Copper Catalyzed sp3 C-H α-Acetylation

2019 ◽  
Author(s):  
Otome Okoromoba ◽  
Eun Sil Jang ◽  
Claire McMullin ◽  
Thomas Cundari ◽  
Timothy H. Warren
Keyword(s):  
Natural Products ◽  
Dft Studies ◽  
Alkyl Radicals ◽  
Important Chemical ◽  
Alkyl Electrophiles ◽  
Synthetic Intermediates ◽  
Alkylation Reactions

<p>α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the sp<sup>3</sup> C-H α-acetylation of sp<sup>3</sup> C-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH<sub>2</sub>R at RT with <sup>t</sup>BuOO<sup>t</sup>Bu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu<sup>II</sup>](CH<sub>2</sub>C(O)Ar) that capture alkyl radicals R• to give R-CH<sub>2</sub>C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH<sub>2</sub>CH<sub>2</sub>C(O)Ar.</p>

Copper Catalyzed sp3 C-H α-Acetylation

2019 ◽  
Author(s):  
Otome Okoromoba ◽  
Eun Sil Jang ◽  
Claire McMullin ◽  
Thomas Cundari ◽  
Timothy H. Warren
Keyword(s):  
Natural Products ◽  
Dft Studies ◽  
Alkyl Radicals ◽  
Important Chemical ◽  
Alkyl Electrophiles ◽  
Synthetic Intermediates ◽  
Alkylation Reactions

<p>α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the sp<sup>3</sup> C-H α-acetylation of sp<sup>3</sup> C-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH<sub>2</sub>R at RT with <sup>t</sup>BuOO<sup>t</sup>Bu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu<sup>II</sup>](CH<sub>2</sub>C(O)Ar) that capture alkyl radicals R• to give R-CH<sub>2</sub>C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH<sub>2</sub>CH<sub>2</sub>C(O)Ar.</p>

Recent Developments in Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles

Synthesis ◽  
2020 ◽  
Author(s):  
Lili Shi ◽  
Junkai Fu ◽  
Shuangqiu Gao ◽  
Le Chang ◽  
Binglin Wang
Keyword(s):  
Heck Reaction ◽  
Alkyl Radicals ◽  
Type Reaction ◽  
The Past ◽  
Alkyl Electrophiles ◽  
Recent Developments ◽  
Palladium Catalyzed ◽  
Initial Work ◽  
Activated Olefins ◽  
Pseudo Halides

AbstractThe Mizoroki–Heck reaction is considered as one of the most ingenious and widely used methods for constructing C–C bonds. This reaction mainly focuses on activated olefins (styrenes, acrylates, or vinyl ethers) and aryl/vinyl (pseudo) halides. In comparison, the studies on unactivated alkenes and alkyl electrophiles are far less due to the low reactivity, poor selectivity, as well as competitive β-H elimination. In the past years, a growing interest has thus been devoted and significant breakthroughs have been achieved in the employment of unactivated alkenes and alkyl electrophiles as the reaction components, and this type of coupling is called as Heck-type or Heck-like reaction, which distinguishes from the traditional Heck reaction. Herein, we give a brief summary on Heck-type reaction between unactivated alkenes and alkyl electrophlies, covering its initial work, recent advancements, and mechanistic discussions.1 Introduction2 Intramolecular Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles2.1 Cobalt-Catalyzed Intramolecular Heck-Type Reaction2.2 Palladium-Catalyzed Intramolecular Heck-Type Reaction2.3 Nickel-Catalyzed Intramolecular Heck-Type Reaction2.4 Photocatalysis and Multimetallic Protocol for Intramolecular Heck-Type Reaction3 Intermolecular Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles3.1 Electrophilic Trifluoromethylating Reagent as Reaction Partners3.2 Alkyl Electrophiles as Reaction Partners4 Oxidative Heck-Type Reaction of Unactivated Alkenes and Alkyl Radicals5 Conclusions and Outlook

scholarly journals Synthesis of 1-(1-Arylvinyl)pyridin-2(1H)-ones from Ketones and 2-Fluoropyridine

2021 ◽  
Author(s):  
Takuji Kawamoto ◽  
shunya ikeda ◽  
Akio Kamimura
Keyword(s):  
Biologically Active ◽  
Mechanistic Study ◽  
Efficient Procedure ◽  
Benzene Rings ◽  
Synthetic Intermediates ◽  
Alkylation Reactions ◽  
Vinyl Triflates

Pyridone skeletons are found in numerous biologically active molecules and pharmaceuticals. 1-(1-Arylvinyl)pyridin-2(<i>1H</i>)-ones are synthetic intermediates derived from the enamide moiety, and only few examples of the synthesis of 1-(1-arylvinyl)-2-pyridones have been reported. In this work, a simple and efficient procedure for the synthesis of <i>N</i>-vinyl-substituted pyridones from ketones and 2-fluoropyridine in the presence of trifluoromethane sulfonic anhydride, followed by base treatment is described. Various ketones with electron-donating or -withdrawing groups at the benzene rings can be used in this reaction. A preliminary mechanistic study indicates that it is not very likely that both vinyl triflates and vinyl cations play major roles as intermediates in this transformation. The thus obtained pyridones can be subsequently transformed via C–H arylation and radical alkylation reactions.

scholarly journals Synthesis of 1-(1-Arylvinyl)pyridin-2(1H)-ones from Ketones and 2-Fluoropyridine

2021 ◽  
Author(s):  
Takuji Kawamoto ◽  
shunya ikeda ◽  
Akio Kamimura
Keyword(s):  
Biologically Active ◽  
Mechanistic Study ◽  
Efficient Procedure ◽  
Benzene Rings ◽  
Synthetic Intermediates ◽  
Alkylation Reactions ◽  
Vinyl Triflates

Pyridone skeletons are found in numerous biologically active molecules and pharmaceuticals. 1-(1-Arylvinyl)pyridin-2(<i>1H</i>)-ones are synthetic intermediates derived from the enamide moiety, and only few examples of the synthesis of 1-(1-arylvinyl)-2-pyridones have been reported. In this work, a simple and efficient procedure for the synthesis of <i>N</i>-vinyl-substituted pyridones from ketones and 2-fluoropyridine in the presence of trifluoromethane sulfonic anhydride, followed by base treatment is described. Various ketones with electron-donating or -withdrawing groups at the benzene rings can be used in this reaction. A preliminary mechanistic study indicates that it is not very likely that both vinyl triflates and vinyl cations play major roles as intermediates in this transformation. The thus obtained pyridones can be subsequently transformed via C–H arylation and radical alkylation reactions.

scholarly journals Co-Occurrence of Enzyme Domains Guides the Discovery of an Oxazolone Synthetase

2020 ◽  
Author(s):  
Tristan de Rond ◽  
Julia E. Asay ◽  
Bradley S. Moore
Keyword(s):  
Natural Products ◽  
Gene Annotation ◽  
Functional Characterization ◽  
Genome Mining ◽  
Catalytic Activities ◽  
Single Protein ◽  
Multifunctional Enzymes ◽  
Synthetic Intermediates ◽  
Functional Gene Annotation ◽  
Proof Of Principle

AbstractMultidomain enzymes are cellular machines that orchestrate two or more catalytic activities to carry out metabolic transformations with increased control and speed. Our understanding of these enzymes’ capabilities drives progress in fundamental metabolic research, biocatalysis, and human health. Here, we report the development of a new genome mining approach for the targeted discovery of novel biochemical transformations through the analysis of co-occurring enzyme domains (CO-ED) in a single protein. CO-ED was designed to identify unannotated multifunctional enzymes for functional characterization and discovery based on the premise that linked enzyme domains have evolved to function collaboratively. Guided by CO-ED, we targeted an unannotated predicted ThiF-nitroreductase di-domain enzyme found in more than 50 proteobacteria. Through heterologous expression and biochemical reconstitution, we discovered a series of new natural products containing the rare oxazolone (azlactone) heterocycle and characterized the di-domain enzyme as the first reported oxazolone synthetase in biology. This enzyme has the potential to become a valuable biocatalyst for the production of versatile oxazolone synthetic intermediates. This proof-of-principle experiment validates CO-ED-guided genome mining as a new method with potential broad utility for both the discovery of novel enzymatic transformations and the functional gene annotation of multidomain enzymes.TOC graphic

On the molecular basis of H2O/DMSO eutectic mixtures by using natural products as molecular sensors: a combined NMR and DFT study

2021 ◽  
Author(s):  
Sana Fatima ◽  
Panayiotis C Varras ◽  
Atia-tul Wahab ◽  
Muhammad I Choudhary ◽  
Michael Siskos ◽  
...  
Keyword(s):  
Natural Products ◽  
1H Nmr ◽  
Molecular Basis ◽  
Molecular Level ◽  
Chemical Shifts ◽  
Dft Study ◽  
Dft Studies ◽  
Molecular Sensors ◽  
Nmr Chemical Shifts ◽  
Eutectic Mixtures

NMR and DFT studies of phenol containing natural products as molecular sensors were carried out to investigate H2O/DMSO eutectic mixtures at a molecular level. The 1H NMR chemical shifts of...

N,O-Heterocycles as synthetic intermediates

2008 ◽  
Vol 80 (4) ◽  
pp. 681-685 ◽  
Author(s):  
Roderick W. Bates ◽  
Jutatip Boonsombat ◽  
Yongna Lu ◽  
Joseph A. Nemeth ◽  
Kanicha Sa-Ei ◽  
...  
Keyword(s):  
Natural Products ◽  
Ring Opening ◽  
Cyclization Reaction ◽  
Synthetic Control ◽  
Synthetic Intermediates

Hydroxylamines can be cyclized under various conditions according to the nature of the unsaturation in the N-substituent. Both isoxazolidines and tetrahydrooxazines can be formed with good synthetic control. The choice of the appropriate cyclization reaction leads to syntheses of the natural products sedamine and monomorine. The related N,O-acetals are shown to undergo efficient ring-opening under Sakurai conditions.

Cobalt(III)-Catalyzed 1,4-Addition of C(sp3)–H Bonds to Maleimides

Synlett ◽  
2018 ◽  
Vol 29 (12) ◽  
pp. 1601-1606 ◽  
Author(s):  
Meng Sun ◽  
Xiang-Xiang Chen ◽  
Jiang-Tao Ren ◽  
Jing-Lei Xu ◽  
Hu Xie ◽  
...  
Keyword(s):  
Natural Products ◽  
Functional Groups ◽  
Crucial Role ◽  
Addition Reactions ◽  
Alkylation Reactions

Quinolines and succinimides play a crucial role in many pharmaceutical and natural products. Although sp2 C–H bond addition reactions have been extensively investigated, Co(III)-catalyzed sp3 C–H bond 1,4-addition reactions are relatively unexplored. In this manuscript, an efficient and atom-economic protocol for alkylation reactions of 8-methylquinolines with maleimides is presented. The reaction exhibits exceptional reactivity, satisfactory yields, excellent chemo- and regioselectivity, and tolerates a variety of functional groups.

scholarly journals Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jia-Wang Wang ◽  
Yan Li ◽  
Wan Nie ◽  
Zhe Chang ◽  
Zi-An Yu ◽  
...  
Keyword(s):  
Catalytic Amount ◽  
Ester Group ◽  
Aliphatic Amines ◽  
Chiral Amines ◽  
Chiral Auxiliaries ◽  
Bioactive Natural Products ◽  
Chiral Carbon ◽  
Alkyl Electrophiles ◽  
Synthetic Intermediates ◽  
Pharmaceutical Agents

AbstractTo increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.

Synthesis of Secosterols as an Arena for C–H Functionalization and C–C Manipulation Tactics

Synlett ◽  
2017 ◽  
Vol 28 (10) ◽  
pp. 1127-1133 ◽  
Author(s):  
Philipp Heretsch ◽  
Robert Heinze
Keyword(s):  
Natural Products ◽  
Chemical Synthesis ◽  
Current Literature ◽  
Ring Expansion ◽  
Biosynthetic Pathways ◽  
Radical Ring ◽  
Synthetic Intermediates ◽  
Synthetic Work ◽  
Shed Light

The chemical synthesis of secosterols is an arena for the application of C–H functionalization methods as well as C–C manipulations. Studies on the innate reactivity of synthetic intermediates to undergo C–C scissions and rearrangements can shed light on biosynthetic pathways, or, provide proof for biosynthetic proposals. Examples of the authors work (synthesis of the 14,15-secosterol strophasterol A), as well as examples from current literature (Tian’s synthetic work on 13,14:14,15-disecosterols glaucogenins C and D, and Baran’s synthesis of 9,10-secosterol cortistatin A) are discussed.1 Introduction2 The Synthesis of Strophasterol A Employing the Concept of Innate Reactivity3 Synthetic Work in the Glaucogenin Family of Natural Products4 The Synthesis of Cortistatin A Using a Radical Ring Expansion5 Conclusion

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