Nitrogen Nucleophiles Research Articles

Synthesis and anticancer activity of novel quinazolinone and benzamide derivatives

In trying to develop new anticancer agents, a series of quinazolinone and benzamide derivatives were synthesized via reaction of 6-iodo-2-phenyl-4H-benzoxazin-4-one with nitrogen nucleophiles, namely, formamide, ammonium acetate, hydrazine hydrate, hydroxylamine hydrochloride, substituted aromatic amines, benzyl amine, and/or thiocarbonohydrazide. All compounds were fully characterized by means of IR, MS, and 1H-NMR spectra. Some of the synthesized compounds were evaluated in vitro for their anti-proliferative activity against HePG-2 and MCF-7 cell lines. 2-(Benzoylamino)-N-(4-hydroxyphenyl)-5-iodobenzamide and tetrazino[1,6-c]quinazoline-3(4H)-thione derivative were the most potent against the two cancer cells comparable to that of doxorubicin. Most of the synthesized compounds also exhibited good cytotoxic activity.

Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines.

Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines, and N-alkyl tetrahydroquinoxalines by treatment with 2-aminobenzylamines, 2-aminopyridines, and N-alkyl 1,2-diaminobenzenes, respectively. Regioselectivity is controlled through attack of the most nucleophilic nitrogen of the unsymmetrical diamine to the β position of the epoxide. These reactions represent an efficient way to prepare privileged bioactive structures.

TiCl2(OTf)-SiO2: A solid stable lewis acid catalyst for Michael addition of α-Aminophosphonates, Amines, Indoles and Pyrrole

ABSTRACTTiCl2(OTf)-SiO2 is simply prepared by immobilization of TiCl3(OTf) on silica gel surface and introduced as a non-hygroscopic Lewis acid catalyst for C-N and C-C bond formation via Michael addition reaction. A variety of structurally diverse nitrogen nucleophiles including α-aminophosphonates, aliphatic and aromatic amines and imidazole were evaluated as Michael donors. Friedel–Crafts alkylation of indoles and pyrrole was also investigated through Michael addition reaction in the presence of TiCl2(OTf)-SiO2 as a catalyst. The reactions were conducted at room temperature or 60 °C under solvent-free conditions and the desired Michael adducts were obtained in high to excellent yields.

Synthesis and antitumor evaluation of novel tetrahydrobenzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-b]isoquinoline derivatives

ABSTRACTIn the present study, a novel 8,9,10,11-tetrahydro-7H,14H-benzo[4′,5′] thieno[2′,3′:4,5]-1,3-oxazino[3,2-b]isoquinoline-7,14-dione 5 was prepared by condensation of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzothiophene with homophthalic anhydride under microwave irradiation, followed by alkaline hydrolysis and cyclization using acetyl chloride. Compound 5 was further allowed to react with different nitrogen nucleophiles to get new tetrahydrobenzothienopyrimido isoquinolinone derivatives. The structures of the prepared compounds were elucidated by IR, 1H-NMR, 13C-NMR, and mass spectroscopy. The newly prepared compounds were tested in vitro against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, and mammary gland breast MCF-7. Almost all the tested compounds showed satisfactory activity.

Silver-catalyzed regioselective hydroamination of alkenyl diazoacetates to synthesize γ-amino acid equivalents.

A simple protocol to directly access γ-amino acid derivatives by intermolecular regioselective hydroamination of trichloroethyl alkenyldiazoacetates with carbamate using a silver tetrafluoroborate catalyst is described. Density functional theory (DFT) calculations to analyze the reaction mechanism revealed that multiple attractive interactions occur in a transition state to promote the vinylogous addition of nitrogen nucleophiles.

Synthesis of new thiophene-based heterocyclic compounds with 1,2,4-triazole ring

Some chemical modifications of the 2-amino-thiophenes prepared via Gewald method were established. A number of new substituted thienotriazolopyrimidines, thienotriazoles and thiophenyl-triazolothiadiazine were obtained. This study provides new approaches to the construction of substituted 1 H -1,2,4-triazoles bearing thiophene core and allows to use data in medical chemistry for further drug discovery. The obtained compounds could have significant potential for biological research, in particular, to discover new anticancer drugs. The ethyl thiophene-3-carboxylate, formed in deamination reaction of 2-aminothiophene, was converted to 4-amino-[1,2,4]triazole-3-thiol. Alkylation of the last with chloroacetamide and subsequent cyclization of the product in excess of POCl 3 resulted in the previously unknown thienyl substituted [1,2,4]triazolo[3,4- b ][1,3,4]thiadiazine formation. Moreover, 2-aminothiophenes were studied in a three-component reaction with hydrazides and orthoester leading to the thieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidines in high yields. Thus, 2-aminothiophene reacting with triethylorthoformiate forms an appropriate ethoxymethylene-aminothiophene, which undergoes an attack by the nucleophilic nitrogen atom of the hydrazide molecule. Further cascade cyclization leads to the formation of thieno[2,3- e ][1,2,4]triazolo [1,5- c ]pyrimidines. Finally, the properties of previously obtained thienopyrimidines were studied and it was found that heating a mixture of 2,3-diaminothieno[2,3- d ]pyrimidine with benzaldehyde and sulphur in DMF afford fused thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidine. A number of new substituted thienyl-1,2,4-triazoles, 3-(thiopen-3-yl)-triazolo[3,4- b ] [1,3,4]thiadiazines, thieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidines, thieno[2,3- d ][1,2,4]triazolo [1,5- a ]pyrimidine were obtained. New heterocyclic compounds that combine thiophene and 1,2,4-triazole cycles in one molecule were synthesized and are of considerable interest as potential biologically active substances, in particular, anti-tumor agents. Кеу words: 2-aminothiophene, 1,2,4-triazole, thieno[2,3- e ][1,2,4]triazolo[1,5- c ] pyrimidine, thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidine, [1,2,4]triazolo[3,4- b ][1,3,4] thiadiazine

Ruthenium complexes of the general formula [RuCl2(PHOX)2] as precatalysts in propargylic substitution reactions

After activation by chloride abstraction utilizing NaBArF as an activator (BArF=tetrakis(3,5-bis(trifluoromethyl)phenyl)borate), a complex of the general formula [RuCl2(PHOX)2] was utilized as a catalyst in propargylic substitution reactions, where PHOX is a phosphinooxazoline ligand. Oxygen and nitrogen-centered nucleophiles could be employed in the substitution of a propargylic acetate to obtain the corresponding propargylic substitution products in 87% to 9% isolated yields (45°C, 16h reaction time, toluene solvent, 1–2mol% catalyst loading, 1–2mol% activator).

Asymmetric Aminalization via Cation-Binding Catalysis.

Asymmetric cation-binding catalysis, in principle, can generate "chiral" anionic nucleophiles, where the counter cations are coordinated within chiral environments. Nitrogen nucleophiles are intrinsically basic, therefore, its use as nucleophiles is often challenging and limiting the scope of the reaction. Particularly, a formation of configurationally labile aminal centers with alkyl substituents has been a formidable challenge due to the enamine/imine equilibrium of electrophilic substrates. Herein, we report enantioselective nucleophilic addition reactions of potassium phthalimides to Boc-protected alkyl- and aryl-substituted α-amido sulfones. In situ generated imines smoothly reacted with the nitrogen nucleophiles to corresponding aminals with good to excellent enantioselectivitiy under mild reaction conditions. In addition, transformation of aminal products gave biologically relevant pyrrolidinone-fused hexahydropyrimidine scaffold with excellent stereoselectivity and good yield.

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-CatalyzedN-Alkylation Reactions of Unactivated Secondary Halides

Despite the long history of SN2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex serving its intended role as a photoredox catalyst, working in conjunction with a second copper complex that mediates C-N bond formation in an out-of-cage process.

Triazaphospholenium Tetrafluoroborate: A Phosphorus Analogue of a 1,2,3-Triazole-Derived Carbene.

3H-1,2,3,4-Triazaphosphole derivatives can be selectively alkylated with Meerwein's reagent at the most nucleophilic nitrogen atom. According to the principle of valence isoelectronicity, the corresponding phosphorus heterocycle represents the first formal phosphorus analogue of the well-known 1,2,3-triazolylidenes (mesoionic carbenes). Theoretical calculations revealed that the cation in triazaphospholenium tetrafluoroborate is an aromatic system with a high degree of π-conjugation. First investigations showed that the cationic phosphorus heterocycle can stabilize a [Cu2 Br4 ]2- dianion by formation of a neutral coordination compound with an unusual bonding situation between phosphorus and copper(I).

Synthesis, antibacterial activity, and fluorescence properties of a novel series from [2,4-dioxochromen-3(4H)methyl]amino acid

A new solvent-free method for synthesis of starting compounds 2,4-dioxochromen-3(4H)methyl amino acetic acid derivatives 1a–e via a green approach is reported. Also, the behavior of compound 1a towards various nitrogen nucleophiles such as primary amines, hydrazine hydrate, and hydroxylamine hydrochloride to give corresponding compounds 2–4 was studied. Furthermore, chlorination of compound 1a using a mixture of PCl5/POCl3 to yield acid chloride derivative 5 and the reaction of the latter compound 5 with various amino acids to obtain dipeptide compounds 6a–e are described. Moreover, cyclization of compound 1a in alkaline medium to afford dihydrochromeno[3,4-c]pyrrole-1-carboxylic acid 7 and cyclization of 6b in acidic medium, namely Ac2O, to yield piperazine derivative 8 are reported. Also, reaction of compound 1a with maleic anhydride in dioxane to afford Diels–Alder adduct 9, which posteriorly reacted with hydrazine hydrate to give 10, was investigated. Most of the newly synthesized compounds were screened against Gram-positive and Gram-negative bacteria, with compound 5 exhibiting the maximum inhibition zone towards all four types of bacteria. In addition, the absorption and fluorescence emission of some of the substituted coumarins were studied in dioxane, revealing that the substituents altered both the absorption and fluorescence emission maxima.

Synthesis and Antimicrobial Activity Evaluation of Some Novel Hydrazone, Pyrazolone, Chromenone, 2-Pyridone and 2-Pyrone Derivatives

A cyanoacetohydrazide derivative underwent a series of reactions with different nucleophilic reagents, such as hydrazine hydrate, p-chlorobenzaldehyde and salicylaldehyde, to give the condensation products. In addition, an arylidene malononitrile was reacted with different nitrogen nucleophiles, such as hydrazine hydrate, thiocarbohydrazide and cyanoacetohydrazide, to afford the hydrazine, hydrazone and pyridin-2-one derivatives, respectively. Furthermore, a pyridin-2-one derivative was reacted with different carbon electrophiles, such as carbon disulfide, p-chlorobenzaldehyde and acetic anhydride. The antimicrobial activities of some of the compounds were examined.

Copper-Catalyzed Synthesis and Applications of Yndiamides.

The first synthetic route to yndiamides, a novel class of double aza-substituted alkyne, has been established by the copper(I)-catalyzed cross-coupling of 1,1-dibromoenamides with nitrogen nucleophiles. The utility of these compounds is demonstrated in a range of transition-metal-catalyzed and acid-catalyzed transformations to afford a wide variety of 1,2-diamide functionalized products.

Copper‐Catalyzed Synthesis and Applications of Yndiamides

AbstractThe first synthetic route to yndiamides, a novel class of double aza‐substituted alkyne, has been established by the copper(I)‐catalyzed cross‐coupling of 1,1‐dibromoenamides with nitrogen nucleophiles. The utility of these compounds is demonstrated in a range of transition‐metal‐catalyzed and acid‐catalyzed transformations to afford a wide variety of 1,2‐diamide functionalized products.

Elemental Sulfur as Reaction Medium for the Synthesis of Fused Nitrogen Heterocycles by Oxidative Coupling between Cycloalkanones and Nitrogen Nucleophiles

AbstractMolten elemental sulfur was found to be an excellent reaction medium for oxidative coupling between bis‐aza nucleophiles and cycloalkanones to the fused diaza heterocycles. No extensive aromatization was observed when cyclohexanone was used. These reaction conditions tolerate a wide range of functional groups and are applicable to oxidation sensitive o‐phenylenediamines.magnified image

Regioselective Intermolecular Allylic C−H Amination of Disubstituted Olefins via Rhodium/π‐Allyl Intermediates

AbstractA method for catalytic intermolecular allylic C−H amination of trans‐disubstituted olefins is reported. The reaction is efficient for a range of common nitrogen nucleophiles bearing one electron‐withdrawing group, and proceeds under mild reaction conditions. Good levels of regioselectivity are observed for a wide range of electronically diverse trans‐β‐alkyl styrene substrates.

Regioselective Intermolecular Allylic C-H Amination of Disubstituted Olefins via Rhodium/π-Allyl Intermediates.

A method for catalytic intermolecular allylic C-H amination of trans-disubstituted olefins is reported. The reaction is efficient for a range of common nitrogen nucleophiles bearing one electron-withdrawing group, and proceeds under mild reaction conditions. Good levels of regioselectivity are observed for a wide range of electronically diverse trans-β-alkyl styrene substrates.

Regiospecific Isomerization of 2‐Benzoxazinon‐2‐yl Benzoic Acid Toward Some Nitrogen Nucleophiles as Environmental Insecticide

Based on the strategies of receptor structure‐guided benzoxazinone design, a series of nitrogen nucleophiles such as benzyl amine, sodium azide, 4,4‐bis o‐toluidine, 4‐butanolamine, glucosamine, 2‐amino pyridine, 2‐picolinyl amine, hydroxyl amine, and hydrazine derivatives, for example, hydrazine hydrate, semicarbazide, thiosemicarbazide, methylhydrazide, phenylhydrazide, could be reacted with 2‐benzoxazine‐2‐yl benzoic acid 1. According the basicity of nucleophiles, regiospecific isomerization of benzoxazinone has been considered through formation of the spiro derivatives. Organic reagents can be controlled on the course of reaction of benzoxazinonyl benzoic acid 1. Preliminary bioassays indicated that the insecticidal spectra of the synthesized compounds were ecofriendly biodegradable materials due to isomerization. Among these analogues, the quinazoline 2–4 showed 100% mortality against Nilaparvata lugens (LC50 = 0.087 mg/L). The insecticidal potency of our designed analogues was dual‐controlled by isomerization to quinazolinone and spiro derivatives that observed in vitro and shed light on the novel insecticidal mechanism. The chemical structure of the products can be confirmed by microanalytical, spectral data, optimized and stimulated by quantum chemical parameters.

Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines.

Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, 1H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.

Synthesis of Novel Phthalazine Derivatives as Potential Anticancer and Antioxidant Agents Based on 1‐Chloro‐4‐(4‐phenoxyphenyl)phthalazine

A new series of phthalazine derivatives was synthesized from the reaction of 1‐chloro‐4‐(4‐phenoxyphenyl)phthalazine as a reactive starting material with different carbon, nitrogen, oxygen, and sulfur nucleophiles. The structural formulae of all products were confirmed and characterized by elemental analyses and spectral data (IR, 1H NMR, 13C NMR, and mass spectra). Some of the synthesized derivatives were screened for their antitumor activity against four human tumor cell lines using MTT assay. In comparison with doxorubicin as standard drug, compounds 1, 20, and 25 showed the most potent cytotoxic effect. In addition, investigation of antioxidant activity revealed that hydrazinylphthalazine 20 has the highest activity.