Intramolecular Substitution Reaction Research Articles

Bis‐Silylene‐Supported Aluminium Atoms with Aluminylene and Alane Character

AbstractThe suitability of electron‐rich bis‐silylenes, specifically the neutral chelating [SiII(Xant)SiII] ligand (SiII=PhC(NtBu)2Si, Xant=9,9‐dimethylxanthene) and the anionic [SiII(NAcrid)SiII)]− pincer ligand (NAcrid=2,7,9,9‐tetramethylacridane), has been successfully probed to stabilize monovalent bis‐silylene‐supported aluminium complexes (aluminylenes). At first, the unprecedented aluminium(III) iodide precursors [SiII(Xant)SiII]AlI2+ I− 1 and [SiII(NAcrid)SiII)]AlI2 2 were synthesized using AlI3 and [SiII(Xant)SiII] or [SiII(NAcrid)SiII)]Li(OEt2)], respectively, and structurally characterized. While reduction of 1 with KC8 led merely to unidentified products, the dehalogenation of 2 afforded the dimer of the desired {[SiII(NAcrid)SiII)]Al:} aluminylene with a four‐membered SiIV2AlIII2 ring. Remarkably, the proposed aluminylene intermediates [SiII(Xant)SiII]AlII and {[SiII(NAcrid)SiII)]Al:} could be produced through reaction of 1 and 2 with Collman's reagent, K2Fe(CO)4, and trapped as AlI:→Fe(CO)4 complexes 5 and 6, respectively. While 6 is stable in solution, 5 loses one CO ligand in solution to afford the silylene‐ and aluminylene‐coordinated iron(0) complex 7 from an intramolecular substitution reaction. The electronic structures of the novel compounds were investigated by Density Functional Theory calculations.

1‐Alkynylphosphorus Compounds in Organic Synthesis，2010‐2024

Since the review of Yorimitsu and Oshima in 2010, the past 15 years have witnessed significant progresses in the application of 1‐alkynylphosphorus compounds in organic synthesis. Owing to the reactive carbon‐carbon triple bond in association with the electron‐withdrawing phosphoryl group, they easily undergo transition metal‐catalyzed nucleophilic addition reactions at the β‐position with carbon‐ and heteroatom‐based nucleophiles to afford structurally diverse 1‐alkenyl phosphorus compounds. Especially, when 1‐alkynylphosphonates or phosphinates are used, intramolecular substitution reactions on P‐atom might occur in some cases, which would result in the formation of P‐based heterocycles. In addition, the existing triple bond makes them prone to go through addition reaction initiated cyclization reactions and [2+2], [2+3], [2+4], [2+5] and [2+2+2] cycloaddition reactions with other unsaturated bonds, which provides an efficient access to various P‐based heterocycles and phosphorylated carbon‐ and heterocycles.

Brønsted Acid Catalyzed Intramolecular Allylic Substitution Reaction of Allylic Alcohols: A Facile Synthesis of 2-Vinylchromans

AbstractBrønsted acid catalyzed intramolecular allylic substitution reaction of secondary and tertiary allylic alcohols has been developed. A variety of 2-vinylchromans were efficiently prepared in moderate to excellent yields. The given method features wide substrate scope, operational simplicity, and mild, metal-free reaction conditions. The practicability of the method was demonstrated by a gram-scale reaction and further derivations of the product. Preliminarily studies on a catalytic asymmetric reaction were also undertaken.

Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors.

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure-activity relationship (SAR) points for delivery of potent ACC inhibitors.

Experimental and Theoretical Investigation of an Azaoxyallyl Cation-Templated Intramolecular Aryl Amination Leading to Oxindole Derivatives.

Herein, development and detailed investigation of a SN '-type intramolecular aromatic substitution reaction involving α-arylazaoxyallyl cation intermediate, is disclosed. The study showcased that while α-aryl-α-chlorohydroxamate could be activated by a combination of base and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) into the corresponding azaoxyallyl cations, it could further emerge into a π-extended species involving the adjacent α-aryl moiety, and this transition is contingent on electronic effects of the aromatic ring as well as on α-substituents. An effective activation of the α-aromatic ring could pave the path for intramolecular Ar(Csp2 )-N bond formation towards oxindoles. Control experiments and DFT calculations suggested that a non-pericyclic nucleophilic amination pathway is most likely operative and precluded the possibility of concerted or electrophilic amination mechanism. HFIP as the reaction solvent plays pivotal roles in the transformation.

Efficient enantioselective synthesis of pyrazolines and isoxazolines enabled by an iridium-catalyzed intramolecular allylic substitution reaction

An efficient Ir-catalyzed enantioselective intramolecular allylic substitution reaction of 2-tosylhydrazono or hydroxyimino carbonates for the synthesis of 5-, 6- and 7-membered heterocyclic compounds containing N–N and N–O bonds has been achieved.

Structural characterization of Chemical Weapons Convention-related phosphonoselenoates by electron ionization and electrospray ionization mass spectrometry.

Organophosphorus compounds with phosphorus atom bonded to one methyl, ethyl or propyl (normal or iso) group are listed in Schedule 2 of the Chemical Weapons Convention (CWC). Selenophosphorus compounds, listed in Schedule 2.B.4, have very limited representation in mass spectral libraries and the open literature. Members of a new category of selenophosphorus compounds were prepared via microsynthetic protocols and their fragmentation pathways were investigated using electron ionization (EI) and positive electrospray ionization (ESI) mass spectrometry. The EI and ESI fragmentation pathways were suggested and supported by acquired fragment ions of deuterated analogs and density functional theory calculations. Mass spectrometric investigations showed some interesting fragmentation pathways, such as McLafferty-type, selenono-selenolo rearrangements, intramolecular electrophilic aromatic substitution reaction and α-cleavage. Efficient microsynthesis was conducted, and EI-MS spectra and ESI-MS/MS spectra of a series of selenophosphorus compounds were collected and studied with the purpose of identifying CWC-related chemicals during on-site inspection and/or off-site analysis.

Acid-Mediated Autocatalysis in Vinylogous Urethane Vitrimers.

Vitrimers are a class of polymeric materials with outstanding properties. Intramolecular substitution reactions lead to a dynamic exchange within the polymer network which enables thermoreversible stress relaxation in yet permanently crosslinked materials. In this paper, the acid-mediated autocatalysis is explored as a rearrangement pathway for vinylogous urethane vitrimers. The autocatalysis enables transimination reactions, resulting in a dynamic exchange among the enamine-one species, without an excess of free amines. Therefore, the enamine-ones are protonated by a Brønsted acid and turn into electrophilic iminium-ones, thus enabling fast backward and substitution reactions with water and free amines. This work provides an in-depth investigation of the mechanism by kinetic studies of selected compounds. In addition, novel elastomeric and thermosetting poly(vinylogous urethane) networks with and without free amine groups and additional para-toluene sulfonic acid as a Brønsted catalyst are prepared by bulk polymerization of hexane-1,6-diylbis(3-oxobutanoate) and tris(2-aminoethyl)amine. The underlying exchange mechanisms are determined by stress-relaxation experiments with stress relaxation times of 0.3-54000s at 110°C.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

AbstractThe mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium‐labeled substrates, and control experiments revealed that nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C−O bonds at fully substituted carbon centers in the synthesis of chiral 2,2‐disubstituted benzomorpholines.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling.

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C-O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Divergent Synthesis of Amino‐Substituted Indolizidine Alkaloids, Decahydropyrazino[2,1,6‐cd]pyrrolizine Triols, and (–)‐Pochonicine Stereoisomers

A reagent‐directed divergent synthesis of three skeletally distinct compounds, namely, amino‐substituted indolizidine alkaloids, decahydropyrazino[2,1,6‐cd]‐pyrrolizine triols and (–)‐pochonicine stereoisomers have been accomplished from a single precursor. Tri‐O‐benzyl‐d‐glucal was converted into a diastereomeric mixture of homoallylic alcohols through a seven‐step sequence developed earlier in our lab. Intramolecular iodo‐amination of the homoallylic alcohols proceeded through a 5‐exo‐tet ring opening of initially formed iodonium ion to give the iodo‐substituted pyrrolizidine {[5,5‐]‐fused} derivatives. Upon exposure to AgOAc, these iodo‐pyrrolizidines underwent a ring enlargement under the reaction condition and delivered polyhydroxylated indolizidine {[5,6]‐fused} derivatives as the main products. On the other hand, when the iodo‐pyrrolizidines were treated with NaH, a smooth intramolecular substitution reaction took place resulting in the formation of novel decahydropyrazino[2,1,6‐cd]pyrrolizine triols in good yields. Diversely, epoxidation of the homoallyic alcohols followed by intramolecular ring opening and subsequent synthetic transformations delivered stereoisomers of (–)‐pochonicine. The structure and stereochemistry of the final compounds were established through detailed 2D‐NMR analysis.

Exploring the Chemistry of Spiroindolenines by Mechanistically-Driven Reaction Development: Asymmetric Pictet-Spengler-type Reactions and Beyond.

The Pictet-Spengler reaction is a fundamental named reaction in organic chemistry, and it is the most straightforward method for the synthesis of tetrahydro-β-carbolines, a core structure embedded in numerous alkaloids. Spiroindolenines are often proposed as possible intermediates in Pictet-Spengler reactions. However, whether the spiroindolenine species is an intermediate in the mechanism of the asymmetric Pictet-Spengler reaction remains unclear. Questions about the role of the spiroindolenine species regarding the mechanism include the following: Can the spiroindolenine species be formed effectively under Pictet-Spengler conditions? If so, what is its fate? Is the delivery of the enantioenriched tetrahydro-β-carboline product related to the spiroindolenine intermediate? Previous studies regarding these questions have not reached a consensus. Therefore, elucidating these questions will advance the field of synthetic organic chemistry.The first highly enantioselective synthesis of spiroindolenines that have the same molecular scaffold as the proposed key intermediate of the Pictet-Spengler reaction was accomplished by an Ir-catalyzed intramolecular asymmetric allylic substitution reaction of an indol-3-yl allylic carbonate. In this reaction, a piperidine, pyrrolidine, or cyclopentane ring can be introduced in conjunction with the indolenine structure.Spiroindolenines were found to undergo ring-expansive migration reactions when treated with a catalytic amount of an acid, leading to tetrahydro-β-carbolines or related tetrahydrocarbazoles. Comprehensive DFT calculations and Born-Oppenheimer molecular dynamics simulations have provided insight into the mechanism of the migration process. It has been found that the stereochemistry is strongly correlated with the electronic properties of the migratory group along with the acidity of the catalyst. Close interactions between the positively charged migratory group and the electron-rich indole ring favor the stereospecificity of the migration. Furthermore, a continuous mechanistic spectrum of the Pictet-Spengler reactions can be obtained on the basis of two readily accessible energetic parameters that are derived from computed energies for competing transition states relative to a key intermediate species. This theoretical model provides a unified mechanistic understanding of the asymmetric Pictet-Spengler reaction, which has been further supported by rationally designed prototype reactions. Chemically and stereochemically controllable migration can be achieved when multiple potential migratory groups are available.The reactivity of spiroindolenines has also been explored beyond Pictet-Spengler reactions. A one-pot Ir-catalyzed asymmetric allylic dearomatization/stereoconvergent migration allows the facile synthesis of enantioenriched tetrahydro-β-carbolines from racemic starting materials. An unprecedented six- to seven-membered ring-expansive migration can be achieved when a vinyliminium moiety is involved as a highly reactive migratory group. This reaction facilitates the stereoselective synthesis of thermodynamically challenging indole-annulated seven-membered rings. It has also been found that the migration process can be interrupted. The electrophilic migratory group released from the retro-Mannich reaction of a spiroindolenine can be captured by an inter- or intramolecular nucleophile, thus providing new entries into structurally diverse polycyclic indole derivatives.Therefore, the mechanism of the Pictet-Spengler reaction can be probed by manipulating the reactivity of the spiroindolenine species. In turn, the mechanistic insights gained herein will aid in chemical transformations toward various target molecules. This study serves as a vivid example of the positive interplay between experimental and theoretical investigations in synthetic organic chemistry.

Radical-Polar Crossover Annulation: A Platform for Accessing Polycyclic Cyclopropanes.

Photoredox-mediated radical/polar crossover (RPC) processes provide unique solutions to challenging annulations. Herein, we describe an approach to the cyclopropanation of olefins that are embedded within bicyclic scaffolds. Whereas these systems are notoriously recalcitrant toward classical cyclopropanation approaches, RPC cyclopropanation can be executed with ease, leading to polycarbocyclic and polyheterocyclic cyclopropanes. The cyclopropanation proceeds through a photoredox-enabled Giese-type radical addition followed by an intramolecular anionic substitution reaction on a neopentyl leaving group.

Selective Cu-Catalyzed Intramolecular Annulation of 3-Aryl/Heteryl-2-(diazoacetyl)-1H-pyrroles: Synthesis of Benzo/Furo/Thieno[e]-Fused 1H-Indol-7-oles and Their Transformations.

The Co(III)-catalyzed reaction of 1,3-dicarbonyl compounds with 2-(diazoacetyl)-2H-azirines, prepared by a simplified procedure from 2H-azirin-2-carbonyl chlorides, led in high yields to the formation of 2-(diazoacetyl)pyrroles, while leaving the diazoacetyl function intact. The intramolecular aromatic substitution reaction of 2-(diazoacetyl)pyrroles, catalyzed by Cu(OTf)2, provided selectively previously unknown benzo[e]- and hetero[e]-fused indol-7-oles in good yields. Formylation of benzo[e]indol-4-ol led selectively to the 5-formyl derivative, which is a good precursor for an unusual salen ligand and its Ni-complex. Triflates prepared from benzo[e]indol-4-oles gave various 4-substituted benzo[e]indoles carrying aryl, 2-thienyl, 2-pyridyl, and alkynyl groups, in excellent yields using cross-coupling reactions. 4-(2-Pyridyl)benzo[e]indoles, upon treatment with BF3·Et2O/Et3N, afforded a new type of fluorescent boron complexes with large Stokes shifts.

Ketones and Aldehydes as O-Nucleophiles in Iridium-Catalyzed Intramolecular Asymmetric Allylic Substitution Reaction.

Ketones and aldehydes are employed as enol O-nucleophiles in an iridium-catalyzed asymmetric allylic substitution reaction. The reaction proceeds well in the presence of a well-defined chiral iridium complex under mild conditions. A series of chiral 2 H-1,4-oxazine skeletons can be obtained in up to 94% yield with 99% ee. The utility of this novel method has been demonstrated by its implementation in the first enantioselective synthesis of (+)-chelonin A.

Copper-catalysed enantioselective intramolecular etherification of propargylic esters: synthetic approach to chiral isochromans.

Enantioselective synthesis of chiral isochromans bearing a terminal alkyne moiety has been accomplished by copper-catalysed enantioselective intramolecular propargylic substitution reactions of propargylic esters with alcoholic nucleophiles. This method represents the first successful example which directly introduced a terminal alkyne group into chiral isochromans.

Understanding Regioselectivities of Corey–Chaykovsky Reactions of Dimethylsulfoxonium Methylide (DMSOM) and Dimethylsulfonium Methylide (DMSM) toward Enones: A DFT Study

The Corey–Chaykovsky reaction, using either in situ generated dimethylsulfoxonium methylide (DMSOM) or dimethylsulfonium methylide (DMSM) to react with ketones or aldehydes, is widely used in the synthesis of epoxides. However, when DMSOM and DMSM react with enones (such as chalcone), the former reactions give cyclopropanation products whereas the latter reactions still generate epoxides. DFT calculations have been carried out to understand these different regioselectivities. We found that the cyclopropanation pathways for both DMSOM and DMSM toward chalcone (a model for enones) start with rate‐determining and irreversible 1,4‐addition reactions, followed by easier intramolecular substitution reactions to give cyclopropanes. The overall activation free energies for cyclopropanation are 17.5 and 15.5 kcal/mol for DMSOM and DMSM, respectively. The epoxidation pathways for both DMSOM and DMSM have reversible 1,2‐addition reactions, followed by rate‐determining intramolecular substitution reactions to give epoxides. The computed barriers for the epoxidation are 23.0 and 13.3 kcal/mol for DMSOM and DMSM, respectively. Therefore, the cyclopropanation pathway is favored for DMSOM while epoxidation is preferred for DMSM. We attribute these different reaction scenarios to thermodynamic reasons that DMSOM is more stable than DMSM. The reaction pathways for reactions of other derivatives of DMSM toward enones have also been discussed.

Front Cover: Alkyl Radical Generation by an Intramolecular Homolytic Substitution Reaction between Iron(II) and Trialkylsulfonium Groups (Chem. Eur. J. 43/2018)

Front Cover: Alkyl Radical Generation by an Intramolecular Homolytic Substitution Reaction between Iron(II) and Trialkylsulfonium Groups (Chem. Eur. J. 43/2018)

Alkyl Radical Generation by an Intramolecular Homolytic Substitution Reaction between Iron(II) and Trialkylsulfonium Groups

AbstractInvited for the cover of this issue are Peter Chen and Stefan Jungen at the Eidgenössische Technische Hochschule (ETH) in Zürich. The image depicts a table‐top firework with the tip of an ion guide used in mass spectrometers that spits out the products of a homolitic substitution reaction between iron(II) and trialkylsulfonium species. Read the full text of the article at 10.1002/chem.201801952.

Alkyl Radical Generation by an Intramolecular Homolytic Substitution Reaction between Iron(II) and Trialkylsulfonium Groups.

Intramolecular, homolytic substitution reactions between iron(II) species and various trialkylsulfonium groups were directly observed in the gas phase upon collision-induced dissociation. In spite of the notoriously low reduction potential of trialkylsulfonium species and the mismatched oxidation potential of iron(II), the reactions proceed at moderate collision energies, forming an alkyl radical as well as a thioether coordinated to the iron. In contrast to classical homolytic substitutions, the attacking radical is a "metalloradical", namely iron(II) that is oxidized to iron(III) during the reaction. With this process we demonstrate that the conceptually analogous, putative radical generation step in radical S-adenosyl methionine (SAM) enzymes is possible and plausible. Further, we show that this kind of reaction only occurs in constrained systems with a defined geometry. Combining experimental measurements with DFT studies and NBO analyses allowed us to gain insights into the reactivity and transition states of these systems. Based on our findings, we challenge the notion of a collinear transition state in the radical generation step of radical SAM enzymes and propose it to be bent instead.