Direct Aldehyde C–H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis
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Abstract:
A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C-H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.Keywords:
Hydrogen atom
Photoredox catalysis
A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde enamines are produced via a previously unrecognized reaction pathway. Some of these aldehyde enamines display unprecedented C-alkylation reactivity toward unactivated primary and secondary alkyl halides. For comparison, the reactivity of aldehyde enamines synthesized via a traditional condensation method was examined. C- rather than N-alkylation was the dominant reaction pathway found with a range of electrophiles, making this route to α-alkylated aldehydes more synthetically useful than previously reported.
Reactivity
Enamine
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Piperidine
Pyrrolidine
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Abstract Alkylation of Cyclopropyl Ketones Reduction and Alkylation of α‐Substituted Ketones Substitutive Alkylation of α‐Halocarbonyl Compounds Substitutive Alkylation of β‐Halocarbonyl Compounds Substitutive Alkylation of α‐Diazocarbonyl Compounds Decarboxylation–Allylation of β‐Keto Acids and Esters
Decarboxylation
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A visible-light-mediated atom transfer radical cyclization of unactivated alkyl iodides is described. This protocol operates under mild conditions and exhibits high chemoselectivity profile while avoiding parasitic hydrogen atom transfer pathways. Preliminary mechanistic studies challenge the perception that a canonical photoredox catalytic cycle is being operative.
Chemoselectivity
Photoredox catalysis
Hydrogen atom
Visible spectrum
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Kinetics of DNA alkylation with 2',3'-o-[N-2-chloroethyl-N-methylamino)benzylidene]uridine (UCHRCL), uridine-5'-methylphosphate (MepUCHRCL) and 4-(N-2-chloroethyl-N-methylamino)benzylamine (NH2CH2RCl) and kinetics of elimination of alkylated bases have been studied. Efficiency of DNA alkylation (p/s-ratio of rate constant of alkylation to the sum of rate constants of by-reactions of an active intermediate formed from the reagent) increases with an increase of the positive charge of the reagents as well as efficiency of tRNA alkylation. Alkylated bases are eliminated from DNA; rate of elimination depends on the structure of the reagent; it decreases in the series NH2CH2R- greater than greater than UCHR-greater than MepUCHR-. Bases alkylated by NH2CH2RCl and UCHRCl are eliminated from DNA during alkylation; therefore plots of DNA alkylation by NH2CH2RCl have a maximum. DNA alkylated by MepUCHRCl is rather stable; alkylated bases are not eliminated during alkylation. Effect of temperature and pH on elimination has been studied.
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Radical additions to heteroaromatic bases are frequently employed for the rapid synthesis of complex products using C–H functionalization strategies. The conditions that are commonly employed are typically harsh, routinely requiring stoichiometric oxidants and other additives. In search for milder reaction environments allowing late‐stage functionalization, we present the alkylation of N‐heteroarenes using primary alcohols and ethers as radical precursors, where the corresponding alkyl radical is formed via hydrogen atom transfer process with a photoredox catalyzed chlorine atom generation as HAT agent. Furthermore, we explore the reduction of the heteroarenes in moderate to high yields when using secondary alcohols.
Photoredox catalysis
Hydrogen atom
Surface Modification
Chlorine atom
Atom-transfer radical-polymerization
Stoichiometry
Primary (astronomy)
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Alkylation is the transfer of an alkyl group (CnH2n+1) from one molecule (alkylating agent) to another where it can attach typically to carbon (C-alkylation), but also to oxygen (O-alkylation), nitrogen (N-alkylation), sulfur (S-alkylation) and phosphorous (P-alkylation) depending on the reaction conditions. This chapter discusses the importance of alkylation reactions, then looks at green improvements made by using solid acid catalysts, ionic liquids in Friedel–Crafts reactions, the atom economic borrowing hydrogen strategy and directed alkylation of C–H bonds using alkenes.
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Abstract Ethyl 4,4,4‐trifluoroacetoacetate (I) reacts with the alkyl halides (II) to give the C‐alkylation products (III) and (IV), together with the enol ethers (V).
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Abstract Visible light‐mediated photoredox activation of 10‐methyl‐9,10‐dihydroacridine in the presence of electron‐deficient alkenes leads to selective γ‐ sp 3 CH alkylation whereby 4‐alkyl‐ N,N‐ dimethylanilines produce substituted tetrahydroquinolines by a subsequent alkylation/cyclization sequence involving interesting mechanistic pathways. magnified image
Photoredox catalysis
Surface Modification
Visible spectrum
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Abstract KF/Al2O3 efficiently catalyzes N‐alkylation of heterocyclic, primary, and secondary amines and S‐alkylation of thiols with a variety of alkyl halides. The N‐alkylation and S‐alkylation adducts were produced in good to excellent yields and in short times.
Primary (astronomy)
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