Nucleophilic Alkylation Research Articles

Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium‐Catalyzed Allylic Alkylation

AbstractPalladium‐catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo‐ and regioselective direct palladium‐catalyzed C‐allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium‐catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium-Catalyzed Allylic Alkylation.

Palladium-catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo- and regioselective direct palladium-catalyzed C-allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium-catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Visible‐Light‐Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N‐Alkoxypyridinium Salts

AbstractMetal‐free, visible‐light‐induced site‐selective heteroarylation of remote C(sp3)−H bonds has been accomplished through the design of N‐alkoxyheteroarenium salts serving as both alkoxy radical precursors and heteroaryl sources. The transient alkoxy radical can be generated by the single‐electron reduction of an N‐alkoxypyridinium substrate by a photoexcited quinolinone catalyst. Subsequent radical translocation of the alkoxy radical forms a nucleophilic alkyl radical intermediate, which undergoes addition to the substrate to achieve remote C(sp3)−H heteroarylation. This cascade strategy provides a powerful platform for remote C(sp3)−H heteroarylation in a controllable and selective manner and is well suited for late‐stage functionalization of complex bioactive molecules.

Visible-Light-Induced Pyridylation of Remote C(sp3 )-H Bonds by Radical Translocation of N-Alkoxypyridinium Salts.

Metal-free, visible-light-induced site-selective heteroarylation of remote C(sp3 )-H bonds has been accomplished through the design of N-alkoxyheteroarenium salts serving as both alkoxy radical precursors and heteroaryl sources. The transient alkoxy radical can be generated by the single-electron reduction of an N-alkoxypyridinium substrate by a photoexcited quinolinone catalyst. Subsequent radical translocation of the alkoxy radical forms a nucleophilic alkyl radical intermediate, which undergoes addition to the substrate to achieve remote C(sp3 )-H heteroarylation. This cascade strategy provides a powerful platform for remote C(sp3 )-H heteroarylation in a controllable and selective manner and is well suited for late-stage functionalization of complex bioactive molecules.

Retaining Alkyl Nucleophile Regiofidelity in Transition-Metal-Mediated Cross-Couplings to Aryl Electrophiles

While the advent of transition-metal catalysis has undoubtedly transformed synthetic chemistry, problems persist with the introduction of secondary and tertiary alkyl nucleophiles into C(sp2) aryl electrophiles. Complications arise from the delicate organometallic intermediates typically invoked by such processes, from which competition between the desired reductive elimination event and the deleterious β-H elimination pathways can lead to undesired isomerization of the incoming nucleophile. Several methods have integrated distinct combinations of metal, ligand, nucleophile, and electrophile to provide solutions to this problem. Despite substantial progress, refinements to current protocols will facilitate the realization of complement reactivity and improved functional group tolerance. These issues have become more pronounced in the context of green chemistry and sustainable catalysis, as well as by the current necessity to develop robust, reliable cross-couplings beyond less explored C(sp2)–C(sp2) constructs. Indeed, the methods discussed herein and the elaborations thereof enable an ‘unlocking’ of accessible topologically enriched chemical space, which is envisioned to influence various domains of application.1 Introduction2 Mechanistic Considerations3 Magnesium Nucleophiles4 Zinc Nucleophiles5 Boron Nucleophiles6 Other Nucleophiles7 Tertiary Nucleophiles8 Reductive Cross-Coupling with in situ Organometallic Formation9 Conclusion

Palladium‐Catalyzed para‐Selective Alkylation of Electron‐Deficient Arenes

AbstractIntermolecular alkylations of electron‐deficient arenes proceed with good para selectivity. Palladium catalysts were used to generate nucleophilic alkyl radicals from alkyl halides, which then directly add onto the arenes. The arene scope and the site of alkylation are opposite to those of classical Friedel–Crafts alkylations, which prefer electron‐rich systems.

Palladium-Catalyzed para-Selective Alkylation of Electron-Deficient Arenes.

Intermolecular alkylations of electron-deficient arenes proceed with good para selectivity. Palladium catalysts were used to generate nucleophilic alkyl radicals from alkyl halides, which then directly add onto the arenes. The arene scope and the site of alkylation are opposite to those of classical Friedel-Crafts alkylations, which prefer electron-rich systems.

Cross-Coupling of Phenol Derivatives with Umpolung Aldehydes Catalyzed by Nickel

A nickel-catalyzed cross-coupling to construct the C(sp2)–C(sp3) bond was developed from two sustainable biomass-based feedstocks: phenol derivatives with umpolung aldehydes. This strategy features the in situ generation of moisture/air-stable hydrazones from naturally abundant aldehydes, which act as alkyl nucleophiles under catalysis to couple with readily available phenol derivatives. The avoidance of using both halides as the electrophiles and organometallic or organoboron reagents (also derived from halides) as the nucleophiles makes this method more sustainable. Water tolerance, great functional group (ketone, ester, free amine, amide, etc.) compatibility, and late-stage elaboration of complex biological molecules exemplified its practicability and unique chemoselectivity over organometallic reagents.

Benzene yields to nucleophilic substitution

With the aid of a powerful calcium reagent, researchers have achieved a bit of molecular trickery to do what many synthetic organic chemists thought wasn’t possible: They have carried out the first nucleophilic alkylation of benzene (Science 2017, DOI: 10.1126/science.aao5923). Friedel-Crafts alkylation is a classic example of electrophilic aromatic substitution. A Lewis acid such as AlCl3 binds the halogen of an alkyl halide, creating a positive charge on the alkyl group. This electron-poor species—an electrophile—is attracted to an electron-rich substrate—a nucleophile—such as benzene’s aromatic ring. The alkyl group then displaces a benzene hydrogen, producing an alkylbenzene. An electron-rich nucleophilic species would normally be repelled by benzene, unless an electron-withdrawing group already on the ring activates it toward nucleophilic attack. Nevertheless, a team led by Michael S. Hill of the University of Bath and Laurent Maron of the University of Toulouse found a way to allow nucleophiles to r...

Organocalcium-mediated nucleophilic alkylation of benzene.

The electrophilic aromatic substitution of a C-H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n-alkyl derivatives-synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride-react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C-D/H bond. These reactions produce the n-alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C-H activation transition state.

An Efficient Route to Highly Substituted Indoles via Tetrahydroindol-4(5H)-one Intermediates Produced by Ring-Opening Cyclization of Spirocyclopropanes with Amines.

An efficient route to highly substituted indoles was developed. It included regioselective functionalization of tetrahydroindol-4(5H)-ones, prepared by ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines, and subsequent oxidation. The 6-substituted indoles were synthesized from a readily available 5-substituted cyclohexane-1,3-dione-2-spirocyclopropane. The synthesis of 5- and 7-substituted indoles was achieved by regioselective electrophilic alkylation of tetrahydroindol-4(5H)-one, followed by oxidation. The 4-substituted indoles were synthesized by nucleophilic alkylation of the corresponding pyrrole derivative, which was prepared by partial oxidation of tetrahydroindol-4(5H)-one, and sequential oxidation. The synthesis of 4-substituted indoles was also accomplished by palladium-catalyzed coupling of 4-hydroxyindole-derived triflates. Furthermore, the synthesis of 4,5,6,7-tetrasubstituted indoles was achieved by using these regioselective alkylations.

Toolbox of Nonmetallocene Lanthanides: Multifunctional Catalysts in Group-Transfer Polymerization.

Herein, we present a fundamental study of isostructural 2-methoxyethylamino-bis(phenolate)-lanthanide complexes [(ONOO)RM(X)(THF)] (M = Lu, Y; R = tBu, CMe2Ph, X = CH2TMS, collidine; THF = tetrahydrofuran; TMS = trimethylsilyl) for rare-earth metal-mediated group-transfer polymerization (GTP). This analysis includes the differentiation of electron-donating and nondonating vinyl monomers and two metal centers with regard to the ionic radius (yttrium and lutetium). In addition, highly nucleophilic alkyl initiators are compared with electron-donating heteroaromatic initiators. Our examinations include the impact of these parameters on the activity, initiator efficiency, and tacticity of the obtained polymers. Density functional theory calculations and proposed catalyst structure determinations via X-ray analysis support these investigations. This facilitates the selection of the best metal and initiator combination to address efficient and stereospecific polymerization of a broad range of Michael monomers. [(ONOO)tBuLu(X)(THF)] shows the highest activity of 2220 h-1 (normalized turnover frequency) for the polymerization of 2-vinylpyridine due to the higher Lewis-acidity of lutetium. Through C(sp3)-H bond activation, catalysts with higher initiator efficiency in N,N'-dimethylacrylamide (DMAA) and diethylvinylphosphonate polymerization were synthesized. Remarkably, [(ONOO)tBuY(collidine)(THF)] was capable of stereospecifically polymerizing DMAA to highly isotactic poly(DMAA) (Pm = 0.94). Overall, the kinetics studies reveal a living-type GTP mechanism for all of the tested catalysts, enabling precise molecular-weight predeterminations with narrow molecular weight distributions (Đ ≤ 1.06).

Selectivity Control in the Palladium-catalyzed Cross-coupling of Alkyl Nucleophiles.

Site-selectivity remains a major challenge in metal-catalyzed C-H bond functionalization. Most existing strategies rely on the introduction of a directing group or on the intrinsic reactivity of the substrate. In this account article, we describe the development of an alternative strategy based on the migration of an organopalladium species along an alkyl chain, wherein the phosphine ligand controls the cross-coupling site. This concept was first implemented with lithium enolates, and then extended to α-zincated alkylamines obtained by directed lithiation and transmetalation. Both the direct and the migrative cross-couplings, which are controlled by simply switching the ligand, furnish synthetically useful organic intermediates.

Nickel- and Photoredox-Catalyzed Cross-Coupling Reactions of Aryl Halides with 4-Alkyl-1,4-dihydropyridines as Formal Nucleophilic Alkylation Reagents.

A combination of nickel and photoredox catalysts promoted novel cross-coupling reactions of aryl halides with 4-alkyl-1,4-dihydropyridines. 4-Alkyl-1,4-dihydropyridines act as formal nucleophilic alkylation reagents through a photoredox-catalyzed carbon-carbon (C-C) bond-cleavage process. The present strategy provides an alternative to classical carbon-centered nucleophiles, such as organometallic reagents.

Nickel‐ and Photoredox‐Catalyzed Cross‐Coupling Reactions of Aryl Halides with 4‐Alkyl‐1,4‐dihydropyridines as Formal Nucleophilic Alkylation Reagents

AbstractA combination of nickel and photoredox catalysts promoted novel cross‐coupling reactions of aryl halides with 4‐alkyl‐1,4‐dihydropyridines. 4‐Alkyl‐1,4‐dihydropyridines act as formal nucleophilic alkylation reagents through a photoredox‐catalyzed carbon–carbon (C−C) bond‐cleavage process. The present strategy provides an alternative to classical carbon‐centered nucleophiles, such as organometallic reagents.

ChemInform Abstract: Direct Alkylation of Heteroarenes with Unactivated Bromoalkanes Using Photoredox Gold Catalysis.

Although visible light photoredox catalysis has emerged as a powerful tool for the construction of C–C bonds, common catalysts and/or their photoexcited states suffer from low redox potentials, limiting their applicability to alkyl radical generation from substrates with activated carbon–halogen bonds. Radicals derived from these activated compounds, being highly electrophilic or stabilized, do not undergo efficient addition to heteroarenes. Herein we describe the photocatalytic generation of nucleophilic alkyl radicals from unactivated bromoalkanes as part of a universal and efficient cross-coupling strategy for the direct alkylation of heteroarenes using a dimeric gold(I) photoredox catalyst, [Au2(bis(diphenylphosphino)methane)2]Cl2. The method proves to be efficient for alkylation of arenes under mild conditions in the absence of directing groups.

Nucleophilic Substitution on 2-Monosubstituted Quinoxalines Giving 2,3-Disubstituted Quinoxalines: Investigating the Effect of the 2-Substituent.

An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl, aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields. 2-Monosubstituted quinoxalines bearing a phenyl and butyl substituent reacted readily with alkyl-, aryl-, heteroaryl- and alkynyl- nucluephiles, giving di-substituted quinoxalines. 2-Monosubstituted quinoxalines bearing an amine and alkynyl substituent only reacted with alkyl nucleophiles. Oxidative rearomatization to give 2,3-disubstituted quinoxaline products occurred in atmospheric O2.

ChemInform Abstract: Generation of the Methoxycarbonyl Radical by Visible‐Light Photoredox Catalysis and Its Conjugate Addition with Electron‐Deficient Olefins

Abstractfor the direct and regioselective construction of a 1,4‐dicarbonyl structural motif

An Eco-Friendly Ultrasound-Assisted Synthesis of Novel Fluorinated Pyridinium Salts-Based Hydrazones and Antimicrobial and Antitumor Screening.

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde (2) followed by the nucleophilic alkylation of the resulting N-(4-fluorobenzylidene)isonicotinohydrazide (3) with a different alkyl iodide. The iodide counteranion of 5–10 was subjected to an anion exchange metathesis reaction in the presence of an excess of the appropriate metal salts to afford a new series of fluorinated pyridinium salts tethering a hydrazone linkage 11–40. Ultrasound irradiation led to higher yields in considerably less time than the conventional methods. The newly synthesized ILs were well-characterized with FT-IR, 1H NMR, 13C NMR, 11B, 19F, 31P and mass spectral analyses. The ILs were also screened for their antimicrobial and antitumor activities. Within the series, the salts tethering fluorinated counter anions 11–13, 21–23, 31–33 and 36–38 were found to be more potent against all bacterial and fungal strains at MIC 4–8 µg/mL. The in vitro antiproliferative activity was also investigated against four tumor cell lines (human ductal breast epithelial tumor T47D, human breast adenocarcinoma MCF-7, human epithelial carcinoma HeLa and human epithelial colorectal adenocarcinoma Caco-2) using the MTT assay, which revealed that promising antitumor activity was exhibited by compounds 5, 12 and 14.

Generation of the Methoxycarbonyl Radical by Visible-Light Photoredox Catalysis and Its Conjugate Addition with Electron-Deficient Olefins.

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.