Alkyl Mesylates Research Articles

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes.

Cross-electrophile coupling reactions involving direct C-O bond activation of unactivated alkyl sulfonates or C-F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickel-catalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoride-substituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C-F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C-O bond.

Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents.

Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.

Nickel-Catalyzed Cyanation of Unactivated Alkyl Sulfonates with Zn(CN)2.

Cyanation of unactivated primary and secondary alkyl mesylates with Zn(CN)2 catalyzed by nickel has been developed. The reaction provides an efficient route for the synthesis of alkyl nitriles with wide substrate scope, good functional group tolerance, and compatibility with heterocyclic compounds. Mechanistic studies indicate that alkyl iodide generated in situ serves as the reactive intermediate and the gradual release of alkyl iodide is crucial for the success of the reaction.

Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides

The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.

Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents.

The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.

Time-dependent selected reaction monitoring-based GC-MS/MS method for estimation of genotoxic impurities in new antibacterial agent: alalevonadifloxacin mesylate

Alalevonadifloxacin mesylate (ALA), pro-drug of levonadifloxacin is a new antibiotic approved in India to treat infections caused by Gram-positive bacteria. Alkyl mesylates (AMs) are known genotoxic impurities (GTI’s) formed in drug substances isolated as mesylate salts. Time-dependent selected reaction monitoring (t-SRM)-based gas chromatography tandem mass spectrometry (GC-MS/MS) method has been developed for trace estimation of AMs, namely, methyl methane sulfonate (MMS), ethyl methane sulfonate (EMS) and isopropyl methane sulfonate (IMS) in ALA. Liquid-liquid extraction (LLE) procedure using dichloromethane (DCM) as an extracting solvent was employed to extract AMs from the drug substance. Automatic selective reaction monitoring (auto-SRM) tool was applied to identify the most intense SRM pair of the ions to achieve the highest sensitivity. The method was validated in terms of specificity, linearity, sensitivity, precision, and accuracy. The limit of quantitation (LOQ) for the MMS, EMS and IMS were 5, 10, and 20 ng/g of ALA, respectively. For all analytes, the correlation coefficient (R) were greater than 0.9975 in the concentration range of 3.0–260 ng/mL. Mean recovery of all analytes was in the range of 91.77 to 97.65%.

Preparation of Enantioenriched Alkylcarbastannatranes via Nucleophilic Inversion of Alkyl Mesylates for Use in Stereospecific Cross-Coupling Reactions.

We report the preparation of enantioenriched secondary alkylcarbastannatranes via a stereoinvertive SN2 reaction of enantioenriched alkyl mesylates and carbastannatranyl anion equivalents. Using this process, enantioenriched secondary alcohols may be converted into highly enantioenriched alkylcarbastannatranes, which are useful in stereospecific cross-coupling reactions.

Remarkable Solvent Effects of Structurally Diverse Alcohols on Nucleophilic Displacement Reactions with Halide Ions

Solvent effects on nucleophilic displacement reactions of alkyl mesylates with halide ions were investigated in a series of protic alcohol solvents. In consideration of Hughes and Ingold's principle, the reaction rates were found to correlate well with the normalized solvent polarities () in all halide reactions.

Mechanism of nucleophilic fluorination promoted by bis‐tert‐alcohol‐functionalized crown‐6‐calix[4]arene

AbstractTheoretical calculations were performed to elucidate the ability of the recently reported bis‐tert‐alcohol‐functionalized crown‐6‐calix[4]arene (BACCA) molecule to promote nucleophilic fluorination of alkyl mesylates with cesium fluoride reagent. It was found that a similar structure, named BACCAt, can separate the cesium fluoride ion pair in tert‐butanol solution. This separation has a free energy cost, even considering the double hydrogen bonds with the fluoride ion. The solvent has an important effect on the stabilization of this complex, due to interaction with the high dipole moment of the separated ion pair. The observed rate acceleration effect involves a structure with double hydrogen bonds between the BACCAt and the centers of negative charges of the SN2 transition state. The predicted free energy barrier of 27.3 kcal mol−1 is in excellent agreement with the estimated experimental value of 26.2 kcal mol−1.

ChemInform Abstract: Catalytic Nucleophilic Fluorination by an Imidazolium Ionic Liquid Possessing Trialkylphosphine Oxide Functionality.

AbstractA series of different fluorine‐substituted compounds is synthesized by fluorination of primary alkyl mesylates using a new alkylmethylimidazolium ionic liquid as effective catalyst.

Catalytic nucleophilic fluorination by an imidazolium ionic liquid possessing trialkylphosphine oxide functionality

Abstract The synthesis of a new alkylmethylimidazolium ionic liquid wherein the alkyl group is functionalized with dihexylphosphine oxide moiety at the terminal position has been achieved in four steps from 1-methylimidazole. This hybrid ionic liquid effectively catalyzed the nucleophilic fluorination of primary alkyl mesylates under mild conditions using CsF as the fluoride source with a faster rate compared to butylmethylimidazolium mesylate. The hybrid catalyst was recycled 5 times without compromising the yield and purity of the product. The nucleophilic fluorination has been used for the synthesis of diethyl 2-(5-fluoropentyl)-2-methyl malonate, a precursor of 18F isotopomer of an apoptosis imaging agent and the protected form of O-(2′-fluoroethyl)- l -tyrosine, a 18F isotopomer of a tumor imaging agent.

A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system

Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalyzed, visible light-induced azide reduction reaction. In contrast with current azide reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates, and disulfides. The remarkable functional group compatibility and mild conditions of this reaction enabled azide reduction to be performed on nucleic acid and oligosaccharide substrates without the detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without loss of enzymatic activity, in contrast with two commonly used azide reduction methods. The visible light dependence of this reaction provides a means of photouncaging functional groups such as amines and carboxylates on biological macromolecules without using UV irradiation.

Greener fluorous chemistry: Convenient preparation of new types of ‘CF 3-rich’ secondary alkyl mesylates and their use for the synthesis of azides, amines, imidazoles and imidazolium salts

2,2,2-Trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and nonafluoro- tert-butyl alcohol were used as precursors for the preparation of the appropriate bis(polyfluoroalkoxymethyl)carbinols [(R FHOCH 2) 2CHOH, 1a– c, R FH = (a) CF 3CH 2, (b) (CF 3) 2CH, and (c) (CF 3) 3C] and the corresponding mesylates [(R FHOCH 2)CHOSO 2CH 3, 2a– c]. This novel design paradigm is introduced to eliminate the persistence and bioaccumulation problems of fluorous chemistry, which are associated with the use of longer linear perfluoroalkyl groups (e.g. R fn ≥ n-C 8F 17, n-C 7F 15). Secondary mesylates 2a, b and the primary tosylate [(CF 3) 3COCH 2CH 2OTs, 2d] displayed acceptable reactivity towards azide and imidazole nucleophiles to allow the syntheses of novel fluorous azides, which on hydrogenolysis with H 2/Pd-C offered fluorous amines [(R FHOCH 2) 2CHNH 2, 8a, b], and 1-(polyfluoroalkyl)imidazoles ( 5a, b, d), respectively, while 2c showed no reactivity due to steric hindrance. The reaction of 8a, b with formaline, glyoxal and hydrochloric acid gave symmetrical 1,3-dialkylated imidazolium chlorides ( 9a, b), while 5a, b, d were effectively alkylated using n-C 8F 17(CH 2) 3I, methyl iodide, 2-bromoethanol, and 2d to yield the corresponding 1,3-dialkylimidazolium iodides, bromides, and tosylates ( 7aa– ec). Some physical properties of new compounds including mp, bp and solubility patterns were also analyzed; and the fluorophilicity values of 1a– c, and 2a– c were experimentally determined by GC and/or 19F NMR spectroscopy.

ChemInform Abstract: Regioselective Synthesis of 3-O-Alkyl Ethers of Ascorbic Acid Without Protecting Groups in a Single Step.

Abstract The direct alkylation of l -ascorbic acid (vitamin C) with alkyl mesylates using sodium hydrogen carbonate as a base without protecting groups proceeds regioselectively and yields the corresponding 3-O-alkyl ethers of l -ascorbic acid exclusively.

Nickel-catalyzed, sodium iodide-promoted reductive dimerization of alkyl halides, alkyl pseudohalides, and allylic acetates

The first general method for the reductive dimerization of alkyl halides, alkyl mesylates, alkyl trifluoroacetates, and allylic acetates is reported which proceeds with low catalyst loading (0.5 to 5 mol%), generally high yields (80% ave yield), and good functional-group tolerance.

Synthesis and properties of glycerylimidazolium based ionic liquids: a promising class of task-specific ionic liquids

A series of task-specific ionic liquids (TSILs) based on glycerylimidazolium cations have been prepared by reaction of 1-chloropropanediol, a compound obtainable from glycerol (a widely available and in-expensive waste product), with the appropriate base (1-H-imidazole, 1,2-dimethylimidazole and 1-methyl-1-H-imidazole). The reaction of 3-(1H-imidazol-1-yl)propane-1,2-diol with chloroalkanes, bromoalkanes and alkyl mesylates gave the corresponding salts which were characterized. The possibility to use these ILs in palladium catalyzed reactions was evaluated, evidencing good catalyst stability and a high recyclability.

Polycyclic Aromatic Compounds‐Mediated Electrochemical Reduction of Alkyl Mesylates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Copper‐Catalyzed Cross‐Coupling Reaction of Grignard Reagents with Primary‐Alkyl Halides: Remarkable Effect of 1‐Phenylpropyne

A general get-together: The Cu-catalyzed cross-coupling reaction of primary-alkyl halides with primary-, secondary-, and tertiary-alkyl and phenyl Grignard reagents proceeds efficiently in THF under reflux in the presence of 1-phenylpropyne (see scheme). The reaction is also applicable to alkyl mesylates (OMs) and tosylates (OTs). The reactivities of alkylX with a Grignard reagent increase in the order X=Cl<F<OMs<OTs<Br. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603451_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Polycyclic Aromatic Compounds-mediated Electrochemical Reduction of Alkyl Mesylates

Abstract Electrochemical reduction of alkyl mesylates was successfully carried out by using an undivided cell equipped with a Pt cathode and an Mg anode in the presence of biphenyl and t-BuOH. The reaction could proceed efficiently under mild conditions to give the corresponding alkanes in moderate to good yields. This procedure could also be applicable to chemoselective reduction of mesylates having functional groups such as epoxide, olefin, acetal, hydroxy, or cyano groups.

Residues of genotoxic alkyl mesylates in mesylate salt drug substances: Real or imaginary problems?

Mesylate esters of short-chain ( n = 1–3) alcohols are reactive, direct-acting, genotoxic and possibly carcinogenic alkylating agents. Their chemical and biological properties appear to correlate well with Swain–Scott s constants; for example, high S N1 character (low s value) is associated with enhanced carcinogenic potential, but also a rapid hydrolysis rate. Concerns over the possible formation of such esters during the preparation of mesylate salt drug substances, by addition of methane sulfonic acid (MSA) to the free base dissolved in an alcoholic solvent, have led regulatory agencies to require applicants to demonstrate that the synthetic method employed does not lead to the presence of detectable levels of alkyl mesylates. Mechanistic considerations, relating mainly to the extremely low nucleophilicity of the mesylate anion, and experimental data, both indicate that alkyl mesylates should not be formed (except from MSA impurities) during mesylate salt synthesis. Mechanistic arguments also predict that residues of alkyl halides (possibly formed in the preparation of amine hydrochlorides or hydrobromides) could represent a similar or greater potential hazard than alkyl mesylates. The perceived risk of alkyl mesylate formation seems to rely on mistaken assumptions and so the concerns appear unjustified. Further reassurance could be achieved however by applying a variety of strategies during synthesis, including pH control, and use of high-purity MSA or of a non-hydroxylic reaction solvent.