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Showing papers on "Alkylation published in 2018"


Journal ArticleDOI
01 Feb 2018
TL;DR: Here, Hu and co-workers report amine alkylation using redox-active esters, using a combination of photoredox catalysis to generate the active electrophile and copper catalysis for the cross-coupling.
Abstract: Amines are a quintessential moiety in bioactive molecules, pharmaceuticals and organic materials. Transition-metal-catalysed C–N coupling of aryl electrophiles has been established as a powerful and reliable method for amine synthesis. However, the analogous C–N coupling of alkyl electrophiles is largely under-developed due to the decomposition of metal alkyl intermediates by β-hydrogen elimination and difficulty in C(sp3)–N reductive elimination. Here, we provide a general strategy for amination of alkyl electrophiles by merging photoredox and copper catalysis. Photoredox catalysis allows the use of alkyl redox-active esters, recently established as a superior class of alkyl electrophiles, whereas copper catalysis enables C(sp3)–N cross-coupling. Decarboxylative amination can be used for the synthesis of a diverse set of alkyl anilines with high chemoselectivity and functional-group compatibility. Rapid functionalization of amino acids, natural products and drugs is demonstrated. While methods for arylation of amines are well established, alkylation is a less well-developed process. Here, Hu and co-workers report amine alkylation using redox-active esters, using a combination of photoredox catalysis to generate the active electrophile and copper catalysis for the cross-coupling.

158 citations


Journal ArticleDOI
TL;DR: The robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups, including hydroxyl, bromo, and iodo substituents and revealed a considerable additive effect on kinetics and on a negative non-linear-effect.
Abstract: The enantioselective cobalt(III)-catalyzed C-H alkylation was achieved through the design of a novel chiral acid. The cobalt(III)-catalyzed enantioselective C-H activation was characterized by high position-, regio- and enantio-control under exceedingly mild reaction conditions. Thereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups, including hydroxyl, bromo, and iodo substituents. Mechanistic studies revealed a considerable additive effect on kinetics and on a negative non-linear-effect.

138 citations


Journal ArticleDOI
TL;DR: CO2 can be used as an activator for the direct transformation of abundant and unprotected primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer catalysis.
Abstract: Primary aliphatic amines are important building blocks in organic synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Experimental and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermolecular HAT by an electrostatically accelerated interaction between the in situ-generated negatively charged carbamate and the positively charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissociation energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.

134 citations


Journal ArticleDOI
TL;DR: Manganese-catalyzed C–C bond-forming reactions via α-alkylation of ketones, amides, and esters, using primary alcohols, usingPrimary alcohols are reported.
Abstract: Herein we report the manganese-catalyzed C-C bond-forming reactions via α-alkylation of ketones, amides, and esters, using primary alcohols. β-Alkylation of secondary alcohols by primary alcohols to obtain α-alkylated ketones is also reported. The reactions are catalyzed by a ( i Pr-PNP)Mn(H)(CO)2 pincer complex under mild conditions in the presence of (catalytic) base liberating water (and H2 in the case of secondary alcohol alkylation) as the sole byproduct.

132 citations


Journal ArticleDOI
TL;DR: This work reports on the site-selective δ-C(sp3 )-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible γ-C-H bonds.
Abstract: The site-selective functionalization of unactivated C(sp3 )-H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective δ-C(sp3 )-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible γ-C(sp3 )-H bonds. Experimental studies revealed that C-H bond cleavage occurs reversibly and preferentially at γ-methyl over δ-methyl C-H bonds while the subsequent alkylation proceeds exclusively at the six-membered palladacycle that is generated by δ-C-H activation. The selectivity can be explained by the Curtin-Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late-stage peptide modifications. Notably, this process is also the first palladium(II)-catalyzed Michael-type alkylation reaction that proceeds through C(sp3 )-H activation.

132 citations


Journal ArticleDOI
TL;DR: A ligand-controlled and site-selective nickel catalyzed Suzuki-Miyaura cross-coupling reaction with aromatic esters and alkyl organoboron reagents as coupling partners was developed, providing a facile route for C(sp2)-C(sp3) bond formation in a straightforward fashion by successful suppression of the undesired β-hydride elimination process.
Abstract: A ligand-controlled and site-selective nickel catalyzed Suzuki–Miyaura cross-coupling reaction with aromatic esters and alkyl organoboron reagents as coupling partners was developed. This methodology provides a facile route for C(sp2)–C(sp3) bond formation in a straightforward fashion by successful suppression of the undesired β-hydride elimination process. By simply switching the phosphorus ligand, the ester substrates are converted into the alkylated arenes and ketone products, respectively. The utility of this newly developed protocol was demonstrated by its wide substrate scope, broad functional group tolerance and application in the synthesis of key intermediates for the synthesis of bioactive compounds. DFT studies on the oxidative addition step helped rationalizing this intriguing reaction chemoselectivity: whereas nickel complexes with bidentate ligands favor the C(aryl)–C bond cleavage in the oxidative addition step leading to the alkylated product via a decarbonylative process, nickel complexes ...

127 citations


Journal ArticleDOI
TL;DR: The terminal-selective, remote C(sp3 )-H alkylation of alkenes was achieved by a relay process combining NiH-catalyzed hydrometalation, chain walking, andAlkylation, enabling the construction of unfunctionalized C( sp3)-C(Sp3 ) bonds under mild conditions from two simple feedstock chemicals, namely olefins and alkyl halides.
Abstract: The terminal-selective, remote C(sp3)−H alkylation of alkenes was achieved by a relay process combining NiH-catalyzed hydrometalation, chain walking, and alkylation. This method enables the construction of unfunctionalized C(sp3)−C(sp3) bonds under mild conditions from two simple feedstock chemicals, namely olefins and alkyl halides. The practical value of this transformation is further demonstrated by the large-scale and regioconvergent alkylation of isomeric mixtures of olefins at low catalyst loadings.

124 citations


Journal ArticleDOI
TL;DR: In this article, a pyridyl-supported pyrazolyl-imidazolyl ligand was used to catalyze the direct β-alkylation of secondary alcohols with primary alcohols under phosphine-free conditions.
Abstract: Manganese(I) complexes bearing a pyridyl-supported pyrazolyl-imidazolyl ligand efficiently catalyzed the direct β-alkylation of secondary alcohols with primary alcohols under phosphine-free conditions. The β-alkylated secondary alcohols were obtained in moderate to good yields with water formed as the byproduct through a borrowing hydrogen pathway. β-Alkylation of cholesterols was also effectively achieved. The present protocol provides a concise atom-economical method for C–C bond formation from primary and secondary alcohols.

124 citations


Journal ArticleDOI
TL;DR: This is the first example of visible-light-induced Cu-catalyzed decarboxylative C(sp3 )-H alkylation of glycine for preparing α-alkylated unnatural α-amino acids.
Abstract: Despite a well-developed and growing body of work in Cu catalysis, the potential of Cu to serve as a photocatalyst remains underexplored. Reported herein is the first example of visible-light-induced Cu-catalyzed decarboxylative C(sp3 )-H alkylation of glycine for preparing α-alkylated unnatural α-amino acids. It merits mentioning that the mild conditions and the good functional-group tolerance allow the modification of peptides using this method. The mechanistic studies revealed that a radical-radical coupling pathway is involved in the reaction.

123 citations


Journal ArticleDOI
TL;DR: A novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis is described, which was able to showcase the utility of this methodology through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.
Abstract: Strategies for the direct C–H functionalization of amines are valuable as these compounds comprise a number of pharmaceuticals, agrochemicals and natural products. This work describes a novel method for the C–H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, organic acridinium photoredox catalyst allows for direct oxidation of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Additionally, we were able to showcase the utility of this methodology through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.

118 citations


Journal ArticleDOI
TL;DR: This work reports on a novel reaction, namely the dehydrogenative alkylation or α-olefination of alkyl-substituted N-heteroarenes with alcohols, which catalyzes the reaction with high efficiency whereas iron and cobalt complexes stabilized by the same ligands are essentially inactive.
Abstract: Catalysis with earth-abundant transition metals is an option to help save our rare noble-metal resources and is especially interesting when novel reactivity or selectivity patterns are observed. We report here on a novel reaction, namely the dehydrogenative alkylation or α-olefination of alkyl-substituted N-heteroarenes with alcohols. Manganese complexes developed in our laboratory catalyze the reaction with high efficiency whereas iron and cobalt complexes stabilized by the same ligands are essentially inactive. Hydrogen is liberated during the reaction, and bromine and iodine functional groups as well as olefins are tolerated. A variety of alkyl-substituted N-heteroarenes can be functionalized, and benzylic and aliphatic alcohols undergo the reaction.


Journal ArticleDOI
TL;DR: Experimental and computational studies support that N-phenoxyacetamides most likely undergo an initial ortho-C-H alkylation with diazo compounds via a Rh( III)-catalyzed C-H activation, and the resulting Rh(III) intermediate subsequently undergoes an intramolecular oxidative addition into the O-N bond to form a Rh (V) nitrenoid species.
Abstract: A Rh(III)-catalyzed unsymmetrical C–H alkylation and amidation of N-phenoxyacetamides with diazo compounds has been developed under mild and redox-neutral conditions, producing dinitrogen as the only byproduct. The reaction represents the first example of one-step, unsymmetrical difunctionalization of two ortho-C–H bonds. Experimental and computational studies support that N-phenoxyacetamides most likely undergo an initial ortho-C–H alkylation with diazo compounds via a Rh(III)-catalyzed C–H activation, and the resulting Rh(III) intermediate subsequently undergoes an intramolecular oxidative addition into the O–N bond to form a Rh(V) nitrenoid species that is protonated and further directed toward electrophilic addition to the second ortho position of the phenyl ring. This work might provide a new direction for unsymmetrical C–H difunctionalization reactions in an efficient manner.

Journal ArticleDOI
TL;DR: The methodology shows broad substrate scope, excellent functional group tolerance, high atom economy and high efficiency, thus enabling the preparation of diverse potentially valuable 3-alkyl quinoxalin-2(1H)-one derivatives.
Abstract: A convenient and efficient transition-metal-free protocol for the synthesis of 3-alkyl quinoxalin-2(1H)-ones from the radical reaction of quinoxalin-2(1H)-ones with ethers was developed with moderate to good yields. The methodology shows broad substrate scope, excellent functional group tolerance, high atom economy and high efficiency, thus enabling the preparation of diverse potentially valuable 3-alkyl quinoxalin-2(1H)-one derivatives.

Journal ArticleDOI
TL;DR: A different mode of radical cyclization that can employ saturated C-H substrates is demonstrated through the development of a Co(II)-based system for catalytic activation of aliphatic diazo compounds for enantioselective radical alkylation of various C(sp3)-H bonds.
Abstract: Radical cyclization represents a powerful strategy for construction of ring structures. Traditional radical cyclization, which is based on radical addition as the key step, necessitates the use of unsaturated substrates. Guided by the concept of metalloradical catalysis, a different mode of radical cyclization that can employ saturated C−H substrates is demonstrated through the development of a Co(II)-based system for catalytic activation of aliphatic diazo compounds for enantioselective radical alkylation of various C(sp3)−H bonds. It allows for efficient construction of chiral pyrrolidines and other valuable 5-membered cyclic compounds. This alternative strategy of radical cyclization provides a new retrosynthetic paradigm to prepare five-membered cyclic molecules from readily available open-chain aldehydes through the union of C−H and C=O elements for C−C bond formation.

Journal ArticleDOI
TL;DR: One hexanuclear Cu(I) cluster of 4,6-dimethylpyrimidine-2-thiolate efficiently catalyzes the dehydrogenative cross-coupling of secondary and primary alcohols to α-alkylated ketones with high selectivity.

Journal ArticleDOI
TL;DR: Synthesis of N-heterocycles, methylation of ketones, and one-pot double alkylation to bis-hetero aryl ketones using two different alcohols with a single catalyst broadens the scope of the catalytic protocol.

Journal ArticleDOI
Wanxing Sha1, Lingling Deng1, Shengyang Ni1, Haibo Mei1, Jianlin Han1, Yi Pan1 
TL;DR: A photoredox and copper catalyzed asymmetric cyanoalkylation reaction of alkenes has been developed, which uses alkyl N-hydroxyphthalimide esters as alkylation reagents as discussed by the authors.
Abstract: A photoredox and copper catalyzed asymmetric cyanoalkylation reaction of alkenes has been developed, which uses alkyl N-hydroxyphthalimide esters as alkylation reagents. In this radical cyanoalkylation reaction, the photoredox induced alkyl radical adds to styrene, and the generated benzylic radical couples with a chiral Box/CuII cyanide complex to achieve the enantioselective cyanation. This reaction features mild conditions, operational simplicity, broad substrate scope, high yields, and high enantioselectivities, which represents an efficient method for the asymmetric radical difunctionalization of alkenes.

Journal ArticleDOI
TL;DR: The strategy established here facilitates straightforward introduction of the privileged fluoro functionalities into homoallylic alcohols from bulk feedstock materials in a highly anti-diastereo and enantioselective manner.
Abstract: A highly enantioselective three-component coupling of 1,3-butadiene with a variety of fluorinated or nonfluorinated alkyl halides and aldehydes has been achieved relying on a Cr/Co bimetallic catalysis system. The strategy established here facilitates straightforward introduction of the privileged fluoro functionalities into homoallylic alcohols from bulk feedstock materials in a highly anti-diastereo and enantioselective manner.

Journal ArticleDOI
TL;DR: Reported is an achiral Cpx RhIII /chiral carboxylic acid catalyzed asymmetric C-H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one.
Abstract: Reported is an achiral Cpx RhIII /chiral carboxylic acid catalyzed asymmetric C-H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C-H cleavage by a concerted metalation-deprotonation mechanism.

Journal ArticleDOI
Barry M. Trost1, Wen-Ju Bai1, Christoph Hohn1, Yu Bai1, James J. Cregg1 
TL;DR: This report drives the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles and represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1 H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA).
Abstract: Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nucleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio-, and enantioselectivities have been realized, providing various indolenine and indoline products. The method is amenable to gram scale and works efficiently with tryptophan derivatives that contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fashion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with d...

Journal ArticleDOI
Xiao-Yu Zhang1, Wei-Zhi Weng1, Hao Liang1, Hua Yang1, Bo Zhang1 
TL;DR: This protocol provides expedient access to substituted N-heterocycles under mild and metal-free conditions and Mechanistic experiments indicate that this reaction proceeds through a visible-light-initiated radical chain propagation mechanism.

Journal ArticleDOI
TL;DR: A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported.

Journal ArticleDOI
TL;DR: A tandem photoredox and copper catalysis was used to achieve decarboxylative C(sp3 )-O coupling of alkyl N-hydroxyphthalimide esters with phenols under mild reaction conditions andplementarity in scope and functional-group tolerance to existing methods was demonstrated.
Abstract: Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp3 )-O cross-coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp2 )-O cross-coupling and SN 2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp3 )-O coupling of alkyl N-hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional-group tolerance to existing methods was demonstrated.

Journal ArticleDOI
TL;DR: The use of a terpyridine ligand is essential for the success of the reaction and is shown to prevent photoinduced copper-catalyzed polymerization of the starting materials.
Abstract: We have developed a photoinduced copper-catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides as electrophiles. The reaction has a broad substrate scope and can be successfully performed in the presence of ester, nitrile, aryl halide, ketone, sulfonamide, epoxide, alcohol, and amide functional groups. The alkylation is promoted by blue light (λ≈450 nm) and proceeds at room temperature in the absence of any additional metal catalysts. The use of a terpyridine ligand is essential for the success of the reaction and is shown to prevent photoinduced copper-catalyzed polymerization of the starting materials.

Journal ArticleDOI
TL;DR: In this article, a Minisci-type alkylation reaction of N-heteroarenes with alkanes under the reagent control of a hypervalent iodine oxidant PFBI-OH was reported.
Abstract: We report a highly efficient and chemoselective Minisci-type alkylation reaction of N-heteroarenes with alkanes under the reagent control of a hypervalent iodine oxidant PFBI-OH. In addition to the high reactivity, PFBI-OH demonstrated a high steric sensitivity for H abstraction of alkanes. This reaction is selective for more sterically accessible secondary C–H bonds over weaker tertiary C–H bonds. High selectivity toward penultimate methylene groups was observed for a wide range of acyclic alkanes.

Journal ArticleDOI
TL;DR: An approach to employ tandem photoredox and copper catalysis to enable the cross-coupling of alkyl N-hydroxyphthalimide esters, readily derived from alkyL carboxylic acids, with benzophenone-derived imines is described.
Abstract: Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal-catalyzed cross-coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross-coupling of alkyl N-hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone-derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.

Journal ArticleDOI
Liang Sun1, Jian-Heng Ye1, Wen-Jun Zhou1, Xin Zeng1, Da-Gang Yu1 
TL;DR: A selective oxy-alkylation of allylamines with unactivated alkyl bromides and CO2 via visible-light-driven palladium catalysis is reported, providing great potential for application in organic synthesis and pharmaceutical chemistry.

Journal ArticleDOI
TL;DR: Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta-position and good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C-H bond and the coordinating heteroatom of the directing group.
Abstract: Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta-position. Good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C-H bond and the coordinating heteroatom of the directing group. The palladium-catalyzed functionalization reactions include alkylation, cyanation, olefination, and acetoxylation. The meta selectivity is exclusively governed by the design of flexible pyrimidine-based scaffolds.

Journal ArticleDOI
TL;DR: The manganese(I) complex bearing a bidentate hydrazone ligand efficiently catalyzes the α-alkylations of nitrile using primary alcohols as alkylating agents as discussed by the authors.
Abstract: The manganese(I) complex bearing a bidentate hydrazone ligand efficiently catalyzes the α-alkylations of nitrile using primary alcohols as alkylating agents. α-Functionalized nitriles were selectively obtained in good to excellent yields. The reaction is environmentally benign, producing water as the sole byproduct. Both benzylic and aliphatic alcohols could be used and functional groups were tolerated.