Methylene Reagents Research Articles

Selective N‐Monomethylation of Anilines with Methanol Catalyzed by Commercial Pd/C as an Efficient and Reusable Catalyst

AbstractN‐methylation of amines is one of the most important C−N bond‐forming reactions and is widely utilized for the synthesis of numerous agrochemicals, drugs, natural products, and dyes. In this paper, the N‐monomethylation of aniline derivatives using Pd/C catalyst and methanol as the methylation reagent was investigated. The N‐monomethylation of various anilines was achieved with high activity and selectivity under relatively mild reaction conditions, and the yield of N‐monomethyl anilines was over 90 %. Notably, the commercial, readily available, and inexpensive heterogeneous catalyst, Pd/C, could be easily recovered and reused more than five times with only a slight decrease in activity; gram‐scale experiments were also successfully performed.

Nickel‐Catalyzed Ortho C–H Methylation of Aromatic Amides with Di‐tert‐butyl Peroxide as Methylation Reagent

A new efficient protocol for the ortho‐methylation of benzamides with DTBP has been developed via Ni(II)‐catalyzed C–H activation directed by 8‐aminoquinoline. This method is performed under base‐free, ligand‐free conditions and utilizes cheap and commercially available reagents. Moreover, the by‐product acetone derived from DTBP does not affect the purification of the product.

Modular Dual-Tasked C-H Methylation via the Catellani Strategy.

We report a dual-tasked methylation that is based on cooperative palladium/norbornene catalysis. Readily available (hetero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and methylating reagent, respectively. Six types of "ipso" terminations can modularly couple with this "ortho" C-H methylation to constitute a versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-labeled methylation by switching to the corresponding reagents CD3OTs or 13CH3OTs. Moreover, this toolbox can be applied to late-stage modification of biorelevant substrates with complete stereoretention. We believe these salient and practical features of our dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.

Novel Pyrano[2,3‐d]thiazole and Thiazolo[4,5‐b]pyridine Derivatives: One‐pot Three‐component Synthesis and Biological Evaluation as Anticancer Agents, c‐Met, and Pim‐1 Kinase Inhibitors

AbstractPreparation of pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives through multicomponent reactions (MCRs) was achieved by the reaction of 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)thiazol‐4(5H)‐one with various active methylene reagents such as ethyl cyanoacetate or malononitrile in basic conditions containing diverse aromatic aldehyde. Furthermore, this study aims to evaluate the in vitro cytotoxic activity of the synthetic compounds against six cancer cell lines, and all the prepared compounds revealed valuable activity compared with the CHS‐828, which is the 2‐[6‐(4‐chlorophenoxy)hexyl]‐1‐cyano‐3‐pyridin‐4‐ylguanidine as the standard drug. Some of the pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives showed the highest antitumor activity towards the six cancer cell lines. Moreover, (c‐Met) enzymatic activity of the most potent compounds showed that compounds 3b 2‐(2‐amino‐4,5,6,7 tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐(2‐hydroxy‐phenyl)‐7H‐pyrano[2,3‐d]thiazole‐6 carbonitrile and 5e 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐phenyl‐4,7‐dihydrothiazolo[4,5‐b]pyridine‐6‐carbonitrile were with higher activities than foretinib. Three compounds were selected to examine their Pim‐1 kinase where compounds 3b and 7b showed the highest inhibitions.

Glycerol: A Promising Benign Solvent for Catalyst‐free One‐pot Multi‐component Synthesis of 1H‐Pyrozolo[1,2‐b]phthalazine‐5,10‐diones and 2H‐Indazolo[2,1‐b]phthalazine‐triones Under Controlled Microwaves Irradiation

A simple green and efficient one‐pot multi‐component synthesis of 1H‐pyrozolo[1,2‐b]phthalazine‐5,10‐diones and 2H‐indazolo[2,1‐b]phthalazine‐triones has been developed utilizing one‐pot multi‐component reaction of aromatic aldehydes, active methylene reagents, phthalic anhydride, and hydrazine hydrate or alternatively phthalhydrazide in glycerol without catalyst under controlled microwave heating. The current synthetic protocol offers several advantages such as excellent yields, high EcoScale and atom economy, simple working up reactants and products, and the absence of hazardous catalysts or solvents.

Polycyclic Aromatic Heterocycles with a Benzo[c][1,2]azaborinine Core

2‐Formylphenylboronic acid condenses with active methylene reagents like α‐amino esters, ketones, and lactams directly to give benzo‐fused 1‐hydroxy‐2,1‐azaborines in good yields within minutes under microwave‐accelerated conditions. The new stable boron heterocycles prepared to demonstrate this approach were characterized by NMR spectroscopy. Three members of a new diboron heteropentacyclic ring system, 5a,12a‐diaza‐5,12‐dibora‐5,12‐dihydroxypentacene‐6,13‐dione, were prepared, and one of these highly fluorescent compounds was characterized by X‐ray crystallography. Some key solid‐state structural features revealed by the X‐ray analysis provide a basis for explaining the limited solubility of these pentaheterocycles in common organic solvents.

The Cascade Methylation/Cyclization of ortho‐Cyanoarylacrylamides with Dicumyl Peroxide

A radical cascade methylation/cyclization of ortho‐cyanoarylacrylamides was developed by utilizing dicumyl peroxide as a methylation reagent. This transformation provides a simple and straightforward approach to methylated quinoline‐2,4(1H,3H)‐diones, and exhibits a wide substrate scope. Furthermore, this reaction could be readily scaled up. A possible mechanism is also proposed.

Methyl Trifluoroacetate as a Methylation Reagent for N−H, O−H, and S−H Functionalities under Mild Conditions

AbstractA methylation reagent for compounds bearing N−H, O−H, and S−H functionalities was developed. Methyl trifluoroacetate (MTFA) was commonly considered as trifluoroacetylating reagent or trifluoromethylating reagent. In this work, we report the methylation behavior of MTFA under mild conditions with good functional group tolerance, allowing the transformation of a wide range of substrates, including N,H‐heteroaromatic compounds, phenolic compounds, carboxylic acids, thiophenols, secondary amides and imides, in high yields. This method was preliminarily applied to the chemoselective methylation of bifunctionalized secondary amide.

Palladium-Catalyzed ortho-C-H Methylation of Benzoic Acids.

A palladium-catalyzed methylation of C-H bonds of benzoic acids with di-tert-butyl peroxide as the methylating reagent under an external oxidant and ligand-free conditions has been achieved. The reaction is found to be directed by a weakly coordinating carboxyl group, offering a facile route for the synthesis of highly functionalized ortho-methyl benzoic acids.

Ruthenium(II)‐Catalyzed β‐Methylation of Alcohols using Methanol as C1 Source

AbstractSelective introduction of methyl branches into the carbon chains of alcohols can be achieved with low loadings of ruthenium precatalyst [RuH(CO)(BH4)(HN(C2H4PPh2)2)] (Ru‐MACHO‐BH) using methanol both as methylating reagent and as reaction medium. A wide range of structurally divers alcohols was β‐methylated with excellent selectivity (>99 %) in fair to high yields (up to 94 %) under standard conditions, and turnover numbers up to 18,000 could be established. The overall reaction rate of the complex catalytic network appears to be governed by interconnection of the individual subcycles through availability of the reactive intermediates. The synthetic procedure opens pathways to important structural motifs following the Green Chemistry principles.

Synthesis of 2-Substituted Propenes by Bidentate Phosphine-Assisted Methylenation of Acyl Fluorides and Acyl Chlorides with AlMe3.

Bidentate phosphine-assisted methylenation of acyl fluorides and acyl chlorides with substituted with aryl, alkenyl, and alkyl groups trimethylaluminum afforded an array of 2-substituted propene derivatives. The addition of a catalytic amount of DPPM increased an efficiency of the reactions. Trimethylaluminum as the methylenation reagent not only eliminates the presynthesis of methylene transfer reagent, but provides an efficient method for the synthesis of a series of 2-substituted propenes.

Iridium-Catalyzed α-Methylation of α-Aryl Esters Using Methanol as the C1 Source.

IrCl(cod)2]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient. By applying the reaction system, the synthesis method of naproxen was provided.

(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl pyrrolidine-1-carbodithioate as a novel, highly selective and sensitive ligand for determination of copper in water and food samples by dispersive liquid–liquid microextraction coupled with microvolume UV–Vis spectrophotometry

In this research, a fast, simple, selective, and sensitive spectrophotometric method based on dispersive liquid–liquid microextraction (DLLME) was developed for the ultratrace determination of copper(II) using newly synthesized chromogenic reagent (4-hydroxy-2-oxo-2H-chromen-3-yl)methyl pyrrolidine-1-carbodithioate (HCDTC). The affecting factors in complexation and microextraction steps were investigated and optimized. HCDTC forms highly sensitive yellow-colored complex with copper(II) (1:4 [copper(II): ligand]) in the wide pH range which shows maximum absorbance at 445 nm. In direct determination, Beer’s law was obeyed in the concentration range from 0.1 to 5.0 mg L−1. Molar absorptivity and Sandell’s sensitivity values for Cu(II)–HCDTC complex were 1.3 × 104 and 0.0047 µg cm−2, respectively. However, by applying DLLME, a detection limit as low as 0.3 µg L−1 with preconcentration factor of 92 and relative standard deviation (n = 6) less than 3.5% were achieved. Moreover, calibration graph was linear in the range of 1.0–200 µg L−1. Finally, the proposed method was successfully applied for preconcentration and determination of the Cu(II) in some water and fruit juice samples, and satisfactory results were obtained. Accuracy and reliability of the method were also verified by GF-AAS.

Regiospecific methylation of all the hydroxyls in (+)-catechin by a stepwise differentiation strategy.

Methylated derivatives of catechins have received great attention for health beneficial effects, especially antiallergic activity. However, the scarce natural abundance of methylated catechins limits further bioactive studies. The objective of this work was to investigate regiospecific methylation of the hydroxyls of (+)-catechin through a stepwise differentiation strategy based on electronic difference between the hydroxyl groups. Selective methylation of the hydroxyls on different rings was realized by employing Meerwein salt as the methylation reagent. Preferential acylation of the phenolic hydroxyls on A and B rings allowed selective exposure of the aliphatic hydroxyl on C ring to methylation. The vicinal phenolic hydroxyls on B ring were preferentially methylated under mild basic condition due to the acidic properties. Methylation of the phenolic hydroxyls on A ring was achieved by sequential protection and deprotection operations. Finally, antioxidant activities of all the individual methylated (+)-catechins were explored by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay. Regiospecific methylation of the phenolic and aliphatic hydroxyls was systematically achieved under mild conditions. Preparation of all the individual methylated (+)-catechins was accomplished with a greener methylation reagent: nonvolatile Meerwein salt. This work laid a solid foundation for preparation of diverse O-methylated catechins for bioactivity studies. © 2019 Society of Chemical Industry.

Aryl Methyl Sulfone Construction from Eco-Friendly Inorganic Sulfur Dioxide and Methyl Reagents.

A three-component cross-coupling protocol of boronic acid, sodium metabisulfite, and dimethyl carbonate was developed for the construction of significant functional methyl sulfones, in which introduction of sulfur dioxide at the last stage was successfully achieved in one step. Inorganic sodium metabisulfite was used as an eco-friendly sulfur dioxide source. Green dimethyl carbonate was employed as methyl reagent in this transformation. Diverse functional methyl sulfones were obtained from various readily available boronic acids. Notably, the last-stage modification of pharmaceuticals and the synthesis of Firocoxib were efficiently established through this strategy.

Trimethyl orthoacetate as a convenient reagent for selective methylation of β-OH groups of (poly)hydroxynaphthazarins

Trimethyl orthoacetate was found to be a convenient reagent for methylation of the β-OH groups of (poly)hydroxynaphthazarins. The substrates bearing one β-OH group react with MeC(OMe)3 to give the corresponding methoxy derivatives in 79–89% yields. Depending on the reaction conditions, methylation of substrates with two β-OH groups on the different and the same rings affords either the corresponding mono-O-methylated (43–70%) or di-Omethylated (71–78%) derivatives. Trimethyl orthoacetate offers a good alternative to CH2N2 in the preparative synthesis of O-methylated (poly)hydroxynaphthazarin derivatives.

Transition metal-free α-methylation of 1,8-naphthyridine derivatives using DMSO as methylation reagent.

A practical approach to the direct α-methylation of 1,8-naphthyridines under mild reaction conditions has been developed using simple and readily available DMSO as a convenient and environmentally friendly carbon source. This method is transition metal-free and highly chemoselective, shows good functional group tolerance, and uses DMSO as a methyl source, providing efficient and rapid access to an important compound class, 2-methyl-1,8-naphthyridines.

N-Methylation of ortho-substituted aromatic amines with methanol catalyzed by 2-arylbenzo[d]oxazole NHC-Ir(iii) complexes.

Seven new chelated cyclometalated Ir complexes of ABON,P, ABON,O, and ABON,C(carbene) based on a rigid and tunable 2-arylbenzo[d]oxazole backbone have been prepared for the N-methylation of amines. Among these three coordinated modes, ABON,C(carbene)-chelated iridium-based catalysts exhibited good performance in the monomethylation of aromatic amines with methanol (MeOH) as the green methylation reagent. The steric-modified synthesis of ABON,C(carbene) complexes was described. The most active ABON,C(carbene) complex with marginal steric hindrance as a catalyst was obtained from the benzoxazole ring without a substituent and methyl group of the benzimidazole ring on the N-heterocyclic carbene (NHC) ligand. A variety of amines including para- and meta-substituted aromatic amines, as well as heterocyclic amines, were formulated as suitable substrates. Importantly, this catalyst considerably promoted the yield of the N-methylation of ortho-substituted aromatic amines. Controlled kinetic experiments and deuterium-labeling reactions of these ortho-substituted amines were conducted under optimized conditions. On the basis of the experimental results, a plausible mechanism was proposed.

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides took place in good yields to give products exclusively with cis-β,γ-olefinic bond.

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents.

Methylation is a well-known structural modification in organic and medicinal chemistry. This review summarizes recent advances in methylation by categorizing specific methylation reagents. The challenges of mono N-methylation of aliphatic amines and N-methylation of peptides are discussed. This review will be useful for chemists wanting to select the appropriate reagents for methylation chemistry. Based on the large diversity of methylation reagents and their wide scope, this review also broadens perspectives on which strategies to select for utilizing a particular methylation, resulting in an increased flexibility in synthetic route planning.