Nucleophilic Alkylation Research Articles

Site-Specific Radical Alkylation of Aryl Cyanide: Visible-Light, Photoredox-Catalyzed, Three-Component Arylalkylation of [1.1.1]Propellane.

We report herein a three-component radical arylalkylation of [1.1.1]propellane toward the synthesis of aryl-substituted bicyclo[1.1.1]pentane derivatives. The use of electron-deficient aryl cyanide as an aryl group source not only reduces the energy barrier of the arylation of the nucleophilic alkyl radical species, but also suppresses the electrophilic Friedel-Crafts alkylation process, enabling the present site-selective arylalkylation.

A Modified Arbuzov-Michalis Reaction for Selective Alkylation of Nucleophiles.

The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.

A Modified Arbuzov‐Michalis Reaction for Selective Alkylation of Nucleophiles

AbstractThe alkylation of nucleophiles is among the most fundamental and well‐developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late‐stage alkylation of natural products and pharmaceutical agents, achieving chemo‐ and site‐selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov‐Michalis reaction.

Expanding the Chemical Space of Electrophilic β-Glycosyl β-Lactams through Photoinduced Diastereoselective Functionalization.

Herein, we present a photoinduced diastereoselective C-3 functionalization of electrophilic β-glycosyl β-lactams. The developed protocol is simple, mild, and scalable and explores the use of 3-exomethylene β-lactams as reaction partners in a Giese type reaction. The key nucleophilic alkyl radical is generated by a photoinduced electron transfer process in the EDA complex formed by NHPI and Hantzsch esters. The diastereoselective hydrogen atom transfer to the β-lactam radical intermediate enables the synthesis of various N-phenyl β-glycosyl β-lactams.

Visible-Light-Induced PhI(OAc)2-Mediated Alkylation of Heteroarenes with Simple Alkanes and Ethers.

The direct alkylation of heteroarenes with alkanes has been successfully achieved through visible-light-induced hypervalent iodine-mediated C-H functionalization of both coupling partners at ambient temperatures. This reaction proceeds via the in situ generation of nucleophilic alkyl radicals from alkanes through hydrogen atom transfer (HAT), followed by a Minisci-type reaction with heteroarenes. These mild reaction conditions have demonstrated their suitability for the alkylation of a wide range of heterocycles, including azoles, pyridines, quinolines, isoquinolines, and quinoxalinones.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Carbocationoids, a concept for controlling highly reactive cationic species

Carbocations, which are positively charged highly electrophilic intermediates, are efficacious for the direct alkylation of low-reactive nucleophiles. The utilization of carbocations in SN1 reactions relies on the activation of their precursors in the presence of a nucleophile. However, undesirable interactions between the nucleophile and the leaving group activator limit the scope of acceptable nucleophiles. Here we report a strategy to conduct SN1 reactions involving unstable carbocations in an alternative stepwise procedure, which was demonstrated by the benzylation of various neutral nucleophiles. In the first step, carbocations were accumulated in a nucleophile-free solution in the form of carbocationoids utilizing the coordinative stabilization of triazinediones. Subsequently, the addition of these solutions in the second step enabled room-temperature alkylation without the need for acidic additives. This methodology overcomes the inherent challenges of carbocations in SN1 reactions.

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres.

To facilitate the discovery and development of new pharmaceuticals, the demand for novel stereofunctionalised building blocks has never been greater. Whilst molecules bearing quaternary and tetrasubstituted stereogenic centres are ideally suited to explore untapped areas of chemical space, the asymmetric construction ofsterically congested carbon centres remains a longstanding challenge in organic synthesis. The enantioselective assembly of acyclic stereogenic centres is even more demanding due to the need to restrict a much wider range of geometries and conformations of the intermediates involved. In this context, the catalytic asymmetric allylicalkylation (AAA) of acyclic prochiral nucleophiles, namely enolates, has become an indispensable tool to access a range of linearα-quaternary andα-tetrasubstituted carbonyl compounds. However, unlike the AAA of cyclic enolates with a fixed enolate geometry, to achieve high levels of stereocontrol in the AAA of acyclic enolates, the stereoselectivity of enolisation must be considered. The aim of this review is to offer acomprehensivediscussion of catalytic AAA reactions of acyclic prochiral enolates and their analogues to generate congested quaternary and tetrasubstituted chiral centres using metal, non-metal and dual catalysis, with particular focus given to the control of enolate geometry and its impact on the stereochemical outcome of the reaction.

Electrocatalytic Asymmetric Nozaki-Hiyama-Kishi Decarboxylative Coupling: Scope, Applications, and Mechanism.

The first general enantioselective alkyl-Nozaki-Hiyama-Kishi (NHK) coupling reactions are disclosed herein by employing a Cr-electrocatalytic decarboxylative approach. Using easily accessible aliphatic carboxylic acids (via redox-active esters) as alkyl nucleophile synthons, in combination with aldehydes and enabling additives, chiral secondary alcohols are produced in a good yield with high enantioselectivity under mild reductive electrolysis. This reaction, which cannot be mimicked using stoichiometric metal or organic reductants, tolerates a broad range of functional groups and is successfully applied to dramatically simplify the synthesis of multiple medicinally relevant structures and natural products. Mechanistic studies revealed that this asymmetric alkyl e-NHK reaction was enabled by using catalytic tetrakis(dimethylamino)ethylene, which acts as a key reductive mediator to mediate the electroreduction of the CrIII/chiral ligand complex.

Study of the Mechanism of 7‐exo‐trig Cyclizations of Aryl, Vinyl, and Alkyl Radicals on Oxime Ethers

AbstractIn this work, we conducted a study of 7‐exo‐trig cyclizations mechanism involving aryl, vinyl, and alkyl radicals on oxime ethers. Initially, the reaction of brominated oxime ether 9 a with (TMS)3SiH and AIBN gave rise to aryl radicals that underwent a 7‐exo‐trig cyclization on the oxime ether, yielding dibenzoxepine 10 a, and the ipso reaction and reduction products were obtained as well. Approximate rate constants at 80 °C for the 7‐exo‐trig (1.0×108 s−1) and the ipso cyclization (4.3×107 s−1) were determined by competition experiments. DFT calculations showed good agreement with the experimental results. The reduction rate constant of the N‐alkoxyaminyl radical with (TMS)3SiH was calculated to be 4.1×10−1 M−1 s−1; while the rate constants for the 7‐exo‐trig cyclizations of vinyl and alkyl radicals on the oxime ether were estimated in the ranges of 106 s−1–108 s−1 and 103 s−1–108 s−1, respectively. The 7‐exo‐trig cyclization reactions involving aryl, vinyl, and alkyl radicals with oxime ethers were found to be an exothermic and irreversible process, with the oximic carbon showing a preference for nucleophilic alkyl radicals. This kinetic study contributes to the deeper understanding of radical‐mediated cyclizations, enabling the efficient design of complex synthetic routes.

Origins of Enhanced Enantioselectivity in the Pd-Catalyzed Decarboxylative Allylic Alkylation of N-Benzoyl Lactams.

We explore the origins of the marked improvement in enantioselectivity in the inner-sphere (PHOX)Pd-catalyzed allylic alkylation of N-benzoyl lactam nucleophiles over their carbocyclic counterparts. We employ density functional theory calculations to aid in the interpretation of experimental results. Ultimately, we propose that the enhancement in enantioselectivity arises primarily from noncovalent interactions between the substrate and ligand rather than secondary substrate chelation, as previously hypothesized.

Synthesis of 1,4‐Dicarbonyl Compounds via Visible‐Light‐Induced Decarboxylative Radical Cascade Reactions

AbstractWe herein report a method for the synthesis of 1,4‐dicarbonyl compounds using light‐activated electron donor‐acceptor (EDA) complexes. This multi‐component reaction involves the photoactivation of EDA complexes formed by carboxylic acid derivatives, triphenylphosphine, and sodium iodide, resulting in single‐electron reduction. The subsequent decarboxylation fragmentation leads to the formation of nucleophilic alkyl free radicals, which can undergo sequential radical coupling reactions with electron‐deficient and electron‐rich olefins. This method has been successfully applied to various aliphatic carboxylic acid derivatives, including tertiary, secondary, and primary ones, as well as multiple types of electron‐deficient olefins and enol silyl ethers. The entire process is conducted under mild conditions, indicating its potential for the synthesis of valuable synthetic compounds.

Preparation of Alkyl Di(p-tolyl)sulfonium Salts and Their Application in Metal-Free C(sp3)-C(sp3) and C(sp3)-C(sp2) Bond Formations.

Alkyldiarylsulfonium salts were synthesized by a combination of active sulfonium species, prepared through the activation of diarylsulfoxide, and alkyl nucleophiles. The isolated sulfonium salts were subjected to the allylation and cyclopropanation of the active methylene compounds and metal-free C(sp3)-C(sp2) couplings via oxyallyl cation intermediates under mild conditions. The series of reactions included an umpolung strategy for the coupling of alkyl nucleophiles and metal-free C-C bond formation using sulfonium salts.

Chiral Phosphine Catalyzed Allylic Alkylation of Benzylidene Succinimides with Morita–Baylis–Hillman Carbonates

Owing to their unique chemical properties, α-alkylidene succinimides generally act as versatile synthons in organic synthesis. Compared with well-established annulations, nucleophilic alkylations of α-alkylidene succinimides are very limited. Accordingly, an organocatalytic allylic alkylation of α-benzylidene succinimides with Morita-Baylis-Hillman (MBH) carbonates was established. In the presence of a chiral phosphine catalyst, α-benzylidene succinimides reacted smoothly with MBH carbonates under mild conditions to furnish a series of optical active succinimides in high yields and enantioselectivities. Different from the reported results, the organocatalytic enantioselective construction of pyrrolidine-2,5-dione frameworks bearing contiguous chiral tertiary carbon centers was achieved via this synthetic strategy. Scaling up the reaction indicated that it is a practical strategy for the organocatalytic enantioselective alkylation of α-alkylidene succinimides. A possible reaction mechanism was also proposed.

Alkoxyphosphorane/Borane Cooperative Alkylations: A Frustrated Lewis Pair Version of the Mitsunobu Reaction.

The combination of the alkoxyphosphoranes, Ph2 P(OR)(O2 C6 Cl4 ) and the borane B(C6 F5 )3 generates the zwitterions 3 which act as FLP to effect the alkylation of several nucleophiles affording C-C, C-N, C-H and C-Cl coupling products. A DFT study shows the reaction proceeds via an FLP activation pathway generating an alkoxyphosphonium intermediate which effects the alkylation of the nucleophiles, akin to the Mitsunobu reaction.

Enantio- and Regioconvergent Synthesis of γ-Stereogenic Vinyl Germanes and Their Use as Masked Vinyl Halides.

A nickel-catalyzed enantio- and regioconvergent alkylation of regioisomeric mixtures of racemic germylated allylic electrophiles with alkyl nucleophiles is reported. Key to success is a newly developed hept-4-yl-substituted Pybox ligand that enables accessing various chiral γ-germyl α-alkyl allylic building blocks in excellent yields and enantioselectivities. The reason for the regioconvergence is the steering effect of the bulky germyl group. The resulting vinyl germanes can be easily halodegermylated without racemization of the allylic stereocenter to afford synthetically valuable γ-stereogenic vinyl halides.

Photoinduced Remote C(sp3)-H Imination Enabled by Vinyl Radical-Mediated 1,5-Hydrogen Atom Transfer.

A vinyl radical-mediated 1,5-hydrogen atom transfer strategy for remote C(sp3)-H imination under visible-light-induced photochemical metal-free conditions afforded diverse γ-imino alkenes with excellent stereoselectivity. Oxime ester-based bifunctional reagents provided not only nucleophilic alkyl radicals for radical addition reactions with electron-deficient alkynes but also long-lived steady-state imine radicals for trapping alkyl radicals following the intramolecular 1,5-hydrogen migration of unstable olefin radicals.

Visible-Light-Photocatalyzed Dicarbofunctionalization of Conjugated Alkenes with Ketone-Based Dihydroquinazolinones.

A visible-light-photocatalyzed 1,2-arylalkylation of N-(arylsulfonyl)acrylamides with ketone-based dihydroquinazolinones is described. The formal C-C bond cleavage of aliphatic ketones is unified with tandem radical alkylation/1,4-aryl migration/desulfonylation to forge two different types of vicinal C-C bonds and construct an all-carbon quaternary α-stereocenter, thus enhancing the carbogenic complexity and tolerating diverse functionalities. Additional to telescopic synthesis and product diversification, this method features a radical dicarbofunctionalization of conjugated N-(arylsulfonyl)acrylamides with a nucleophilic alkyl radical precursor (dihydroquinazolinone) utilizing oxygen as a green oxidant at ambient temperature.

Enantioselective 1,6-Addition of Chiral Boryl–Alkyl Nucleophiles to para-Quinone Methides

Key words copper catalysis - para-quinone methides - asymmetric catalysis - conjugate addition

Organo-Group 2 Metal-Mediated Nucleophilic Alkylation of Benzene: Crucial Role of Strong Cation−π Interaction

Organo-Group 2 Metal-Mediated Nucleophilic Alkylation of Benzene: Crucial Role of Strong Cation−π Interaction