Functionalization Of Benzylic Research Articles

A General Copper‐Box System for the Asymmetric Arylative Functionalization of Benzylic, Propargylic or Allenylic Radicals

AbstractRadical‐involved arylative cross‐coupling reactions have recently emerged as an attractive strategy to access valuable aryl‐substituted motifs. However, there still exist several challenges such as limited scope of radical precursors/acceptors, and lack of general asymmetric catalytic systems, especially regarding the multicomponent variants. Herein, we reported a general copper‐Box system for asymmetric three‐component arylative radical cross‐coupling of vinylarenes and 1,3‐enynes, with oxime carbonates and aryl boronic acids. The reactions proceed under practical conditions in the absence or presence of visible‐light irradiation, affording chiral 1,1‐diarylalkanes, benzylic alkynes and allenes with good enantioselectivities. Mechanistic studies imply that the copper/Box complexes play a dual role in both radical generation and ensuing asymmetric cross‐coupling. In the cases of 1,3‐enynes, visible‐light irradiation could improve the activity of copper/Box complex toward the initial radical generation, enabling better efficiency match between radical formation and cross‐coupling.

A General Copper-Box System for the Asymmetric Arylative Functionalization of Benzylic, Propargylic or Allenylic Radicals.

Radical-involved arylative cross-coupling reactions have recently emerged as an attractive strategy to access valuable aryl-substituted motifs. However, there still exist several challenges such as limited scope of radical precursors/acceptors, and lack of general asymmetric catalytic systems, especially regarding the multicomponent variants. Herein, we reported a general copper-Box system for asymmetric three-component arylative radical cross-coupling of vinylarenes and 1,3-enynes, with oxime carbonates and aryl boronic acids. The reactions proceed under practical conditions in the absence or presence of visible-light irradiation, affording chiral 1,1-diarylalkanes, benzylic alkynes and allenes with good enantioselectivities. Mechanistic studies imply that the copper/Box complexes play a dual role in both radical generation and ensuing asymmetric cross-coupling. In the cases of 1,3-enynes, visible-light irradiation could improve the activity of copper/Box complex toward the initial radical generation, enabling better efficiency match between radical formation and cross-coupling.

Syntheses of Diarylmethanes Via an Oxidative Benzylic Functionalization of P-Alkyl Phenol Derivatives Under Quaternary Ammonium Hypoiodite Catalysis.

We herein report two strategies for the quaternary ammonium hypoiodite-mediated oxidative benzylic functionalization of p-alkyl phenol derivatives. By using either dibenzoylperoxide or H2O2 in hexafluoroisopropanol in the presence of tetrabutyl ammonium iodide gives access to activated intermediates which can then be coupled with electron-rich aromatic compounds. Overall, this sequential two-step one-pot procedure gives access to diversely decorated diarylmethane derivatives straightforwardly. Furthermore, the suitability of these products to undergo further oxidation reactions was successfully demonstrated.

Novel ligands from direct benzylic functionalisation of tris(2-pyridylmethyl)amine.

Tris-(2-pyridylmethyl)amines (TPA or TPMA) are polipyrydine-based ligands extensively used in catalysis and supramolecular chemistry due their capability to form stable tetradentate complexes with a large variety of metals. The unsubstituted ligand, which is also commercially available, can be synthesised by consecutive alkylation of a picoline or by reductive amination of a pyridine aldehyde. In this article, we report a novel synthetic method which opens to the post-functionalisation of these ligands in the benzylic position. This novel derivatization strategy, beside providing synthetic access to novel structures and functions, has been used to prepare a series of metal complexes which have been tested in photochemical hydrogen evolution.

Copper-Catalyzed Benzylic Functionalization of Lignin-Derived Monomers.

Within the field of lignin biorefining, significant research effort has been dedicated to the advancement of catalytic methods for lignocellulose depolymerization. However, another key challenge in lignin valorization is the conversion of the obtained monomers into higher value-added products. To address this challenge, new catalytic methods that can fully embrace the inherent complexity of their target substrates are needed. Here, we describe copper-catalyzed reactions for benzylic functionalization of lignin-derived phenolics via intermediate formation of hexafluoroisopropoxy masked para-quinone methides (p-QMs). By controlling the rates of copper catalyst turnover and p-QM release, we have developed copper-catalyzed allylation and alkynylation reactions of lignin-derived monomers to install various unsaturated fragments amenable to further synthetic applications.

Benzylic functionalization of dehydroabietane derivatives as a convenient way to sulfur compounds

Benzylic functionalization of dehydroabietane derivatives as a convenient way to sulfur compounds

Asymmetric C(sp3)\u2013H functionalization of unactivated alkylarenes such as toluene enabled by chiral Br\xf8nsted base catalysts

Benzylic functionalisation of unactivated alkylarenes remains as a significant challenge in asymmetric catalysis due to their less reactive nature. Here, we show development of catalytic asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene with imines. The reactions proceeded smoothly under proton-transfer conditions using a chiral, strong Brønsted base catalyst system. A chiral Brønsted base prepared from an alkylpotassium and a chiral amine ligand was found to effectively form a promising asymmetric environment around a benzyl anion. Optimization of the reaction conditions revealed that the use of the alkaline metal amide, potassium hexamethyldisilazide (KHMDS), as an additive was most effective, and enantioselective and atom economical carbon–carbon bond-forming reactions at the benzylic positions of unactivated alkylarenes was achieved without using any transition-metal catalyst.

Easy access to drug building-blocks through benzylic C-H functionalization of phenolic ethers by photoredox catalysis.

A visible light-mediated photocatalyzed C-C-bond forming method for the benzylic C-H functionalization of phenolether containing synthetic building blocks based on a radical-cation/deprotonation strategy is reported. This method allows the mild, selective generation of benzyl radicals in phenolic complex molecules and drug-like compounds, providing new entries in synthetic and medicinal chemistry.

Benzylic C(sp3)-C(sp2) cross-coupling of indoles enabled by oxidative radical generation and nickel catalysis.

A mechanistically unique functionalization strategy for a benzylic C(sp3)–H bond has been developed based on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical generation at the benzylic position of the substrate, with subsequent transition metal catalysis to complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp2)-based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer (HAT) processes, which are frequently encountered in conventional methods, are not involved in the product formation process of the developed strategy.

In Situ Generation of Allenes and their Application to One‐Pot Assembly of Functionalized Fluoreno[3,2‐b]furans by Calcium‐Catalyzed, Regioselective, 3‐Component Reactions

We have developed a novel synthetic methodology for the preparation of tetra‐annulated fluorenofurans and fluorenopyrans using calcium(II)‐catalyzed one‐pot, three‐component reaction. In this reaction, tert‐propargyl alcohols react with 1,3‐dicarbonyls to form tetra‐substituted allenes, which are subsequently undergoing regiodivergent annulation with sec‐propargyl alcohols to produce the fluorene‐fused furan compounds. Broad substrate scope, regioselectivity, gram‐scale synthesis, and benzylic functionalization of products are some of the highlights of this protocol.

Electrosynthesis 2.0 in 1,1,1,3,3,3‐Hexafluoroisopropanol/Amine Mixtures

AbstractThe intention of this review is to highlight the innovative electrolyte combination of 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP) with tertiary nitrogen bases in electro‐organic synthesis. This easy applicable and promising mixture is not yet well established in electro‐organic synthesis, but expands the various possibilities in the latter. Combinations of fluorinated alcohols with nitrogen bases form highly conductive electrolyte systems, which can be evaporated completely. Consequently, no additional supporting electrolyte is required and work‐up procedures are tremendously simplified. With this electrolyte mixture carbon‐carbon homo‐ and cross‐coupling reactions of arenes and phenols have been established with substrates that have not been previously susceptible to the anodic dehydrogenative coupling reaction. The intermediate installation of highly fluorinated alkoxy moieties can be exploited for subsequent conversions as well as various benzylic functionalization, including asymmetric transformations. These transformations show unique selectivity and functional group tolerance making them highly applicable to the synthesis of sophisticated structural motifs, including natural products.

Preparation of Degradable Polymeric Nanoparticles with Various Sizes and Surface Charges from Polycarbonate Block Copolymers

ABA-type polycarbonate block copolymers with pendant vinyl ether and benzyl functionalities were synthesized by sequential ring-opening polymerization of functional cyclic carbonate monomers using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an organobase catalyst. The vinyl ether moieties on the resulting block copolymers were readily conjugated with 3-mercaptopropionic acid, cysteamine hydrochloride, and L-cysteine hydrochloride monohydrate through thiol-ene “click” reactions, yielding anionic, cationic, and zwitterionic self-assembled nanoparticles, respectively, in corresponding buffers. The effect of pH on the size and surface charge of nanoparticles were examined.

Direct benzylic functionalization of pyridines: Palladium-catalyzed mono-α-arylation of α-(2-pyridinyl)acetates with heteroaryl halides

Herein, we report a Pd-catalyzed mono-α-arylation reaction for pyridine benzylic functionalization. This approach serves as an efficient alternative to synthesize di-heteroaryl acetates in good yields and selectivities. Moreover, the method is applicable to heteroaryl substrate combinations, and exhibits great functional group tolerance. A streamlined protocol also enables the rapid synthesis of diheteroaryl ketones. The synthetic value was also demonstrated by scale-up experiments

Copper-Catalyzed Oxidative Multicomponent Annulation Reaction for Direct Synthesis of Quinazolinones via an Imine-Protection Strategy.

Via an imine-protection strategy, we herein present an unprecedented copper-catalyzed oxidative multicomponent annulation reaction for direct synthesis of quinazolinones. The construction of various products is achieved via formation of three C-N and one C-C bonds in conjunction with the benzylic functionalization. The merits of easily available feedstocks, naturally abundant catalyst, good functional group and substrate compatibility, and release of H2O as the byproduct make the developed chemistry a practical way to access quinazolinones.

First Report on the Validated Classification-Based Chemometric Modeling of Human Rhinovirus 3C Protease (HRV 3Cpro) Inhibitors

Human rhinoviruses (HRVs), a major cause of common cold and upper respiratory infections, may trigger severe respiratory complications like asthma and COPD. To date, no drugs are available in the market which are designed as novel HRV inhibitors despite the involvement of some pharmaceutical companies' due to economical and clinical constraints. HRV 3C protease may be a potential target for drug design as it plays crucial role in viral RNA replication and virion assembly process. Therefore, designing novel HRV 3Cpro inhibitors is necessary and demanding in the field of antiviral drug design. In this article, statistically significant and validated classification-based QSARs of a series of HRV 3Cpro inhibitors were performed for the first time as per the authors' knowledge. Results suggest that oxopyrrolidine and piperidinone rings are favored whereas carboxybenzyl and unsubstituted benzyl functions may be unfavorable. Moreover, this group, along with cyclic alkyl or aryl ring structures may favor HRV 3Cpro inhibition. These observations may be utilized for the design of a higher active anti-HRV agent in future.

Potassium Amide-Catalyzed Benzylic C-H Bond Addition of Alkylpyridines to Styrenes.

The benzylic functionalization of alkylpyridines is an important pathway for pyridine derivatives synthesis. The reaction partners, however, were mostly limited to highly reactive polar electrophiles. Herein, we report a potassium amide-catalyzed selective benzylic C-H bond addition of alkylpyridines to styrenes. Potassium bis(trimethylsilyl)amide (KHMDS), a readily available Brønsted base, showed excellent catalytic activity and chemoselectivity. A series of alkylpyridine derivatives, including benzylic quaternary carbon substituted pyridines, were obtained in good to high yield. Preliminary mechanistic studies revealed that the deprotonation equilibrium is probably responsible for the excellent selectivity.

Potassium Amide‐Catalyzed Benzylic C−H Bond Addition of Alkylpyridines to Styrenes

AbstractThe benzylic functionalization of alkylpyridines is an important pathway for pyridine derivatives synthesis. The reaction partners, however, were mostly limited to highly reactive polar electrophiles. Herein, we report a potassium amide‐catalyzed selective benzylic C−H bond addition of alkylpyridines to styrenes. Potassium bis(trimethylsilyl)amide (KHMDS), a readily available Brønsted base, showed excellent catalytic activity and chemoselectivity. A series of alkylpyridine derivatives, including benzylic quaternary carbon substituted pyridines, were obtained in good to high yield. Preliminary mechanistic studies revealed that the deprotonation equilibrium is probably responsible for the excellent selectivity.

Recent Development of Metal-Free Direct Asymmetric Functionalization of Benzylic C(sp3)—H Bond

芳基结构广泛存在于天然产物和生物活性分子中，含芳基的化合物是重要的有机合成中间体.近年来，基于苄位C（sp 3 ）—H键的不对称直接官能团化能够高立体选择性地引入芳环及杂芳环结构，受到化学家们的广泛关注.其中有机小分子催化下无金属参与的催化模式具有较好的应用前景.本综述介绍了几种重要的无金属参与的苄位C（sp 3 ）—H键不对称直接官能团化的反应模式，总结了该领域近年来的主要研究进展.

An Efficient Synthesis of Functionalized 2-Oxoindole Derivatives by Organocatalytic Z/E-Selective Benzylic Functionalization of (o-Aminobenzyl)indoles with Isatins

An efficient method has been established for the synthesis of functionalized 2-oxoindole derivatives through chemospecific benzylic functionalization of (o-aminobenzyl)indoles with isatins. This protocol not only provides ready access to functionalized 2-oxoindole derivatives in high yields (≤97%) and excellent Z/E-selectivities (Z/E > 95:5), but also serves as a good example of catalytic benzylic functionalization of (o-aminobenzyl)indoles.

ChemInform Abstract: Benzylic Functionalization of Anthrones via the Asymmetric Ring Opening of Oxabicycles Utilizing a Fourth‐Generation Rhodium Catalytic System.

ChemInformVolume 47, Issue 8 Preparative Organic Chemistry ChemInform Abstract: Benzylic Functionalization of Anthrones via the Asymmetric Ring Opening of Oxabicycles Utilizing a Fourth-Generation Rhodium Catalytic System. Charles C. J. Loh, Charles C. J. Loh Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorXiang Fang, Xiang Fang Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorBrendan Peters, Brendan Peters Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorMark Lautens, Mark Lautens Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this author Charles C. J. Loh, Charles C. J. Loh Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorXiang Fang, Xiang Fang Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorBrendan Peters, Brendan Peters Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this authorMark Lautens, Mark Lautens Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.Search for more papers by this author First published: 04 February 2016 https://doi.org/10.1002/chin.201608021Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue8February, 2016 RelatedInformation