LongLarf

Publication date: 30 July 2021

Source: Tetrahedron, Volume 93

Author(s): Rima Thakur, Yogesh Jaiswal, Amit Kumar

Nature, Published online: 28 June 2021; doi:10.1038/s41586-021-03730-w

We report a light-promoted 4,5-dichlorofluorescein (DCFS)-enabled para-selective C−H trifluoromethylation of arylcarbamates using the Langlois reagent. Arylcarbamates, including the bioactive compound chlorzoxazone, vorinostat precursor, chlorpropham, and teriflunomide precursors, were suitable for this reaction, leading to the formation of the corresponding products in moderate to good yields.

Abstract

The direct incorporation of a trifluoromethyl group on an aromatic ring using a radical pathway has been extensively investigated. However, the direct highly para-selective C−H trifluoromethylation of a class of arenes has not been achieved. In this study, we report a light-promoted 4,5-dichlorofluorescein (DCFS)-enabled para-selective C−H trifluoromethylation of arylcarbamates using Langlois reagent. The preliminary mechanistic study revealed that the activated organic photocatalyst coordinated with the arylcarbamate led to para-selective C−H trifluoromethylation. Ten-gram scale reaction performs well highlighting the synthetic importance of this new protocol.

Synlett
DOI: 10.1055/a-1523-3336

Deuterium incorporation can effectively stabilize the chiral centers of drug and agrochemical candidates that hampered by rapid in vivo racemization. In this work, the synthetically challenging chiral-center deuteration of alcohols has been achieved via a single-electron umpolung reductive-deuteration protocol using benign D2O as deuterium source and mild SmI2 as electron donor. The broad scope and excellent functional group tolerance of this method has been showcased by the synthesis of 43 respective α-deuterioalcohols in high yields and ≥98% deuterium incorporations. The potential application of this versatile method has been exemplified in the synthesis of 6 deuterated drug derivatives, 1 deuterated human hormone, and 3 deuterated natural products. This method using D2O is greener and more efficient compared to traditional pyrophoric-metal-deuteride-mediated reductive deuterations.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Abstract

We report the first example of homogeneously catalyzed hydrogenation of the N=N bond of azo compounds using a complex of an earth-abundant-metal. The hydrogenation reaction is catalyzed by a manganese pincer complex, proceeds under mild conditions, and yields amines, which makes this methodology a sustainable alternative route for the conversion of azo compounds. A plausible mechanism involving metal-ligand cooperation and hydrazine intermediacy is proposed based on mechanistic studies.

The application of hexafluoroisopropanol (HFIP) as a reagent in the cycloisomerization of alkyne-tethered carbamoyl chlorides is demonstrated. The chlorinated methylene oxindole products are obtained in excellent E-selectivities. This reactivity was also extended towards the synthesis of chlorinated methylene pyrrolidones and 2-quinolinones.

Abstract

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Nature Reviews Chemistry, Published online: 22 June 2021; doi:10.1038/s41570-021-00288-z

Nature, Published online: 22 June 2021; doi:10.1038/s41586-021-03717-7

Nature Reviews Chemistry, Published online: 22 June 2021; doi:10.1038/s41570-021-00284-3

Synthesis
DOI: 10.1055/a-1509-6078

The facile synthesis of highly functionalized building blocks with potential biological activity is of great interest to medicinal chemistry. The benzoxepinone core structures commonly exhibit biological activity. Thus, a short and efficient synthetic route towards benzoxepine containing scaffold, which enables late stage modification was developed. Namely, base-free catalytic Wittig reactions enabled the synthesis of bromobenzoxepinones from readily available starting materials. Subsequent, Suzuki–Miyaura and Stille reactions proved to be suitable methods to access a variety of benzoxepinone diaryl derivatives by late stage modification in only three steps. This three-step reaction sequence is suitable for high throughput applications and gives facile access to highly complex molecular structures, which are suitable for further functionalization. The antiproliferative properties of selected arylbenzoxepinones­ were tested in vitro on monolayer tumor cell line A549. Notably, in this initial screening, these compounds were found to be active in the micromolar range.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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

This Minireview summarizes recent developments in which both noble and non-noble metal-based heterogeneous catalysts are used to synthesize N-heterocycles from alcohols and N-nucleophiles via acceptorless dehydrogenation or borrowing hydrogen methodologies. The strategies for the preparation and functionalization of heterogeneous catalysts, reaction mechanisms, and the roles of heterogeneous catalysts in these reactions are also discussed.

Abstract

N-Heterocycles, such as pyrroles, pyrimidines, quinazolines, and quinoxalines, are important building blocks for organic chemistry and the fine-chemical industry. For their synthesis, catalytic borrowing hydrogen and acceptorless dehydrogenative coupling reactions of alcohols as sustainable reagents have received significant attention in recent years. To overcome the problems of product separation and catalyst reusability, several metal-based heterogeneous catalysts have been reported to achieve these transformations with good yields and selectivity. In this Minireview, we summarize recent developments using both noble and non-noble metal-based heterogeneous catalysts to synthesize N-heterocycles from alcohols and N-nucleophiles via acceptorless dehydrogenation or borrowing hydrogen methodologies. Furthermore, this Minireview introduces strategies for the preparation and functionalization of the corresponding heterogeneous catalysts, discusses the reaction mechanisms and the roles of metal electronic states, and the influence of support Lewis acid–base properties on these reactions.

Bridged bicyclic nitrogen scaffolds are conformationally restricted analogues of important aminocarbo- and aminoheterocycles. Fixation of functional groups in a biologically active conformation provides efficient and selective ligands for various targets, featuring improved ADME parameters. Long synthetic sequences relying on traditional organic chemistry currently limit the drug discovery process. New step-economic synthetic procedures are therefore highly sought after.

Abstract

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed γ-C(sp³)-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed γ-C(sp³)-H olefination is achieved.

Synthesis
DOI: 10.1055/a-1509-8624

Herein, a direct method for the synthesis of 3-fluoroindoles and 3,3-difluoroindolines from easily accessible 2,2-difluoro-2-phenyl­ethan-1-amines is presented. This protocol was performed by Pd-catalyzed direct C–H/N–H coupling and employed picolinamide as a directing group. By controlling the temperature for this transformation, various 3,3-difluoroindolines and 3-fluoroindoles could be isolated with moderate to good yields.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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

A fresh start! Catalyst reusability in liquid-phase reactions is usually tested by catalyst separation from a reaction mixture followed by the next run. Another procedure called “fresh start” consists of adding a new portion of reagents to the reaction mixture without catalyst separation. In the present work, these procedures were compared in testing the reusability of Pd/C catalysts in liquid-phase hydrogenations of O-, S-, and N-vinyl derivatives.

Abstract

The reusability of metal catalysts is a key issue for the potential application of new catalysts in research and industrial practice. The most common procedure for testing catalyst reusability in liquid-phase heterogeneous reactions is based on separating a catalyst from a reaction mixture followed by the next run. An alternative procedure called “fresh start” consists of the addition of a new portion of reagents to the reaction mixture without any isolation operation. In this work, we compare both procedures in a model Pd/C-catalyzed hydrogenation with different heteroatoms, e. g., O-, S-, and N-vinyl derivatives. It was shown that regardless of whether the catalyst is stable or potentially poisoned during the reaction, both procedures lead to comparable results. It appears that a much easier implementation of a fresh start procedure may be an option of choice. The possibilities of using both procedures to rationalize the experimental protocol for assessing Pd/C catalyst reusability in liquid-phase hydrogenations are discussed.

Nature Communications, Published online: 17 June 2021; doi:10.1038/s41467-021-23971-7

In a joint endeavor, a ruthenium catalyst and a catalytic amine enable the deuteration of aromatic aldehydes and ketones using cheap and convenient D₂O as deuterium source. The amine serves as a transient directing group, forming imines in situ and thus facilitating coordination of the ruthenium catalyst to the substrates. The practical applicability of this novel methodology is demonstrated by the successful deuteration of a range of (hetero)aromatic carbonyl compounds as well as pharmaceuticals. More information can be found in the Full Paper by H. Neumann, M. Beller, et al. (DOI: 10.1002/chem.202100468).