two C–S bonds in one step was also achieved in this transformation.
TL;DR: Unexpected improvement of yield over 55% is observed using alcohols as additives, which is explained by in situ formed alkoxides and their participation in oxidative addition.
Abstract: The effect of liquid-assisted grinding has been studied using mechanical Suzuki–Miyaura reaction of aryl chlorides as the model reaction. Catalytic systems of Davephos and PCy3 are tested respectively showing strong influences from different liquids. Unexpected improvement of yield over 55% is observed using alcohols as additives, which is explained by in situ formed alkoxides and their participation in oxidative addition. Further expansion of substrates using Pd(OAc)2/PCy3/MeOH system gives desired products in good to high yields.
TL;DR: A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselectives direct assembly of unsymmetric β,β-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described.
Abstract: A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric β,β-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.