Halogen-lithium Exchange Reaction Research Articles

One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Abstract4-Bromopyridine is a building block that can be converted into valuable compounds, but due to its low stability, it is commercially available in the form of hydrochloride salt. Therefore, the hydrochloride salt is usually desalted with a basic aqueous solution and dried before organic reaction. In this study, to simplify the preparation and reaction procedure of 4-bromopyridine, multiple operations, desalting with a base, separation of the aqueous layer, and subsequent halogen–lithium exchange reaction were integrated into a single flow reaction. The reaction sequence was completed within 20 seconds and the yields were higher than the conventional methods. This is because the subsequent reaction can be performed immediately after the generation of 4-bromopyridine, which is unstable under ambient conditions.

A machine learning-enabled process optimization of ultra-fast flow chemistry with multiple reaction metrics

An automated flow chemistry platform was designed to collect data for a lithium-halogen exchange reaction. The data was used to train a Bayesian multi-objective optimization algorithm to optimize the process parameters and build process knowledge.

Bisaryl and Bisalkynyl Diruthenium (III,III) Compounds Based on an Electron-Deficient Building Block.

Reported herein is a new series of diruthenium(III,III) bisalkynyl and bisaryl diruthenium(III,III) compounds supported with 2-amino-3-(trifluoromethyl)pyridinate (amtfmp). Using Ru2(amtfmp)4Cl2 from a modified preparation, cis 2:2 Ru2(amtfmp)4(C≡CPh)2 (1), cis 2:2 Ru2(amtfmp)4(Ph)2 (2), and 3:1 Ru2(amtfmp)4(Ph)2 (3) were synthesized via a lithium-halogen exchange reaction using LiC2Ph and LiPh, respectively. Compounds 1-3 are all Ru2(III,III) species with a ground-state configuration of π4δ2(π*)4 (S = 0) and were characterized via mass spectrometry, electron absorption and 1H/19F NMR spectroscopies, and voltammetry. The molecular structures of 1-3 were established using single-crystal X-ray diffraction analysis, and preliminary density functional theory analysis was performed to elaborate the electronic structures of 1 and 2. Comparisons of the electrochemical properties of 1-3 against the Ru2(amtfmp)4Cl2 starting material reveal cathodic shifts of the Ru27+/6+ oxidation and the Ru26+/5+ and Ru25+/4+ reduction potentials. In comparison to related Ru2(III,III) bisalkynyl and bisaryl compounds, the electrode potentials for 1-3 are anodically shifted up to ca. 0.95 V, highlighting the strong electron-withdrawing nature of the amtfmp ligand.

Trifluoromethyl ketone P3HT-CNT composites for chemiresistive amine sensors with improved sensitivity

Chemiresistive sensors, wherein conductivity is changed by exposure to analytes, are widely used in various disciplines and in our daily lives. Carbon nanotubes (CNTs) are excellent materials with exceptional conductivity, and polymer/CNT composites have been extensively deployed in chemiresistive sensors. To improve sensitivity, we herein report the covalent functionalization of poly(3-hexylthiophene)s (P3HTs) with highly electrophilic trifluoromethyl ketones, referred to as TFMK-P3HT, and its composite with CNT and amine sensing were investigated. The synthesis was begun with the bromination of commercial P3HT, followed by a lithium-halogen exchange reaction and subsequent quenching with trifluoroacetic anhydride, producing TFMK-P3HT. Homogeneous CNT networks with TFMK-P3HT were confirmed by atomic force microscopy (AFM). The sensing of three representative amines with TFMK-P3HT/CNT showed four times higher sensitivity than P3HT/CNT samples. The sensors were selective to amines and less responsive to competitive gas species such as alcohols and H2S. The sensitivity improvements of the TFMK-P3HT sensor were maintained in humid conditions. This work suggests a facile synthetic method to improve the sensitivity of CNT-based chemical sensors and provides an effective gas sensor platform for the selective detection of amine gas.

Scalable Subsecond Synthesis of Drug Scaffolds via Aryllithium Intermediates by Numbered-up 3D-Printed Metal Microreactors.

Continuous-flow microreactors enable ultrafast chemistry; however, their small capacity restricts industrial-level productivity of pharmaceutical compounds. In this work, scale-up subsecond synthesis of drug scaffolds was achieved via a 16 numbered-up printed metal microreactor (16N-PMR) assembly to render high productivity up to 20 g for 10 min operation. Initially, ultrafast synthetic chemistry of unstable lithiated intermediates in the halogen–lithium exchange reactions of three aryl halides and subsequent reactions with diverse electrophiles were carried out using a single microreactor (SMR). Larger production of the ultrafast synthesis was achieved by devising a monolithic module of 4 numbered-up 3D-printed metal microreactor (4N-PMR) that was integrated by laminating four SMRs and four bifurcation flow distributors in a compact manner. Eventually, the 16N-PMR system for the scalable subsecond synthesis of three drug scaffolds was assembled by stacking four monolithic modules of 4N-PMRs.

Switchable Chemoselectivity of Reactive Intermediates Formation and Their Direct Use in A Flow Microreactor.

A chemoselectivity switchable microflow reaction was developed to generate reactive and unstable intermediates. The switchable chemoselectivity of this reaction enables a selection for one of two different intermediates, an aryllithium or a benzyl lithium, at will from the same starting material. Starting from bromo-substituted styrenes, the aryllithium intermediates were converted to the substituted styrenes, whereas the benzyl lithium intermediates were engaged in an anionic polymerization. These chemoselectivity-switchable reactions can be integrated to produce polymers that cannot be formed during typical polymerization reactions.

Halogen–Lithium Exchange of Sensitive (Hetero)aromatic Halides under Barbier Conditions in a Continuous Flow Set-Up

AbstractA halogen–lithium exchange reaction of (hetero)aromatic halides performed in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, and imines using BuLi as exchange reagent and a commercially available flow set-up is reported. The organolithiums generated in situ were instantaneously trapped with various electrophiles (Barbier conditions) resulting in the formation of polyfunctional (hetero)arenes. This method enables the functionalization of (hetero)arenes containing highly sensitive functional groups such as esters­, which are not tolerated in batch conditions.

Integrated Synthesis Using Isothiocyanate-Substituted Aryllithiums by Flow Chemistry

The isothiocyanate (NCS) group is an attractive functional group in the field of organic and pharmaceutical chemistry. It can be transformed into other heteroatomic functional groups. It usually acts as the inductive group of biological activity and has also been traditionally used as the fluorescent-labeling reagent. However, it is not compatible with strong bases. When the NCS group is at para position in halobenzenes, it generally undergoes nucleophilic additions upon reaction with strong bases. To the best of our knowledge, there is currently no general methodology for the formation and reactions of NCS-functionalized aryllithiums for meta and para substituents. Herein, we report the continuous-flow generation of NCS-substituted aryllithiums from the corresponding haloarenes via a selective halogen–lithium exchange reaction and its reaction with various electrophiles to yield NCS-containing products. We also achieved an integrated synthesis through sequential reactions of the NCS-containing compounds with additional nucleophiles using the continuous-flow reactors.

Intramolecular Activation of C-O Bond by an o-Boryl Group in o-(Alkoxysilyl)(diarylboryl)benzenes.

Halogen–lithium exchange reaction of o-(silyl)bromobenzene 5 with tert-BuLi afforded o-(silyl)lithiobenzene 6, which was reacted with (alkoxy)diarylboranes 7 to form borate intermediates 8. Treatment of 8 with chlorotrimethylsilane formed o-(alkoxysilyl)(diarylboryl)benzenes 4. The C–O bond in 4 was activated by intramolecular interaction between the oxygen atom and the boron atom. 4a readily reacted with MeOH and EtOH to afford the corresponding alkoxysilanes 10 and 11, respectively. Treatment of 10 with 1,4-diazabicyclo[2.2.2]octane (DABCO) afforded the silyloxyborate complex 13.

Bisaryl Diruthenium(III) Paddlewheel Complexes: Synthesis and Characterization

Aryls represent a class of both σ- and π-donating electron-rich axial ligands that is underexplored in the field of metal–metal multiply bonded paddlewheel species. By a decrease in the steric bulk around the diruthenium axial sites and an increase in the basicity of the bridging ligands, the first examples of bisaryl diruthenium(III) paddlewheel complexes have been isolated. Compounds of the form Ru2(DMBA)4Ar2 (DMBA = N,N′-dimethylbenzamidinate, Ar = C6H4-4-tBu (1), C6H5 (2), C6H3-3,5-(OCH3)2 (3)) were synthesized via a lithium–halogen exchange reaction between Ru2(DMBA)4Cl2 and excess LiAr and characterized using mass spectrometry, electronic absorption spectroscopy, cyclic and differential pulse voltammetry, and 1H NMR spectroscopy. The molecular structures of compounds 1–3 were established using single-crystal X-ray diffraction analysis and their electronic structures (both ground and excited state) analyzed using density functional theory calculations.

An alternative method for the synthesis of 2′-halogeno-1′,2′-unsaturated uridine derivatives through syn-elimination of pivalic acid of 2′-halogeno- 2′-deoxy-1′-pivaloyloxyuracil nucleoside: preparation of its 2′-C-branched nucleosides

An alternative method for the preparation of 2′-bromo- (5b) and 2′-iodo- (5c) 1′,2′-unsaturated uracil nucleosides has been developed. The protocol was on the basis of the syn-elimination of pivalic acid from 2′-bromo-(7a,b) and 2′-iodo-(9a,b) 1′-pivaloyloxy-2′-deoxyuridine derivatives, which were derived from the halo-pivaloyloxylation of 3′,5′-bis-O-TBDMS-1′,2′-unsaturated uridine 1. Compounds 5b and 5c were shown to serve as versatile synthons for the respective 2′-C-branched 1′,2′-unsaturated uracil nucleosides, through palladium-catalyzed cross-coupling or halogen-lithium exchange reactions.

Forging Ru–Csp2 Bonds in Paddlewheel Complexes Using the Lithium–Halogen Exchange Reaction

Reported herein are the first examples of the formation of Ru-Csp2 bonds in paddlewheel diruthenium species. A series of six Ru2( ap)4(C6H4-4-X) type compounds ( ap = 2-anilinopyridinate; X = NMe2 (1), N,N-(C6H4-4-OMe)2 (2), tBu (3), H (4), Br (5), CF3 (6)) was synthesized by employing the lithium-halogen exchange reaction with a variety of para-substituted aryl halides. These compounds have been characterized via electronic absorption spectroscopy, cyclic voltammetry, mass spectrometry, and magnetism studies, and their molecular structures have been established by single-crystal X-ray diffraction studies. All compounds are in the Ru25+ oxidation state, with a ground-state electronic configuration of σ2π4δ2(π*δ*)3. Crystal structures of 1-6 confirm this, indicating a Ru-Ru bond order of 2.5. Electrochemical data suggest that the σ-aryls are stronger donors than the σ-alkynyls. A range of electronically different substituents allows for a closer inspection of the extent of electronic conjugation across the diruthenium paddlewheel core and the axial aryl ligand.

Syntheses and Crystal Structures of Phenyl-Lithium Derivatives

Although organolithium compounds have been studied and applied for ∼100 years, only few crystal structures of pure, unsolvated organolithium compounds have been reported so far. Therefore, several phenyl-lithium derivatives were synthesized by lithium-halogen exchange reactions, yielding fairly soluble polymers in the cases of 4- and 2-methylphenyl-lithium ( p-TolLi and o-TolLi). Their crystal structures have been determined by X-ray powder diffraction. Remarkably, o-TolLi crystallizes in the noncentrosymmetric space group P212121 with two independent monomers, whereas the crystal structure of p-TolLi is described in spacegroup P21/ a. In contrast, no polymer of 5- m-XyLi (3,5-dimethyl-phenyl-lithium) could be observed, but single crystals of a [(5- m-XyLi)3(MTBE)3LiBr] adduct were isolated (MTBE = methyl- tert-butylether). This gives hints on the nature of lithium-halogen exchange reactions. Steric and electronic effects of the phenyl-lithium substitution are further discussed in conjunction with related compounds.

Halogen–Lithium Exchange Reaction Using an Integrated Glass Microfluidic Device: An Optimized Synthetic Approach

A telescoped approach was developed for the efficient synthesis of methoxybenzene through the generation of an unstable intermediate reagent, based on the Br–Li exchange reaction of p-bromoanisole and n-BuLi, followed by its reaction with water. In the first stage, p-methoxyphenyllithium was synthesized and consumed immediately in the second stage. For this purpose, an integrated glass microfluidic device was fabricated using laser ablation followed by the thermal fusion bonding method. The impact of various parameters, including solvent, reaction time, molar ratio, concentration of reagents, and flow rates were investigated to achieve the highest yield of the desired product, leading to an optimized condition for the synthetic approach. It was found that the yield varies significantly with change in solvent composition. While p-bromoanisole does not react with n-BuLi in pure n-hexane, the existence of a small amount of THF (or 2-MeTHF) in n-hexane facilitates p-bromoanisole reaction with n-BuLi. Moreover...

Regenerable Thiophenolic Radical-Trapping Antioxidants.

Diphenyl disulfides carrying alkyltelluro groups in the o-, m-, and p-positions were prepared using ortho-lithiation and lithium halogen exchange reactions. The novel antioxidants showed only minimal inhibitory effect on the azo-initiated peroxidation of linoleic acid in chlorobenzene until reduced to the corresponding thiophenols by tris(2-carboxyethyl)phosphine (TCEP). The best in situ generated thiophenol (from 7c) under these conditions quenched peroxyl radicals more efficiently than α-tocopherol with an almost 3-fold increase in inhibition time.

4-Bromo-2,3-dihydroisoxazoles: synthesis and application in halogen-lithium exchange reactions

The synthesis of novel types of 4-bromo-2,3-dihydroisoxazoles using pyridinium tribromide in the presence of base is described. Reactivity of the initial substrates and the yields depend on the substituent at C3. To demonstrate a practical scope of the 4-bromo-substituted 2,3-dihydroisoxazoles, representative 2-benzyl-4-bromo-3,5-diphenyl-2,3-dihydroisoxazole is subjected to halogen-lithium exchange reaction. The corresponding (2,3-dihydroisoxazol-4-yl)lithium reacts with three selected electrophiles to afford 4-substituted 2,3-dihydroisoxazoles in moderate yields.

Benzosiloxaboroles: Silicon Benzoxaborole Congeners with Improved Lewis Acidity, High Diol Affinity, and Potent Bioactivity

The synthesis and physicochemical properties of benzosiloxaboroles, the silicon analogues of an important class of heterocyclic compounds—benzoxaboroles—is presented. They were prepared by halogen–lithium exchange reactions of (2-bromophenyl)boronates with n-BuLi followed by the silylation or boronation of (2-lithiophenyl)dimethylsilanes. The cyclization of the resulting 2-(dimethylsilyl)phenylboronates apparently occurs through intramolecular dehydrogenative cyclization reaction in the presence of water. Unlike the case for benzosiloxaborole, the formation of its analogue containing a thiophene ring is thermodynamically unfavorable, which was confirmed by theoretical calculations. The presence of a B–O–Si linkage results in increased Lewis acidity with respect to the analogous benzoxaboroles. The acidity is strongly enhanced by fluorination or introduction of phenyl groups at the silicon atom. Selected compounds show good antifungal activity, and thus they are potential small-molecule therapeutic agents....

Synthesis, crystal structure, and application of an acenaphtho[1,2-k] fluoranthene diimide derivative

Organic electron acceptor materials play an important role in organic electronics. Recently, many organic electron acceptors have been developed, in which aromatic fused-imides have proved to be a promising family of excellent electron acceptors. We report the first synthesis of a novel aromatic fused-imide, acenaphtho[1, 2-k]fluoranthene diimide derivative (AFI), using lithium-halogen exchange and Diels-Alder reactions. The construction of a large conjugated plane and the introduction of electron-withdrawing imide groups endow AFI with a low lowest unoccupied molecular orbital (LUMO) level of −3.80 eV. AFI exhibits a regular molecular arrangement and strong π-π interactions in the single-crystal structure, which indicates its potential application in organic electronic devices. Solar cell devices that were fabricated using AFI as the electron acceptor and P3HT as the electron donor achieved an energy conversion efficiency of 0.33%.

Chloromethyllithium

Chloromethyllithium (LiCH2Cl) is a synthetically useful reagent belonging to the category of carbenoids, which are known to exhibit an ambiphilic behavior ranging from nucleophilic (at low temperatures) to electrophilic (at higher temperatures). This fact can be deduced by the resonance structures represented in Scheme [1], in which the extreme ionization of the polar bonds could lead, in principle, to the carbanionic (1a) or carbocationic (1b) species.[1] Chloromethyllithium can be prepared via a halogen–lithium exchange reaction on a given dihalomethane. Iodo- and bromo-chloromethane (ICH2Cl and BrCH2Cl) are the ideal precursors jointly with methyllithium–lithium bromide complex or n-butyllithium.[2] It is highly unstable except at very low temperatures (–78 °C or below); however, performing the reaction in the presence of the electrophile (i.e. Barbier-type conditions) allows to realize efficient processes. The presence of lithium halides and the use of ethereal-type solvents (THF or diethyl ether) had beneficial effects on its stability.[3]

Generation and Reactions of Heteroaromatic Lithium Compounds by Using In-Line Mixer in a Continuous Flow Microreactor System at Mild Conditions

A lithium–halogen exchange reaction procedure was applied to introduce electrophilic substituents to the heteroaromatics, which exhibited potential in the syntheses of pharmaceutical intermediates. In this contribution, generation and reactions of heteroaromatic lithium compounds were successfully accomplished at 10 °C in a continuous flow microreactor equipped with an in-line mixer. Extensive reaction results revealed that such a synthetic method was widely applicable for different kinds of heteroaromatics with various substituents. All results highlighted that the lithium–halogen exchange reaction for large-scale syntheses might be realized by microreactor systems.