Cyclic Secondary Amines Research Articles

Synthesis of New 2′-(2- and 3-Aminopropanoyl)-6′,7′-dimethoxy-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-isoquinoline]-1′-carboxamides

6′,7′-Dimethoxy-N-methyl-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-isoquinoline]-1′-carboxamide reacted with 2-bromopropanoyl chloride to give the corresponding 2-bromopropanamide which was converted to substituted 2-aminopropanoyl derivatives via reactions with cyclic secondary amines. The reaction of 6′,7′-dimethoxy-N-methyl-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-isoquinoline]-1′-carboxamide with acryloyl chloride, followed by treatment of the resulting acrylamide with amines, afforded 3-aminopropanoyl derivatives.

SYNTHESIS OF N -SUBSTITUTED TETRAPROPARGYLAMINES BY CATALYTIC AMINOMETHYLATION OF Α,Ω-DIACETYLENES

A catalytic method was developed for the synthesis of N-substituted tetrapropargylamines by reactions of α,ω-diacetylenes with 1,5,3-dioxazepanes, aldehydes (benzaldehydes, formaldehyde), and cyclic secondary amines.

Synthesis of N-substituted tetrapropargylamines by catalytic aminomethylation of α,ω-diacetylenes

A catalytic method was developed for the synthesis of N-substituted tetrapropargylamines by reactions of α,ω-diacetylenes with 1,5,3-dioxazepanes, aldehydes (benzaldehydes, formaldehyde), and cyclic secondary amines.

Synthesis and Neurotropic Activity of 4-Phenylpyridine-3-Carboxylic Acid and 3-Hydroxy-4-Phenylthieno[2,3-b]-Pyridine Derivatives

Aseries of pyridine-3-carboxylic acid derivatives were synthesized via recyclization of a thiopyran ring using cyclic secondary amines and then converted into substituted thieno[2,3-b]pyridines. Studies of the neurotropic properties identified several synthesized compounds with anticonvulsant activity against corazole-induced seizures. The compounds were active as psychological sedatives and, in contrast with the tranquilizer diazepam, were inactive as central myorelaxants at anticonvulsant doses.

Naphthol-derived Betti bases as potential SLC6A14 blockers

Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na+- and Cl-- dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.

Electrochemical TEMPO-catalyzed multicomponent C(sp3)–H α-carbamoylation of free cyclic secondary amines

The electrochemical α-carbamoylation of free cyclic secondary amines has been realized under an original TEMPO-catalyzed multicomponent coupling.

IBX-mediated oxidative addition of isocyanides to cyclic secondary amines: total syntheses of alangiobussine and alangiobussinine

The present study describes a robust and general method for the synthesis of C(1)-carboxamides through IBX-mediated oxidative addition of isocyanides to tryptolines and 1,2,3,4-tetrahydroisoquinolines. In this transformation, IBX plays a dual role of an oxidant and Lewis acid to activate imine facilitating isocyanide addition. Detailed mechanistic investigations were performed by isotopic labeling and real-time NMR experiments. The method was utilized for the gram scale syntheses of two alkaloids alangiobussine and alangiobussinine in 63% and 45% overall yield, respectively.

Unexpected medium effect on the mechanism for aminolysis of aryl phenyl carbonates in acetonitrile and H2O: transition-state structure in the catalytic pathway

Upward curvature in the kinetic plots of pseudo first-order rate constants (kobsd) vs. [amine] for the aminolysis of aryl phenyl carbonates (5a–5j) in MeCN demonstrates that these reactions proceed via a zwitterionic tetrahedral intermediate (T±) that partitions between catalyzed and uncatalyzed routes to give the products. Yukawa–Tsuno plots for the reactions of 5a–5j with piperidine result in excellent linear correlations with ρY = 4.82 and r = 0.47 for the uncatalyzed reaction versus ρY = 2.21 and r = 0.21 for the catalyzed reaction. Brønsted plots for reactions of 4-(ethoxycarbonyl)-phenyl phenyl carbonate (5f) with a series of cyclic secondary amines exhibit excellent linear correlations with βnuc = 0.87 and 0.58 for the uncatalyzed and catalyzed reactions, respectively. The ΔH‡ and ΔS‡ values are 0.92 kcal/mol and –50.1 cal/mol K, respectively, for the catalyzed reaction of 5f with piperidine. Deuterium kinetic isotope effects found for reactions of 5f with piperidine/deuterated piperidine are 0.84 (uncatalyzed) and 1.42 (catalyzed). Multi-parameter analysis supports a concerted catalytic pathway involving a six-membered cyclic transition state rather than a traditionally accepted stepwise pathway with an anionic intermediate. The current unexpected results, where T± is the essential central intermediate in this aminolysis, contrast with previous calculation studies that deemed T± unstable in gas phase or MeCN.

Methanol Promoted Palladium‐Catalyzed Amine Formylation with CO2 and H2 by the Formation of HCOOCH3

AbstractThe N‐formylation reaction of amines is one of the most effective measures to make the best use of CO2, since the formamides have widespread applications in industry. Herein, we performed the N‐formylation reaction over Mg−Al layered double hydroxide (Mg−Al LDH) supported Pd catalyst (Pd/LDH) for the first time and studied the relation between the solvent and the mechanism. In this reaction, the methanol can greatly improve the yield of the desired product by forming the HCOOCH3. The catalytic system is effective for various amines including cyclic and alkyl secondary amines. Under the optimized reaction condition, we gained 88.5 %–97.4 % yields of the formamides for various substrates.

An efficient Synthesis of New Fused Oxazinocarbazoles

Background: Oxazinocarbazoles are molecules of particular interest as they possess a broad spectrum of pharmacological activities, such as antiproliferative, antibacterial, antimalarial and antiplasmodial activities. Despite few synthetic methods reported in the literature for their synthesis, there appear to be no reports on the synthesis for oxazinocarbazole fused from simple starting materials. Method: The Mannich condensation of 4-hydroxycarbazole, aldehyde and secondary cyclic amine was carried out to get the corresponding carbazole Mannich base and its subsequent copper(II)acetate catalyzed intramolecular oxidative α-functionaliation of tertiary amine to achieve 1,3-oxazine core. The structures of obtained carbazole Mannich bases and fused oxazinocarbazoles were confirmed by NMR, IR and mass spectra. Results: Various substituted carbazole Mannich bases such as fluoro-, nitro-, dimethoxy-, trimethoxyderivatives reacted smoothly in the presence of copper(II)acetate to give the corresponding fused oxazinocarbazoles in good yields. Conclusion: We have developed a two step method for the synthesis of new oxazino[5,6-c]carbazole derivatives in good yields. This protocol is simple, atom-economic and proceeds smoothly under mild reaction conditions. Keywords: Carbazole mannich base, hydroxycarbazole, oxazinocarbazoles, antibacterial, antimalarial, antiproliferative.

Direct Copper-Catalyzed Three-Component Synthesis of Sulfonamides

First introduced into medicines in the 1930s, the sulfonamide functional group continues to be present in a wide range of contemporary pharmaceuticals and agrochemicals. Despite their popularity in the design of modern bioactive molecules, the underpinning methods for sulfonamide synthesis are essentially unchanged since their introduction, and rely on the use of starting materials with preinstalled sulfur-functionality. Herein we report a direct single-step synthesis of sulfonamides that combines two of the largest monomer sets available in discovery chemistry, (hetero)aryl boronic acids and amines, along with sulfur dioxide, using a Cu(II) catalyst, to deliver a broad range of sulfonamides. Sulfur dioxide is provided by the surrogate reagent DABSO. The reaction tolerates broad variation in both coupling partners, including aryl, heteroaryl and alkenyl boronic acids, as well as cyclic and acyclic alkyl secondary amines, and primary anilines. We validate the method by showing that a variety of drugs, and drug-fragments, can be incorporated into the process.

Chan–Evans–Lam Couplings with Copper Iminoarylsulfonate Complexes: Scope and Mechanism

Copper(II) pyridyliminoarylsulfonate complexes with chloride or triflate counteranions were employed in Chan–Evans–Lam (CEL) couplings of N-nucleophiles and arylboronic acids. The complexes avoided typical side reactions in CEL couplings, and an excess of boronic acid was not required. Water was tolerated, and addition of neither base nor other additives was necessary. Primary amines, acyclic and cyclic secondary amines, anilines, aminophenol, imidazole, pyrazole, and phenyltetrazole can be quantitatively arylated at either 25 or 50 °C with 2.5 mol % of the catalyst. Reaction kinetics were investigated in detail. Kinetic and spectroscopic studies provide evidence for the formation of unproductive copper–substrate complexes. Formation of an aniline–phenylboronic acid adduct was responsible for the zero-order dependence of reaction rates on phenylboronic acid concentration. Kinetic evidence indicates that the order of reaction steps is transmetalation, nucleophile coordination, and oxidation. Couplings perf...

Kinetics and quantification of the electrophilic reactivities of substituted thiophenes and structure‐reactivity relationships

AbstractSecond‐order rate constants (k1) have been measured spectrophotometrically for reactions of 2‐methoxy‐3‐X‐5‐nitrothiophene 1a‐c (X = NO2, CN, and COCH3) with secondary cyclic amines (pyrrolidine 2a, piperidine 2b, and morpholine 2c) in CH3CN and 91:9 (v/v) CH3OH/CH3CN at 20°C. The experimental data show that the rate constants (k1) values exhibit good correlation with the parameters of nucphilicity (N) of the amines 2a‐c and are consistent with the Mayr's relationship log k (20°C) = s(E + N). We have shown that the electrophilicity parameters E derived for 1a–c and those reported previously for the thiophenes 1d‐g (X = SO2CH3, CO2CH3, CONH2, and H) are linearly related to the pKa values for their gem‐dimethoxy complexes in methanol. Using this correlation, we successfully evaluated the electrophilicity E values of 12 structurally diverse electrophiles in methanol for the first time. In addition, a satisfactory linear correlation (r2 = 0.9726) between the experimental (log kexp) and the calculated (log kcalcd) values for the σ‐complexation reactions of these 12 electrophiles with methoxide ion in methanol has been observed and discussed.

Unusual product formation in tungsten(0)-catalysed reactions of propargylic alcohols and secondary amines: Hydroamination and the construction of the tetrahydrofuran ring

In reactions of propargylic alcohols, RH(HO)CCCH (prop-2-yn-1-ol, meso-but-3-yn-2-ol), with secondary cyclic amines (piperidine, pyrrolidine, morpholine, 1-methylpiperazine, 4-methylpiperidine and meso-3,5-dimethylpiperidine), catalysed by cis-[W(CO)4(pip)2], previously unknown diamines containing the tetrahydrofuran ring were isolated in relatively good yield, up to 80%, identified by GC–MS, and characterized by NMR spectroscopy. The new structures were studied by DFT: the 1H and 13C chemical shifts were calculated and compared with those observed experimentally.

Synthesis of cellulose impregnated copper nanoparticles as an efficient heterogeneous catalyst for C[sbnd]N coupling reactions under mild conditions

Highly efficient copper nanoparticles supported over nanocellulose have been prepared by a simple chemical reduction method. The cellulose was extracted from the inner stem of Hibiscus sabdariffa and used as a polymer matrix for the synthesis of copper nanoparticles. The formation of the nanoparticles was validated through different characterization techniques like X-ray diffraction (XRD), Fourier transform infra-red spectroscopy (FTIR), UV–vis spectroscopy (UV) and Energy dispersive X-Ray Spectroscopy (EDX). Moreover the morphology of the cellulose supported copper nanoparticles was investigated using field emission scanning electron microscope (FESEM) and field emission transmission electron micrograph (FETEM) which revealed the formation of spherical nanoparticles with an average size of 7 nm. The synthesized catalyst was then utilized effectively in the CN coupling reactions involving open chained as well as cyclic secondary amines and electron deficient vinylic compounds. The catalyst demonstrated excellent yield (82%–95%) and was easily recycled for upto six cycles without any significant loss of catalytic activity.

New thiazolidine‐2,4‐dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity

Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.

Synthesis of new α-amino nitriles with insecticidal action on Aedes aegypti (Diptera: Culicidae)

Aedes aegypti is the principal vector of arboviral pathogens that may cause diseases as dengue fever, chikungunya and zika. The harmful environmental effects of commercial pesticides coalesced with the development of insecticide-resistant populations encourage the discovery and generation of new alternative products as a tool to reduce the incidence of vector-borne diseases. In this work, through the classic three component Strecker reaction of commercial benzaldehydes, cyclic secondary amines and KCN, a new series of nine α-amino nitriles, girgensohnine analogs, has been synthetized and screened for larvicide and adulticide properties against A. aegypti, one of the dominant vectors of dengue, chikungunya and zika in tropical and subtropical areas all over the world. Molecules 3 and 4 were identified as potential larvicidal agents with LC50 values of 50.55 and 69.59ppm, respectively. Molecule 3 showed 100% of mortality after 2h of treatment when a concentration of 30ppm in adulticidal assays was evaluated. Additionally, in order to elucidate the mode of action of these molecules, their acetylcholinesterase (AChE) inhibitory properties were evaluated using the Ellman assay. It was found that the molecules possess a weak AChE inhibitory activity with IC50 values between 148.80 and 259.40μM, indicating that AChE could not be a principal target for insecticide activity.

Iridium-Catalyzed Dehydrogenative α-Functionalization of (Hetero)aryl-Fused Cyclic Secondary Amines with Indoles.

Herein, by employing dehydrogenation as a substrate-activating strategy, a new iridium-catalyzed direct α-functionalization of (hetero)aryl-fused cyclic secondary amines with indoles has been demonstrated, which proceeds with merits that include high step- and atom-efficiency, readily available feedstocks, a simple catalyst system, good functional group tolerance, and operational simplicity.

Synthesis and Characterization of New Cyclic Aminobenzoquinones

The aim of this research is to synthesize and characterize of new cyclic members of cyclic aminobenzoquinones. Mono amino substituted products; 2-chloro-5,6-dimethyl-3-(pyrrolidin-1-yl)-1,4-benzoquinone (2), 2-chloro-5,6-dimethyl-3-(piperidin-1-yl)-1,4-benzoquinone (3), 2-chloro-5,6-dimethyl-3-morpholino-1,4-benzoquinone (4), and 2-chloro-5,6-dimethyl-3-thiomorpholino-1,4-benzoquinone (5) have been synthesized by a green methodology using water as solvent by means of nucleophilic substitution reactions between 2,3-dichloro-5,6-dimethyl-1,4-benzoquinone (1) and cyclic secondary amines. Structure determination of the new products (2-5) was established on the basis of IR, 1H NMR, 13C NMR, and mass spectrometry.

Study on the Synthesis, Structure and Antimicrobial activity of the new Mannich base and its Transition Metal Complexes Derived from Phthalimide

Cyclic aromatic secondary amines, like phthalimides, and related compounds possess structural features, which makes them to exert potential biological activities and pharmaceutical applications. A new Mannich base has been synthesized from phthalimide and its transition metal complexes also were prepared. The Mannich base ligand was synthesized by using phthalimide, formaldehyde and piperidine. The ligand as well as the metal complexes were characterized by various physical methods. The structure of the synthesized compounds are confirmed by UV, IR, and 1H NMR spectroscopic techniques. The antimicrobial activity of the ligand and the complexes were examined using different bacteria by disc diffusion technique.