N-alkylation Reaction Research Articles

Focus on Physico-Chemical Properties of Sulfoximines: Acidity, Basicity and Lipophilicity.

Despite the numerous published syntheses and applications of sulfoximines, very few studies describe their physico-chemical properties and in particular their acidic, basic and lipophilic or hydrophilic characters. We report for the first time the acidity values (pKa) of fluorinated sulfoximines in water and in acetonitrile, as well as the basicity (pKaH) measurements of fluorinated and non-fluorinated sulfoximines in acetonitrile. The same sulfoximine library was also studied in terms of lipophilicity with measurement of the Hansch parameters of the sulfoximine moieties. Finally, these new data allowed us to optimize the N-alkylation reaction of fluorinated sulfoximines.

Directed Design, Screening and Antiglycation Activity for 3-Substituted Thiazolium Derivatives, New Analogs of Alagebrium.

Preliminary abinitio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored invitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors. Potential mechanisms of actions are discussed therein. The compound 4-meth-yl-3-[2-(4-methylbiphenyl-4-yl)-2-oxoethyl] thiazolium bromide displayed high activity across all three assays, establishing it as a lead compound. The cytotoxicological properties of the compounds were evaluated using LDH and MTT assays. However, the lead compound exhibited cytotoxicity, indicating the need for additional investigations aimed at decreasing toxicity while maintaining activity. The targeted thiazolium salts were synthesized through an N-alkylation reaction between the corresponding thiazoles and phenacyl bromides.

Synthesis and structural analysis of 1,4′-pyrazolo[3,4-e][1,4]thiazepin-7′(6H)ones: An example of conformational chirality in seven-membered heterocycles

A series of five new N-alkylspiro[1,4]thiazepin-2-ones was obtained in good yields using a two-step synthesis strategy involving the preparation of the spirothiazepinone core, followed by the N-alkylation using alkyl halides in alkaline conditions. The latter N-alkylation reaction gave rise to conformational chirality, evidenced in NMR spectra, polarimetry, chiral HPLC, and X-ray diffraction analysis. X-ray studies revealed the presence of enantiomorphic boat-type conformers in centrosymmetric unit cells interacting by van der Waals forces, in contrast to a predominant conformer in solution supported by the chiral properties of the N-alkylated derivatives. The present work makes an important contribution to the study of the structural properties of 1,4-thiazepinone systems and the phenomenon of conformational chirality in seven-membered N-heterocycles.

Metal-Free Switchable Chemo- and Regioselective Alkylation of Oxindoles Using Secondary Alcohols.

In this study, we have disclosed N-alkylation and C-alkylation reactions of 2-oxindoles with secondary alcohols. Interestingly, these chemoselective reactions are tunable by changing the reaction conditions. Utilization of protic solvent and Brønsted acid catalyst afforded C-alkylation, whereas, aprotic solvent and Lewis acid catalyst afforded N-alkylation of 2-oxindoles in good to excellent yields. Regioselectivity is achieved by protecting the N-center of the oxindole and C5 alkylated product is furnished exclusively. This protocol is notable because it demonstrates functionalization at the C7 position of oxindole without the need for any directing group at the N-center. Further, a new protocol has been reported for C-H oxygenation at the benzylic position of one of the C5 alkylated derivative.

Silica supported Schiff-based palladium nanocatalyst for n-alkylation at room temperature

This works documents a new silica gel-supported nanocatalyst (Si@NSBPdNPs 3) with low Pd loadings for n-alkylation reactions at room temperature. Post synthesis characterisation using SEM-EDX and ICP techniques provided a quantitative assessment of palladium species. Additionally, TEM analysis unveiled an average palladium nanoparticle size of 5.87 ± 0.2 nm. In-depth X-ray Photoelectron Spectroscopy (XPS) analysis revealed its predominant composition as Pd(0) complexed to a Schiff base ligand on low cost silica matrix. The nanocatalyst exhibited high efficacy in the catalysis of n-alkylation (Michael addition) reactions with various α,β-unsaturated Michael acceptors, yielding the corresponding n-alkyl products at room temperature with exceptional yields. Notably, the catalyst exhibited good stability and could be easily separated from the reaction mixture. Moreover, the catalyst displayed recyclability potential, maintaining its original catalytic efficacy for up to seven cycles without any discernible loss.

Construction of Trisubstituted Hydrazones via Base-Mediated Cascade Condensation N-Alkylation.

A practical base-promoted tandem condensation N-alkylation reaction for the formation of trisubstituted hydrazones has been developed employing aldehydes and hydrazines with alkyl halides. Crucially, this reaction successfully overcomes chemoselectivity problems, allowing for the reaction of multiple components in a one-pot manner. Halo- and heterofunctional groups, as well as free hydroxyl and amino groups, are tolerated in this transformation to produce a wide range of trisubstituted hydrazones in good to excellent yields.

Design, synthesis, insilco study and biological evaluation of new isatin-sulfonamide derivatives by using mono amide linker as possible as histone deacetylase inhibitors.

Aim: To evaluate the cytotoxic activity of newly synthesized a series of novel HDAC inhibitors comprising sulfonamide as zinc binding group and Isatin derivatives as cap group joined by mono amide linker as required to act as HDAC inhibitors. Materials and Methods: The utilization of sulfonamide as zinc binding group joined by N-alkylation reaction with ethyl-bromo hexanoate as linker group that joined by amide reaction with Isatin derivatives as cap groups which known to possess antitumor activity in the designed of new histone deacetylase inhibitors and using the docking and MTT assay to evaluate the compounds. Results: Four compounds have been synthesized and characterized successfully by ART-FTIR, NMR and ESI-Ms. the compounds were synthesized and characterized by successfully by ART-FTIR, NMR and ESI- Ms. Assessed for their cytotoxic activity against human colon adenocarcinoma MCF-7 (IC50, I=105.15, II=60.00, III=54.11, IV=56.57, vorinostat=28.41) and hepatoblastoma HepG2 (IC50, I=63.91, II=135.18, III=118.85, IV=51.46, vorinostat=37.50). Most of them exhibited potent HDAC inhibitory activity and significant cytotoxicity. Conclusions: The synthesized compounds (I, II, III and IV) showed cytotoxicity toward MCF-7 and HepG2 cancer cell lines and their docking analysis provided a preliminary indication that they are viable [HDAC6] candidates.

Highly dispersed ruthenium capsulated in UiO-66-NH2 for hydrogen-borrowing-mediated N-alkylation reactions

Herein, atomically dispersed Ru sites are encapsulated within UiO-66–NH2 frameworks to serve as a highly active, selective, and stable catalyst for amine synthesis via N-alkylation reactions of o-phenylenediamine with monohydric alcohols.

Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction.

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α-aryl and α-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X-H (X=N, O, S et al.) and C-H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

A New Soluble Copper Phthalocyanine Derivative as a Smart Material

Copper phthalocyanine (CuPc) and its derivatives are considered as candidate materials in many applications. Particularly, easy and sensitive film-forming ability, commercial availability, chemical stability, and ease in tailoring its molecular structure make CuPc a versatile material. On the other hand, main challenge that Pcs often exhibit is their poor solubility in organic solvents. In this sense, this work involves designing of new CuPc derivatives by introducing suitable substitutions to improve the solubility in organic solvents. Specifically, [2,9,16,23-tetra{(4,5-Diphenyl-1H-imidazole)-2-yl-thio}phthalocyaninato-copper(II)] (1) and [2,9,16,23-tetra{(4,5-Diphenyl-1-methyl-1H-imidazole)-2-yl-thio}phthalocyaninato-copper(II)] (2) were prepared. The results show that compound 1 is soluble in tetrahydrofuran (THF), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and compound 2 is soluble in chloroform, acetone, methanol, THF, DMF, and DMSO. Optical and spectroscopic properties of the synthesized compounds were also investigated, and it was determined that the energy bang gaps of compounds 1 and 2 are 1.70 eV and 1.56 eV, respectively. Strikingly, we demonstrate that compound 1 is exhibiting a rapid and reversible color change behavior upon altering pH in the entire pH spectrum. As it is known, materials that respond reversibly to chemical and/or physical stimuli in a controllable fashion are regarded as smart materials. Hence, we report that compound 1 is actually a smart material that can be used as a simple yet efficient pH sensor.

Synthesis and antitumor activity of 1,3,4-oxadiazole substituted 2-(5-ylidene-2,4-dioxothiazolidin-3-yl)-acetamides

A series of novel 1,3,4-oxadiazole substituted 2-(5-aryl/heterylidene-2,4-dioxothiazolidine-3-ylidene)-acetamides and their 5-unsubstituted analogues have been synthesized following N-alkylation reaction of 2-chloro-N-(5-aryl-[1,3,4]oxadiazol-2-yl)-acetamides with thiazolidinedione and potassium salts of its arylidene derivatives. The structures of target compounds were confirmed by using 1H NMR spectroscopy and elemental analysis. Evaluation of anticancer activity in vitro for the synthesized compounds was performed in accordance with the National Cancer Institute protocol. A selective influence of some tested compounds against leukaemia MOLT-4 (3e, GP = 76.85%) and K-562 (3e, GP = 79.84%), colon cancer HCT-15 (3d, GP = 76.86%), renal cancer A498 (4a, GP = 74.37%), CAKI-1 (3d, GP = 68.49%) and UO-31 (3b-e, 4a-b, GP = 66.67 ÷ 86.30%) cell lines was established. Grafical abstract:

Catalytic Amination of Alcohols Using Diazo Compounds under Manganese Catalysis Through Hydrogenative N-Alkylation Reaction.

Sustainable chemical production requires fundamentally new types of catalysts and catalytic technologies. The development of coherent and robust catalytic systems based on earth-abundant transition metals is essential, but highly challenging. Herein, we systematically explored a general hydrogenative cleavage/N-alkylation tandem of cyclic and acyclic diazo (N=N) compounds to value-added amines under manganese catalysis. The reaction is catalyzed by a single-site molecular manganese complex and proceeds via tandem dehydrogenation, transfer hydrogenation, and borrowing hydrogenation strategies. Interestingly, the reaction involves abundantly available renewable feedstocks, such as alcohols, that can act as (transfer)hydrogenating and alkylating agents. The synthetic application of our approach in large-scale pharmaceutical synthesis and easy access to highly demanding N-CH3 /CD3 derivatives are also demonstrated. Kinetic studies show that the reaction rate depends on the concentration of alcohol and Mn-catalyst and follows fractional orders. Several selective bond activation/formation reactions occur sequentially via amine-amide metal-ligand cooperation.

Facile synthesis of quinolines and N-alkylation reactions catalyzed by ruthenium(II) pincer type complexes: Reaction mechanism and evidences for ruthenium hydride intermediate

Amines, N-heterocyclic compounds, and their derivatives are ubiquitous in all naturally occurring compounds, particularly alkaloids, and are widely used in pharmaceuticals, agrochemicals, lubricants, and surfactants. The design of pincer type ligands and corresponding metal complexes is a fundamental step with a unique reactivity. In this article, the NNN-pincer type of ruthenium complexes were synthesized and analyzed using a variety of spectroscopic techniques, including UV-Visible, infrared, and NMR. The molecular structures of the complexes were examined by X-ray crystallography. These complexes were also employed to activate carbon and nitrogen (C-N bond) bonds in C-N coupling processes. This paper describes the synthetic approach, product purification, and spectroscopic characterization, and nuclear magnetic resonance (NMR) spectroscopy was used to demonstrate the catalytically synthesized substrates. A total number of 16 quinolines and 22 N-alkylated substrates were synthesized and characterized by NMR spectroscopic technique.

A General Protocol for the Chemo- and Stereoselective Construction of α,β-Unsaturated γ-Amino Sulfonyl Fluorides

AbstractA general protocol for the simple, efficient, and mild synthesis of α,β-unsaturated γ-amino sulfonyl fluorides is developed via a base-catalyzed N-alkylation reaction of aromatic amines with (E)-3-bromoprop-1-ene-1-sulfonyl fluoride. This transformation exhibits excellent chemo- and stereoselectivity, mild conditions, broad functional group compatibility and operational simplicity, making it a potentially valuable procedure in medicinal chemistry, chemical biology, and drug discovery.

Design, Synthesis, and Anti-Cancer Activity Evaluation of a 3-methyleneisoindolin- 1-One Library.

Isoindolin-1-ones are medicinally privileged heterocyclic compounds. Due to the interesting biological activities exhibited by these compounds, several synthetic and medicinal research groups have developed numerous synthetic approaches for these compounds. We have also previously reported two efficient approaches for the synthesis of the isoindolin-1-ones through iodoaminocyclization of alkynyl amides using n-BuLi and phosphazene superbases. This study aimed to construct a medium-size library of multi-substituted 3- methyleneisoindolin-1-ones and study its biological profile, specifically anti-cancer activity. Solution phase parallel synthesis was performed for the synthesis of the 3- methyleneisoindolin-1-ones library through n-BuLi-mediated iodoaminocyclization of 2(1- Alkynyl)benzamides. The iodocyclized products were further derivatized through palladiumcatalyzed Sonogashira and Suzuki Miyaura couplings and N-alkylation reactions. In silico evaluation of the physicochemical and ADMET properties was performed to examine the drug-likeness of the library compounds. Selected isoindolin-1-one analogues were evaluated for in vitro antiproliferative activity in various human cancer cell lines (MCF-7, A-549, and U-373 MG). A library of 46 multisubstituted 3-methyleneisoindolin-1-ones has been synthesized. The iodo-isoindolin-1-ones were synthesized in 66-76% yields through n-BuLi-mediated iodoaminocyclization of 2(1-Alkynyl)benzamides. Further diversification afforded the diverse library members in yields of 40-96%. Two of the library compounds exhibited GI50 values of < 10 μM in the human breast cancer cell line (MCF-7). Isoindolin-1-one library was constructed through electrophilic cyclization. The diversification was successfully performed through various C-C and C-N bond formation reactions. The anti-proliferative activity of the library members appears to be arising from the interaction of the compounds with the protein kinase drug targets.

A new synthetic ultrasound-assisted method for dibenzoepines

In this study, we have developed a new ultrasonic synthesis method of dibenzoepines using olanzapine and quetiapine, which are well-known drugs for the treatment of schizophrenia and bipolar disorder. The method is based on the N-alkylation reaction of the piperazine fragment in tricyclic compounds with methyl iodide or 2-(2-chloroethoxy)ethanol as the alkylating agent, respectively. The synthesis reactions were carried out in an ultrasonic bath with solvents such as acetonitrile or dimethylformamide in the presence of potassium or sodium carbonate or sodium hydroxide and metal-free, ecological phase transfer catalyst at a temperature of 40–50 °C. This allowed us to obtain olanzapine in 1 h (Y = 67%), and quetiapine in 3 h (Y = 72%). An ultrasonic reactor (Qsonica Q700) was used in the synthesis of olanzapine and made it possible to shorten the reaction time to 10 min and obtain 90% yield with very high purity. The developed method allows obtaining compounds in mild conditions and in a short time, thanks to which the process is more ecological than others described in the literature.

Design, synthesis, biological evaluation on immune cell proliferation, crystal structures, spectroscopic characterizations, DFT calculations, ADME analysis, and molecular docking studies with COX of novel tetrazole-Galactopyranosyl analogues

The new 5-(substituted)-3-(1,2,3,4-di-O-isopropylidene-(D)-galactopyranose) tetrazoles(1c-8c) have been achieved by using as starting materials substituted tetrazole (1b-8b) and 1,2,3,4-di-O-isopropylidene-6-O-p-tolylsulfonyl-alpha-D-galactose (A) via N-alkylation reactions under phase transfer catalysis (PTC) conditions. All the obtained compounds were characterized by nuclear magnetic resonance spectroscopy. The molecular and crystal structures of two compounds (5b and 5c) were examined by single crystal X-ray crystallography. The Density Functional Theory estimations for compound 5c at the DFT/B3LYP level via 6-31+G(d, p) replicate the structure and geometry. Finally, HOMO and LUMO analysis was used for the charge transfer interface of the structure. Against Cytochrome c Peroxidase (2 × 08), the compounds 3c and 7c interacted with the least binding energy of -9.73kcal/mol and -9.13kcal/mol along with the inhibition constant of 74.23nM and 204.28nM, respectively. All the synthesized compounds showed the excellent anticancer activity and have potential to be used as immunomodulatory agents. The compounds 1c, 3c, 4c, 5c, 6c, 7c and 8c caused an immunostimulatory effect, while compound 2c showed an immuno inhibitory effect.

A new way of synthesizing heterocyclic primary sulfonamide probes for carbonic anhydrase

An N,N-bis(p-methoxybenzyl)-protected α-acetyl-α-diazo-methane sulfonamide proved to be a useful building block for accessing new 5-methyl-1,2,3-thiadiazole-4-sulfonamide as well as methyl 3-sulfamoyl-1H-pyrazole-5-carboxylate. The latter was further subjected to N-alkylation and N-arylation reactions. All resulting compounds showed potent inhibition of I, II and particularly of cancer-related IX and XII isoforms of human carbonic anhydrase.

N-Alkylation of Amines by C1-C10 Aliphatic Alcohols Using A Well-Defined Ru(II)-Catalyst. A Metal-Ligand Cooperative Approach.

A Ru(II)-catalyzed efficient and selective N-alkylation of amines by C1-C10 aliphatic alcohols is reported. The catalyst [Ru(L1a)(PPh3)Cl2] (1a) bearing a tridentate redox-active azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L1a) is air-stable, easy to prepare, and showed wide functional group tolerance requiring only 1.0 mol % (for N-methylation and N-ethylation) and 0.1 mol % of catalyst loading for N-alkylation with C3-C10 alcohols. A wide array of N-methylated, N-ethylated, and N-alkylated amines were prepared in moderate to good yields via direct coupling of amines and alcohols. 1a efficiently catalyzes the N-alkylation of diamines selectively. It is even suitable for synthesizing N-alkylated diamines using (aliphatic) diols producing the tumor-active drug molecule MSX-122 in moderate yield. 1a showed excellent chemo-selectivity during the N-alkylation using oleyl alcohol and monoterpenoid β-citronellol. Control experiments and mechanistic investigations revealed that the 1a-catalyzed N-alkylation reactions proceed via a borrowing hydrogen transfer pathway where the hydrogen removed from the alcohol during the dehydrogenation step is stored in the ligand backbone of 1a, which in the subsequent steps transferred to the in situ formed imine intermediate to produce the N-alkylated amines.

2-(3-Bromophenyl)imidazo[2,1-b]oxazole

The microwave-assisted reaction of 2-nitroimidazole with 3-bromophenacyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent afforded 2-(3-bromophenyl)imidazo[2,1-b]oxazole. The formation of this compound was explained via a domino mechanism comprising an initial N-alkylation reaction of the imidazole substrate, followed by the base-promoted deprotonation of the position adjacent to the carbonyl to give an enolate anion that finally cyclizes via an intramolecular SNAr reaction, with the loss of the nitro group as potassium nitrite. Then, the proposed 1-(3-bromophenacyl)-2-nitroimidazole intermediate could be isolated by reducing the reaction time and was shown to be a precursor of the imidazo[2,1-b]oxazole final product.