Showing papers on "Alkylation published in 2019"
TL;DR: It is found that a combination of triphenylphosphine and sodium iodide under 456-nanometer irradiation by blue light–emitting diodes can catalyze the alkylation of silyl enol ethers by decarboxylative coupling with redox-active esters in the absence of transition metals.
Abstract: Most photoredox catalysts in current use are precious metal complexes or synthetically elaborate organic dyes, the cost of which can impede their application for large-scale industrial processes. We found that a combination of triphenylphosphine and sodium iodide under 456-nanometer irradiation by blue light–emitting diodes can catalyze the alkylation of silyl enol ethers by decarboxylative coupling with redox-active esters in the absence of transition metals. Deaminative alkylation using Katritzky’s N-alkylpyridinium salts and trifluoromethylation using Togni’s reagent are also demonstrated. Moreover, the phosphine/iodide-based photoredox system catalyzes Minisci-type alkylation of N-heterocycles and can operate in tandem with chiral phosphoric acids to achieve high enantioselectivity in this reaction.
435 citations
TL;DR: The use of pyridinium‐activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst‐free conditions is described to demonstrate broad functional group tolerance.
Abstract: The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et3 N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.
217 citations
TL;DR: The use of the native iron-haem cofactor of these enzymes to mediate sp3 C-H alkylation suggests that diverse haem proteins could serve as potential catalysts for this abiological transformation, and will facilitate the development of new enzymatic C–H functionalization reactions for applications in chemistry and synthetic biology.
Abstract: Although abundant in organic molecules, carbon–hydrogen (C–H) bonds are typically considered unreactive and unavailable for chemical manipulation. Recent advances in C–H functionalization technology have begun to transform this logic, while emphasizing the importance of and challenges associated with selective alkylation at a sp^3 carbon. Here we describe iron-based catalysts for the enantio-, regio- and chemoselective intermolecular alkylation of sp^3 C–H bonds through carbene C–H insertion. The catalysts, derived from a cytochrome P450 enzyme in which the native cysteine axial ligand has been substituted for serine (cytochrome P411), are fully genetically encoded and produced in bacteria, where they can be tuned by directed evolution for activity and selectivity. That these proteins activate iron, the most abundant transition metal, to perform this chemistry provides a desirable alternative to noble-metal catalysts, which have dominated the field of C–H functionalization. The laboratory-evolved enzymes functionalize diverse substrates containing benzylic, allylic or α-amino C–H bonds with high turnover and excellent selectivity. Furthermore, they have enabled the development of concise routes to several natural products. The use of the native iron-haem cofactor of these enzymes to mediate sp^3 C–H alkylation suggests that diverse haem proteins could serve as potential catalysts for this abiological transformation, and will facilitate the development of new enzymatic C–H functionalization reactions for applications in chemistry and synthetic biology.
194 citations
TL;DR: It is found that N-heterocyclic carbene catalysis promoted the unprecedented decarboxylative coupling of aryl aldehydes and tertiary or secondary alkyl carboxylic acid-derived redox-active esters to produce ary lkyl ketones.
Abstract: We found that N-heterocyclic carbene catalysis promoted the unprecedented decarboxylative coupling of aryl aldehydes and tertiary or secondary alkyl carboxylic acid-derived redox-active esters to produce aryl alkyl ketones. The mild and transition-metal-free reaction conditions are attractive features of this method. The power of this protocol was demonstrated by the functionalization of pharmaceutical drugs and natural product. A reaction pathway involving single electron transfer from an enolate form of Breslow intermediate to a redox ester followed by recombination of the resultant radical pair to form a carbon–carbon bond is proposed.
170 citations
TL;DR: This review summarizes the early adventures and recent advancements in catalytic transformation of unactivated C(sp3)-H bonds into C( sp3)-C(sp2) bonds, representing the future trend in green and atom-economic chemistry.
Abstract: The construction of carbon–carbon bonds is a central tenet of modern synthetic chemistry. Metal-catalyzed C–H functionalization can serve as a particularly powerful tool for achieving carbon–carbon bond formation. This review summarizes the early adventures and recent advancements in catalytic transformation of unactivated C(sp3)–H bonds into C(sp3)–C(sp3) bonds. To date, three main strategies have emerged to enable this transformation, namely, metallocarbene-triggered C(sp3)–H alkylation, auxiliary-directed C(sp3)–H alkylation, and photo-induced C(sp3)–H alkylation. Compared with traditional cross-coupling reactions having both coupling partners activated with functional groups or base-promoted enolate chemistry, catalytic alkylation of unactivated C(sp3)–H bonds for C(sp3)–C(sp3) bond formation not only offers novel disconnections in retrosynthetic analysis, but also represents the future trend in green and atom-economic chemistry.
166 citations
TL;DR: The merger of electrocatalysis and photoredox catalysis provides a chemical oxidant-free approach for the generation and functionalization of alkyl radicals from organotrifluoroborates.
Abstract: A photoelectrochemical method for the C-H alkylation of heteroarenes with organotrifluoroborates has been developed. The merger of electrocatalysis and photoredox catalysis provides a chemical oxidant-free approach for the generation and functionalization of alkyl radicals from organotrifluoroborates. A variety of heteroarenes were functionalized using primary, secondary, and tertiary alkyltrifluoroborates with excellent regio- and chemoselectivity.
150 citations
TL;DR: Synthesis of functionalized gem-difluoroalkenes was achieved through nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters.
Abstract: Herein, we report a nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes through reductive decarboxylation of redox-active esters. The present reaction enables the preparation of functionalized gem-difluoroalkenes with the formation of sterically hindered C(sp3)–C(sp3) bonds under very mild reaction conditions, while tolerating many sensitive functional groups and requiring minimal substrate protection. Therefore, this method provides an efficient and convenient approach for late-stage modification of biologically interesting molecules.
142 citations
TL;DR: A catalytic deaminative alkylation of unactivated olefins is described, unlocking a new catalytic platform to forge sp3-sp3 linkages, even in the context of late-stage functionalization.
Abstract: A catalytic deaminative alkylation of unactivated olefins is described. The protocol is characterized by its mild conditions, wide scope, including the use of ethylene as substrate, and exquisite site-selectivity pattern for both α-olefins and internal olefins, thus unlocking a new catalytic platform to forge sp3-sp3 linkages, even in the context of late-stage functionalization.
128 citations
TL;DR: In this article, a decarboxylative alkylation of quinoxalin-2(1H)-ones with visible-light-mediated decarsignalization was proposed.
Abstract: A efficient and sustainable approach for the synthesis of 3-alkylquinoxalin-2(1H)-ones has been developed through visible-light-mediated decarboxylative alkylation of quinoxalin-2(1H)-ones with phe...
121 citations
TL;DR: Zn-mediated reduction of readily accessible dialkyl oxalates derived from tertiary alcohols provides an efficient approach to C-O bond fragmentation and alkyl radical formation.
Abstract: Zn-mediated reduction of readily accessible dialkyl oxalates derived from tertiary alcohols provides an efficient approach to C-O bond fragmentation and alkyl radical formation. With MgCl2 as the indispensable additive and Ni as the promoter, trapping the radical with activated alkenes and aryl-Ni intermediates allows for the generation of alkylated and arylated all-carbon quaternary centers.
119 citations
TL;DR: Insightful alkylations of C-H bonds in (hetero)arenes will be overviewed comprehensively in this Review, in which electronic and steric properties, governed by the presence of one (or multiple) heteroatom(s), ensure high levels of regioselectivity.
Abstract: Alkylation of arenes is one of the most fundamental transformations in chemical synthesis and leads to privileged scaffolds in many areas of science. Classical methods for the introduction of alkyl groups to arenes are mostly based on the Friedel-Crafts reaction, radical additions, metalation, or prefunctionalization of the arene: these methods, however, suffer from limitations in scope, efficiency, and selectivity. Moreover, they are based on the innate reactivity of the starting arene, favoring the alkylation at a certain position and rendering the introduction of alkyl chains at other positions much more challenging. This can be addressed by the use of a directing group that facilitates, in the presence of a metal catalyst, the regioselective alkylation of a C-H bond. These directed alkylations of C-H bonds in arenes will be comprehensively summarized in this Review.
TL;DR: A Mn/Ni dual catalytic system that hydroalkylates unactivated olefins with unactivated alkyl halides, yielding aliphatic quaternary carbons is described.
Abstract: Metal-hydride hydrogen atom transfer (MHAT) functionalizes alkenes with predictable branched (Markovnikov) selectivity. The breadth of these transformations has been confined to π-radical traps; no sp3 electrophiles have been reported. Here we describe a Mn/Ni dual catalytic system that hydroalkylates unactivated olefins with unactivated alkyl halides, yielding aliphatic quaternary carbons.
TL;DR: Bifunctional N-aminopyridinium salts reagents are shown delivering both the aminyl radical and the pyridyl group to an olefin with C4-pyridy regioselectivity.
Abstract: The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful aminoethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of β-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late-stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity.
TL;DR: This work reports peptide modification via radical-mediated chemoselective C-H alkylation of histidine using C4-alkyl-1,4-dihydropyridine (DHP) reagents under visible light promoted conditions and exhibits an exceptionally broad scope for both peptides and DHPAlkylation reagents.
Abstract: Histidine (His) carries a unique heteroaromatic imidazole side chain and plays irreplaceable functional roles in peptides and proteins. Existing strategies for site-selective histidine modification predominantly rely on the N-substitution reactions of the moderately nucleophilic imidazole group, which inherently suffers from the interferences from lysine and cysteine residues. Chemoselective modification of histidine remains one of the most difficult challenges in peptide chemistry. Herein, we report peptide modification via radical-mediated chemoselective C-H alkylation of histidine using C4-alkyl-1,4-dihydropyridine (DHP) reagents under visible-light-promoted conditions. The method exploits the electrophilic reactivity of the imidazole ring via a Minisci-type reaction pathway. This method exhibits an exceptionally broad scope for both peptides and DHP alkylation reagents. Its utility has been demonstrated in a series of important peptide drugs, complex natural products, and a small protein. Distinct from N-substitution reactions, the unsubstituted nitrogen groups of the modified imidazole ring are conserved in the C-H alkylated products.
TL;DR: Minisci alkylation is of prime importance for its applicability in functionalizing diverse heteroarenes, which are core structures in many bioactive compounds.
Abstract: Minisci alkylation is of prime importance for its applicability in functionalizing diverse heteroarenes, which are core structures in many bioactive compounds. In alkyl radical generation processes, precious metal catalysts, high temperatures and excessive oxidants are generally involved, which lead to sustainability and safety concerns. Herein we report a new strategy using diacetyl (2,3-butanedione) as an abundant, visible light-sensitive and “traceless” hydrogen atom abstractor to achieve metal-free cross-dehydrogenative Minisci alkylation under mild conditions. Mechanistic studies supported hydrogen atom transfer (HAT) between an activated C(sp3)–H substrate and diacetyl. Moreover, with the assistance of di-tert-butyl peroxide (DTBP), the scope of the reaction could be extended to strong aliphatic C–H bonds via diacetyl-mediated energy transfer. The robustness of this strategy was demonstrated by functionalizing complex molecules such as quinine, fasudil, nicotine, menthol and alanine derivatives.
TL;DR: The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ε-alkylation of enals with alkyl radicals worked well for the synthesis ofγ-multisubstituted-α,β-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers.
Abstract: The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ϵ-alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ-oxidized enals with alkyl halides worked well for the synthesis γ-multisubstituted-α,β-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers. The synthesis of ϵ-multisubstituted-α,β-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ϵ-functionalization was also established.
TL;DR: Experimental and computational studies suggest an outer-sphere mechanism for this NHC-Mn system catalyzed selective N-alkylation of anilines with alcohols by a bis-NHC manganese complex.
TL;DR: The synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α-alkylalkanoic amides on large scale.
Abstract: Reported here is a terminal-selective, remote asymmetric hydroalkylation of olefins with racemic α-bromo amides. The reaction proceeds by NiH-catalyzed alkene isomerization and subsequent alkylation reaction, and can enantioconvergently introduce an unsymmetrical secondary alkyl group from a racemic α-bromo amide onto a terminal C(sp3 )-H position along the hydrocarbon chain of the alkene. This mild process affords a range of structurally diverse chiral α-alkylalkanoic amides in excellent yields, and high regio- and enantioselectivities. In addition, the synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α-alkylalkanoic amides on large scale.
TL;DR: A protocol for direct visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated alkyl halides using molecular oxygen as an oxidant at room temperature is reported.
Abstract: Herein, we report a protocol for direct visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated alkyl halides using molecular oxygen as an oxidant at room temperature. This mild protocol is compatible with a wide array of sensitive functional groups and has a broad substrate scope. Notably, functionalization of (iso)quinolines, pyridines, phenanthrolines, quinazoline, and other heterocyclic compounds with unactivated primary, secondary, and tertiary alkyl halides proceeds smoothly under the standard conditions. The robustness of this protocol is further demonstrated by the late-stage functionalization of complex nitrogen-containing natural products and drugs.
TL;DR: A metal-catalyzed methylation process has been developed by employing an air- and moisture-stable manganese catalyst together with isotopically labeled methanol and a series of D-, CD3 -, and 13 C-labeled products were obtained in good yields under mild reaction conditions with water as the only byproduct.
Abstract: A metal-catalyzed methylation process has been developed. By employing an air- and moisture-stable manganese catalyst together with isotopically labeled methanol, a series of D-, CD3 -, and 13 C-labeled products were obtained in good yields under mild reaction conditions with water as the only byproduct.
TL;DR: Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group, which was leveraged to achieve excellent α/δ site-selectivity.
Abstract: The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivatives through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.
TL;DR: This method provides a simple and general strategy for the C(sp3 )-H alkylation/arylation of ethers through the combination of a photo-organocatalyst (benzaldehyde) and a transition-metal catalyst (nickel).
Abstract: Herein we report a highly selective photoredox C(sp3 )-H alkylation/arylation of ethers through the combination of a photo-organocatalyst (benzaldehyde) and a transition-metal catalyst (nickel). This method provides a simple and general strategy for the C(sp3 )-H alkylation/arylation of ethers. A selective late-stage modification of (-)-ambroxide has also been conducted to demonstrate the applicability of the method.
TL;DR: The C-H alkylation proceeds efficiently using diverse hydrocarbons and complex molecules as the limiting reagent and represents a new approach to the catalytic functionalization of unactivated C(sp3)-H bonds.
Abstract: The direct, site-selective alkylation of unactivated C(sp3)-H bonds in organic substrates is a long-standing goal in synthetic chemistry. General approaches to the activation of strong C-H bonds include radical-mediated processes involving highly reactive intermediates, such as heteroatom-centered radicals. Herein, we describe a catalytic, intermolecular C-H alkylation that circumvents such reactive species via a new elementary step for C-H cleavage involving multisite-proton-coupled electron transfer (multisite-PCET). Mechanistic studies indicate that the reaction is catalyzed by a noncovalent complex formed between an iridium(III) photocatalyst and a monobasic phosphate base. The C-H alkylation proceeds efficiently using diverse hydrocarbons and complex molecules as the limiting reagent and represents a new approach to the catalytic functionalization of unactivated C(sp3)-H bonds.
TL;DR: The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way and it is the first example of combining the non-natural catalytic activity of hydrolases with visible-light catalysis for enantioselective organic synthesis and it does not require any cofactors.
Abstract: The combination of photoredox and enzymatic catalysis for the direct asymmetric one-pot synthesis of 2,2-disubstituted indol-3-ones from 2-arylindoles through concurrent oxidization and alkylation reactions is described. 2-Arylindoles can be photocatalytically oxidized to 2-arylindol-3-one with subsequent enantioselective alkylation with ketones catalyzed by wheat germ lipase (WGL). The chiral quaternary carbon center at C2 of the indoles was directly constructed. This mode of concurrent photobiocatalysis provides a mild and powerful strategy for one-pot enantioselective synthesis of complex compounds. The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way. This reaction is the first example of combining the non-natural catalytic activity of hydrolases with visible-light catalysis for enantioselective organic synthesis and it does not require any cofactors.
TL;DR: Computational modeling supports a mechanism involving formation of a tetracoordinate borinic ester, which accelerates hydrogen atom transfer with the quinuclidine-derived radical cation through polarity-matching and/or ion-pairing effects.
Abstract: Diphenylborinic acid serves as a cocatalyst for site- and stereoselective C-H alkylation reactions of carbohydrates under photoredox conditions using quinuclidine as the hydrogen atom transfer mediator. Products arising from selective abstraction of the equatorial hydrogens of cis-1,2-diol moieties, followed by C-C bond formation with net retention of configuration, are obtained. Computational modeling supports a mechanism involving formation of a tetracoordinate borinic ester, which accelerates hydrogen atom transfer with the quinuclidine-derived radical cation through polarity-matching and/or ion-pairing effects.
TL;DR: A cytochrome P450 variant with 11 amino acid substitutions and a large deletion of the non-catalytic P450 reductase domain is evolved for highly efficient carbene transfer to indoles, pyrroles, and cyclic alkenes, showcasing the tunability of hemoproteins for highly selective functionalization of cyclic targets and the power of directed evolution to enhance the scope of new-to-nature enzyme catalysts.
Abstract: Transfers of carbene moieties to heterocycles or cyclic alkenes to obtain C(sp2)–H alkylation or cyclopropane products are valuable transformations for synthesis of pharmacophores and chemical buil...
TL;DR: An efficient photocatalytic decarboxylative 3-positionAlkylation of coumarins by using alkyl N-hydroxyphthalimide esters as alkylation reagents has been developed, affording a broad scope of 3-alkylated coumarin derivatives in moderate to excellent yields.
TL;DR: Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C-H cleavage and reveal that the Z/ E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.
Abstract: The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- a...
TL;DR: In this article, the redox-active azo ligand can store hydrogen generated during alcohol oxidation and redelivers the same to an in-situ-generated imine bond to result in N-alkylation of amines.
Abstract: We report herein a well-defined and bench-stable azo-phenolate ligand-coordinated nickel catalyst which can efficiently execute N-alkylation of a variety of anilines by alcohol. We demonstrate that the redox-active azo ligand can store hydrogen generated during alcohol oxidation and redelivers the same to an in-situ-generated imine bond to result in N-alkylation of amines. The reaction has wide scope, and a large array of alcohols can directly couple to a variety of anilines. Mechanistic studies including deuterium labeling to the substrate establishes the borrowing hydrogen method from alcohols and pinpoints the crucial role of the redox-active azo moiety present on the ligand backbone. Isolation of the ketyl intermediate in its trapped form with a radical quencher and higher kH/kD for the alcohol oxidation step suggest altogether a hydrogen-atom transfer (HAT) to the reduced azo backbone to pave alcohol oxidation as opposed to the conventional metal–ligand bifunctional mechanism. This example clearly de...