Showing papers in "Journal of Organic Chemistry in 2014"
TL;DR: A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity.
Abstract: A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity. Recent synthetic advances and mechanistic studies have shed light on four possible methods for overcoming this challenge: (1) employing an excess of one reagent; (2) electronic differentiation of starting materials; (3) catalyst–substrate steric matching; and (4) radical chain processes. Each method is described using examples from the recent literature.
382 citations
TL;DR: The recent rapid evolution of cobalt-catalyzed C-H transformations with organic electrophiles is reviewed and set the stage for challenging direct alkylations with primary and sterically hindered secondary alkyl halides.
Abstract: Catalytic C–H functionalizations are increasingly viable tools for sustainable syntheses. In recent years, inexpensive cobalt complexes were identified as powerful catalysts for C–H arylations with challenging organic electrophiles. In particular, cobalt complexes of N-heterocyclic carbenes enabled high catalytic efficacy under exceedingly mild reaction conditions. This strategy set the stage for challenging direct alkylations with primary and sterically hindered secondary alkyl halides. Herein, the recent rapid evolution of cobalt-catalyzed C–H transformations with organic electrophiles is reviewed until summer 2014.
304 citations
TL;DR: Recent advances in the synthesis of substituted saturated N-heterocycles are discussed, focusing on approaches that offer generality and convenience from widely available building blocks.
Abstract: Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaffolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that offer generality and convenience from widely available building blocks.
224 citations
TL;DR: A detailed account of the design and synthesis of a new class of photochromes based on furfural, termed donor-acceptor Stenhouse adducts (DASAs), which respond to visible light and heat and display an unprecedented level of structural modularity and tunabilty.
Abstract: The development of an easily synthesized, modular, and tunable organic photoswitch that responds to visible light has been a long-standing pursuit. Herein we provide a detailed account of the design and synthesis of a new class of photochromes based on furfural, termed donor–acceptor Stenhouse adducts (DASAs). A wide variety of these derivatives are easily prepared from commercially available starting materials, and their photophysical properties are shown to be dependent on the substituents of the push–pull system. Analysis of the switching behavior provides conditions to access the two structural isomers of the DASAs, reversibly switch between them, and use their unique solubility behavior to provide dynamic phase-transfer materials. Overall, these negative photochromes respond to visible light and heat and display an unprecedented level of structural modularity and tunabilty.
196 citations
TL;DR: A simple and efficient visible-light-promoted method for the C-3 thiocyanation of indoles has been developed and is mild, high-yielding, and environmentally benign.
Abstract: A simple and efficient visible-light-promoted method for the C-3 thiocyanation of indoles has been developed. The transformation uses Rose Bengal as the photocatalyst and air as the terminal oxidant. The reaction is mild, high-yielding, and environmentally benign.
172 citations
TL;DR: This Perspective presents an analysis of the origin of the inception of bidentate benzylidene ligands for Ru-based OM catalysts and the intellectual basis that culminated in the development of Mo-based diolates and stereogenic-at-Ru complexes for enantioselective OM.
Abstract: There have been numerous significant advances in catalytic olefin metathesis (OM) during the past two decades. Such progress has transformed this important set of reactions to strategically pivotal processes that generate stereochemical identity while delivering molecules that cannot be easily prepared by alternative routes. In this Perspective, an analysis of the origin of the inception of bidentate benzylidene ligands for Ru-based OM catalysts is first presented. This is followed by an overview of the intellectual basis that culminated in the development of Mo-based diolates and stereogenic-at-Ru complexes for enantioselective OM. The principles accrued from the study of the latter Ru carbenes and Mo alkylidenes and utilized in the design of stereogenic-at-Mo, -W, and -Ru species applicable to enantioselective and Z-selective OM are then discussed. The influence of the recently introduced catalytic OM protocols on the design of synthesis routes leading to complex organic molecules is probed. The impact of a better understanding of the mechanistic nuances of OM toward the discovery of stereoselective catalysts is reviewed as well.
170 citations
TL;DR: It is shown that co-catalytic oxidants can be important in the design of synthetic reactions involving visible light photoredox catalysis, and p-toluidine serves as a redox mediator that is capable of catalyzing the otherwise inefficient photooxidation of thiols to the key thiyl radical intermediate.
Abstract: Synthetically useful radical thiol–ene reactions can be initiated by visible light irradiation in the presence of transition metal polypyridyl photocatalysts. The success of this method relies upon the use of p-toluidine as an essential additive. Using these conditions, high-yielding thiol–ene reactions of cysteine-containing biomolecules can be accomplished using biocompatibile wavelengths of visible light, under aqueous conditions, and with the thiol component as the limiting reagent. We present evidence that p-toluidine serves as a redox mediator that is capable of catalyzing the otherwise inefficient photooxidation of thiols to the key thiyl radical intermediate. Thus, we show that co-catalytic oxidants can be important in the design of synthetic reactions involving visible light photoredox catalysis.
166 citations
TL;DR: C–H functionalization reactions are explored as an alternative approach to access pseudodimeric cyclobutane natural products, such as the dictazole and the piperarborenine families, in a variety of complex settings.
Abstract: The application of C–H functionalization logic to target-oriented synthesis provides an exciting new venue for the development of new and useful strategies in organic chemistry. In this article, C–H functionalization reactions are explored as an alternative approach to access pseudodimeric cyclobutane natural products, such as the dictazole and the piperarborenine families. The use of these strategies in a variety of complex settings highlights the subtle geometric, steric, and electronic effects at play in the auxiliary guided C–H functionalization of cyclobutanes.
160 citations
TL;DR: A series of phosphine-ligated palladium precatalysts based on N-methyl- and N-phenyl-2-aminobiphenyl have been developed as discussed by the authors.
Abstract: A series of phosphine-ligated palladium precatalysts based on N-methyl- and N-phenyl-2-aminobiphenyl have been developed. Substitution at the nitrogen center prevents the presence of traces of aminobiphenyls that contain a free −NH2 group from contaminating cross-coupling products. These precatalysts produce N-substituted carbazoles upon activation, which cannot consume starting materials. These precatalysts were efficiently generated from 2-aminobiphenyl with minimal purification and found to be highly effective in Suzuki–Miyaura and C–N cross-coupling reactions.
159 citations
TL;DR: A simple derivation of indoles and pyrroles to N-carboxamides with oxidative bidentate directing group could enable rhodacycle formation and late-stage redox-neutral cyclization with alkynes, alkenes and diazo compounds, for access to five- and six-membered fused heterocycles.
Abstract: We report herein a new strategy of the Rh(III)-catalyzed C–H activation/cyclization of indoles and pyrroles, for the divergent synthesis of privileged heterocycles. A simple derivation of indoles and pyrroles to N-carboxamides with oxidative bidentate directing group could enable rhodacycle formation and late-stage redox-neutral cyclization with alkynes, alkenes and diazo compounds, for access to five- and six-membered fused heterocycles, such as pyrimido[1,6-a]indol-1(2H)-one, 3,4-dihydropyrimido[1,6-a]indol-1(2H)-one, and 1H-imidazo[1,5-a]indol-3(2H)-ones. Kinetic isotope effect study was conducted, and a plausible mechanism was proposed. Furthermore, this protocol was applied to concise synthesis of 5-HT3 receptor antagonist in gram-scale.
146 citations
TL;DR: Families of very powerful neutral organic super-electron-donors (SEDs) have been developed that carry out metal-free reductions of a range of functional groups and display original selectivities in preferentially reducing benzenes over malonates or cyanoacetates.
Abstract: Based on simple ideas of electron-rich alkenes, exemplified by tetrakis(dimethylamino)ethene, TDAE, and on additional driving force associated with aromatization, families of very powerful neutral organic super-electron-donors (SEDs) have been developed. In the ground state, they carry out metal-free reductions of a range of functional groups. Iodoarenes are reduced either to aryl radicals or, with stronger donors, to aryl anions. Reduction to aryl radicals allows the initiation of very efficient transition-metal-free coupling of haloarenes to arenes. The donors also reduce alkyl halides, arenesulfonamides, triflates, and triflamdes, Weinreb amides, and acyloin derivatives. Under photoactivation at 365 nm, they are even more powerful and reductively cleave aryl chlorides. They reduce unactivated benzenes to the corresponding radical anions and display original selectivities in preferentially reducing benzenes over malonates or cyanoacetates. Additionally, they reductively cleave ArC-X, ArX-C (X = N or O) and ArC-C bonds, provided that the two resulting fragments are somewhat stabilized.
TL;DR: A palladium-catalyzed and picolinamide-directed C-H thiolation of naphthylamine derivatives with diaryl disulfides has been developed to provide a convenient route to 8-sulfenyl-1-naphthyamines with perfect site-selectivity.
Abstract: A palladium-catalyzed and picolinamide-directed C–H thiolation of naphthylamine derivatives with diaryl disulfides has been developed to provide a convenient route to 8-sulfenyl-1-naphthylamines. The reaction proceeds via a 5-membered palladacycle intermediates to afford the peri-thiolated products exclusively, in contrast to the conventional ortho-functionalization. Moreover, the related direct selenation was also achieved with diaryl diselenides, giving the corresponding selenated products with perfect site-selectivity.
TL;DR: Quinoline N-oxides were found to undergo Cp*Rh(III)-catalyzed coupling with internal diarylalkynes to provide 8-functionalized quinolines through a cascade process that involves remote C-H bond activation, alkyne insertion, and intramolecular oxygen atom transfer.
Abstract: Quinoline N-oxides were found to undergo Cp*Rh(III)-catalyzed coupling with internal diarylalkynes to provide 8-functionalized quinolines through a cascade process that involves remote C–H bond activation, alkyne insertion, and intramolecular oxygen atom transfer. In this reaction, the N-oxide plays a dual role, acting as a traceless directing group as well as a source of oxygen atom, as confirmed by an 18O-labeling experiment.
TL;DR: It is shown that Nok usually affords yields that are, in general, as good or better than those typically obtained with TPGS-750-M, and yet is far less costly.
Abstract: The third-generation designer amphiphile/surfactant, “Nok” (i.e., SPGS-550-M; β-sitosterol methoxypolyethyleneglycol succinate), soon to be commercially available from Aldrich, can be prepared in two steps using an abundant plant feedstock and β-sitosterol, together with succinic anhydride and PEG-550-M. Upon dissolution in water, it forms nanomicelles that serve as nanoreactors, which can be characterized by both cryo-TEM and dynamic light scattering analyses. Several transition-metal-catalyzed reactions have been run under micellar conditions to evaluate this surfactant relative to results obtained in nanoparticles composed of TPGS-750-M (i.e., a second-generation surfactant). It is shown that Nok usually affords yields that are, in general, as good or better than those typically obtained with TPGS-750-M, and yet is far less costly.
TL;DR: A solvent- and metal-free method for the synthesis of 3-chalcogenyl-indoles from indoles and diorganyl dichalcogenides using an equivalent amount of DMSO as an oxidant, under catalysis by molecular iodine is described.
Abstract: Herein, we describe a solvent- and metal-free method for the synthesis of 3-chalcogenyl-indoles from indoles and diorganyl dichalcogenides using an equivalent amount of DMSO as an oxidant, under catalysis by molecular iodine. This mild and eco-friendly approach allowed the preparation of a wide range of 3-selenyl- and 3-sulfenyl-indoles in good to excellent yields.
TL;DR: Regioselective ring opening of three-membered heterocyclic compounds at various temperatures was observed in coupling reactions with CO2 by the use of an aluminum-salen catalyst in conjunction with intramolecular quaternary ammonium salts as cocatalysts, affording the corresponding five- Membered cyclic products with complete configuration retention at the methine carbon.
Abstract: Regioselective ring opening of three-membered heterocyclic compounds (epoxides or N-substituted aziridines) at various temperatures was observed in coupling reactions with CO2 by the use of an aluminum–salen catalyst in conjunction with intramolecular quaternary ammonium salts as cocatalysts, affording the corresponding five-membered cyclic products with complete configuration retention at the methine carbon. Notably, this bifunctional aluminum-based catalyst exhibited nearly 100% regioselectivity for the ring opening at the methylene C–O bond for various terminal epoxides. This was true for those bearing an electron-withdrawing group, such as styrene oxide or epichlorohydrin, thereby affording the synthesis of various enantiopure cyclic carbonates that have previously been obtained only rarely by other methods. An intramolecular cooperative catalysis is suggested to contribute to the high activity and excellent stereochemistry control observed. Surprisingly, the highly selective ring opening at the methi...
TL;DR: Efficient and general preparations of zinc and magnesium organometallic reagents, as well as their most practical and useful reactions, are presented in this Perspective.
Abstract: Polyfunctional zinc and magnesium organometallic reagents occupy a central position in organic synthesis. Most organic functional groups are tolerated by zinc organometallic reagents, and Csp2-centered magnesium organometallic reagents are compatible with important functional groups, such as the ester, aryl ketone, nitro, cyano, and amide functions. This excellent chemoselectivity gives zinc– and magnesium–organometallic reagents a central position in modern organic synthesis. Efficient and general preparations of these organometallic reagents, as well as their most practical and useful reactions, are presented in this Perspective. As starting materials, a broad range of organic halides (iodides, bromides, and also to some extent chlorides) can be used for the direct insertion of magnesium or zinc powder; the presence of LiCl very efficiently promotes such insertions. Alternatively, aromatic or heterocyclic bromides also undergo a smooth bromine–magnesium exchange when treated with i-PrMgCl·LiCl. Alternat...
TL;DR: Transition metal-free acylation of isoquinoline, quinoline, and quinoxaline derivatives has been developed employing a cross dehydrogenative coupling (CDC) reaction with aldehydes using substoichiometric amount of TBAB and K2S2O8 as an oxidant.
Abstract: Transition metal-free acylation of isoquinoline, quinoline, and quinoxaline derivatives has been developed employing a cross dehydrogenative coupling (CDC) reaction with aldehydes using substoichiometric amount of TBAB (tetrabutylammonium bromide, 30 mol %) and K2S2O8 as an oxidant. This intermolecular acylation of electron-deficient heteroarenes provides an easy access and a novel acylation method of heterocyclic compounds. The application of this CDC strategy for acylation strategy has been illustrated in synthesizing isoquinoline-derived natural products.
TL;DR: The Ni(II)-catalyzed direct arylation of C(sp(3))-H (methyl and methylene) bonds in aliphatic amides containing an 8-aminoquinoline moiety as the directing group with diaryliodonium salts as coupling electrophiles is described.
Abstract: The Ni(II)-catalyzed direct arylation of C(sp3)–H (methyl and methylene) bonds in aliphatic amides containing an 8-aminoquinoline moiety as the directing group with diaryliodonium salts as coupling electrophiles is described. A wide variety of functional groups are tolerated in the reaction. The reaction represents the first example of the Ni-catalyzed direct arylation of C(sp3)–H bonds with diaryliodonium salts.
TL;DR: A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium/isocyanide insertion/cyclization sequence has been developed.
Abstract: A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium-catalyzed isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity.
TL;DR: Different enzymatic methods for synthesis of modified oligonucleotides and DNA by polymerase incorporation of modified nucleotides are summarized, and the applications in redox or fluorescent labeling, as well as in bioconjugations and modulation of interactions of DNA with proteins, are outlined.
Abstract: The synthesis of 2′-deoxyribonucleoside triphosphates (dNTPs) either by classical triphosphorylation of nucleosides or by aqueous cross-coupling reactions of halogenated dNTPs is discussed. Different enzymatic methods for synthesis of modified oligonucleotides and DNA by polymerase incorporation of modified nucleotides are summarized, and the applications in redox or fluorescent labeling, as well as in bioconjugations and modulation of interactions of DNA with proteins, are outlined.
TL;DR: It is found that the cleavage of C-H bonds is reversible on the basis of the deuterium labeling experiments, and the results of mechanistic experiments suggest that a Ni(0)/Ni(II) catalytic cycle is not involved.
Abstract: Arylation via the cleavage of the ortho C–H bonds by a nickel-catalyzed reaction of aromatic amides containing an 8-aminoquinoline moiety with aryl iodides is reported. The reaction shows a high functional group compatibility. The reaction proceeds in a highly selective manner at the less hindered C–H bonds in the reaction of meta-substituted aromatic amides, irrespective of the electronic nature of the substituents. Electron-withdrawing groups on the aromatic amides facilitate the reaction. Various mechanistic experiments, such as deuterium labeling experiments, Hammett studies, competition experiments, and radical trap experiments, have been made for better understanding the reaction mechanism. It is found that the cleavage of C–H bonds is reversible on the basis of the deuterium labeling experiments. Both Ni(II) and Ni(0) show a high catalytic activity, but the results of mechanistic experiments suggest that a Ni(0)/Ni(II) catalytic cycle is not involved.
TL;DR: A process for tunable and chemo-, regio-, and stereoselective photocatalytic trifluoromethylation of styrenes was developed.
Abstract: A process for tunable and chemo-, regio-, and stereoselective photocatalytic trifluoromethylation of styrenes was developed. Thermodynamically stable E-trifluoromethylated alkenes were prepared using Togni’s reagent in the presence of Ru(bpy)3Cl2·6H2O under visible light irradiation, whereas less thermodynamically stable Z-trifluoromethylated alkenes were obtained by employing Umemoto’s reagent and photocatalyst Ir(ppy)3.
TL;DR: A direct method has been developed for iodine-mediated thiolation of naphthols/naphthylamines and arylsulfonyl hydrazides through the formation of C-S bond and cleavage of S-N/S-O bonds.
Abstract: A direct method has been developed for iodine-mediated thiolation of naphthols/naphthylamines and arylsulfonyl hydrazides through the formation of C-S bond and cleavage of S-N/S-O bonds. In this transformation, a range of valuable thioethers are easily achieved in moderate to good yields.
TL;DR: The present methodology, which utilizes very cheap CF3 reagent and a simple oxidant, provides a convenient and practical approach to CF3-containing oxindoles with a wide variety of functional groups.
Abstract: A metal-free and cost-effective synthesis protocol has been initially proposed for the construction of CF3-containing oxindoles via the direct oxidative trifluoromethylation of activated alkenes with Langlois’ reagent (CF3SO2Na). The present methodology, which utilizes very cheap CF3 reagent and a simple oxidant, provides a convenient and practical approach to CF3-containing oxindoles with a wide variety of functional groups.
TL;DR: The reaction of terminal alkynes with n-BuLi, and then with aldehydes, followed by the treatment with molecular iodine, and subsequently hydrazines or hydroxylamine provided the corresponding 3,5-disubstituted pyrazoles or isoxazoles in good yields with high regioselectivity through the formations of propargyl secondary alkoxides and α-alkynyl ketones.
Abstract: The reaction of terminal alkynes with n-BuLi, and then with aldehydes, followed by the treatment with molecular iodine, and subsequently hydrazines or hydroxylamine provided the corresponding 3,5-disubstituted pyrazoles or isoxazoles in good yields with high regioselectivity, through the formations of propargyl secondary alkoxides and α-alkynyl ketones. The present reactions are one-pot preparation of 3,5-disubstituted pyrazoles from terminal alkynes, aldehydes, molecular iodine, and hydrazines, and 3,5-disubstituted isoxazoles from terminal alkynes, aldehydes, molecular iodine, and hydroxylamine.
TL;DR: The LR-HSQMBC NMR experiment can be extended to provide data similar to that afforded by 1,n-ADEQUATE even in sample-limited situations by optimizing responses for very small (n)JCH coupings as opposed to relying on the markedly less sensitive detection of long-range coupled ( 13)C-(13)C homonuclear pairs at natural abundance.
Abstract: HMBC is one of the most often used and vital NMR experiments for the structure elucidation of organic and inorganic molecules. We have developed a new, high sensitivity NMR pulse sequence that overcomes the typical 2,3JCH limitation of HMBC by extending the visualization of long-range correlation data to 4-, 5-, and even 6-bond long-range nJCH heteronuclear couplings. This technique should prove to be an effective experiment to complement HMBC for probing the structure of proton-deficient molecules. The LR-HSQMBC NMR experiment can, in effect, extend the range of HMBC to provide data similar to that afforded by 1,n-ADEQUATE even in sample-limited situations. This is accomplished by optimizing responses for very small nJCH coupings as opposed to relying on the markedly less sensitive detection of long-range coupled 13C–13C homonuclear pairs at natural abundance. DFT calculations were employed to determine whether the very long-range correlations observed for cervinomycin A2 were reasonable on the basis of ...
TL;DR: The results of this study revealed the unique potential of Cp*Ir complexes bearing a functional bipyridonate ligand for the development of C-C bond-forming reactions with the activation of primary alcohols as electrophiles.
Abstract: A Cp*Ir complex bearing a functional bipyridonate ligand was found to be a highly effective and versatile catalyst for the α-alkylation of ketones with primary alcohols under extremely environmentally benign and mild conditions (0.1 equiv of Cs2CO3 per substrate, reflux in tert-amyl alcohol under an air atmosphere for 6 h). Furthermore, this complex also exhibited a high level of catalytic activity for the α-methylation of ketones with methanol. The mechanistic investigation revealed that the carbonyl group on the ligand is of critical importance for catalytic hydrogen transfer. Notably, the results of this study revealed the unique potential of Cp*Ir complexes bearing a functional bipyridonate ligand for the development of C–C bond-forming reactions with the activation of primary alcohols as electrophiles.
TL;DR: A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum and represents a significant improvement over other existing methods.
Abstract: The highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is described. The reaction is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III), and the results show that the presence of water is crucial. The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. An example of its use is an intramolecular application in the synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one, which is the bicyclic core of diltiazem and structurally related drugs (Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr. Med. Chem. 2007, 14, 279-287). A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum. This methodology represents a significant improvement over other existing methods; it can be performed in air and with wet or technical grade solvents.
TL;DR: An I2-mediated metal-free oxidative C-N bond formation methodology has been established for the regioselective pyrazole synthesis and provides a facile access to a variety of di-, tri-, and tetrasubstituted pyrazoles from readily available α,β-unsaturated aldehydes/ketones and hydrazine salts.
Abstract: An I2-mediated metal-free oxidative C–N bond formation methodology has been established for the regioselective pyrazole synthesis. This practical and eco-friendly one-pot protocol requires no isolation of the less stable intermediates hydrazones and provides a facile access to a variety of di-, tri-, and tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazoles from readily available α,β-unsaturated aldehydes/ketones and hydrazine salts.