Intermolecular Nucleophilic Addition Research Articles

N-BuLi-promoted nucleophilic addition of unactivated C(sp3)–H bonds to diazo compounds as N-terminal electrophiles: efficient synthesis of hydrazine derivatives

A n-BuLi-promoted intermolecular nucleophilic addition of unactivated C(sp3)–H bonds to diazo compounds has been developed. This reaction provides a simple method for the synthesis of benzylhydrazines and alkylthio-substituted ethylhydrazines.

Synthesis of acridones through the ring expansion of isatins with arynes oxidated by O2 in air

A simple and environmental-friendly method for the construction of acridone derivatives with isatins and arynes was described. The isatins underwent a ring expansion process oxidized by O2 in the air and a broad scope of acridones in moderate to good yields were obtained. Baeyer-Villiger-type oxidation and intermolecular-nucleophilic addition were included, and no extra oxidant except O2 was needed.

Green Synthesis of Novel [1,3,4]Thiadiazolo[3,2-a]Pyrimidines via Three-Component Reaction of 5-Amino-1,3,4-Thiadiazole-2-Thiol, Aromatic Aldehydes, and Meldrum’s Acid

A novel and highly efficient synthetic route to [1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives from 5-amino-1,3,4-thiadiazole-2-thiol, various aromatic aldehydes, and Meldrum’s acid in the presence of acetic acid in dry ethanol has been reported. We designed the three-component reaction with the incorporation of Knoevenagel condensation followed by an intermolecular nucleophilic addition reaction in one pot under mild conditions. The structural diversities of these synthesized compounds have been confirmed spectroscopically, by IR, 1H-, and 13C NMR, and elemental analysis, which agree with the proposed structures.

Intermolecular Nucleophilic Addition Reaction of a C-7 Anion from N-[Bis(dimethylamino)phosphoryl]indole to Electrophiles/Arynes: Synthesis of 7-Substituted Indoles

AbstractA novel approach to the C-7 substitution of N-[bis(dimethylamino)phosphoryl]indole by nucleophilic addition of the corresponding C-7 carbanion to electrophiles or arynes is described. The directing group can be easily removed, providing a simple route to the synthesis of 7-functionalized indoles.

Recent Advances in Theoretical Studies on Transition-Metal-Catalyzed Carbene Transformations.

Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions.Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene.In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.

A green and efficient method for one-step synthesis of novel oxazolo[3,2-c]pyrimidine derivatives in lactic acid

A new method for one-step synthesis of oxazolo[3,2-c] pyrimidine core and its derivatives has been developed in inexpensive and green bio-based solvent lactic acid without any additional catalysts and additives. Density functional theory calculations located the reaction pathway and identified the intermolecular nucleophilic addition step to be the rate-limiting step. By this method, twenty new oxazolo[3,2-c] pyrimidine derivatives were synthesized in high yield and characterized by spectroscopic analysis and X-ray diffraction.

Iodine Catalyzed Oxidative Coupling of Diaminoazines and Amines for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles.

A simple, convenient, transition metal-free one pot synthesis of 3,5-disubstituted-1,2,4-triazoles has been established. The innovation in this reaction is the use of easily available 1,1-diaminoazines as substrates. This method provides the products with wider substrate scope, at an expedited rate, and with relatively better yields in comparison to the reported methods. The reaction mechanism involves an initial intermolecular nucleophilic addition (facilitated by I2) followed by intramolecular nucleophilic cyclization.

Photochemical Orifice Expansion of a Cage-Opened C60 Derivative.

Upon light irradiation, a tetraketosulfoxide derivative of C60 was transformed into a diketosulfide carboxylic anhydride via intermolecular nucleophilic addition of the sulfoxide moiety. The thus-formed 18-membered ring enables a spontaneous insertion of an Ar atom. In this encapsulation/release process, the phenyl ring on the orifice works as a dynamic stopper, which potentially adopts three conformations: an open form reduces distortion energy at the transition state while semiopen and closed forms reduce the orifice size.

Gold-catalyzed ketene dual functionalization and mechanistic insights: divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed. Mechanistic studies and density function theory (DFT) calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate, followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates. In the case with alcohols as the nucleophiles, the reaction goes through a C-5-endo-dig carbocyclization to give the indene products; whereas, O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles, delivering the 7-membered benzo[d]oxepines. In comparison with the well-documented cycloaddition and nucleophilic addition reactions, this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.

Difunctionalization of Alkenes and Alkynes via Intermolecular Radical and Nucleophilic Additions.

Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions. Difunctionalization is a topic of current interest due to its high efficiency, substrate versatility, and operational simplicity. Presented in this article are radical addition followed by oxidation and nucleophilic addition reactions for difunctionalization of alkenes or alkynes. The difunctionalization could be accomplished through 1,2-addition (vicinal) and 1,n-addition (distal or remote) if H-atom or group-transfer is involved in the reaction process. A wide range of moieties, such as alkyl (R), perfluoroalkyl (Rf), aryl (Ar), hydroxy (OH), alkoxy (OR), acetatic (O2CR), halogenic (X), amino (NR2), azido (N3), cyano (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through the difunctionalization reactions. Radicals generated from peroxides or single electron transfer (SET) agents, under photoredox or electrochemical reactions are employed for the reactions.

C-N and C-O Bond Formation in Copper-Catalyzed/Mediated sp3 C-H Activation: Mechanistic Studies from Experimental and Computational Aspects.

Mechanistic studies on Cu-catalyzed/mediated sp3 C-H amidation and acetoxylation are investigated from experimental and computational aspects. The concerted metalation-deprotonation (CMD) mechanism rather than a radical-involved pathway is proved to occur in amidation and acetoxylation reactions, and this is the rare example of the CMD mechanism involved in the more challenging sp3 C-H activations. Theoretical calculations demonstrated that CMD is the rate-determining step either for methylic or benzylic positions in amidation and acetoxylation reactions, and intermolecular nucleophilic addition of acetate anions is more favorable than the ring opening of β-lactams and intramolecular acetoxylation. These mechanistic studies on the divergent and condition-dependent product formation are critical for developing Cu-promoted C-H functionalization via the CMD mechanism.

Functionalization of Diazo Groups by the Nucleophilic Addition of Two Molecules of a Dimethylsulfonium Ylide to α-Diazo-β-ketoesters/ketones: Synthesis of Highly Functionalized Hydrazones

The intrinsic electrophilic feature for the terminal nitrogen of α-diazo-β-ketoesters/ketones has been elucidated by the intermolecular nucleophilic addition of two molecules of a dimethylsulfonium ylide. This methodology allows for access to highly functionalized hydrazones with a broad scope and good functional group tolerance. The reaction operates under simple and mild conditions without using a catalyst.

Metal-free synthesis of pyridin-2-yl ureas from 2-aminopyridinium salts

An unprecedented base promoted domino approach has been developed for the synthesis of pyridin-2-yl urea derivatives via the reaction of 2-aminopyridinium salts and arylamines. The developed strategy tolerated a wide range of functional groups and afforded pyridin-2-yl ureas in moderate to good yields. The reaction was postulated to involve tandem cyclization, intermolecular nucleophilic addition, ring opening, and demethylation.

An Electrochemical Cinnamyl C—H Amination Reaction Using Carbonyl Sulfamate

Summary of main observation and conclusionAn electrochemical cinnamyl C—H amination reaction in the absence of transition metal catalyst and oxidant was reported. The choice of carbonyl sulfamate as nitrogen source is the key to achieve desired chemoselectivity. A series of terminal amine derivatives are prepared using this protocol and the sulfonyl group can be removed with basic hydrolysis. The reaction is suggested to proceed via a continuous anodic oxidation, deprotonation, anodic oxidation, and intermolecular nucleophilic addition pathway, demonstrating the first example of electrochemical cinnamyl C—H amination.

Direct N-sec-Alkylation of Amides by Reaction of α-Halohydroxamates and Sulfonylindoles: An Approach to 3-Indolyl Methanamines

A catalyst-free, base-mediated N-sec-alkylation of amides by reaction of sulfonylindoles and α-halohydroxamates has been developed. The N-sec-alkylation of amides reaction is based on an intermolecular nucleophilic addition of vinylogous imine with N-(benzyl­oxy)meth-acrylamide/azaoxyallyl cations formed in situ and represents a simple way to give polyfunctionalized 3-indolyl methanamines in good to excellent yields.

Heterobimetallic Catalysis: Platinum‐Gold‐Catalyzed Tandem Cyclization/C−X Coupling Reaction of (Hetero)Arylallenes with Nucleophiles

AbstractHeterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt‐Au heterobimetallic catalyst system for the synthesis of a family of multi‐heteroaromatic structures through tandem cyclization/C−X coupling reaction. Au‐catalyzed 6‐endo‐cyclization takes place as the first fast step. Pt‐Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer‐sphere mechanism by hybrid homogeneous‐heterogeneous catalysis.

Heterobimetallic Catalysis: Platinum-Gold-Catalyzed Tandem Cyclization/C-X Coupling Reaction of (Hetero)Arylallenes with Nucleophiles.

Heterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt-Au heterobimetallic catalyst system for the synthesis of a family of multi-heteroaromatic structures through tandem cyclization/C-X coupling reaction. Au-catalyzed 6-endo-cyclization takes place as the first fast step. Pt-Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer-sphere mechanism by hybrid homogeneous-heterogeneous catalysis.

Predictive Model for Oxidative C-H Bond Functionalization Reactivity with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a highly effective reagent for promoting C-H bond functionalization. The oxidative cleavage of benzylic and allylic C-H bonds using DDQ can be coupled with an intra- or intermolecular nucleophilic addition to generate new carbon-carbon or carbon-heteroatom bonds in a wide range of substrates. The factors that control the reactivity of these reactions are well-defined experimentally, but the mechanistic details and the role of substituents in promoting the transformations have not been firmly established. Herein, we report a detailed computational study on the mechanism and substituent effects for DDQ-mediated oxidative C-H cleavage reactions in a variety of substrates. DFT calculations show that these reactions proceed through a hydride transfer within a charge transfer complex. Reactivity is dictated by the stability of the carbocation intermediate, the degree of charge transfer in the transition states, and, in certain cases, secondary orbital interactions between the π orbital of the forming cation and the LUMO of DDQ. A linear free energy relationship was established to offer a predictive model for reactivity of different types of C-H bonds based on the electronic properties of the substrate.

TBuLi‐Promoted Intermolecular Regioselective Nucleophilic Addition of Arenes to Diazo Compounds as N‐Terminal Electrophiles: Efficient Synthesis of Hydrazine Derivatives

The tBuLi‐promoted intermolecular direct nucleophilic addition of arenes to diazo compounds as the N‐terminal electrophiles has been developed. This reaction proceeds in a completely regioselective manner and is an efficient method for the preparation of hydrazine derivatives in high to excellent yields. This transformation not only provides an efficient approach for aromatic C–N bond formation under transition‐metal‐free and oxidant‐free conditions but also represents a strategy for the 3‐amination of pyridines and the dearomatization of indoles.

Synthesis of 2,2-Difluorinated 4-Isoflavanols/4-Thioisoflavanols via a Base-Catalyzed [4 + 2] Annulation Reaction of gem-Difluoroolefins.

DBU-catalyzed sequential intermolecular and intramolecular nucleophilic addition reactions between gem-difluoroolefins and o-hydroxy/mercapto benzaldehydes have been developed to provide a [4 + 2] annulation strategy for facile synthesis of gem-difluorinated isoflavanol derivatives. The competitive addition-elimination reaction of gem-difluoroolefins with nucleophiles was avoided under mild conditions, affording 2,2-difluorinated 4-isoflavanols or 2,2-difluoriated 4-thioisoflavanols in good to excellent yields.