Cyclic Secondary Amines Research Articles

New Fluorine-Containing Derivatives of 4-Anilino-2-(methylsulfanyl)quinazolines

A number of new 4-anilinoquinazolines were synthesized starting from 6,7,8-trifluoro-2-(methyl­sulfanyl)quinazolin-4(3H)-one. Reactions of the title compounds with cyclic secondary amines involved substitu­tion of the 7-fluorine atom with retention of the methylsulfanyl group on C2. 6,7,8-Trifluoro-4-(2-me­thoxyanilno)-2-(methylsulfanyl)quinazoline showed in vitro tuberculostatic activity with a minimum inhibitory concentration of 1.5 μg/mL.

Description of the thermodynamic properties and fluid‐phase behavior of aqueous solutions of linear, branched, and cyclic amines

AbstractThe SAFT‐γ Mie group‐contribution equation of state is used to represent the fluid‐phase behavior of aqueous solutions of a variety of linear, branched, and cyclic amines. New group interactions are developed in order to model the mixtures of interest, including the like and unlike interactions between alkyl primary, secondary, and tertiary amine groups (NH2, NH, N), cyclic secondary and tertiary amine groups (cNH, cN), and cyclic methine‐amine groups (cCHNH, cCHN) with water (H2O). The group‐interaction parameters are estimated from appropriate experimental thermodynamic data for pure amines and selected mixtures. By taking advantage of the group‐contribution nature of the method, one can describe the fluid‐phase behavior of mixtures of molecules comprising those groups over broad ranges of temperature, pressure, and composition. A number of aqueous solutions of amines are studied including linear, branched aliphatic, and cyclic amines. Liquid–liquid equilibria (LLE) bounded by lower critical solution temperatures (LCSTs) have been reported experimentally and are reproduced here with the SAFT‐γ Mie approach. The main feature of the approach is the ability not only to represent accurately the experimental data employed in the parameter estimation, but also to predict the vapor–liquid, liquid–liquid, and vapor–liquid–liquid equilibria, and LCSTs with the same set of parameters. Pure compound and binary phase diagrams of diverse types of amines and their aqueous solutions are assessed in order to demonstrate the main features of the thermodynamic and fluid‐phase behavior.

Redox-neutral functionalization of α-Csp3–H bonds of secondary cyclic amines: a highly atom-economical strategy forN-arylation/formal cross-dehydrogenative couplings

An efficient redox-neutral method has been developed for α-Csp3–H functionalization of secondary cyclic aminesviaconcurrentN-arylation/formal cross dehydrogenation coupling (CDC) with sp2-C–H and sp3-C–H bonds of arenes and ketones, respectively.

DMF·HCl as a versatile and straightforward N- and O-formylating agent

Inspired by the serendipitous isolation of N-formylpiperazines when we attempted the synthesis of a series of piperazines, we have developed a straightforward methodology for the N- and O- formylation of secondary cyclic amines, anilines and steroids, respectively. Such approach is based on the hitherto non-reported use of DMF·HCl complex, as a versatile and easily-available formylating system that can be stored without apparent loss of activity.

TiO2-SO42−: A recyclable heterogeneous catalyst for the microwave-mediated synthesis of benzylamino coumarin derivatives in water

Abstract A new and environmentally benign protocol was developed for the synthesis of a series of benzylamino coumarin derivatives via the multicomponent reactions of 4-hydroxycoumarin, aromatic aldehyde and cyclic secondary amine in water using sulfated titania (TiO2-SO42−) as a heterogeneous solid acid catalyst under microwave irradiation at 100 °C. The proposed method is advantageous due to its simple reaction procedure, high yield, easy work-up, short reaction time, and reusability of sulfated titania (TiO2-SO42−) and its high adaptability for the synthesis of benzylamino coumarin derivatives in good to excellent yields. The catalyst can be easily recovered and reused with almost the same catalytic activity. The structure of the benzylamino coumarin derivatives was confirmed by melting points, elemental analysis, IR, 1H, and 13C NMR and 2D NMR spectral data. Higher catalytic activity of sulfated titania (TiO2-SO42−) is due to its increased Bronsted acidity.

Three-Component Reaction of Dimethyl Malonate with α,β-Acetylenic Aldehydes and Amines. Synthesis of Push–Pull Buta-1,3-dienes

Three-component reaction of dimethyl malonate with α,β-acetylenic aldehydes and cyclic secondary amines (pyrrolidine, piperidine, morpholine, and piperazine) under mild conditions afforded dimethyl 2-(3-aminoprop-2-en-1-ylidene)malonates in 50–91% yields. The products were formed preferentially as E isomers, and the described reaction provides a convenient method for the synthesis of push–pull buta-1,3-dienes that are interesting as fluorescent, solvatochromic, and nonlinear optical materials and starting compounds in the synthesis of carbo- and heterocycles. A plausible reaction mechanism involves Knoevenage condensation of dimethyl malonate with α,β-acetylenic aldehyde to give dimethyl 2-(prop-2-yn-1-ylidene)malonate and subsequent nucleophilic addition of cyclic amine to the latter.

Synthesis and structure of new 2,4-dicyano-6-oxo-3-phenylbicyclo[3.2.1]octane-2,4-dicarboxylates

The sequential reaction of furfural with cyclic secondary amines and further with benzaldehyde and cyanoacetates affords new 2,4-dicyano-8-(R2N)-6-oxo-3-phenylbicyclo[3.2.1]-octane-2,4-dicarboxylates as rac-(1R,2R,3R,4S,5S,8R)-diastereomers. The structures of the reaction products were determined by X-ray diffraction.

CuI/2-Aminopyridine 1-Oxide Catalyzed Amination of Aryl Chlorides with Aliphatic Amines.

A class of 2-aminopyridine 1-oxides are discovered to be effective ligands for the Cu-catalyzed amination of less reactive (hetero)aryl chlorides. A wide range of functionalized (hetero)aryl chlorides reacted with various aliphatic amines to afford the desired products in good to excellent yields under the catalyst of CuI/2-aminopyridine 1-oxides. Furthermore, the catalyst system worked well for the coupling of cyclic secondary amines and N-methyl benzylamine with (hetero)aryl chlorides.

Iodine mediated direct coupling of benzylic alcohols with dithiocarbamate anions: An easy access of S-benzyl dithiocarbamate esters under neat reaction condition

An efficient, metal and solvent free synthesis of S-benzylic dithiocarbamate esters has been demonstrated via the iodine mediated direct C-S coupling of benzylic alcohols with dithiocarbamate anions generated in-situ by the reactions of amines and carbon disulphide. All the reactions were very fast (15–30 min) and performed under open air atmosphere. Cyclic and acyclic secondary amines, primary amine, aromatic amine actively participated in the one-pot coupling reactions with different benzylic alcohols. Non benzylic alcohols offer the synthesis of O-thiocarbamate compounds under the identical reaction condition.

3-Hetarylisocoumarins in the synthesis of 1-functionalized 3-hetarylisoquinolines

A convenient method was developed for the synthesis of novel isoquinolin-1(2H)-ones, 1-chloroisoquinolines, and 1-aminoisoquinolines with a heterocyclic substituent in position 3 via a recyclization of 3-hetarylisocoumarins with (NH4)2CO3. 1-Aminoisoquinolines were efficiently obtained from corresponding 1-chloro-3-hetarylisoquinolines (obtained by interaction of isoquinolin-1(2H)-ones with POCl3) and cyclic secondary amines (morpholine or 1-methylpiperazine). Literature data and preliminary results of biological assays allow to consider 1-amino-3-hetarylisoquinolines a promising family of anticancer compounds.

Using the Competing Enantioselective Conversion Method to Assign the Absolute Configuration of Cyclic Amines with Bode's Acylation Reagents.

The competing enantioselective conversion (CEC) method is a quick and reliable means to determine absolute configuration. Previously, Bode's chiral acylated hydroxamic acids were used to determine the stereochemistry of primary amines, as well as cyclic and acyclic secondary amines. The enantioselective acylation has been evaluated for 4-, 5-, and 6-membered cyclic secondary amines, including medicinally relevant compounds. The limitations of the method were studied through computational analysis and experimental results. Piperidines with substituents at the 2-position did not behave well unless the axial conformer was energetically accessible, which is consistent with the transition state geometries proposed by Bode and Kozlowski. Control experiments were performed to investigate the cause of degrading selectivity under the CEC reaction conditions. The present study expands the scope of the CEC method for secondary amines and provides a better understanding of the reaction profile.

Catalyst-Free Synthesis of Chromane-Type N,O-Acetals via Intramolecular Addition of Phenols to Enamines

A new strategy to 2-aminochromanes through catalyst-free cascade reaction of 3-trifluoroacetyl-4H-chromenes and 4H-chromene-3-carbaldehydes with cyclic secondary amines is presented. The reaction proceeds through subsequent 1,4- and 1,2-additions of amine, bimolecular elimination of trifluoroacetamide or formamide, and 6-exo-trig cyclization. The latter stage is a very rare example of addition of phenols to enamines. The obtained semicyclic N,O-acetals were applied as useful precursors for the synthesis of other chromanes.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel C (7) Modified Analogues of Chrysin

Background:: Most of the currently available pharmaceutical drugs are either natural products or analogues of natural products. Flavonoids are plant based natural polyphenolic compounds which exhibit a wide range of biological activities. Chrysin, a natural flavone, exhibits several biological activities like antiallergic, anti-inflammatory and anticancer. Many efforts were made to enhance the biological activity of chrysin. In continuation of our work on synthetic modifications of chrysin, amino-alcohol containing heterocyclic moiety is linked to chrysin at C (7) position to enhance its biological activity. Methods:: A series of new C (7) modified analogues of chrysin (3a-k) have been designed and synthesized in two steps. Chrysin, on reacting with epichlorohydrin in the presence of K2CO3 in DMF gave epoxide (2) which was made to react with cyclic secondary amines in the presence of LiBr to form the designed products (3a-k). All the synthesized compounds (3a-k) were well characterized by 1H NMR, 13C NMR and mass spectral data. The synthesized analogues (3a-k) were screened for their in vitro biological activities against a panel of bacterial and fungal strains. Molecular docking studies were also performed on these compounds with E. coli FabH (1HNJ) and S. cerevisiae (5EQB) enzymes, to support the observed biological activities. Results:: A series of new 2-hydroxy 3-amino chrysin derivatives (3a-k) were synthesized in two steps, starting with chrysin and their structures were characterized by spectral analysis. In vitro biological activities of these analogues against a panel of bacterial and fungal strains indicated that some of the derivatives manifested significant activities compared to standard drugs. Molecular docking and binding energy values were also correlated with experimental antimicrobial screening results. Lipinski’s “rule of five” is also obeyed by these analogues (3a-k) and exhibit drug-likeness. Conclusion:: In the present study, a series of new C (7) modified chrysin analogues (3a-k) were synthesized and tested for their in vitro antimicrobial activities. These biological studies indicated that some of the derivatives exhibited moderate to good antimicrobial activities compared to standard drugs. Molecular docking studies performed on these compounds correlated with the experimental antimicrobial activities. The results obtained in the study will be useful in establishing new drug entities to control the pathogenic epidemics.

α-amination reaction of different ketones mediated by carbohydrate Cu2+ complexes

The α-amination reaction of ketones was studied and the reaction conditions were analysed by green metrics. Propiophenone and two aliphatic ketones, saturated cyclic and acyclic secondary amines were used, carbohydrate Cu2+ complexes were the catalysts to obtain the brominate intermediates. Traditional stirring and ultrasound methods were compared. The use of α-CDCuBr2 complex in the presence of propiophenone, morpholine and O2 was the best condition to carry out the α-amination reaction using a One Pot synthesis, with an 80 % yield of product isolated and no by-product was detected.

A Simple Protocol for the Stereoselective Construction of Enaminyl Sulfonyl Fluorides.

A clickable connective hub 1-bromo-2-triazolethane-1-sulfonyl fluoride BTESF (1) was developed and successfully applied for the fluorosulfonylvinylation of a host of primary and secondary cyclic or acyclic amines including amino acids and pharmaceuticals. Further antimicrobial experiments revealed that vinyl sulfonyl fluoride functionalized norfloxacin (3ak), ciprofloxacin (3am), and lomefloxacin (3an) exhibited 4-fold improved antimicrobial activity against Gram-positive bacteria compared to their parent drugs.

Tertiary Amine Synthesis by Radical Carbonyl Alkylative Amination

Highly efficient access to structurally diverse branched tertiary amines is a long-standing challenge in synthetic chemistry. In a recent paper published in Nature, Gaunt and co-workers disclose a practical strategy for the construction of synthetically intractable tertiary amines through visible-light-mediated radical carbonyl alkylative amination of aldehydes, amines, and alkyl halides.

Systematic Investigation of the Scope of Transannular C-H Heteroarylation of Cyclic Secondary Amines for Synthetic Application in Medicinal Chemistry.

Transannular C-H heteroarylation of amines provides rapid access to complex scaffolds that are otherwise difficult to synthesize. Wide adaptation of this emerging reaction for medicinal chemistry requires a broad understanding of substrate scope and more robust experimental conditions. In this article, we report a new ligand to promote the transannular reaction of a range of fused- and bridged-bicyclic secondary amines with a broad set of heteroarenes. The method was also successfully applied to the arylation of one spiro-bicyclic amine, a class of substrates that has not been studied in the context of transannular C-H activation reactions. The broad application of this transannular C-H heteroarylation methodology is currently hampered by the difficulty of removing the directing group. The development of a new directing group that is easier to remove will expand the utility of this reaction.

Structure-reactivity relationships on Michael additions of secondary cyclic amines with 3-cyanomethylidene-2-oxindoline derivatives

A kinetic study of the nucleophilic addition reactions of 3-cyanomethylidene-2-oxindoline derivatives with cyclic amines (namely: piperidine, morpholine and pyrrolidine) in MeCN solution at 20 °C is reported. The second-order rate constants showed of this process fit nicely the Brönsted equation log k1 = βnuc pKa + C, allowing the determination of the βnuc parameter in the range of 0.63 < βnuc < 0.77 that indicates that the degree of formation of N–C bond in the transition state is more half complete. Moreover, the analysis of the kinetic measurements based on a good linear log k (20 °C) = sN (E + N) free enthalpy relationship are used to assess the electrophilic reactivity in term of E parameter of these series of 2-oxindoline derivatives Michael acceptors. Of major interest is that the estimated E values were established to cover a domain of reactivity of ~3 units of E, ranging from −17.5 for 2-(5-chloro-2-oxindolin-3-ylidene)malononitrile (the most reactive electrophile) to −20.3 for ethyl 2-(5-chloro-1-methyl-2-oxindolin-3-ylidene)-2-cyanoacetate (the least reactive electrophile). The theoretical reactivity indices ω based on the conceptual Density Functional Theory (DFT) explains correctly the experimental electrophilicity E ordering founded in terms of experimental scales.

Stereoselective synthesis of δ-amino-α,β,γ,δ-unsaturated cycloketones via Mannich-type reaction

A new Mannich-type reaction of aryl propiolaldehydes with benzofuran-3(2H)-one and cyclic secondary amines was established, enabling a completely stereoselective protocol to access a series of unreported δ-amino-α,β,γ,δ-unsaturated cycloketones in generally good yields. This approach could tolerate various cyclic secondary amines including four-, five-, six-membered and bicyclic rings with water as a major by-product.

Aminomethoxy derivatives of norbornenylmethanol as biocorrosion inhibitors

Norbornenylmethanol was synthesized by the reaction of cyclopentadiene and allyl alcohol, on the basis of which aminomethoxy derivatives of norbornenylmethanol were synthesized in the presence of formaldehyde and secondary amines by Mannich condensation. The yield of the target products was 43-71%. On the basis of 5-morpholinomethoxymethylbicyclo[2.2.1]-hept-2-ene and hexylbromide (1:1) in the presence of isopropyl alcohol, its complex was obtained. The physic-chemical properties of the synthesized compounds and the resulting complex were determined, their 1% solutions in isopropyl alcohol and 5% solution of 5-morpholinomethoxymethylbicyclo[2.2.1]-hept-2-ene were prepared. Their influence on the vital activity of sulfate-reducing bacteria of the type «Desulfovibrio desulfuricans» in three concentrations (5; 50; 100 mg/L) was studied. Bactericide inhibitors used in industry – AMDOR IK-7 and AMDOR IК-10 were taken as standards. It was determined that all the synthesized compounds and the resulting complex showed high bactericidal properties, moreover, compounds obtained on the basis of cyclic secondary amines showed a higher bactericidal effect against sulfate-reducing bacteria, unlike compounds obtained on the basis of aliphatic secondary amines. Considering that these aminomethoxy derivatives of norbornenylmethanol affect bacteria at very low concentrations, they can be proposed as effective inhibitors against sulfate-reducing bacteria.