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The switchable synthesis of 3-aminoindolines and 2′-aminoaryl acetic acids from the same substrates, 3-azido-2-hydroxyindolines, was developed through denitrogenative electrophilic amination of Grignard reagents. The key to success is the serendipitous discovery that the reaction conditions, including solvents and reaction temperature, can affect the chemoselectivity. It is noteworthy that isotope-labeling experiments revealed the occurrence of the aziridine intermediate in the production of 2′-aminoaryl acetic acids. [ABSTRACT FROM AUTHOR]

A series of dinuclear sulfur‐bridged titanium derivatives [Ti(η5‐C5Me5)R(μ‐S)]2 (R=NMe2 (1), Ph (2), CH2Ph (3), CH2SiMe3 (4)) has been synthesized from the reaction of [Ti(η5‐C5Me5)Cl(μ‐S)]2 with the corresponding lithium salt or Grignard reagent. Formulation of 1–4 as symmetric dimers has been confirmed by crystallographic studies. The analogous reaction with Mg(C3H5)Cl afforded the paramagnetic mixed‐valence Ti(III)/Ti(IV) compound [{Ti(η5‐C5Me5)(μ‐S)}2(μ‐C3H5)] (5). Contrasting with complexes 1–4, compound 5 exhibits a bridging μ‐CH2CHCH2 fragment between the titanium atoms, which prevents the formation of a planar Ti2S2 core in the solid‐state structure. Complex 1 reacts with SiH3Ph to give [{Ti(η5‐C5Me5)(μ‐S)}2(μ‐NMe2)] (6), a paramagnetic mixed‐valence Ti(III)/Ti(IV) compound, structurally and electronically similar to 5. Under mild conditions, treatment of compounds 3 and 4 with H2 (1 atm) generates quantitatively the Ti(III) tetrametallic sulfide cluster [Ti(η5‐C5Me5)(μ3‐S)]4, along with the corresponding alkane. [ABSTRACT FROM AUTHOR]

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N‐heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N‐heteroaryl sulfur(IV) and N‐heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N‐heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis. Here we present a ligand coupling‐enabled formal SO2 extrusion of fluoroalkyl 2‐azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N‐heteroaromatic fluoroalkylation. [ABSTRACT FROM AUTHOR]

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N‐heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N‐heteroaryl sulfur(IV) and N‐heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N‐heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis. Here we present a ligand coupling‐enabled formal SO2 extrusion of fluoroalkyl 2‐azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N‐heteroaromatic fluoroalkylation. [ABSTRACT FROM AUTHOR]

This research introduces an eco‐friendly and innovative technique for efficiently producing p‐tolylmethanol derivatives 4(a–k) using electro‐organic synthesis based on the Grignard reaction. By employing electrochemical methods, this approach offers several advantages, including enhanced reaction efficiency and reduced environmental impact. The process involves the electrochemical generation of the Grignard reagent, followed by its reaction with appropriate substrates to yield the desired p‐tolylmethanol derivatives. Our team optimized various reaction parameters like choice of solvent, electrode material, and reaction conditions to achieve high yields and selectivity. The developed electro‐organic method demonstrated outstanding efficiency and presents a fresh and environmentally conscious approach to synthesizing p‐tolylmethanol derivatives from benzaldehyde 1(a–e) and bromobenzene 2(a–h) via the Grignard reaction, yielding excellent results (85–93%). The resulting compounds were comprehensively characterized using melting point, 1H NMR spectroscopy, and CHN analysis to verify their structures. This electro‐organic approach holds significant potential as a sustainable strategy for synthesizing valuable organic compounds. [ABSTRACT FROM AUTHOR]

A broadly improved second generation catalytic two‐phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C‐, N‐, O‐ and S‐ substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP‐catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second‐generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late‐stage enantiospecific SN2@P reactions with Grignard reagents. [ABSTRACT FROM AUTHOR]

A broadly improved second generation catalytic two‐phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C‐, N‐, O‐ and S‐ substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP‐catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second‐generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late‐stage enantiospecific SN2@P reactions with Grignard reagents. [ABSTRACT FROM AUTHOR]

Two mixed peri-substituted phosphine-chlorostibines, Acenap(PiPr2)(SbPhCl) and Acenap(PiPr2)(SbCl2) (Acenap = acenaphthene-5,6-diyl) reacted cleanly with Grignard reagents or nBuLi to give the corresponding tertiary phosphine-stibines Acenap(PiPr2)(SbRR') (R, R' = Me, iPr, nBu, Ph). In addition, the Pt(II) complex of the tertiary phosphine-stibine Acenap(PiPr2)(SbPh2) as well as the Mo(0) complex of Acenap(PiPr2)(SbMePh) were synthesised and characterised. Two of the phosphine-stibines and the two metal complexes were characterised by single-crystal X-ray diffraction. The peri-substituted species act as bidentate ligands through both P and Sb atoms, forming rather short Sb-metal bonds. The tertiary phosphine-stibines display through-space J(CP) couplings between the phosphorus atom and carbon atoms bonded directly to the Sb atom of up to 40 Hz. The sequestration of the P and Sb lone pairs results in much smaller corresponding J(CP) being observed in the metal complexes. QTAIM (Quantum Theory of Atoms in Molecules) and EDA-NOCV (Energy Decomposition Analysis employing Naturalised Orbitals for Chemical Valence) computational techniques were used to provide additional insight into a weak n(P)→σ*(Sb-C) intramolecular bonding interaction (pnictogen bond) in the phosphine-stibines. [ABSTRACT FROM AUTHOR]

The reaction of calcium carbide with water has been widely used as a source of acetylene for the synthesis of organic molecules. In contrast with this traditional approach, we use the CaC2 reaction under water‐starved conditions and show reactions that involve a calcium acetylide intermediate, reminiscent of Grignard reaction intermediates, which are stabilized by the solvent. Using this reaction pathway may allow for new chemistry, finer reaction control, and safety by limiting the formation of acetylene gas during the reaction. For example, reaction with bromoarenes, readily yields the corresponding diaryl acetylene. [ABSTRACT FROM AUTHOR]

New amides of (5Z,9Z)-eicosa-5,9-dienoic acid, which is a highly active topoisomerase I/II inhibi-tor, were synthesized via Cp2TiCl2-catalyzed intermolecular cross-cyclomagnesiation of aliphatic and oxygen-containing 1,2-dienes as the key step. [ABSTRACT FROM AUTHOR]

This article discusses the development of a catalytic method for the magnesiation of alkyl fluorides using magnesium powder. Alkylmagnesium reagents, such as Grignard reagents, are important tools in organic synthesis, but the preparation of alkylmagnesium reagents from alkyl fluorides has been challenging due to the high bond-dissociation energy of C-F bonds. The researchers used a bimetallic rhodium-aluminum complex as a catalyst to activate the C-F bond and successfully magnesiate alkyl fluorides, including secondary and tertiary ones. The method offers a new approach for the synthesis of alkylmagnesium reagents and expands the range of available starting materials. [Extracted from the article]

Diabrotica balteata LeConte is one of the most important polyphagous agricultural pests. The sex pheromone of this pest was synthesized using Evans asymmetric alkylation, ring‐opening reaction of (R)‐2‐methyloxirane, SN2 alkylation of secondary tosylate, and coupling of chiral tosylate with Grignard reagent as central strategies. The sex pheromone prepared herein would be useful to control D. balteata. [ABSTRACT FROM AUTHOR]

Poly(3‐hexylthiophene) (P3HT) is a well‐studied conjugated polymer; however, the end‐group functionalization of these polymers is limited by fundamental synthetic challenges. Generally, end‐capping agents are used to terminate the Kumada catalyst transfer polycondensation (KCTP) to install functional end‐groups at the propagating chain end. In this work, it is shown that P3HT can be prepared with a novel SNAr‐active external initiator, followed by end capping to afford heterobifunctional end‐groups that exhibit orthogonal chemical reactivity. This orthogonal chemistry can be leveraged in sequential "click"‐type reactions to ultimately achieve the synthesis of triblock copolymers. More specifically, it is shown that the synthesis of a new pentafluorophenyl initiator allows one to append this readily functionalized group at the initiating end during P3HT synthesis. After reaching the desired degree of polymerization, an ethynyl group is incorporated at the polymer terminus using an end‐capping Grignard reagent. Critically, this heterobifunctional P3HT allows for both orthogonal para‐fluoro thiol reactions, a subset of nucleophilic aromatic substitution (SNAr), and copper‐catalyzed alkyne‐azide cycloadditions (CuAAC). The efficacy of this heterobifunctional polymer design is demonstrated by assessing sequential "click" reactions with different nonconjugated polymer blocks to either end of the P3HT polymer block. [ABSTRACT FROM AUTHOR]

The title triarylamine N,N‐bis(9,9‐dimethyl‐9H‐fluoren‐2‐yl)‐3′,3′,4′,7′‐tetramethyl‐2′,3′‐dihydrospiro[fluorene‐9,1′‐indene]‐2‐amine is a new hole transport material for organic solar cells. After investigating different discovery approaches (Schemes 1 + 2), a multi gram‐scale synthetic sequence was developed (Scheme 4). The key intermediate 2‐bromo‐9‐(2,5‐dimethylphenyl)‐9H‐fluorene was accessible from 2‐bromo‐9‐fluorenone by either the sequence Grignard reaction, Et3SiH/BF3 reduction or by direct arylation of the corresponding 2‐bromo‐9‐fluorenol. Alkylation at C(9) of 2‐bromo‐9‐(2,5‐dimethylphenyl)‐9H‐fluorene with methallyl chloride and cyclization by an intramolecular Friedel‐Crafts alkylation led to the key building block 2‐bromo‐3′,3′,4′,7′‐tetramethyl‐2′,3′‐dihydrospiro[fluorene‐9,1′‐indene] (Scheme 4). A Buchwald‐Hartwig coupling was employed (Scheme 3 + 4) for the assembly of the final triarylamines. The developed gram‐scale synthesis of the title compound is scalable and chromatography‐free with an overall yield >25 % over 5 steps. [ABSTRACT FROM AUTHOR]

A regio‐ and diastereoselective conjugate addition reaction of Grignard reagents to fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was disclosed. A range of different fluoroalkyls and Grignard reagents were well tolerated, giving up to 99% diastereomeric and regioisomeric ratios. This reaction provided a straightforward method for the synthesis of a variety of enantiomerically enriched α‐fluorinated enamines and derivatives which are difficult to achieve with other methods. [ABSTRACT FROM AUTHOR]

Synthesis of alkyl, aryl, and vinyl boronic esters carrying various chiral and achiral diol‐protecting groups were synthesized starting from the corresponding alkyl, aryl, and vinyl lithium or Grignard reagents. Good to excellent yields were obtained for a large range of substrates. The reaction can be conducted in a gram scale to obtain the product over 80 % yield. This approach provides direct access to neopentyl, pinene, and other boronic esters that are difficult to achieve. Using trimethoxyborane or 2‐isopropoxy pinacolboronic ester. Detailed mechanistic studies have been conducted to understand the mechanism behind the formation of boronic ester starting from organometallic reagents. [ABSTRACT FROM AUTHOR]

This document provides spectroscopic data and experimental procedures for the synthesis of various compounds, including triarylmethanes and 1,1-diarylalkanes. The compounds were synthesized using specific reactions and characterized using NMR and IR spectroscopy. The yields and physical properties of the compounds are also reported. The data presented in the document match the literature. The compounds mentioned include (methoxymethylene)dibenzene, 1-(methoxy(phenyl)methyl)-4-methylbenzene, 1-methoxy-4-(methoxy(phenyl)methyl)benzene, (4-(methoxy(phenyl)methyl)phenyl)(methyl)sulfane, 4-(methoxy(phenyl)methyl)-N,N-dimethylaniline, 4-(4-(methoxy(phenyl)methyl)phenyl)morpholine, 4-(methoxy(phenyl)methyl)-1,1'-biphenyl, 1-fluoro-4-(methoxy(phenyl)methyl)benzene, 1-chloro-4-(methoxy(phenyl)methyl)benzene, 1-(methoxy(phenyl)methyl)-4-(trifluoromethyl)benzene, 1-(methoxy(phenyl)methyl)-2-methylbenzene, 1-methoxy-2-(methoxy(phenyl)methyl)ben [Extracted from the article]

A Cu‐catalyzed asymmetric synthesis of silicon‐stereogenic benzoxasiloles has been realized via intramolecular Si−O coupling of [2‐(hydroxymethyl)phenyl]silanes. Cu(I)/difluorphos is found to be an efficient catalytic system for enantioselective Si−C bond cleavage and Si−O bond formation. In addition, kinetic resolution of racemic substituted [2‐(hydroxymethyl)phenyl]silanes using Cu(I)/ PyrOx (pyridine‐oxazoline ligands) as the catalytic system is developed to afford carbon‐ and silicon‐stereogenic benzoxasiloles. Ring‐opening reactions of chiral benzoxasiloles with organolithiums and Grignard reagents yield various enantioenriched functionalized tetraorganosilanes. [ABSTRACT FROM AUTHOR]

The redox‐active nature of a pincer has been exploited to conduct C−C cross‐coupling reactions under mild conditions. A nickel complex with a NNN pincer was dimeric in the solid state, and the structure displayed a Ni2N2 diamond core. In the dimeric structure, both ligand backbones house an electron, in the iminosemiquinonate form, to keep the metal's oxidation state at +2. In the presence of an aryl Grignard reagent, only 3 mol % loading the nickel complex generates a Kumada cross‐coupled product in good yield from a wide variety of aryl‐X (X= I, Br, Cl) substrates. That the ligand‐based radical remains responsible for promoting such a coupling reaction following a radical pathway is suggested by TEMPO quenching. Furthermore, a radical‐clock experiment along with tracing product distribution unambiguously supported the radical's involvement through the catalytic cycle. A series of thorough mechanistic probation, including computational DFT analysis, disclosed the cooperative action of both redox‐active pincer ligand and the metal centre to drive the reaction. [ABSTRACT FROM AUTHOR]

A Cu‐catalyzed asymmetric synthesis of silicon‐stereogenic benzoxasiloles has been realized via intramolecular Si−O coupling of [2‐(hydroxymethyl)phenyl]silanes. Cu(I)/difluorphos is found to be an efficient catalytic system for enantioselective Si−C bond cleavage and Si−O bond formation. In addition, kinetic resolution of racemic substituted [2‐(hydroxymethyl)phenyl]silanes using Cu(I)/ PyrOx (pyridine‐oxazoline ligands) as the catalytic system is developed to afford carbon‐ and silicon‐stereogenic benzoxasiloles. Ring‐opening reactions of chiral benzoxasiloles with organolithiums and Grignard reagents yield various enantioenriched functionalized tetraorganosilanes. [ABSTRACT FROM AUTHOR]

Routes to the framework of perylenequinone‐derived mycotoxins of the dihydroanthracene type are described. Starting with anthracene derivatives, attachment of C3 units at positions 9 and 10 and twofold cyclization would furnish the required pentacycle. Heck‐type couplings, SN2 additions of enolates, alkynyl and allyl additions turned out to be not successful, while addition of a Grignard reagent prepared from acetal‐protected 3‐bromopropionaldehyde to anthraflavic acid methyl ester, subsequent acetal cleavage, and Birch reduction furnished octahydroperylene in only four steps. [ABSTRACT FROM AUTHOR]

In this study, various halogen-substituted Grignard reagents were assessed as deprotonating agents for the oxazoline-amido-phenolate ligand, leading to the formation of magnesium complexes. The newly synthesized complexes with halogen substituents displayed three distinct coordinative modes, all extensively characterized through crystallographic methods. The introduction of halogen substituents induced changes in the Lewis acid properties of the complexes, thereby impacting their structural attributes and catalytic behavior during the initiation and propagation of ring polymerization of cyclic esters. [ABSTRACT FROM AUTHOR]

Herein, we demonstrate the formation of monofluoroallenes through copper‐catalyzed defluoroalkylation or defluoroarylation of gem‐difluoroallenes using affordable and readily available Grignard reagents. Additionally, alkyl lithium or alkyl zinc reagents proved successful in these transformations. Under mild conditions, monofluoroallenes can be converted into fluorinated olefinic compounds or non‐fluorinated alkyne compounds. Initial mechanistic studies suggest that the reaction may start with an organocopper reagent and undergo a rapid β‐F elimination step. Although the current enantiomeric excess is low, chiral ligands could facilitate the asymmetric transformation of this reaction. [ABSTRACT FROM AUTHOR]

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression. [ABSTRACT FROM AUTHOR]

Sulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective "SO" donor to enable the one‐pot, three‐component synthesis of sulfoxides and sulfinamides. [ABSTRACT FROM AUTHOR]

Sulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective "SO" donor to enable the one‐pot, three‐component synthesis of sulfoxides and sulfinamides. [ABSTRACT FROM AUTHOR]

A three-stage synthetic approach made the imidazole series structurally related to clotrimazole. Firstly, benzophenone derivatives were converted to corresponding triphenylmethanol using the Grignard reaction. Then, the triphenylmethanols were reacted with thionyl chloride (SOCl2) to form triphenylchloromethanes. Finally, imidazole derivatives were obtained from substitution reactions with higher yields. All compounds and clotrimazole were characterized using spectroscopic methods, including FTIR, 1H NMR, 13C NMR, 19F NMR, and MS spectroscopies. The biological activity of the resulting compounds was tested against Candida albicans yeast and bacteria (Micrococcus luteus and Escherichia coli) using the agar diffusion test as a technique. The synthesized chemical's imidazole moiety (6b) showed significant antibacterial activity and in vitro activity against Micrococcus luteus. Molecular docking experiments were also performed to determine the modes of interactions between the produced compounds and the active site of anticandidal azole target enzyme lanosterol 14-α-demethylase (CYP51). The bioavailability of the most synthesized compounds was excellent, as evidenced by their drug-likeness and in silico ADMET characteristics. As a result, the synthesized chemicals can be thought of as potential therapeutic candidates for further research. [ABSTRACT FROM AUTHOR]

H SB 2 sb O was added and the product was extracted with CH SB 2 sb Cl SB 2 sb , the combined organic layers were washed with brine, dried (MgSO SB 4 sb ) and evaporated. Keywords: diheteroaryl ketone; pyrido[3,4- g ]quinazoline; (pyrimidin-4-yl)(pyridin-4-yl)methanone; Grignard reagents; molecular shape; protein kinase inhibitors EN diheteroaryl ketone pyrido[3,4- g ]quinazoline (pyrimidin-4-yl)(pyridin-4-yl)methanone Grignard reagents molecular shape protein kinase inhibitors 3825 3832 8 11/01/23 20231116 NES 231116 Graph As part of our ongoing studies focused on the design and synthesis of new heteroaromatic compounds with potential- protein kinases inhibitory potencies, we recently reported the identification of pyrido[3,4- I g i ]quinazolines as nanomolar Cdc-like kinase 1 (CLK1) and Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors (Figure 1). Purification by flash column chromatography using EtOAc/MeOH (90:10) as eluent afforded compound B 12 b (47.9 mg, 0.186 mmol) in 81% yield as a beige powder; I R SB f sb i = 0.70 (EtOAc/MeOH 90:10); mp 149-150 °C. In the case of the I E i -isomer, SP 1 sp H- SP 1 sp H-NOESY showed a correlation between hydrazone NH SB 2 sb , and a 3-pyridinyl proton. [Extracted from the article]

Herein we disclose an efficient one‐pot route to a wide range of 3‐substituted fused pyridinyl‐lactones, so called aza‐phthalides. The developed strategy involves a Metal/Halogen Exchange (MHE) reaction as key step, followed by an electrophile trapping using various carbonyl derivatives and a subsequent lactonization. To promote the MHE reaction with high chemoselectivity, our investigations have particularly focused on the nature of mono‐ or bimetallic derivatives as metalation reagents including organolithiums, Grignard reagents and lithium organomagnesiate complexes, and highlighted the positive salt effect on reactional sequence. An extension to fused heteroaryl‐lactones (benzothienyl‐, benzofuranyl‐ and naphthofuranyl scaffolds) was explored. [ABSTRACT FROM AUTHOR]

In this study, a continuous flow process intensification approach is applied to the Grignard reaction for the kilogram-scale production of 9-aryl-fluoren-9-ols at room temperature and the production efficiency was up to 357 g h−1. Compared with batch, the yield increased from 45% to >99%, the raw material cost was reduced by 35%, the emission of solid waste was reduced by 64%, and the production period was reduced by 86%. What's more, the continuous flow process demonstrated significantly higher atom efficiency (Ae = 75.8%), reaction mass efficiency (RME = 69.93%), and carbon efficiency (CE = 92.97%) in comparison with the traditional batch synthesis method (Ae = 34.46%, RME = 31.47%, and CE = 41.83%). Moreover, the environmental impact factor (E-factor) of the continuous flow process was impressively reduced by 92.57% compared to the batch process (26.5882 kg kg−1), reaching an outstandingly low value of 1.9747 kg kg−1. More importantly, the end-to-end synthesis of 9,9′-spirobi[9H-fluorene] (SBF) was realized through a tandem Grignard reaction and Friedel–Crafts reaction, and the theoretical productivity could reach 123 g h−1, providing a new green production route for diarylfluorene derivatives. [ABSTRACT FROM AUTHOR]

Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value‐added chemicals are highly sought‐after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2‐hydrofunctionalization, dicarbofunctionalization, and branched‐selective Heck‐type cross‐coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N‐heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes. [ABSTRACT FROM AUTHOR]

Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value‐added chemicals are highly sought‐after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2‐hydrofunctionalization, dicarbofunctionalization, and branched‐selective Heck‐type cross‐coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N‐heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes. [ABSTRACT FROM AUTHOR]

1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. [ABSTRACT FROM AUTHOR]

The reaction between the Grignard reagent formed from Mg and 2‐bromobenzylmethyl ether and SnCl4 produced four products: [2‐(MeOCH2)C6H4]3SnBr (1), [2‐(MeOCH2)C6H4]2SnX2 (2, X2=Br2 (a) and BrCl (b)), [{2‐(MeOCH2)C6H4}3Sn]2 (3), and [{2‐(MeOCH2)C6H4}2SnBr]2O (4). In the case of 1, two of the three dangling arm O atoms coordinate to the central tin atom with O−Sn internuclear distances of 2.53 (O1) and 2.91 (O2) Å, the shorter interaction being trans to the Br atom, the other trans to a phenyl carbon atom. In the case of 2a the resulting hexacoordinate structure exhibits two very short O−Sn interactions of 2.42 and 2.50 Å, well below the sum of the VdW radii of O and Sn, 3.69 Å. The sterically crowded ditin compound 3 was obtained in trace amounts and the structure demonstrates no dangling O−Sn interactions. General changes in structure compared to other distannane systems are reflective of the great steric crowding. Distannoxane 4, has a Sn−O−Sn bond angle of 148.1(2)° which is larger compared to other distannoxane structures. The intermolecular interactions between Sn−O 2.470(3) and 2.521(3)Å and 2.665(3) and 2.629(3)Å for Sn1 and Sn2 respectively are responsible for a distorted octahedral geometry around the two tin atoms. The various 119Sn,13C and 1H NMR spectra are in accord with their structural analysis for 1 and 2, and in the solid state 13C NMR spectrum of 1 the dangling methylene group is observable whereas is solution there is a rapid dynamic equilibrium resulting in a single resonance for all methylene groups. [ABSTRACT FROM AUTHOR]

A simple and rapid access to fluorinated dithioesters was developed by a one-pot sequence corresponding to a Grignard reaction—Mitsunobu type substitution. These activated dithioesters have shown excellent reactivity in an aminolysis reaction from simple or more complex primary amines such as cinchona alkaloids. A stoichiometric amount of amine was sufficient to prepare various thioamides, including a 4-styrenylthioamide cinchonidine monomer, under environmentally friendly conditions, at room temperature, and in a very short time. [ABSTRACT FROM AUTHOR]

Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern—cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C−C/C−Si or C−C/C−C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low‐cost CrCl2, enabling the sluggishness of competitive Kumada‐type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C‐halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C−C and C−Si bonds via a novel inner‐sphere radical coupling mechanism. These three‐component geminal cross couplings are value‐addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry. [ABSTRACT FROM AUTHOR]

The presence of complex Schlenk equilibria is a central property of synthetically invaluable Grignard reagents substantially affecting their reactivity and selectivity in chemical transformations. In this work, the steric effects of aryl substituents on the Schlenk‐type equilibria of their lighter congeners, arylberyllium bromides, are systematically studied. Combination of diarylberyllium complexes Ar2Be(OEt2) (1Ar, Ar=Tip, Tcpp; Tip=2,4,6‐iPr3C6H3, Tcpp=2,4,6‐Cyp3C6H3, Cyp=c‐C5H9), containing sterically demanding aryl groups, and BeBr2(OEt2)2 (2) affords the Grignard‐analogous arylberyllium bromides ArBeBr(OEt2) (3Ar, Ar=Tip, Tcpp). In contrast, Mes2Be(OEt2) (1Mes, Mes=2,4,6‐Me3C6H3) and 2 exist in a temperature‐dependent equilibrium with MesBeBr(OEt2) (3Mes) and free OEt2. Ph2Be(OEt2) (1Ph) reacts with 2 to afford dimeric [PhBeBr(OEt2)]2 ([3Ph]2). Moreover, the influence of replacing the OEt2 donor by an N‐heterocyclic carbene, IPr2Me2 (IPr2Me2=C(iPrNCMe)2), on the redistribution reactions was investigated. The solution‐ and solid‐state structures of the diarylberyllium and arylberyllium bromide complexes were comprehensively characterized using multinuclear (1H, 9Be, 13C) NMR spectroscopic methods and single‐crystal X‐ray diffraction, while DFT calculations were employed to support the experimental findings. [ABSTRACT FROM AUTHOR]

Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern—cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C−C/C−Si or C−C/C−C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low‐cost CrCl2, enabling the sluggishness of competitive Kumada‐type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C‐halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C−C and C−Si bonds via a novel inner‐sphere radical coupling mechanism. These three‐component geminal cross couplings are value‐addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry. [ABSTRACT FROM AUTHOR]

3 Conclusions and Future Directions A versatile sulfinylative cross-coupling for the synthesis of sulfoxides and sulfinamides was developed employing easily prepared, bench-stable sulfoxide reagents B 1a b and B 1b b . Keywords: sulfinylative cross-coupling; Grignard reagents; one-pot synthesis; sulfinamides; sulfoxides EN sulfinylative cross-coupling Grignard reagents one-pot synthesis sulfinamides sulfoxides 1939 1942 4 10/09/23 20231024 NES 231024 Graph 1 Introduction Sulfoxides and sulfinamides represent versatile sulfur functional groups in medicinal and synthetic chemistry, and, as a result, considerable efforts have been made toward their synthesis. Optimization of conditions allowed the isolation of sulfoxide B 8 b in 77% yield (Scheme 2), while sulfoxide B 1b b , a Cl-substituted variant of B 1a b , was identified as another viable SO-donating reagent. Despite the demonstrated utility of sulfoxides B 1a b and B 1b b , minor side reactions, such as sulfoxide/magnesium exchange [49] were observed for some of the Grignard reagents tested. [Extracted from the article]

Access to enantioenriched tertiary and quaternary α‐chiral allysilanes without any transition‐metal catalyst is reported. This was achieved by enantioselective allylic displacement of γ‐silylated allylic bromides through Lewis base activation of Grignard reagents by a bidentate chiral NHC ligand. The process afforded both high γ‐regio‐ and enantioselectivity and is compatible with a wide range of silyl groups on the substrates. [ABSTRACT FROM AUTHOR]

The reduction in esters, nitriles, and imines requires harsh conditions (highly reactive reagents, high temperatures, and pressures) or complex metal-ligand catalytic systems. Catalysts comprising earth-abundant and less toxic elements are desirable from the perspective of green chemistry. In this study, we developed a green hydroboration protocol for the reduction in esters, nitriles, and imines at room temperature (25 °C) using pinacolborane as the reducing agent and a commercially available Grignard reagent as the catalyst. Screening of various alkyl magnesium halides revealed MeMgCl as the optimal catalyst for the reduction. The hydroboration and subsequent hydrolysis of various esters yielded corresponding alcohols over a short reaction time (~0.5 h). The hydroboration of nitriles and imines produced various primary and secondary amines in excellent yields. Chemoselective reduction and density functional theory calculations are also performed. The proposed green hydroboration protocol eliminates the requirements for complex ligand systems and elevated temperatures, providing an effective method for the reduction in esters, nitriles, and imines at room temperature. [ABSTRACT FROM AUTHOR]

Cu (II) complexes anchored to a regioregular polythiophene possessing a carboxyl functionality were synthesized and characterized using analytical and spectroscopic techniques. Copper catalytic platforms, which were immobilized on either water-soluble poly[3-(carboxypropy)thiophene-2,5-diyl] (PCPT) or PCPT wrapped in carbon nanotubes (PCPT@CNT) were subjected to investigate the catalytic activity for the cross-coupling reactions of organomagnesium reagents with acid chlorides, furnishing the desired ketones in a satisfactory manner in a heterogeneous environment. In addition, the functional group transformation of arylboronic acids also proceeded smoothly and provided the corresponding phenols via ipso-hydroxylation using the Cu@PCPT@CNT platform iunder aerobic conditions. The recyclability of the present platforms for Kumada coupling was also investigated, demonstrating the superiority of Cu@PCPT@CNT over Cu@PCPT. Novel Cu catalytic platforms, Cu@PCPT and Cu@PCPT@CNT, were prepared and characterized. The catalytic activity of the platforms was explored via the cross-coupling reaction of Grignard reagents and the functional group transformation of arylboronic acids, furnishing the desired products in satisfactory results. [ABSTRACT FROM AUTHOR]

Using the Grignard reaction, both heptanal and 3-phenylpropanal independently converted to 1-phenyl-3-nonanol which subsequently converted to target compound 4-methoxydecanoic acid. A short, efficient, and protective groupfree total synthesis of novel antifungal (±)-4-methoxydecanoic acid in three high-yielding steps with >75% overall yield using the oxidation of phenyl group using ruthenium trichloride to carboxy group as the key step is described. Easily available starting materials, high yield and freedom from protection and deprotection are some salient features of the synthesis. [ABSTRACT FROM AUTHOR]

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon‐carbon and carbon‐heteroatom bond‐forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air‐ and moisture‐sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, thereby limiting the scope of its application. Here, we report a mechanochemical adaptation of the Mg‐mediated Barbier reaction, which overcomes these limitations and facilitates the coupling of versatile organic halides (e.g. allylic, vinylic, aromatic, aliphatic) with a diverse range of electrophilic substrates (e.g. aromatic aldehydes, ketones, esters, amides, O‐benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C−C, C−N, C−Si, and C−B bonds. The mechanochemical approach has the advantage of being essentially solvent‐free, operationally simple, immune to air, and surprisingly tolerant to water and some weak Brønsted acids. Notably, solid ammonium chloride was found to improve yields in the reactions of ketones. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating the generation of transient organometallics facilitated by improved mass transfer and activation of the surface of magnesium metal. [ABSTRACT FROM AUTHOR]

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon‐carbon and carbon‐heteroatom bond‐forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air‐ and moisture‐sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, thereby limiting the scope of its application. Here, we report a mechanochemical adaptation of the Mg‐mediated Barbier reaction, which overcomes these limitations and facilitates the coupling of versatile organic halides (e.g. allylic, vinylic, aromatic, aliphatic) with a diverse range of electrophilic substrates (e.g. aromatic aldehydes, ketones, esters, amides, O‐benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C−C, C−N, C−Si, and C−B bonds. The mechanochemical approach has the advantage of being essentially solvent‐free, operationally simple, immune to air, and surprisingly tolerant to water and some weak Brønsted acids. Notably, solid ammonium chloride was found to improve yields in the reactions of ketones. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating the generation of transient organometallics facilitated by improved mass transfer and activation of the surface of magnesium metal. [ABSTRACT FROM AUTHOR]

Described herein is the development of an organoaluminium‐mediated tandem conjugate addition‐cyclization sequence of p‐quinone monoacetals with 2‐siloxyphenyl Grignard reagents to afford a collection of phenol‐bridged cyclohexanone derivatives. Furthermore, a tandem conjugate‐addition and dimerization reaction of p‐quinone monoacetals with Grignard reagents is also reported to offer a straightforward and diastereoselective synthesis of complex bridged‐ring compounds bearing tricyclo[6.2.2.02,7]dodecene skeletons. [ABSTRACT FROM AUTHOR]

The preparation of triphenylmethanol is a classic teaching experiment in the field of chemistry and serves as an important combination of organic chemistry theory and practical laboratory skills. However, the experiment has a low success rate due to the complexity of the apparatus, difficulties in handling Grignard reagents, and the strict requirements for anhydrous and oxygen-free conditions. Moreover, repeated solvent transfers result in solvent exposure for both teachers and students. In this study, we designed and constructed a continuous flow apparatus for the preparation of Grignard reagents using a medium-pressure syringe pump and a fixed-bed continuous flow reactor, achieving the continuous production of triphenylmethanol. The continuous flow apparatus for Grignard reagent preparation is simple to assemble, completely eliminates organic solvent exposure for teachers and students, and exhibits good reproducibility in the conversion of bromobenzene to Grignard reagent. Within this continuous flow setup, the preparation of Grignard reagents is stable, controllable, and safe. Excess magnesium turnings do not require quenching and can be reused. [ABSTRACT FROM AUTHOR]

We report a copper‐catalyzed, regioselective, and stereospecific alkylation of unbiased internal allylic carbonates with functionalized alkyl and aryl Grignard reagents. The reactions exhibit high stereospecificity and regioselectivity for either SN2 or SN2′ products under two sets of copper‐catalyzed conditions, which enables the preparation of a broad range of products with E‐alkene selectivity. Density functional theory calculations reveal the origins of the regioselectivity based on the different behaviors of homo‐ and heterocuprates. [ABSTRACT FROM AUTHOR]

We report a copper‐catalyzed, regioselective, and stereospecific alkylation of unbiased internal allylic carbonates with functionalized alkyl and aryl Grignard reagents. The reactions exhibit high stereospecificity and regioselectivity for either SN2 or SN2′ products under two sets of copper‐catalyzed conditions, which enables the preparation of a broad range of products with E‐alkene selectivity. Density functional theory calculations reveal the origins of the regioselectivity based on the different behaviors of homo‐ and heterocuprates. [ABSTRACT FROM AUTHOR]

In this article, a novel synthetic route was described for the total synthesis of Sporiolide B from inexpensive and commercially available starting materials by a concise fourteen-step sequence in 6.50% overall yield. This convergent synthesis utilizes Grignard reaction, Asymmetric dihydroxylation, Yamaguchi macrolactonization and ring closing metathesis as the key steps. [ABSTRACT FROM AUTHOR]