LongLarf

Nature, Published online: 07 June 2022; doi:10.1038/d41586-022-01541-1

Publication date: 13 August 2022

Source: Tetrahedron, Volume 120

Author(s): Aina Bai, Yongxin Zhang, Jiajie Tian, Yaodong Huang, Junjiao Yang

A de-risking approach was developed to evaluate the robustness of the Staudinger aza-Wittig sequence. This technology is based on [¹⁴C]CO₂ screening that allowed to investigate the tolerance of the procedure with most representative heterocycles and functional groups found in FDA drugs.

Abstract

Carbon isotope labeling is a useful technology for tracking the fate of organic compounds in the environment and in living organisms. In this context, the development of robust and general methodologies amenable to the direct functionalization of CO₂ remains a significant task. In this communication, a de-risking approach was developed to evaluate the robustness of the Staudinger aza-Wittig sequence for carbon isotope labeling. This technology is based on [¹⁴C]CO₂ screening that allowed to investigate the tolerance of the procedure with most representative heterocycles and functional groups found in FDA approved drugs.

The combination of N-heterocyclic carbene and hydrogen-bond donor enables new modes of reactivity not previously available by using either catalyst alone. Clever selection of hydrogen-bond donor can lead to increased yields, enhanced reactivity, and improved stereoselectivity. This minireview summarized the advances of bifunctional NHC and some of the development of NHC and hydrogen-bond donor for dual catalytic enantioselective reactions.

Abstract

N-heterocyclic carbene (NHC) catalysis has become a versatile catalysis strategy for building molecules via unique reaction modes. Dual catalytic processes using NHCs in combination with additional modulating agents such as another organocatalyst or transition-metal catalyst have also been studied. The clear selection of cocatalysts has led to enhanced reactivity, increased yields, and/or improved stereoselectivity. This minireview is to provide readers with a brief overview of the development and applications of NHC and hydrogen-bond donor for dual catalytic reactions.

Synlett
DOI: 10.1055/s-0041-1737489

A new route to 2-(trifluoromethyl)benzimidazoles is described which involves the condensation of (2-arylamino)iminophosphoranes with trifluoroacetyl esters or trifluoroacetic anhydride. The method allows the synthesis of the title compounds from simple nitroarenes without the use of separate reduction steps and metallic reagents or expensive catalysts.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Synlett
DOI: 10.1055/s-0041-1738384

The present article presents a personalized Account on the synthesis of nitrogen heterocycles by domino C–N coupling/hydroamination reactions and related processes. The starting materials, 2-alkynyl-1-halohetarenes, are regioselectively available by Sonogashira reactions of various 1,2-dihalogenated heterocycles, such as thiophenes, benzothiophenes, furans and benzofurans, pyridines, quinolines, pyrimidines, and other ring systems. More complex products are formed by domino C–N coupling/hydroamination/C–H arylation reactions of 2-alkynyl-1-halohetarenes with 2-bromoanilines. In these reactions, not only two, but three bonds are formed in one step. In many cases, the products constitute new heterocyclic core structures and show interesting pharmacological or fluorescence properties.1 Introduction2 Domino C–N Coupling/Hydroamination Reactions3 Domino C–N Coupling/Hydroamination/C–H Arylation Reactions4 Conclusions
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Preparation of 1-alkynylphosphorus compounds has seen significant developments. Transition metals proved to be particularly suitable catalysts allowing the transfer of alkynyl units to various phosphorus reagents forming phosphines, phosphine boranes, phosphine oxides and phosphonates. This review also reports metal-free approaches that use acidic or basic activation, hypervalent iodine reagents and desulfonative reactions.

Abstract

Since the review of Savignac, the past 20 years have seen significant progresses on the synthesis of alkynylphosphorus compounds considerably expanding the original and rather limited organic toolbox. This comprehensive review explores the latest and potentially greener methodologies using sustainable catalysis or direct metal-free couplings from stable and easy to handle precursors. Recent progress and mechanistic insights for metal-catalyzed reactions with a particular emphasis on copper, palladium, nickel and silver catalytic systems, photocatalytic and metal-free reactions are detailed covering most of the publications related to this field since 2000 until March 2022.

Come together: Asymmetric aminocatalysis plays a pivotal role on the development in stereoselective transformations, synergistically combined with organo-, metal, photoredox and electrocatalysis. In this scenario, the HOMO-raising and LUMO-lowering activation of carbonyl compounds open new gateways to complex architectures and new sustainable reactivities. Last but not least, this research area will keep driving the development of the whole organocatalysis, toward its synergistic combination with other activation strategies.

Abstract

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.

An on-resin iodination-substitution approach is established to easily introduce various functional modifications into peptides at a late synthesis stage. The method allows access to methionine-like thioethers, selenoethers, thioglycosides, pyridinium salts, and fluorescent labels in a combinatorial manner. Using this approach, we synthesised an iFRET-based Zn^II sensor by labelling a designed β-sheet minireceptor prototype with 7-mercapto-4-methylcoumarin.

Abstract

The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on-resin iodination-substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines. In this way, methionine-like thioethers or thioesters and thiosulfonates are accessible. Next to sulfur nucleophiles, selenols, pyridines and carboxylic acids were successfully used as nucleophiles, whereas phenols did not react. The late-stage iodination-substitution approach is not only applicable to short peptides but also to the more complex 34-amino-acid WW domains. We applied this strategy to introduce 7-mercapto-4-methylcoumarin into a switchable Zn^II responsive WW domain to design an iFRET-based Zn^II sensor.

Ecotoxicity: Organocatalysis is a widely used method of green and sustainable chemistry. The toxicity of a library of selected organocatalysts is determined, and it is found that aminocatalysts are of low ecotoxicity, but thioureas and squaramides prove about 10-fold more toxic. Thus, the latter compounds may be harmful to the environment and need more thorough (eco)toxicological evaluation.

Abstract

The importance of asymmetric organocatalysis in contemporary organic synthesis is widely acknowledged. However, there are practically no data on the environmental safety of organocatalysts, although this aspect is crucial for the sustainability of all new materials, chemicals, and technologies. To start to fill this data-gap, a library of 26 organocatalysts containing hydrogen-bonding catalysts [(thio)ureas and squaramides] and aminocatalysts (primary or secondary amines) was evaluated for their toxicity using the naturally luminescent Vibrio fischeri bacteria (ISO assay; one of the most widely used ecotoxicity tests). Thioureas and squaramides were shown to be relatively toxic: none of them was ranked as “not harmful” (i. e., half maximal effective concentration EC₅₀>100 mg L⁻¹), whereas the presence of the trifluoromethyl moiety increased their toxic effect. Importantly, the aminocatalysts, whose EC₅₀ values ranged from 25 to >300 mg L⁻¹, could be considered remarkably more environmentally safe or green alternatives.

Methyltransferases are enzymes that will in the future enable clean and green alkylation of amino and hydroxy groups as well as reactive carbon atoms. These enzymes, their cofactor SAM (S-adenosylmethionine) and the opportunities’ they offer for new S_N2 chemistries are highlighted.

Abstract

In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs, and approaches to utilise SAM as a cofactor in synthesis are introduced with different supply and regeneration approaches evaluated. The use of SAM analogues are also described. Finally O-, N-, C- and S-MTs, their synthetic applications and potential for compound diversification is given.

Nature Chemistry, Published online: 06 June 2022; doi:10.1038/s41557-022-00960-x

Abstract

A synthetic strategy for the construction of 2,2-disubstituted indolin-3-ones from 2-alkynylnitroarenes and ketones has been described. The corresponding indolin-3-one derivatives were afforded in moderate to excellent product yields by using mild conditions. After a Wittig-like process, the key intermediates 3H-indol-3-ones were generated from 2-alkynylnitroarenes, which could be further transformed to the desired products through a Mannich addition.

An unprecedented P-based catalyst able to promote hydrazine disproportionation has been synthesized. The available set of experimental results and theoretical calculations suggest that this reactivity is unlocked by the cooperation between a redox-active bis(amidophenolate) ligand and the highly electrophilic central P-atom.

Abstract

We present herein the synthesis of a nearly square-pyramidal chlorophosphorane supported by the tetradentate bis(amidophenolate) ligand, N,N′-bis(3,5-di-tert-butyl-2-phenoxy)-1,2-phenylenediamide. After chloride abstraction the resulting phosphonium cation efficiently promotes the disproportionation of 1,2-diphenylhydrazine to aniline and azobenzene. Mechanistic studies, spectroscopic analyses and theoretical calculations suggest that this unprecedented reactivity mode for P^V-centres is induced by the high electrophilicity at the cationic P^V-center, which originates from the geometry constraints imposed by the rigid pincer ligand, combined with the ability of the o-amidophenolate moieties to act as electron reservoir. This study illustrates the promising role of cooperativity between redox-active ligands and phosphorus for the design of organocatalysts able to promote redox processes.

Publication date: 11 August 2022

Source: Chem, Volume 8, Issue 8

Author(s): Dahye Kang, Sanghyeon Lee, Justin Kim

Bis-imidazolium-diphosphete-diide, (IPr)₂C₂P₂, acts as an electronically remarkably flexible ligand to iron carbonyl fragments, giving access to complexes of the general formula [Fe(CO) _x {(IPr)₂C₂P₂}] ⁿ⁺ (x=2, 3; n=0, +1, +2). Redox events involve either the metal ion or C₂P₂ ligand, as demonstrated by EPR, Mössbauer and computational analyses and characterize (IPr)₂C₂P₂ as a redox active ligand.

Abstract

Reaction of the 6π-electron aromatic four-membered heterocycle (IPr)₂C₂P₂ (1) (IPr=1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene) with [Fe₂CO₉] gives the neutral iron tricarbonyl complex [Fe(CO)₃-η³-{(IPr)₂C₂P₂}] (2). Oxidation with two equivalents of the ferrocenium salt, [Fe(Cp)₂](BArF₂₄), affords the dicationic tricarbonyl complex [Fe(CO)₃-η⁴-{(IPr)₂C₂P₂}](BArF₂₄)₂ (4). The one-electron oxidation proceeds under concomitant loss of one CO ligand to give the paramagnetic dicarbonyl radical cation complex [Fe(CO)₂-η⁴-{(IPr)₂C₂P₂}](BArF₂₄) (5). Reduction of 5 allows the preparation of the neutral dicarbonyl complex [Fe(CO)₂-η⁴-{(IPr)₂C₂P₂}] (6). An analysis by various spectroscopic techniques (⁵⁷Fe Mössbauer, EPR) combined with DFT calculations gives insight into differences of the electronic structure within the members of this unique series of iron carbonyl complexes, which can be either described as electron precise or Wade–Mingos clusters.