Intermediates In Synthetic Chemistry Research Articles

Organoelectrocatalytic cyclopropanation of alkenyl trifluoroborates with methylene compounds

Cyclopropanes are not only privileged motifs in many natural products, agrochemicals, and pharmaceuticals, but also highly versatile intermediates in synthetic chemistry. As such, great effort has been devoted to the cyclopropane construction. However, novel catalytic methods for cyclopropanation with two abundant substrates, mild conditions, high functional group tolerance, and broad scope are still highly desirable. Herein, we report an intermolecular electrocatalytic cyclopropanation of alkenyl trifluoroborates with methylene compounds. The reaction uses simple diphenyl sulfide as the electrocatalyst under base-free conditions. And thus, a broad scope of various methylene compounds as well as vinyltrifluoroborates is demonstrated, including styrenyl, 1,3-dienyl, fluorosulfonyl, and base-sensitive substrates. Preliminary mechanistic studies are presented, revealing the critical role of the boryl substituent to facilitate the desired pathway and the role of water as the hydrogen atom source.

Aziridine Group Transfer via Transient N-Aziridinyl Radicals.

Aziridines are the smallest nitrogen-containing heterocycles. Strain-enhanced electrophilicity renders aziridines useful synthetic intermediates and gives rise to biological activity. Classical aziridine syntheses─based on either [2 + 1] cycloadditions or intramolecular substitution chemistry─assemble aziridines from acyclic precursors. Here, we introduce N-aziridinyl radicals as a reactive intermediate that enables the transfer of intact aziridine fragments in organic synthesis. Transient N-aziridinyl radicals are generated by the reductive activation of N-pyridinium aziridines and are directly characterized by spin-trapped EPR spectroscopy. In the presence of O2, N-aziridinyl radicals are added to styrenyl olefins to afford 1,2-hydroxyaziridination products. These results establish aziridinyl radicals as new reactive intermediates in synthetic chemistry and demonstrate aziridine group transfer as a viable synthetic disconnection.

Stereoselective Vinylic C-H Addition via Metallaphotoredox Migration.

Geometrically defined allylic alcohols with SE, SZ, RE and RZ stereoisomers serve as valuable intermediates in synthetic chemistry, attributed to the stereoselective transformations enabled by the alkenyl and hydroxyl functionalities. When an ideal scenario presents itself with four distinct stereoisomers as potential products, the simultaneous control vicinal stereochemistry in a single step would offer a direct pathway to any desired stereoisomer. Here, we unveil a metallaphotoredox migration strategy to access stereodefined allylic alcohols through vinylic C-H activation with aldehydes. This method harnesses a chiral nickel catalyst in concert with a photocatalyst to enable a 1,4-Ni migration by using readily accessible 2-vinyl iodoarenes as starting materials. The efficacy of this methodology is highlighted by the precise construction of all stereoisomers of allylic alcohols bearing analogous substituents and the efficient synthesis of key intermediates en route to Myristinin family. Experimental and computational studies have shed light on pivotal aspects including the synergy of metal catalysis and photocatalysis, the driving forces behind the migration, and the determination of absolute configuration in the C-H addition process.

Fluorine‐Effect‐Enabled Photocatalytic 4‐Exo‐Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes

AbstractCyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio‐ and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4‐exo‐trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C‐F interactions, accounts for the regio‐reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4‐exo‐trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary‐carbon‐containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Phosphinoyl-Substituted Ketenyl Anions: Synthesis and Substituent Effects on the Structural Properties.

Ketenyl anions are versatile intermediates in synthetic chemistry and have recently become accessible as isolable reagents from metalated ylides by exchange of the phosphine with CO. Herein, we report on a systematic study of substituent effects on the structure and bonding situation in ketenyl anions. A series of phosphinoyl-substituted ketenyl anions {[R2P(X)CCO]- with X = O, NTol, S, Se} were prepared by carbonylation of the corresponding yldiides and isolated as their corresponding potassium salts. NMR and IR spectroscopic analyses together with computational studies demonstrate that the more electron-withdrawing oxo- and iminophosphinoyl substituents increase the s-character in the bond to the ketene moiety and hence the ynolate character of the anion. This trend is particularly seen in solution, whereas the solid-state properties are influenced by packing effects affecting the bonding situation.

Recent Advances in Application of Alkoxy Radical in Organic Synthesis

Alkoxy radicals have been identified as versatile intermediates in synthetic chemistry in the last few decades. Over the last decade, various catalytic processes for the in situ generation of alkoxy radicals have been explored, leading to the development of new synthetic methodologies based on alkoxy radicals. In this review, we provided a comprehensive review of recent developments in the utilization of alkoxy radicals in diverse organic transformations, natural product synthesis, and the late-stage modification of bioactive molecules through the implementation of the photoredox methodology.

Synthesis of α-Chloroarylacetic Acid via Electrochemical Carboxylation of α,α-Dichloroarylmethane Derivatives.

The electrocarboxylation of α,α-dichloroarylmethane derivatives in the presence of CO2 was achieved, providing several α-chloroarylacetic acid derivatives with modest yields but high selectivity (chlorinated vs. non-chlorinated or dicarboxylic acid products). The obtained products were then involved in several chemical transformations, underlining their potential as versatile intermediates in synthetic chemistry. A mechanism was also proposed based upon a control experiment and cyclic voltammetry (CV) study.

Highly Regioselective Propargylation/Allenylation of Organolanthanum Reagents with Aldehydes.

The metal-mediated propargylation or allenylation of carbonyl compounds is well-adapted to the preparation of homopropargylic or allenylic alcohols, which are multifunctional intermediates in synthetic chemistry. However, the regioselectivity of reactions using propargyl or allenyl metal reagents is difficult to control, owing to the equilibrium between the two species. In our study, propargyl or allenyl organolanthanum reagents were prepared using trimethylsilylpropyne or prop-1-yn-1-ylbenzene substrates. The treatment of the organolanthanum reagents with aldehydes yielded the regioselective products, respectively. This study provides a better understanding of structural specificity and the special chemoselectivity of rare earth metal reagents.

Electron‐Rich Oxycarbenes: New Synthetic and Catalytic Applications beyond Group 6 Fischer Carbene Complexes

AbstractOxycarbenes have emerged as useful intermediates in synthetic chemistry. Compared to the widely studied oxycarbene metal complexes bearing Group 6 metals, the synthetic and catalytic applications of oxycarbenes beyond Group 6 Fischer carbene complexes are less explored because of the difficulty in controlling their reactivity and the need to use a stoichiometric amount of a presynthesized Group 6 metal carbene complex as the starting material. This Minireview summarizes early synthetic and catalytic applications of late‐transition‐metal oxycarbene complexes and highlights recent advances in free oxycarbene reactions and transition‐metal‐catalyzed reactions involving oxycarbenes. We hope this Minireview will inspire further developments in this emerging area.

Electron-Rich Oxycarbenes: New Synthetic and Catalytic Applications beyond Group 6 Fischer Carbene Complexes.

Oxycarbenes have emerged as useful intermediates in synthetic chemistry. Compared to the widely studied oxycarbene metal complexes bearing Group 6 metals, the synthetic and catalytic applications of oxycarbenes beyond Group 6 Fischer carbene complexes are less explored because of the difficulty in controlling their reactivity and the need to use a stoichiometric amount of a presynthesized Group 6 metal carbene complex as the starting material. This Minireview summarizes early synthetic and catalytic applications of late-transition-metal oxycarbene complexes and highlights recent advances in free oxycarbene reactions and transition-metal-catalyzed reactions involving oxycarbenes. We hope this Minireview will inspire further developments in this emerging area.

Aminium-Radical-Mediated Intermolecular Hydroamination of Nonactivated Olefins

AbstractAminium radicals are attractive intermediates in synthetic chemistry that readily participate in a series of C–N bond-forming processes. Here, we briefly discuss strategies for generating aminium radicals from various precursors in the context of intermolecular alkene amination, and we highlight recent advances in aminium-radical-mediated hydroaminations of nonactivated olefins to directly approach alkylamines.1 Introduction2 Intermolecular Hydroamination of Nonactivated Alkenes with Alkylamines under Photoredox Catalysis3 Intermolecular Hydroamination of Nonactivated Alkenes with Aliphatic Azides4 Conclusions

SYNTHESIS OF THIOESTERS AND THIOAMIDES USING POTASSIUM THIOCYANATE UNDER MICROWAVE IRRADIATION

Microwave-assisted synthesis provides more time for chemists to expand their creativeness, develop new processes and new theories. Recent developments in chemical sciences created microwave energy a new proficient way of heating the reaction.1 Microwave energy bids abundant benefits for the execution of synthesis comprising enhanced reaction rates, improved yield and cleaner chemistries. Using this technique, reactions can be performed in minutes, instead of spending hours to days in a conventional manner. The difficulty accompanying effluent disposal is overcome by executing the reactions without the use of solvent under microwave irradiation. Microwave irradiation reaction under solvent-free conditions, mineralsupported catalyzed reactions etc. provides better chemical methods with higher reaction rate, improved yield, good selectivity.2 Chemical reactions that took an hour to days the completion can be performed in minutes. The microwave region is positioned between IR and radio waves in the electromagnetic spectrum. The wavelength of microwave radiation is 1 mm-1 m with the frequencies 0.3-300 GHz. Dielectric heating in microwaves utilizes the capability of various solids and liquids to convert electromagnetic energy into heat to progress the reactions. The microwave technique has been applied in various research technologies like drug release/targeting,3 polymer technology,4 waste treatment,5 ceramics,6 alkane decomposition,7 etc. Consequently, microwave technology entertains as a potential method in green chemistry.8 This technology unlocks new openings as a new heating technique which is very difficult by the regular heating method.9 Organosulfur compounds are versatile intermediates in synthetic chemistry, possess many imperative biological properties.10 The applications and choice of organo-sulfur compounds have augmented enormously as sulfur comprising groups continue to function as an imperative supplementary function in synthetic arrangements.11 Thiocarbonyl comprising compounds are useful synthetic intermediates, that find numerous uses in the preparation of natural products.12 Although various reagents are accessible for the preparation of thioesters or thioamides, there are some drawbacks. Some of the important reagents used for thionation comprises lawessons reagent,13 H2S,14 phosphorous pentasulfide,15 hexamethyldisilathine,16 R3OBF4/NaSH,17 R2PSX,18 (Et2Al)2S,19 bis(tricyclcohexylstannyl) sulfide/BCl3, 20 thiourea,21 etc. Many of these reagents involve high temperatures, prolonged reaction times, or harsh conditions for reaction execution and frequently require problematic column chromatography to separate and remove the unwanted products. Batool A. et al. described a green procedure for the synthesis of thieranes from oxiranes by using ammonium thiocyanate.22 Encouraged by this, and in persistence to our work on the development of biologically active heterocycles,23-26 we thought of using simple and commercially available reagent potassium thiocyanate for the transformation of esters into thioesters by making use of microwave irradiation.

Iron-catalyzed tandem oxidative coupling and acetal hydrolysis reaction to prepare formylated benzothiazoles and isoquinolines.

The aldehyde group is one of the most versatile intermediates in synthetic chemistry, and the introduction of an aldehyde group into heteroarenes is important for the transformation of molecular structure. Herein, we achieved the direct formylation of benzothiazo/les and isoquinolines. The reaction features a novel iron-catalyzed Minisci-type oxidative coupling process using commercially available 1,3-dioxolane as a formylated reagent followed by acetal hydrolysis without a separation process. The reaction can be performed under exceedingly mild reaction conditions and exhibits broad functional group tolerance.

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

Abstract Metal homoenolates represent uniquely useful organometallic intermediates in synthetic chemistry, allowing umpolung synthesis of β-functionalized carbonyl compounds. While siloxycyclopropanes had been established as reliable precursors to homoenolates, often stoichiometric, for diverse carbon–carbon bond forming reactions, unprotected cyclopropanols have emerged as alternative and attractive precursors to homoenolates, often catalytically generated, in carbon–carbon and carbon–heteroatom bond-forming reactions. This review article provides an overview of the development of such homoenolate transformations, as classified with respect to the metals involved in the cyclopropane ring opening.

Rapid functionalization of multiple C-H bonds in unprotected alicyclic amines.

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C-H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C-H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α'-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry.

The Simplest, Isolable, Alkynyl Isocyanate HC≡CNCO: Synthesis and Characterization

AbstractAlkynyl isocyanates have been postulated as highly reactive intermediates in synthetic chemistry. Herein, the parent molecule HC≡CNCO is isolated for the first time. In sharp contrast to the previously reported short lifetime (ca. 15 s) at room temperature, we found that HC≡CNCO has a lifetime of 55 h in the gas phase (2 mbar, 300 K) with a melting point of −79.5 °C and vaporization enthalpy (ΔHvap) of 23.1(1) kJ mol−1. Apart from the IR (gas, solid, and matrix), 1H and 13C NMR, and UV/Vis spectroscopic characterization, its photoisomerization with a acylnitrene HC≡CC(O)N and cyanoketene NCC(H)CO has been observed.

The Simplest, Isolable, Alkynyl Isocyanate HC≡CNCO: Synthesis and Characterization.

Alkynyl isocyanates have been postulated as highly reactive intermediates in synthetic chemistry. Herein, the parent molecule HC≡CNCO is isolated for the first time. In sharp contrast to the previously reported short lifetime (ca. 15 s) at room temperature, we found that HC≡CNCO has a lifetime of 55 h in the gas phase (2 mbar, 300 K) with a melting point of -79.5 °C and vaporization enthalpy (ΔHvap ) of 23.1(1) kJ mol-1 . Apart from the IR (gas, solid, and matrix), 1 H and 13 C NMR, and UV/Vis spectroscopic characterization, its photoisomerization with a acylnitrene HC≡CC(O)N and cyanoketene NCC(H)CO has been observed.

N-Heterocyclic Carbenes as Key Intermediates in the Synthesis of Fused, Mesoionic, Tricyclic Heterocycles.

Coupling between 5-bromoimidazo[1,5-a]pyridinium salts and malonate or arylacetate esters leads to a facile and straightforward access to the new mesoionic, fused, tricyclic system of imidazo[2,1,5-cd]indolizinium-3-olate. Mechanistic studies show that the reaction pathway consists of nucleophilic aromatic substitution on the cationic, bicyclic heterocycle by an enolate-type moiety and in the nucleophilic attack of a transient free N-heterocyclic carbene (NHC) species on the ester group; the relative order of these two steps depends on the nature of the starting ester. This work highlights the valuable implementation of free NHC species as key intermediates in synthetic chemistry, beyond their classical use as stabilizing ligands or organocatalysts.

Flash vacuum pyrolysis of sulfamoyl azides and chlorides: Facile gas-phase generation of transient N-sulfonylamines

Two sulfamoyl azides, H2NS(O)2N3 and MeN(H)S(O)2N3, have been isolated as neat substances and characterized. The solid-state structure of the parent molecule H2NS(O)2N3 has been established with X-ray crystallography. The thermal decomposition of both azides has been studied by combining flash vacuum pyrolysis (FVP, 400 °C) and matrix-isolation IR spectroscopy. In addition to the complete dissociation fragments for H2NS(O)2N3 (SO2, N2, and H2) and MeN(H)S(O)2N3 (SO2, N2, and CH2NH), the retro-ene decomposition products HN3 and N-sulfonylamines HNSO2 and MeNSO2 form, respectively. Alternatively, quantitative yield of both N-sulfonylamines in the gas phase occurs when sulfamoyl chlorides H2NS(O)2Cl and MeN(H)S(O)2Cl are used as the FVP precursors (400 °C). Consistent with these experimental observations, computational studies on the potential energy profiles for the decomposition of the two azides at the CCSD(T)/aug-cc-pVTZ//B3LYP/6-311++G(3df,3pd) level conclusively suggest that the N2-elimination is energetically more favorable than the HN3-elimination through either retro-ene reaction or 1,2-elimination. In contrast, the facile HCl-elimination from sulfamoyl chlorides provides a general method for the gas-phase generation of N-sulfonylamines, which were known as transient reactive intermediates in synthetic chemistry.