Showing papers in "Journal of Organic Chemistry in 2017"
TL;DR: This Perspective highlights a few selected examples that illustrate the value of mechanochemistry in uncovering interesting chemical reactivity, which is often masked in typical liquid-phase synthesis.
Abstract: Mechanochemical activation achieved by grinding, shearing, pulling, or milling opens unique opportunities in synthetic organic chemistry. Common features are that mechanochemistry facilitates reactions with insoluble reactants, enables high-yielding solvent-free synthetic procedures, and shortens reaction times, among others. However, mechanochemical techniques can also alter chemical reactivity and selectivity compared to the analogous solution-based protocols. As a consequence, solvent-free milling can lead to different product compositions or equilibration mixtures than in solution. Reactions by milling have also allowed the trapping and characterization of elusive intermediates and materials. In this Perspective we highlight a few selected examples that illustrate the value of mechanochemistry in uncovering interesting chemical reactivity, which is often masked in typical liquid-phase synthesis.
385 citations
TL;DR: A metal-free cross-dehydrogenative coupling between quinoxalinones and amines in the presence of catalytic iodine is reported, which provides a practical access to pharmaceutically active 3-aminoquinoxalinone derivatives.
Abstract: A metal-free cross-dehydrogenative coupling between quinoxalinones (sp2 C–H) and amines (N–H) in the presence of catalytic iodine is reported. The reaction yields 3-aminoquinoxalinones in moderate to high yields under ambient conditions in dioxane as solvent and aqueous tert-butyl hydroperoxide (TBHP) as the terminal oxidant. The reaction is highly versatile and exhibits good functional group tolerance with a range of primary and secondary amines. It provides a practical access to pharmaceutically active 3-aminoquinoxalinone derivatives. Preliminary mechanistic studies reveal in situ iodination of the amine as the putative mode of activation.
120 citations
TL;DR: Using indolylmethanols as reactants in catalytic asymmetric reactions enables the enantioselective construction of a variety of indole-containing frameworks.
Abstract: Indolylmethanols have emerged as versatile reactants in catalytic asymmetric reactions because of the facile generation of reactive intermediates from these compounds. The most common indolylmethanols are 3-indolylmethanols and 2-indolylmethanols, and the reaction types applicable to these heterocycles mainly include catalytic enantioselective substitutions and cyclizations. Using indolylmethanols as reactants in catalytic asymmetric reactions enables the enantioselective construction of a variety of indole-containing frameworks.
117 citations
TL;DR: Examples of palladium-catalyzed carbonylation reactions found broad application in total synthesis of natural products, including macrolide and spirocyclic molecule synthesis are presented to highlight recent progress.
Abstract: Carbon monoxide is an important one-carbon source and can be incorporated in complex molecules via various transition-metal-catalyzed carbonylation reactions. In particular, palladium-catalyzed carbonylation reactions have found broad application in total synthesis of natural products. Examples are presented in this Synopsis to highlight recent progress in this area, including our own work in macrolide and spirocyclic molecule synthesis. In these selected cases, carbon monoxide functions as a one-carbon linchpin to facilitate building structural complexity and improving synthetic efficiency.
114 citations
TL;DR: A one-pot Pd-catalyzed conversion of aryl iodide to aryL sulfonyl fluorides using DABSO and Selectfluor has been developed generating ary l sulfonamides and sulfonic esters in good to excellent yields.
Abstract: A one-pot Pd-catalyzed conversion of aryl iodide to aryl sulfonyl fluorides using DABSO and Selectfluor has been developed generating aryl sulfonyl fluorides in good to excellent yields. The reaction results in the generation of electronically and sterically diverse sulfonyl fluorides. Additionally, sulfonyl fluorides can be converted to aryl sulfonamides and sulfonic esters using Cs2CO3 under mild conditions.
109 citations
TL;DR: In this paper, the authors show that molecular iodine is a similar if not superior catalyst for Michael additions compared with typical Lewis acids, and suggest a halogen bond activation instead of hidden Bronsted acid catalysis.
Abstract: Molecular iodine, an easy to handle solid, has been successfully employed as a catalyst in different organic transformations for more than 100 years. Despite being active even in very small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogen bond mechanism as well as hidden Bronsted acid catalysis are frequently discussed as possible explanations. Our kinetic analyses reveal a reaction order of 1 in iodine, indicating that higher iodine species are not involved in the rate-limiting transition state. Our experimental investigations rule out hidden Bronsted acid catalysis by partial decomposition of I2 to HI and suggest a halogen bond activation instead. Finally, molecular iodine turned out to be a similar if not superior catalyst for Michael additions compared with typical Lewis acids.
104 citations
TL;DR: This investigation demonstrates the importance of internal structural preorganization on photostationary composition and explicates the augmented Z-selectivity upon hydrogen-alkyl exchange at the β-position of the alkene.
Abstract: Iteratively executed with exquisite spatial and temporal control, the selective isomerization of polarized alkenes underpins a plethora of complex biological processes ranging from natural product biosynthesis through to the mammalian visual cycle. However, nature’s proficiency conceals the inherent difficulties in replicating this contra-thermodynamic transformation in the laboratory. Recently, we disclosed the first highly Z-selective isomerization of polarized alkenes, employing the cinnamoyl chromophore as a retinal surrogate under UV-irradiation (402 nm) with (−)-riboflavin (vitamin B2) as an inexpensive, organic photocatalyst (J. Am. Chem. Soc. 2015, 137, 11254–11257). This study was inspired by the propensity of crystalline (−)-riboflavin in the eyes of vertebrates to invert the intrinsic directionality of retinal isomerization. Herein, we extend this methodology to include a bioinspired, catalytic E → Z isomerization of α,β-unsaturated nitriles, thereby mimicking the intermediate Opsin-derived, pr...
102 citations
TL;DR: Among organic azides, vinyl azides have shown versatile chemical reactivities in the recent development of new synthetic methodologies mainly for nitrogen-containing molecules.
Abstract: Among organic azides, vinyl azides have shown versatile chemical reactivities in the recent development of new synthetic methodologies mainly for nitrogen-containing molecules. This synopsis highlights and discusses recent advances on use of vinyl azides in chemical synthesis as a radical acceptor and an enamine-type nucleophile.
101 citations
TL;DR: The studies described represent the first use of versatile PEPPSI type of Pd-NHC complexes as catalysts for the cross-coupling of amides by N-C bond activation by providing a significant improvement over all current Pd/phosphane catalystsfor amide N- C bond activation.
Abstract: Pd-PEPPSI-IPr serves as a highly reactive precatalyst in the direct Suzuki–Miyaura cross-coupling of amides. An array of amides can be cross-coupled with a range of arylboronic acids in very good yields using a single, operationally simple protocol. The studies described represent the first use of versatile PEPPSI type of Pd-NHC complexes as catalysts for the cross-coupling of amides by N–C bond activation. The method is user-friendly, since it employs a commercially available, air- and moisture-stable Pd-PEPPSI-IPr complex. Pd-PEPPSI-IPr provides a significant improvement over all current Pd/phosphane catalysts for amide N–C bond activation. Mechanistic studies provide insight into the reaction rates of Pd-NHC-catalyzed cross-coupling of different amides, with Pd-PEPPSI-IPr being particularly effective for the cross-coupling of N-Boc carbamates under the developed conditions.
100 citations
TL;DR: The case is made for transitioning organic chemistry from a developed discipline that remains highly dependent upon organic solvents to one that will be sustainable, based on water as the reaction medium.
Abstract: The case is made for transitioning organic chemistry from a developed discipline that remains highly dependent upon organic solvents to one that will be sustainable, based on water as the reaction medium. Processes in hand that today achieve the same bond constructions characteristic of traditional organic synthesis, but can be accomplished under environmentally responsible conditions, are discussed as representative of the potential that lies ahead.
98 citations
TL;DR: This paper examines more than 100 structures of halogenated terpenoids and other natural products with the new parametric approach and demonstrates that the accuracy of the combined method is sufficient to identify misassignments and suggest revisions in most cases.
Abstract: Halogenated natural products constitute diverse and promising feedstock for molecular pharmaceuticals. However, their solution-structure elucidation by NMR presents several challenges, including the lack of fast methods to compute 13C chemical shifts for carbons bearing heavy atoms. We show that parametric corrections to DFT-computed chemical shifts in conjunction with rff-computed spin–spin coupling constants allow for fast and reliable screening of a large number of reported halogenated natural products, resulting in expedient structure validation or revision. In this paper, we examine more than 100 structures of halogenated terpenoids and other natural products with the new parametric approach and demonstrate that the accuracy of the combined method is sufficient to identify misassignments and suggest revisions in most cases (16 structures are revised). As the 1D 1H and 13C NMR data are ubiquitous and most routinely used in solution structure elucidation, this fast and efficient two-criterion method (n...
TL;DR: A general, efficient, and environmentally benign method for the one-pot cascade synthesis of quinazolin-4(3H)-ones via acceptorless dehydrogenative coupling of o-aminobenzamide with alcohols catalyzed by a simple Ni(II) catalyst, featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA).
Abstract: In this paper, we report a general, efficient, and environmentally benign method for the one-pot cascade synthesis of quinazolin-4(3H)-ones via acceptorless dehydrogenative coupling of o-aminobenzamide with alcohols catalyzed by a simple Ni(II) catalyst, [Ni(MeTAA)], featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)). A wide variety of substituted quinazolin-4(3H)-ones were synthesized in high yields starting from readily available benzyl alcohols and o-aminobenzamides. Several controlled reactions along with deuterium labeling studies were carried out to establish the acceptorless dehydrogenative nature of the reactions.
TL;DR: The factors that control the kinetics and regio-/stereochemical outcomes of the autoxidation of both polyunsaturated fatty acids and sterols and the subsequent decomposition of the hydroperoxide products to cytotoxic derivatives are discussed.
Abstract: Recent advances in our understanding of lipid peroxidation, a degenerative process that is believed to play a key role in the pathogenesis of many diseases, are highlighted. In particular, the factors that control the kinetics and regio-/stereochemical outcomes of the autoxidation of both polyunsaturated fatty acids and sterols and the subsequent decomposition of the hydroperoxide products to cytotoxic derivatives are discussed. These advances promise to help clarify the role of lipid peroxidation in cell death and human disease.
TL;DR: An operationally convenient room temperature hydroboration of aldehydes and ketones employing Fe(acac)3 as precatalyst using a σ-bond metathesis mechanism in which an Fe-H intermediate is postulated to be a key reactive species.
Abstract: We report an operationally convenient room temperature hydroboration of aldehydes and ketones employing Fe(acac)3 as precatalyst. The hydroboration of aldehydes and ketones proceeded efficiently at room temperature to yield, after work up, 1° and 2° alcohols; chemoselective hydroboration of aldehydes over ketones is attained under these conditions. We propose a σ-bond metathesis mechanism in which an Fe–H intermediate is postulated to be a key reactive species.
TL;DR: A copper-catalyzed aerobic oxidative reaction between aromatics or heteroaromatics with KSCN is developed by using O2 as the oxidant, affording substituted thiocyanation products and 2-aminobenzothiazoles in excellent yields.
Abstract: A copper-catalyzed aerobic oxidative reaction between aromatics or heteroaromatics with KSCN is developed by using O2 as the oxidant. The combination of Cu(OTf)2, N,N,N′,N′-tetramethylethylenediamine (TMEDA) and BF3·Et2O provides an efficient catalytic system, affording substituted thiocyanation products and 2-aminobenzothiazoles in excellent yields. The reaction also possesses a good functional group tolerance for both strong electron-withdrawing and electron-donating groups.
TL;DR: A stereoselective synthesis of (E)-vinyl sulfones has been developed via electrochemical oxidative N-S bond cleavage of aromatic sulfonylhydrazides, followed by cross-coupling reactions with cinnamic acids to form the C-S Bond.
Abstract: A stereoselective synthesis of (E)-vinyl sulfones has been developed via electrochemical oxidative N–S bond cleavage of aromatic sulfonylhydrazides, followed by cross-coupling reactions with cinnamic acids to form the C–S bond. The protocol proceeded smoothly to afford (E)-vinyl sulfones in good yields with wide substrate scope under metal-free and halogen-free conditions.
TL;DR: This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.
Abstract: A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI2 as Lewis acid, donor–acceptor cyclopropanes or corresponding cyclobutanes were treated with 1,3,5-triazinanes, leading to the five- or six-membered ring systems under mild conditions in yields up to 93%. This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.
TL;DR: This work demonstrates the potential benefits of chlorophyll as photosensitizer in visible light catalysis by using it in a visible-light photoredox catalysis for the efficient synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides in an air atmosphere.
Abstract: Natural pigment chlorophyll was used as a green photosensitizer for the first time in a visible-light photoredox catalysis for the efficient synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides in an air atmosphere. The reaction involves direct cyclization via an sp3 C–H bond functionalization process to afford products in moderate to high yields (61–98%) from a wide range of substrates with a low loading of chlorophyll under mild conditions. This work demonstrates the potential benefits of chlorophyll as photosensitizer in visible light catalysis.
TL;DR: Additive-based reaction screening is utilized as a tool for the objective comparison of reaction conditions as demonstrated in four case studies and contributes to an understanding of factors limiting a reaction's FG tolerance and the identification of truly mild reactions.
Abstract: Herein, we describe an approach to quantifying and comparing functional group (FG) tolerance of synthetic reactions. Additive-based reaction screening is utilized as a tool for the objective comparison of reaction conditions as demonstrated in four case studies. This contributes to an understanding of factors limiting a reaction’s FG tolerance and the identification of truly mild reactions.
TL;DR: An efficient, direct C6-arylation of 2-pyridones has been successfully accomplished with quinone diazides under Rh(III)-catalyzed redox-neutral conditions and provides a facile access to complex heteroarylated phenol moieties by wide-ranging heterocyclic scaffolds.
Abstract: An efficient, direct C6-arylation of 2-pyridones has been successfully accomplished with quinone diazides under Rh(III)-catalyzed redox-neutral conditions. The optimized method is simple, mild, and highly regioselective with a broad substrate scope. The strict regioselectivity is guided by the pyridyl substituent attached to the nitrogen of the pyridone ring. As the directing 2-pyridyl group can easily be removed at any suitable stage after functionalization, the method provides a facile access to complex heteroarylated phenol moieties by wide-ranging heterocyclic scaffolds.
TL;DR: It is demonstrated that amide nN → π*C═O resonance in simple anilides can be varied by as much as 10 kcal/mol, which has important implications for the design of N-C(O) amide cross-coupling reactions and control of the molecular conformation of anilide by resonance effects.
Abstract: Transition-metal-catalyzed activation of amide N–C(O) bonds proceeds via selective metal insertion into the carbon–nitrogen amide bond. Herein, we demonstrate that N-acylanilines (anilides), the first class of planar amides that have been shown to undergo selective amide N–C cross-coupling reactions, feature a significantly decreased barrier to rotation around the amide N–C(O) bond. Most significantly, we demonstrate that amide nN → π*C═O resonance in simple anilides can be varied by as much as 10 kcal/mol. The data have important implications for the design of N–C(O) amide cross-coupling reactions and control of the molecular conformation of anilides by resonance effects.
TL;DR: An efficient, green, and novel method for the synthesis of N-heterocycle-fused quinoxalines is reported herein.
Abstract: An efficient, green, and novel method for the synthesis of N-heterocycle-fused quinoxalines is reported herein. Dimethyl sulfoxide was used as both a reactant and a solvent in this reaction. A wide range of products in moderate to excellent yields were obtained, including pyrrolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxalines, 1H-pyrrolo[3,2-c]quinolines, and benzo[4,5]imidazo[1,2-c]quinazolines.
TL;DR: 2'-Aminoacetophenones undergo a C(sp3)-H oxidation followed by intramolecular C-N bond formation by virtue of a simple electrochemical oxidation in the presence of n-Bu4NI, providing various isatins with moderate to good yields.
Abstract: 2′-Aminoacetophenones undergo a C(sp3)–H oxidation followed by intramolecular C–N bond formation by virtue of a simple electrochemical oxidation in the presence of n-Bu4NI, providing various isatins with moderate to good yields. The reaction intermediates were detected, and a radical-based pathway was proposed.
TL;DR: The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins leads to the synthesis of bioactive spiroisoindolone derivatives in moderate to high yields.
Abstract: The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the β-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.
TL;DR: Photoredox-catalyzed hydrodifluoroalkylation of alkenes proceeded smoothly in the presence of a Hantzsch ester as a hydrogen source under visible light irradiation.
Abstract: Photoredox-catalyzed hydrodifluoroalkylation of alkenes proceeded smoothly in the presence of a Hantzsch ester as a hydrogen source under visible light irradiation. The reaction was also applicable to the hydrodifluoroalkylation of alkynes, and a continuous photo flow reaction was also successful.
TL;DR: This approach will not only provide an important strategy for the diversified synthesis of bis(indolyl)methane and 3,3'-bisindole derivatives but also serve as a good example for substrate-controlled regioselective reactions.
Abstract: A substrate-controlled regioselective arylation of 2-indolylmethanols with indoles has been established, which efficiently afforded bis(indolyl)methane and 3,3'-bisindole derivatives in high yields and with a broad substrate scope (up to 98% yield, 36 examples). This approach will not only provide an important strategy for the diversified synthesis of bis(indolyl)methane and 3,3'-bisindole derivatives but also serve as a good example for substrate-controlled regioselective reactions.
TL;DR: The present oxidative coupling reaction, not only expands the scope of functionalization of alkenes with thiols, but also makes it a practical and powerful complement to traditional methods for the synthesis of (E)-vinyl sulfones.
Abstract: A facile I2O5-mediated direct oxidative coupling of aromatic alkenes with thiols toward vinyl sulfones has been developed under metal-free conditions. This methodology provides a convenient and efficient approach to various (E)-vinyl sulfones from readily available starting materials with excellent regioselectivity. The present oxidative coupling reaction, not only expands the scope of functionalization of alkenes with thiols, but also makes it a practical and powerful complement to traditional methods for the synthesis of (E)-vinyl sulfones.
TL;DR: Radical alkylation of imines with 4-alkyl-1,4-dihydropyridines cocatalyzed by iridium/ruthenium complex and Brønsted acid under visible light irradiation has been achieved.
Abstract: Radical alkylation of imines with 4-alkyl-1,4-dihydropyridines cocatalyzed by iridium/ruthenium complex and Bronsted acid under visible light irradiation has been achieved. Both aldimines and ketimines can undergo this transformation. Common functional groups, such as hydroxyl groups, ester, amide, ether, cyanide, and heterocycles, can be tolerated in this reaction. A variety of structurally diverse amines (57 examples) have been produced with up to 98% isolated yields using this method.
TL;DR: The palladium-catalyzed ortho-selective chlorination of N-quinolinylbenzamide derivatives with hydrochloric acid was achieved under anodic oxidation conditions and the use of 5,7-dichloro-8-quinlinyl group as directing group was effective for the selective chlorination.
Abstract: The palladium-catalyzed ortho-selective chlorination of N-quinolinylbenzamide derivatives with hydrochloric acid was achieved under anodic oxidation conditions. The use of 5,7-dichloro-8-quinolinyl group as directing group was effective for the selective chlorination, and the reaction was applicable to benzamide derivatives bearing various functional groups. Synthesis of vismodegib was also completed using the palladium-catalyzed electrochemical C–H chlorination in two different steps.
TL;DR: Mechanochemical conditions have been applied to a highly efficient cobalt(III)-catalyzed C-H bond activation for the first time and this method constitutes an environmentally friendly and powerful alternative to the common solution-based approaches.
Abstract: Mechanochemical conditions have been applied to a highly efficient cobalt(III)-catalyzed C–H bond activation for the first time. In a subsequent step to the olefin insertion and β-oxygen elimination, N-pyrimidinylindoles were allylated with vinylethylene carbonates in the absence of organic solvent under high-speed ball-milling condition. As the reaction afforded the desired products in up to 98% yields within a short time, this method constitutes an environmentally friendly and powerful alternative to the common solution-based approaches.