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Organic Letters Aug 2022Herein we report the use of indoles, one of the most common nitrogen-containing heterocycles in FDA-approved drugs, as nucleophiles in the Pd-catalyzed aza-Wacker...
Herein we report the use of indoles, one of the most common nitrogen-containing heterocycles in FDA-approved drugs, as nucleophiles in the Pd-catalyzed aza-Wacker reaction. This -functionalization of indoles is a Markovnikov selective olefin functionalization of simple alkenes using catalytic Pd(NPhth)(PhCN) and O as the terminal oxidant in the presence of catalytic BuNBr. Various substituted indoles and alkenes are found to participate; 21 examples are presented with yields ranging from 41 to 97% isolated yield. Additionally, lactams and oxazolidinones are shown to participate under the reaction conditions. Mechanistic investigations suggest that the phthalimide ligand and BuNBr additive slow undesired side reactions: indole decomposition and olefin isomerization, respectively.
Topics: Alkenes; Amination; Catalysis; Indoles; Molecular Structure; Oxidative Stress; Palladium
PubMed: 35905441
DOI: 10.1021/acs.orglett.2c02190 -
Nature Chemistry May 2022α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of...
α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical and pharmaceutical properties. Here we report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalysed C(sp)-H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic-acid-containing drugs and natural products.
Topics: Amination; Amines; Amino Acids; Catalysis; Nitrogen; Stereoisomerism
PubMed: 35379900
DOI: 10.1038/s41557-022-00895-3 -
Accounts of Chemical Research Sep 2021Titanium is an attractive metal for catalytic reaction development: it is earth-abundant, inexpensive, and generally nontoxic. However-like most early transition...
Titanium is an attractive metal for catalytic reaction development: it is earth-abundant, inexpensive, and generally nontoxic. However-like most early transition metals-catalytic redox reactions with Ti are difficult because of the stability of the high-valent Ti state. Understanding the fundamental mechanisms behind Ti redox processes is key for making progress toward potential catalytic applications. This Account details recent progress in Ti-catalyzed (and -mediated) oxidative amination reactions that proceed through formally Ti/Ti catalytic cycles.This class of reactions is built on our initial discovery of Ti-catalyzed [2 + 2 + 1] pyrrole synthesis from alkynes and azobenzene, where detailed mechanistic studies have revealed important factors that allow for catalytic turnover despite the inherent difficulty of Ti redox. Two important conclusions from mechanistic studies are that (1) low-valent Ti intermediates in catalysis can be stabilized through coordination of π-acceptor substrates or products, where they can act as "redox-noninnocent" ligands through metal-to-ligand π back-donation, and (2) reductive elimination processes with Ti proceed through π-type electrocyclic (or pericyclic) reaction mechanisms rather than direct σ-bond coupling.The key reactive species in Ti-catalyzed oxidative amination reactions are Ti imidos (Ti≡NR), which can be generated from either aryl diazenes (RN═NR) or organic azides (RN). These Ti imidos can then undergo [2 + 2] cycloadditions with alkynes, resulting in intermediates that can be coupled to an array of other unsaturated functional groups, including alkynes, alkenes, nitriles, and nitrosos. This basic reactivity pattern has been extended into a broad range of catalytic and stoichiometric oxidative multicomponent coupling reactions of alkynes and other reactive small molecules, leading to multicomponent syntheses of various heterocycles and aminated building blocks.For example, catalytic oxidative coupling of Ti imidos with two different alkynes leads to pyrroles, while stoichiometric oxidative coupling with alkynes and nitriles leads to pyrazoles. These heterocycle syntheses often yield substitution patterns that are complementary to those of classical condensation routes and provide access to new electron-rich, highly substituted heteroaromatic scaffolds. Furthermore, catalytic oxidative alkyne carboamination reactions can be accomplished reaction of Ti imidos with alkynes and alkenes, yielding α,β-unsaturated imine or cyclopropylimine building blocks. New catalytic and stoichiometric oxidative amination methods such as alkyne α-diimination, isocyanide imination, and ring-opening oxidative amination of strained alkenes are continuously emerging as a result of better mechanistic understanding of Ti redox catalysis.Ultimately, these Ti-catalyzed and -mediated oxidative amination methods demonstrate the importance of examining often-overlooked elements like the early transition metals through the lens of modern catalysis: rather than a lack of utility, these elements frequently have undiscovered potential for new transformations with orthogonal or complementary selectivity to their late transition metal counterparts.
Topics: Amination; Catalysis; Models, Molecular; Molecular Structure; Oxidation-Reduction; Titanium
PubMed: 34420307
DOI: 10.1021/acs.accounts.1c00368 -
Accounts of Chemical Research Jun 2020In organic synthesis, ligand-modified copper(I) hydride (CuH) complexes have become well-known reagents and catalysts for selective reduction, particularly toward...
In organic synthesis, ligand-modified copper(I) hydride (CuH) complexes have become well-known reagents and catalysts for selective reduction, particularly toward Michael acceptors and carbonyl compounds. Recently, our group and others have found that these hydride complexes undergo migratory insertion (hydrocupration) with relatively unactivated and electronically unpolarized olefins, producing alkylcopper intermediates that can be leveraged to forge a variety of useful bonds. The resulting formal hydrofunctionalization reactions have formed the basis for a resurgence of research in CuH catalysis. This Account chronicles the development of this concept in our research group, highlighting its origin in the context of asymmetric hydroamination, evolution to more general C-X bond-forming reactions, and applications in the addition of olefin-derived nucleophiles to carbonyl derivatives.Hydroamination, the formal insertion of an olefin into the N-H bond of an amine, is a process of significant academic and industrial interest, due to its potential to transform widely available alkenes and alkynes into valuable complex amines. We developed a polarity-reversed strategy for catalytic enantioselective hydroamination relying on the reaction of olefins with CuH to generate chiral organocopper intermediates, which are intercepted by electrophilic amine reagents. By engineering the auxiliary ligand, amine electrophile, and reaction conditions, the scope of this method has since been extended to include many types of olefins, including challenging internal olefins. Further, the scope of amine reagents has been expanded to enable the synthesis of primary, secondary, and tertiary amines as well as amides, N-alkylated heterocycles, and anilines. All of these reactions exhibit high regio- and stereoselectivity and, due to the mild conditions required, excellent tolerance for heterocycles and polar functional groups.Though the generation of alkylcopper species from olefins was originally devised as a means to solve the hydroamination problem, we soon found that these intermediates could react efficiently with an unexpectedly broad range of electrophiles, including alkyl halides, silicon reagents, arylpalladium species, heterocycles, and carbonyl derivatives. The general ability of olefins to function as precursors for nucleophilic intermediates has proved particularly advantageous in carbonyl addition reactions because it overcomes many of the disadvantages associated with traditional organometallic reagents. By removing the need for pregeneration of the nucleophile in a separate operation, CuH-catalyzed addition reactions of olefin-derived nucleophiles feature improved step economy, enhanced functional group tolerance, and the potential for catalyst control over regio- and stereoselectivity. Following this paradigm, feedstock olefins such as allene, butadiene, and styrene have been employed as reagents for asymmetric alkylation of ketones, imines, and aldehydes.
Topics: Aldehydes; Alkenes; Amination; Catalysis; Copper; Ketones; Ligands; Stereoisomerism
PubMed: 32401530
DOI: 10.1021/acs.accounts.0c00164 -
ELife Jul 2022Ammonium (NH) is essential to generate the nitrogenous building blocks of life. It gets assimilated via the canonical biosynthetic routes to glutamate and is further...
Ammonium (NH) is essential to generate the nitrogenous building blocks of life. It gets assimilated via the canonical biosynthetic routes to glutamate and is further distributed throughout metabolism via a network of transaminases. To study the flexibility of this network, we constructed an glutamate auxotrophic strain. This strain allowed us to systematically study which amino acids serve as amine sources. We found that several amino acids complemented the auxotrophy either by producing glutamate via transamination reactions or by their conversion to glutamate. In this network, we identified aspartate transaminase AspC as a major connector between many amino acids and glutamate. Additionally, we extended the transaminase network by the amino acids β-alanine, alanine, glycine, and serine as new amine sources and identified d-amino acid dehydrogenase (DadA) as an intracellular amino acid sink removing substrates from transaminase reactions. Finally, ammonium assimilation routes producing aspartate or leucine were introduced. Our study reveals the high flexibility of the cellular amination network, both in terms of transaminase promiscuity and adaptability to new connections and ammonium entry points.
Topics: Amination; Amines; Amino Acids; Ammonium Compounds; Escherichia coli; Glutamic Acid; Transaminases
PubMed: 35876664
DOI: 10.7554/eLife.77492 -
Molecules (Basel, Switzerland) May 2020The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a...
The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a "pseudohalogen" character, while the chemical properties of the synthesized compound, especially heterocycles with such a group, are less studied. As trifluoromethoxy-substituted pyrazines are still unknown, we have developed efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, showing the synthetic utility of this molecule for Buchwald-Hartwig amination and the Kumada-Corriu and Suzuki and Sonogashira coupling reactions. Some comparisons of chlorine atom and trifluoromethoxy group stability in these transformations have been carried out.
Topics: Amination; Halogenation; Molecular Structure; Proton Magnetic Resonance Spectroscopy; Pyrazines
PubMed: 32397388
DOI: 10.3390/molecules25092226 -
Nature Chemistry Jun 2018Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties...
Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.
Topics: Amination; Benzyl Compounds; Carbon; Catalysis; Coordination Complexes; Hydrogen; Indoles; Manganese
PubMed: 29713037
DOI: 10.1038/s41557-018-0020-0 -
Journal of the American Chemical Society Dec 2019The enantioselective, vicinal diamination of alkenes represents one of the stereocontrolled additions that remains an outstanding challenge in organic synthesis. A...
The enantioselective, vicinal diamination of alkenes represents one of the stereocontrolled additions that remains an outstanding challenge in organic synthesis. A general solution to this problem would enable the efficient and selective preparation of widely useful, enantioenriched diamines for applications in medicinal chemistry and catalysis. In this article, we describe the first enantioselective, diamination of simple alkenes mediated by a chiral, enantioenriched organoselenium catalyst together with a bistosyl urea as the bifunctional nucleophile and fluorocollidinium tetrafluoroborate as the stoichiometric oxidant. Diaryl, aryl-alkyl, and alkyl-alkyl olefins bearing a variety of substituents are all diaminated in consistently high enantioselectivities but variable yields. The reaction likely proceeds through a Se(II)/Se(IV) redox catalytic cycle reminiscent of the dichlorination reported previously. Furthermore, the -stereospecificity of the transformation shows promise for highly enantioselective diaminations of alkenes with no strong steric or electronic bias.
Topics: Alkenes; Amination; Catalysis; Diamines; Organoselenium Compounds; Oxidants; Oxidation-Reduction; Stereoisomerism; Urea
PubMed: 31742399
DOI: 10.1021/jacs.9b11261 -
Molecules (Basel, Switzerland) Oct 2018Oxaziridines have emerged as powerful and elegant oxygen- and nitrogen-transfer agents for a broad array of nucleophiles, due to the remarkably high and tunable... (Review)
Review
Oxaziridines have emerged as powerful and elegant oxygen- and nitrogen-transfer agents for a broad array of nucleophiles, due to the remarkably high and tunable reactivities. However, the asymmetric catalysis involving oxaziridines is still in its infancy. Herein, this review aims to examine recent advances in the catalytic asymmetric transformations of oxaziridines, including oxidation, amination, cycloaddition and deracemization.
Topics: Amination; Aziridines; Catalysis; Cycloaddition Reaction; Molecular Structure
PubMed: 30332802
DOI: 10.3390/molecules23102656 -
Science (New York, N.Y.) Jan 2016To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the...
To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.
Topics: Amination; Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Peptides; Pharmaceutical Preparations
PubMed: 26816372
DOI: 10.1126/science.aad6252