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Showing papers in "Journal of Organic Chemistry in 2019"


Journal ArticleDOI
TL;DR: The current challenges of peptide synthesis and purification in terms of sustainability are summarized, possible solutions are highlighted, and synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations are encouraged.
Abstract: In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and >200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.

210 citations


Journal ArticleDOI
TL;DR: A mechanism-based categorization via C-H activation strategies are pre-sented herein, which could be vital for future CDC designs and will help more synthetic chemists gain insight into the design of CDC reactions.
Abstract: Cross-coupling reaction between two C–H bonds has become a fundamental strategy in synthetic organic chemistry. With its increasing importance in green chemistry, atom economy, and step economy, it...

152 citations


Journal ArticleDOI
TL;DR: The visible light induced C-H bond thiocyanation on the α-site of tertiary enaminones has been realized under metal-free, photocatalytic conditions in the presence of Rose Bengal, which enables the synthesis of thuocyanated alkene derivatives and chromones using NH4SCN as the thiOCyano source under an aerobic atmosphere.
Abstract: The visible light induced C–H bond thiocyanation on the α-site of tertiary enaminones has been realized under metal-free, photocatalytic conditions in the presence of Rose Bengal, which enables the...

113 citations


Journal ArticleDOI
TL;DR: An overview about the most important experimental aspects of a VCD-based AC determination and the theoretical analysis are given and the comparison of experimental and computational spectra that leads to the final conclusion about the AC of the target molecules are described.
Abstract: Vibrational circular dichroism (VCD) spectroscopy is one of the most powerful techniques for the determination of absolute configurations (AC), as it does not require any specific UV/vis chromophor...

89 citations


Journal ArticleDOI
TL;DR: Insight was carried out into the reaction mechanism which shows that the nickel and the coordinated diamine ligands participate in a synergistic way during the dehydrogenation of alcohols.
Abstract: Simple, straightforward, and atom economic methods for the synthesis of quinolines, 2-aminoquinolines, and quinazolines via biomimetic dehydrogenative condensation/coupling reactions, catalyzed by well-defined inexpensive and easy to prepare singlet diradical Ni(II)-catalysts featuring two antiferromagnetically coupled singlet diradical diamine type ligands are described. Various polysubstituted quinolines, 2-aminoquinolines, and quinazolines were synthesized in moderate to good yields from different low-cost and readily accessible starting materials. Several control experiments were carried out to get insight into the reaction mechanism which shows that the nickel and the coordinated diamine ligands participate in a synergistic way during the dehydrogenation of alcohols.

85 citations


Journal ArticleDOI
TL;DR: An effective method for the halogenation of imidazo-fused heterocycles using readily available sodium salts (NaCl/NaBr/NaI) as halogen source and K2S2O8 (or) oxone as promoter is reported.
Abstract: We report herein an effective method for the halogenation of imidazo-fused heterocycles using readily available sodium salts (NaCl/NaBr/NaI) as halogen source and K2S2O8 (or) oxone as promoter. A variety of C-3 halogenated imidazo[1,2- a]pyridines and benzo[d]imidazo[2,1- b]thiazoles were obtained in good to excellent yields. The present method of halogenation has been also extended to 2-aminopyridines, 2-aminopyrimidine, indole, and isoquinoline with moderate to excellent yields.

81 citations


Journal ArticleDOI
TL;DR: The cleavage of the C-N bond in enaminones is confirmed by the experiment using 15 N-labeled enaminone and the reactions proceed well in the medium of pure water in the presence of molecular iodine, TBHP, and NaHCO3 via cascade C-H sulfonylation and pyrazole annulation.
Abstract: The cascade reactions between NH2-functionalized enaminones and sulfonyl hydrazines have been developed for the synthesis of fully substituted pyrazoles. By making use of the hydrophilic primary amino group in the enaminones, the reactions proceed well in the medium of pure water in the presence of molecular iodine, TBHP, and NaHCO3 via cascade C-H sulfonylation and pyrazole annulation. The cleavage of the C–N bond in enaminones is confirmed by the experiment using 15N-labeled enaminone.

72 citations


Journal ArticleDOI
TL;DR: This assay summarizes recent developments in the burgeoning area of Ti radical catalysis with a focus on innovative catalytic strategies such as radical redox-relay and dual catalysis.
Abstract: New catalytic strategies that leverage single-electron redox events have provided chemists with useful tools for solving synthetic problems. In this context, Ti offers opportunities that are comple...

69 citations


Journal ArticleDOI
TL;DR: A summary of the investigation and applications of the inverse electron demand Diels-Alder reaction is provided that have been conducted in the laboratory over a period of more than 35 years, which continues to provide solutions to complex synthetic challenges.
Abstract: A summary of the investigation and applications of the inverse electron demand Diels-Alder reaction is provided that have been conducted in our laboratory over a period that now spans more than 35 years. The work, which continues to provide solutions to complex synthetic challenges, is presented in the context of more than 70 natural product total syntheses in which the reactions served as a key strategic step in the approach. The studies include the development and use of the cycloaddition reactions of heterocyclic azadienes (1,2,4,5-tetrazines; 1,2,4-, 1,3,5-, and 1,2,3-triazines; 1,2-diazines; and 1,3,4-oxadiazoles), 1-aza-1,3-butadienes, α-pyrones, and cyclopropenone ketals. Their applications illustrate the power of the methodology, often provided concise and nonobvious total syntheses of the targeted natural products, typically were extended to the synthesis of analogues that contain deep-seated structural changes in more comprehensive studies to explore or optimize their biological properties, and highlight a wealth of opportunities not yet tapped.

67 citations


Journal ArticleDOI
TL;DR: Control experiments and deuterium labelling studies indicate that both copper and the coordinated azo-aromatic ligand participate in a cooperative manner during the catalytic cycle.
Abstract: A simple metal-ligand cooperative approach for the dehydrogenative functionalization of alcohols to various substituted quinolines and quinazolin-4(3H)-ones under relatively mild reaction conditions (≤90 °C) is reported. Simple and easy-to-prepare air-stable Cu(II) complexes featuring redox-active azo-aromatic scaffolds, 2-arylazo-(1,10-phenanthroline) (L1,2), are used as catalyst. A wide variety of substituted quinolines and quinazolin-4(3H)-ones were synthesized in moderate to good isolated yields via dehydrogenative coupling reactions of various inexpensive and easily available starting materials under aerobic conditions. A few control experiments and deuterium labeling studies were carried out to understand the mechanism of the dehydrogenative coupling reactions, which indicate that both copper and the coordinated azo-aromatic ligand participate in a cooperative manner during the catalytic cycle.

64 citations


Journal ArticleDOI
TL;DR: A machine learning model is presented able to predict the reactive site of an electrophilic aromatic substitution with an accuracy of 93% (internal validation set) and on an external validation set, 90% of all molecules were correctly predicted.
Abstract: At the early stages of the drug development process, thousands of compounds are synthesized in order to attain the best possible potency and pharmacokinetic properties. Once successful scaffolds ar...

Journal ArticleDOI
Na Liu1, Chao Fei1, Ming-Guo Liu1, Huang Nianyu1, Kun Zou1, Long Wang1 
TL;DR: This paper reports the tandem reaction strategy of the Passerini/Staudinger/aza-Wittig reaction based on the in situ capture of isocyanides, which includes five-step transformations in one pot.
Abstract: This paper reports the tandem reaction strategy of the Passerini/Staudinger/aza-Wittig reaction based on the in situ capture of isocyanides. According to this strategy, isocyanides are synthesized in situ and immediately work as the substrate for the Passerini reaction and postmodification tandem reaction in one pot. In addition, two types of new compounds, 5-oxo-3,5-dihydrobenzo[e][1,4]oxazepines and 6-oxo-5,6-dihydro-2H-1,4-oxazines, were synthesized using the tandem reaction strategy that includes five-step transformations in one pot.

Journal ArticleDOI
TL;DR: Iridium(I) complexes having an imidazol-2-ylidene ligand with benzylic wingtips efficiently catalyzed the β-alkylation of secondary alcohols with primary alcohols and acceptorless dehydrogenative cyclization of 2-aminobenzyl alcohol with ketones through a borrowing hydrogen pathway.
Abstract: Iridium(I) complexes having an imidazol-2-ylidene ligand with benzylic wingtips efficiently catalyzed the β-alkylation of secondary alcohols with primary alcohols and acceptorless dehydrogenative c...

Journal ArticleDOI
TL;DR: A facile, highly chemoselective method for transamidation of N-Boc activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives, expected to have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond.
Abstract: Transamidation reactions represent a fundamental chemical process involving conversion of one amide functional group into another. Herein, we report a facile, highly chemoselective method for transamidation of N-tert-butoxycarbonylation (N-Boc) activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives. Because this reaction is performed in the absence of metals, oxidants, or reductants, the reaction tolerates a large number of useful functionalities. The reaction is compatible with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields through direct nucleophilic addition to the amide bond. The utility of this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic, directly from the amide bond. We expect that this new metal-free transamidation will have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond as a key step.

Journal ArticleDOI
TL;DR: A visible-light-promoted regioselective C(sp2)-H/C(sp3)-H cross-dehydrogenative coupling between 2 H-indazoles and ethers has been achieved using rose bengal as an organophotoredox-catalyst and tert-butyl hydroperoxide as an oxidant at ambient temperature under aerobic conditions.
Abstract: A visible-light-promoted regioselective C(sp2)-H/C(sp3)-H cross-dehydrogenative coupling between 2 H-indazoles and ethers has been achieved using a catalytic amount of rose bengal as an organophotoredox-catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant at ambient temperature under aerobic conditions. A variety of C-3 oxyalkylated 2 H-indazoles have been synthesized in moderate to good yields. Mechanistic studies suggest a radical pathway of the present reaction.

Journal ArticleDOI
TL;DR: The mechanistic investigations support the multiple role of the metal-ligand manganese catalyst, the dehydrogenativeactivation of the alcohol, α-C-H activation of the nitrile, and hydrogenation of the in-situ-formed unsaturated intermediate.
Abstract: A general and chemoselective catalytic alkylation of nitriles using a homogeneous nonprecious manganese catalyst is presented. This alkylation reaction uses naturally abundant alcohols and readily available nitriles as coupling partners. The reaction tolerates a wide range of functional groups and heterocyclic moieties, efficiently providing useful cyanoalkylated products with water as the only side product. Importantly, methanol can be used as a C1 source and the chemoselective C-methylation of nitriles is achieved. The mechanistic investigations support the multiple role of the metal-ligand manganese catalyst, the dehydrogenative activation of the alcohol, α-C-H activation of the nitrile, and hydrogenation of the in-situ-formed unsaturated intermediate.

Journal ArticleDOI
TL;DR: Visible-light photoredox chlorosulfonation of alkenes and alkynes is achieved using a Cu photocatalyst that has high functional group tolerance and broad scope.
Abstract: Visible-light photoredox chlorosulfonation of alkenes and alkynes is achieved using a Cu photocatalyst. The reactions occur under mild conditions, have broad scope, and have high functional group tolerance.

Journal ArticleDOI
TL;DR: A facile and effective alkoxylation protocol of quinoxalin-2(1H)-ones with primary or secondary alcohols via cross-dehydrogenative coupling under catalyst-free conditions has been disclosed.
Abstract: A facile and effective alkoxylation protocol of quinoxalin-2(1H)-ones with primary or secondary alcohols via cross-dehydrogenative coupling under catalyst-free conditions has been disclosed. This method provides a powerful and convenient access to 3-alkoxylquinoxalin-2(1H)-ones in good to excellent yields by utilizing PhI(OTFA)2 as an oxidant and allows to easily obtain potential drug molecules containing 3-alkoxylquinoxalin-2(1H)-one skeletons.

Journal ArticleDOI
TL;DR: This reaction represents the first catalytic asymmetric cyclization of benzofuran-derived azadienes, and provides a useful strategy for the enantioselective construction of five-membered ring-based chiral spirooxindole scaffolds.
Abstract: A chiral guanidine-catalyzed asymmetric [4 + 1] cyclization of benzofuran-derived azadienes with 3-chlorooxindoles has been established, which constructed chiral spirooxindole frameworks with in situ generation of a five-membered ring with high diastereoselectivities (up to >95:5 dr) and good enantioselectivities (up to 94:6 er). This reaction represents the first catalytic asymmetric [4 + 1] cyclization of benzofuran-derived azadienes, which will enrich the research field of catalytic asymmetric cyclizations of such reactants. In addition, this reaction provides a useful strategy for the enantioselective construction of five-membered ring-based chiral spirooxindole scaffolds.

Journal ArticleDOI
TL;DR: A general and efficient protocol for the direct preparation of various S-thiocarbamates with readily available and inexpensive sulfonyl chlorides as an odorless sulfur source was developed.
Abstract: A general and efficient protocol for the direct preparation of various S-thiocarbamates with readily available and inexpensive sulfonyl chlorides as an odorless sulfur source was developed. The employment of easily available reactants, excellent functional group tolerability, and mild reaction conditions make this process very practical.

Journal ArticleDOI
TL;DR: A perspective will describe the stages involved in developing this chemistry and illustrate the scope of the donor/acceptor carbene C-H functionalization.
Abstract: Catalyst-controlled C–H functionalization by means of the C–H insertion chemistry of rhodium carbenes has become a powerful synthetic method. The key requirements for the development of this chemistry are donor/acceptor carbenes and the chiral dirhodium tetracarboxylate catalysts. This perspective will describe the stages involved in developing this chemistry and illustrate the scope of the donor/acceptor carbene C–H functionalization.

Journal ArticleDOI
TL;DR: This synopsis describes the selectivity challenges inherent in oxidative coupling reactions while at the same time presents the mechanistic-driven strategy employed to confront them.
Abstract: The iron-catalyzed oxidative coupling of phenols has emerged as a powerful method for preparing complex phenolic frameworks from simple and readily available compounds. This synopsis describes the selectivity challenges inherent in oxidative coupling reactions while at the same time presents our mechanistic-driven strategy employed to confront them.

Journal ArticleDOI
TL;DR: A practical synthetic approach to the difluoro-substituted bicyclo[1. 1.1.1]pentanes was developed, which are suggested as saturated bioisosteres of the benzene ring for drug discovery projects.
Abstract: A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]pentanes was developed. The key step was an addition of difluorocarbene (:CF2) to electron-rich bicyclo[1.1.0]butanes by the CF3TMS/NaI system. The obtained difluoro-bicyclo[1.1.1]pentanes are suggested to be used as saturated bioisosteres of benzene rings for the purpose of drug discovery projects.

Journal ArticleDOI
TL;DR: This study reveals cobalt catalyzed sustainable synthesis of benzimidazoles by redox-economical coupling of o-nitroanilines and alcohols by hydrogen autotransfer without using any additional external redox reagent and costly ligand system.
Abstract: This study reveals cobalt-catalyzed sustainable synthesis of benzimidazoles by redox-economical coupling of o-nitroanilines and alcohols. The major advantage of this report is the use of a commerci...

Journal ArticleDOI
TL;DR: In the last two decades, hydrogen bonds have been established as useful interactions to control the selectivity of various chemical transformations and catalysts have been developed which combine, in an enzyme-like fashion, a site for substrate binding and a catalytically active site.
Abstract: In the last two decades, hydrogen bonds have been established as useful interactions to control the selectivity of various chemical transformations. In this Perspective, the contributions by our group to this growing field of research are summarized and analyzed. In the first section, a chiral template is presented which displays a 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one skeleton with a lactam binding site and that has been used in superstoichiometric quantities in a variety of photochemical and radical reactions. Chiral catalysts with a related architecture evolved from the template by introducing a suitable chromophore for harvesting photons in the ultraviolet (benzophenone, xanthone) or visible region (thioxanthone). They act mainly by sensitization and allow for a high catalytic turnover in enantioselective [2 + 2] photocycloadditions and in deracemization reactions. Eventually, the concept of lactam hydrogen bonding was transferred to transition-metal catalysis, and catalysts have been developed which combine, in an enzyme-like fashion, a site for substrate binding and a catalytically active site. Substrate binding has been mainly achieved by a V-shaped ligand based on a tricyclic octahydro-1H-4,7-methanoisoindol-1-one scaffold with a lactam hydrogen-bonding site. The catalytically active metal (ruthenium, manganese, rhodium) is perfectly positioned to the substrate for a site- and enantioselective transfer of an oxygen atom (oxidation, oxygenation) or a nitrogen-based fragment (aziridination, amination).

Journal ArticleDOI
TL;DR: Recent progress in Earth-abundant-metal-catalyzed, branched-selective hydroboration of alkenes is summarized while overviewing the historical contributions to this reaction using precious metals.
Abstract: Catalytic hydroboration of alkenes is a well-established method to access borane-functionalized hydrocarbons. While linear-selective hydroboration was predominantly reported, catalysts enabling opposite selectivity (branched-selective) are attracting considerable interest, especially when Earth-abundant metals are utilized. This Synopsis summarizes recent progress in Earth-abundant-metal-catalyzed, branched-selective hydroboration of alkenes while overviewing the historical contributions to this reaction using precious metals. Lessons learned from the current state of this topic that can guide future catalyst design are presented, along with challenging issues that remain to be addressed.

Journal ArticleDOI
TL;DR: A visible-light-promoted regioselective C3-H trifluoromethylation of 2 H-indazole under metal-free conditions, which proceeds via a radical mechanism through the combination of photocatalysis and hypervalent iodine reagent.
Abstract: Trifluoromethyl-substituted heteroarenes are biologically active compounds and useful building blocks. In this sequence, we have developed a visible-light-promoted regioselective C3-H trifluoromethylation of 2 H-indazole under metal-free conditions, which proceeds via a radical mechanism. The combination of photocatalysis and hypervalent iodine reagent provides a practical approach to a library of trifluoromethylated indazoles in 35-83% yields.

Journal ArticleDOI
TL;DR: Commercial available carbon-supported palladium (Pd/C) catalyzed N-methylation of nitroarenes and amines using MeOH as both C1 and H2 source with high atom-economy and environmental-friendly way via borrowing hydrogen mechanism.
Abstract: Herein, we report commercially available carbon-supported-palladium (Pd/C)-catalyzed N-methylation of nitroarenes and amines using MeOH as both a C1 and a H2 source. This transformation proceeds wi...

Journal ArticleDOI
TL;DR: Taking advantage of ligand centered redox events, the high-energetic Ni(0)/Ni(II) or Ni(I/Ni(III) redox steps were avoided in the catalytic cycle.
Abstract: A simple and efficient approach of C-S cross-coupling of a wide variety of (hetero)aryl thiols and (hetero)aryl halides under mild conditions, mostly at room temperature, catalyzed by well-defined singlet diradical Ni(II) catalysts bearing redox noninnocent ligands is reported. Taking advantage of ligand centered redox events, the high-energetic Ni(0)/Ni(II) or Ni(I)/Ni(III) redox steps were avoided in the catalytic cycle. The cooperative participation of both nickel and the coordinated ligands during oxidative addition/reductive elimination steps allowed us to perform the catalytic reactions under mild conditions.

Journal ArticleDOI
TL;DR: A highly efficient iridium-catalyzed cascade annulation of pyrazolones and sulfoxonium ylides to access various pyrazolo[1,2-α]cinnoline derivatives has been achieved and this novel approach expanded the application scope of coupling partners to y lides.
Abstract: A highly efficient iridium-catalyzed cascade annulation of pyrazolones and sulfoxonium ylides to access various pyrazolo[1,2-α]cinnoline derivatives has been achieved. This novel approach expanded the application scope of coupling partners to ylides. The control experiments were performed to give insight into the mechanism of this reaction.