Catalytic Benzolactamization Through Isonitrile Insertion Enabled 1,4-Palladium Shift

Isoindolinone is a class of versatile N-heterocycles embedded in many bioactive molecules and natural products. The invention of new methods to synthesize these heterocyclic compounds with easily accessible chemicals is always attractive. Herein, a conceptually novel approach to access this bicyclic system via isonitrile insertion enabled 1,4-pallaidum shift is described. Compared with conventional isonitrile participated C-H bond activation, both carbon and nitrogen atoms in isonitrile moiety are engaged in new bond formation. Notably, two different isoindolinones can be obtained selectively by switching the bases employed. Mechanistic studies including DFT calculations have shed lights on the reaction mechanism and explained the selectivity led to different products. Moreover, the power of current benzolactamization is further demonstrated by providing concise routes to key intermediates of indoprofen, indobufen, aristolactams, lennoxamine and falipamil.

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Non-Classical Amide Bond Formation: Transamidation and Amidation of Activated Amides and Esters by Selective N–C/O–C Cleavage

Synthesis ◽

10.1055/s-0040-1707101 ◽

2020 ◽

Vol 52 (18) ◽

pp. 2579-2599 ◽

Cited By ~ 1

Author(s):

Michal Szostak ◽

Guangchen Li

Keyword(s):

Transition Metal ◽

Bond Activation ◽

Bond Formation ◽

Amide Bond ◽

Acyl Transfer ◽

Metal Free ◽

Amide Bond Formation ◽

New Methods ◽

Formidable Challenge ◽

Tetrahedral Intermediates

In the past several years, tremendous advances have been made in non-classical routes for amide bond formation that involve transamidation and amidation reactions of activated amides and esters. These new methods enable the formation of extremely valuable amide bonds via transition-metal-catalyzed, transition-metal-free, or metal-free pathways by exploiting chemoselective acyl C–X (X = N, O) cleavage under mild conditions. In a broadest sense, these reactions overcome the formidable challenge of activating C–N/C–O bonds of amides or esters by rationally tackling nN → π*C=O delocalization in amides and nO → π*C=O donation in esters. In this account, we summarize the recent remarkable advances in the development of new methods for the synthesis of amides with a focus on (1) transition-metal/NHC-catalyzed C–N/C–O bond activation, (2) transition-metal-free highly selective cleavage of C–N/C–O bonds, (3) the development of new acyl-transfer reagents, and (4) other emerging methods.1 Introduction2 Transamidation of Amides2.1 Transamidation by Metal–NHC Catalysis (Pd–NHC, Ni–NHC)2.2 Transition-Metal-Free Transamidation via Tetrahedral Intermediates2.3 Reductive Transamidation2.4 New Acyl-Transfer Reagents2.5 Tandem Transamidations3 Amidation of Esters3.1 Amidation of Esters by Metal–NHC Catalysis (Pd–NHC, Ni–NHC)3.2 Transition-Metal-Free Amidation of Esters via Tetrahedral Intermediates3.3 Reductive Amidation of Esters4 Transamidations of Amides by Other Mechanisms5 Conclusions and Outlook

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Tandem C–O and C–H Activation at Palladium Enables Catalytic Direct C–H Alkenylation with Enol Pivalates

10.33774/chemrxiv-2021-s62r6 ◽

2021 ◽

Author(s):

Nahiane Pipaon Fernandez ◽

Gregory Gaube ◽

Kyla Woelk ◽

Mathias Burns ◽

David Leitch

Keyword(s):

Bond Activation ◽

Bond Formation ◽

Palladium Catalysis ◽

Oxidative Addition ◽

Cross Coupling ◽

Addition Product ◽

Pivalic Acid ◽

Mechanistic Studies ◽

Limiting Step ◽

Strong Bond Activation

The use of oxygen-based electrophiles in cross-coupling remains challenging for substrates with strong C–O bonds, with few examples that can combine C–O activation with an-other strong-bond activation in tandem. We report the first example of a direct, tandem C–O/C–H activation approach to C–C bond formation using palladium catalysis. This reaction combines C–O oxidative addition at enol pivalates with con-certed metallation deprotonation of functionalized heterocycles to achieve base-free direct C–H alkenylation, with pivalic acid as the only byproduct. Mechanistic studies reveal that the Pd(II) C–O oxidative addition product is the major catalyst resting state, indicating that C–H activation is the turnover-limiting step.

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Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

10.26434/chemrxiv.11521827 ◽

2020 ◽

Author(s):

Sukdev Bag ◽

Sadhan Jana ◽

Sukumar Pradhan ◽

Suman Bhowmick ◽

Nupur Goswami ◽

...

Keyword(s):

Organic Molecules ◽

Bond Activation ◽

Bond Formation ◽

Ancillary Ligand ◽

Significant Challenge ◽

Site Selectivity ◽

Directing Group ◽

Covalently Linked ◽

Complex Organic ◽

Post Functionalization

Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing group (DG) served as an ancillary ligand to ensure proximal ortho-, distal meta- and para-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. We introduce here a transient directing group for distal C(sp2)-H functionalization via reversible imine formation. By overruling facile proximal C-H bond activation by imine-N atom, a suitably designed pyrimidine-based transient directing group (TDG) successfully delivered selective distal C-C bond formation. Application of this transient directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the distal position has been explored.

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Carbon Dioxide-Mediated C(sp2)–H Arylation of Primary and Secondary Benzylamines

10.26434/chemrxiv.7138088.v2 ◽

2018 ◽

Author(s):

Mohit Kapoor ◽

Pratibha Chand-Thakuri ◽

Michael Young

Keyword(s):

Carbon Dioxide ◽

Transition Metal ◽

Bond Activation ◽

Bond Formation ◽

Carbon Bond ◽

Chelate Effect ◽

Free Amine ◽

Carbon Carbon Bond ◽

New Strategy ◽

Metal Catalyzed

Carbon-carbon bond formation by transition metal-catalyzed C–H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C–C bond formation from C–H bond activation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 is critical to allowing this transformation to proceed under milder conditions than previously reported, and that are necessary to furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, a chelate effect is demonstrated to facilitate selective monoarylation.

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Design and Development of Fe-Catalyzed Intra- and Intermolecular Carbofunctionalization of Vinyl Cyclopropanes

10.26434/chemrxiv.9858500.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Lei Liu ◽

Wes Lee ◽

Mingbin Yuan ◽

Chris Acha ◽

Michael B. Geherty ◽

...

Keyword(s):

Bond Formation ◽

Cross Coupling ◽

Alkyl Halides ◽

Grignard Reagents ◽

Mechanistic Studies ◽

Radical Intermediates ◽

Design And Implementation ◽

Solvent Cage ◽

Radical Cascade ◽

Radical Processes

Design and implementation of the first (asymmetric) Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes (VCPs) with alkyl halides and aryl Grignard reagents has been realized via a mechanistically driven approach. Mechanistic studies support the diffusion of the alkyl radical intermediates out of the solvent cage to participate in an intra- or -intermolecular radical cascade with the VCP followed by re-entering the Fe radical cross-coupling cycle to undergo selective C(sp2)-C(sp3) bond formation. Overall, we provide new design principles for Fe-mediated radical processes and underscore the potential of using combined computations and experiments to accelerate the development of challenging transformations.

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Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200310171547 ◽

2020 ◽

Vol 15 (6) ◽

pp. 482-491 ◽

Cited By ~ 1

Author(s):

Milena Kostadinova ◽

Milena Mourdjeva

Keyword(s):

Cancer Cells ◽

Small Population ◽

Tumor Formation ◽

Bioactive Molecules ◽

Cancer Therapies ◽

New Methods ◽

Cycle Arrest ◽

Anti Cancer ◽

Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

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Microwave-accelerated Carbon-carbon and Carbon-heteroatom Bond Formation via Multi-component Reactions: A Brief Overview

Current Microwave Chemistry ◽

10.2174/2213346107666200218124147 ◽

2020 ◽

Vol 7 (1) ◽

pp. 23-39 ◽

Cited By ~ 2

Author(s):

Kantharaju Kamanna ◽

Santosh Y. Khatavi

Keyword(s):

Organic Synthesis ◽

Bond Formation ◽

Cycloaddition Reaction ◽

Nanoparticle Synthesis ◽

Single Step ◽

Bioactive Molecules ◽

One Pot ◽

Bond Forming ◽

Material Interest ◽

Carbon Carbon Bond

Multi-Component Reactions (MCRs) have emerged as an excellent tool in organic chemistry for the synthesis of various bioactive molecules. Among these, one-pot MCRs are included, in which organic reactants react with domino in a single-step process. This has become an alternative platform for the organic chemists, because of their simple operation, less purification methods, no side product and faster reaction time. One of the important applications of the MCRs can be drawn in carbon- carbon (C-C) and carbon-heteroatom (C-X; X = N, O, S) bond formation, which is extensively used by the organic chemists to generate bioactive or useful material synthesis. Some of the key carbon- carbon bond forming reactions are Grignard, Wittig, Enolate alkylation, Aldol, Claisen condensation, Michael and more organic reactions. Alternatively, carbon-heteroatoms containing C-N, C-O, and C-S bond are also found more important and present in various heterocyclic compounds, which are of biological, pharmaceutical, and material interest. Thus, there is a clear scope for the discovery and development of cleaner reaction, faster reaction rate, atom economy and efficient one-pot synthesis for sustainable production of diverse and structurally complex organic molecules. Reactions that required hours to run completely in a conventional method can now be carried out within minutes. Thus, the application of microwave (MW) radiation in organic synthesis has become more promising considerable amount in resource-friendly and eco-friendly processes. The technique of microwaveassisted organic synthesis (MAOS) has successfully been employed in various material syntheses, such as transition metal-catalyzed cross-coupling, dipolar cycloaddition reaction, biomolecule synthesis, polymer formation, and the nanoparticle synthesis. The application of the microwave-technique in carbon-carbon and carbon-heteroatom bond formations via MCRs with major reported literature examples are discussed in this review.

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Kinetic resolution of indolines by asymmetric hydroxylamine formation

Nature Communications ◽

10.1038/s41467-021-22658-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Gang Wang ◽

Ran Lu ◽

Chuangchuang He ◽

Lei Liu

Keyword(s):

Hydrogen Peroxide ◽

Chemical Synthesis ◽

Late Stage ◽

Kinetic Resolution ◽

High Efficiency ◽

Bond Formation ◽

Bioactive Molecules ◽

Environmentally Benign ◽

Secondary Amines

AbstractCatalytic kinetic resolution of amines represents a longstanding challenge in chemical synthesis. Here, we described a kinetic resolution of secondary amines through oxygenation to produce enantiopure hydroxylamines involving N–O bond formation. The economic and practical titanium-catalyzed asymmetric oxygenation with environmentally benign hydrogen peroxide as oxidant is applicable to a range of racemic indolines with multiple stereocenters and diverse substituent patterns in high efficiency with efficient chemoselectivity and enantio-discrimination. Late-stage asymmetric oxygenation of bioactive molecules that are otherwise difficult to synthesize was also explored.

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PCl3-mediated transesterification and aminolysis of tert-butyl esters via acid chloride formation

Journal of Chemical Research ◽

10.1177/1747519820987530 ◽

2021 ◽

pp. 174751982098753

Author(s):

Xiaofang Wu ◽

Lei Zhou ◽

Fangshao Li ◽

Jing Xiao

Keyword(s):

Acid Chloride ◽

Bioactive Molecules ◽

Mechanistic Studies ◽

One Pot ◽

Tert Butyl ◽

Butyl Esters

A PCl3-mediated conversion of tert-butyl esters into esters and amides in one-pot under air is developed. This novel protocol is highlighted by the synthesis of skeletons of bioactive molecules and gram-scale reactions. Mechanistic studies revealed that this transformation involves the formation of an acid chloride in situ, which is followed by reactions with alcohols or amines to afford the desired products.

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