Academic literature on the topic 'Thiochromenes'

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.

An iron(iii) catalyzed carboarylation of alkynes is reported for the synthesis of highly substituted 1,2-dihydroquinolines, quinolines, 2H-chromenes, and 2H-thiochromenes under mild reaction conditions.

Enantioselective organocatalysis has become a field of central importance within asymmetric chemical synthesis and appears to be efficient approach toward the construction of complex chiral molecules from simple achiral materials in one-pot transformations under mild conditions with high stereocontrol. This review addresses the most significant synthetic methods reported on chiral-amine-catalyzed tandem Michael conjugate addition of heteroatom-centered nucleophiles to α,β-unsaturated compounds followed by cyclization reactions for the enantioselective construction of functionalized chiral chromenes, thiochromenes and 1,2-dihydroquinolines in optically enriched forms found in a myriad of bioactive natural products and synthetic compounds.

Le développement de nouvelles méthodologies de synthèse toujours plus efficaces, sélectives et éco-compatibles apparaît comme un défi permanent tant l’intérêt suscité pour les composés hétérocycliques est important. Ce projet de thèse s’articule autour de plusieurs axes dans ce domaine.Tout d’abord, nous avons exploité la réactivité des N-(sulfonyl) et N-(sulfamoyl)aziridines en tant que précurseurs de dipôles 1,3 en vue de préparer divers 1-azaspiro[5.n]alcanes. L’étude mécanistique de cette réaction de cycloaddition [3+2] réalisée par calculs DFT permet de montrer que l’étape cinétiquement déterminante de la réaction est la formation du dipôle 1,3 ; la force motrice étant la fermeture du cycle à cinq chaînons.Nous nous sommes également attachés à valoriser le savoir-faire du laboratoire dans le domaine des transferts catalytiques de nitrènes (aziridination et amination C-H) dans le cadre du projet de synthèse totale de la pactamycine, aminocyclopentitol hautement fonctionnalisé.Par ailleurs, la mise au point d’une cascade Passerini-Smiles/Réduction/Cyclisation et d’une séquence monotope Passerini-Double-Smiles/SNAr permet un accès rapide et efficace à des motifs hétérocycliques de type 1,4-benzoxazin-3-ones. Conduisant à des familles régioisomères de produits, ces deux voies de synthèse se sont avérées complémentaires.Parallèlement, une nouvelle méthodologie basée sur l’ouverture pallado-catalysée de thiocyclopropanes a permis d’obtenir de nouveaux hétérocycles de type thiochromènes. Compte tenu des nombreuses fonctionnalisations envisageables, ces composés semblent très prometteurs dans le domaine de la chimie hétérocyclique.Enfin, des études électrochimiques et RMN couplées à des calculs DFT ont été entreprises afin d’élucider le mécanisme mis en jeu lors des couplages pallado-catalysés entre un halogénure d’aryle, un isonitrile et un nucléophile
The development of new and more efficient synthetic methodologies, selective and eco-friendly seems to be an ongoing challenge as the interest in the heterocyclic compounds is important. All the studies performed during the last three years are divided in several axes in this field.First, the reactivity of N-(sulfonyl) and N-(sulfamoyl) aziridines as precursors of 1,3-zwitterionic species was explorated in order to obtain various 1-azaspiro[5.n]alkanes. The mechanism of the reaction has been studied by DFT calculations. The initial formation of the zwitterionic 1,3-dipole has been found to be the rate-determining step whereas the five-membered ring closure appeared to be the driving force.We tried to apply our expertise in the field of catalytic nitrene transfers (aziridination and C-H amination) to the total synthesis of pactamycin, highly functionalized aminocyclopentitol compound.Furthermore, the developments of a Passerini-Smiles/reduction/cyclization cascade and of a one-pot Passerini-Double-Smiles/SNAr sequence provide straightforward and efficient accesses to 1,4-benzoxazin-3-ones. These paths are complementary as they lead to regioisomers.Meanwhile, a new methodology based on Pd-catalyzed thiocyclopropanes ring opening gave thiochromenes. Due to their high synthetic potential, these compounds appear to be very promising scaffolds in heterocyclic chemistry.Finally, electrochemical and NMR studies coupled with DFT calculations have been done in order to elucidate the mechanism involved in the Pd-catalyzed couplings between an aryl halide, an isocyanide and a nucleophile

碩士
國立臺灣師範大學
化學系
100
The contents of this thesis divided into two parts summarizing the results based on the experimental works performed during the course of study. The first part of this thesis describes the copper-catalyzed intramolecular amination reaction of 2-(2-halophenyl)chroman-3-amine to construct a variety of 2-((1H-indol-2-yl)methyl)phenol derivatives. This method offers an easy access to a wide variety of 2-benzyl-1H-indole derivatives under mild reaction conditions in high yields. The second part focuses on the synthesis thio-nitrochromene derivatives from β-nitrostyrene and 2,2’-dithiodibenzaldehyde in the presence of organocatalyst. This method is a simple, efficient and environmentally friendly in line with the concept of green chemistry.

The thesis entitled “Enantioselective Carbon-Carbon and Carbon-Heteroatom Bond Formation: from Bifunctional to Anion-Binding Catalysis” is divided into four chapters. Chapter 1: Organocatalytic Asymmetric Direct Vinylogous Michael Addition of α,β-Unsaturated γ-Butyrolactam to Nitroolefins Chiral γ-butyrolactams are privileged structural motifs present in a plethora of natural products as well as pharmaceutically important compounds, such as haplophytine and (+)-lactacystin. They are also been used as a key intermediate for the stereoselective synthesis of anti-influenza drug A-315675. Though the initial works were concentrated over 2-silyloxy pyrroles as nucleophile, the direct use of γ-butyrolactam as nucleophile in enantioselective transformation gained pace during the past decade. Direct use of α,β-unsaturated γ-butyrolactam in vinylogous Michael reaction is not only desirable but also a challenging task due to the need of controlling regio-, diastereo- and enantioselectivity simultaneously. The presence of rather poorly acidic protons at the γ-position of butyrolactam makes the activation via an organocatalyst even more difficult. In this chapter, the first organocatalytic direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactam to nitroolefins has been demonstrated. Using quinidine and a simply modified dihydroquinine derivative as the bifunctional catalysts, both the product enantiomers are accessible as single regioisomer (only γ-addition product) and diastereomer with moderate to good enantioselectivity. A range of nitroolefins, bearing aryl, alkyl and heteroaryl substituents were found to be suitable electrophilic partner for this direct vinylogous Michael reaction. We have also successfully utilized α,β-unsaturated moiety of the butyrolactam as a Michael acceptor in a vinylogous Michael/oxa-Michael cascade reaction for the diastereo- and enantioselective synthesis of a tricyclic compound. A plausible mechanistic model is also presented to rationalize the observed stereochemical outcome. Reference: Ray Choudhury, A.; Mukherjee, S. Org. Biomol. Chem. 2012, 10, 7313-7320. Chapter 2: A Catalytic Sulfa-Michael Addition/Horner-Wadsworth-Emmons Cascade Reaction for Enantioselective Synthesis of Thiochromenes Thiochromene derivatives are venerable bioactive molecules having found application as analgesics, anti-cancer, anti-inflammatory and anti-bacterial agents. Although hetero-Michael-initiated cascade reactions involving α,β-unsaturated aldehydes and ketones has been profoundly used for their enantioselective synthesis, similar reactions of the corresponding ester equivalents remained relatively underexplored and almost always require an additional binding site. In this chapter, a catalytic enantioselective sulfa-Michael addition/Horner-Wadsworth-Emmons olefination cascade is presented. This cascade sequence is initiated by a sulfa-Michael addition to a vinylphosphonate catalyzed by a chiral bifunctional urea derivative and provides an easy access to enantioenriched 2,3-disubstituted thiochromene derivatives. Several aryl and heteroaryl substituted thiochromenes were obtained in excellent yield with high level of enantioselectivity. Our report represents the first example of the use of phosphonate as a traceless binding site in a catalytic asymmetric transformation. The use of a simple catalyst, mild reaction conditions (ambient temperature) and one-pot strategy highlights the benefits of our protocol. Synthetic utility of the products is demonstrated and a model is proposed to rationalize the stereochemical outcome of the reaction. References: Ray Choudhury, A.; Mukherjee, S. Adv. Synth. Catal. 2013, 355, 1989-1995. Chapter 3: Organocatalytic Enantioselective Umpolung Vinylation of Cyclic β-Ketoesters Considering the wide abundance of natural products having vinyl containing quaternary stereocenter, we became interested in an efficient protocol for enantioselective vinylation. We became aware of the fact that all C-H vinylation reported till date couples nucleophile with β-carbon of an electron withdrawing group. However, there is no example of C-H vinylation which couples nucleophile with α-carbon of an electron withdrawing group. Considering the fact that α-carbon of an electron withdrawing group is nucleophilic in nature, such a combination would lead to “mismatched polarity” and render the reaction electronically impossible. Therefore, a reversal of polarity or umpolung reactivity would be necessary for this coupling. In this chapter, an efficient formal enantioselective umpolung α-vinylation of cyclic β-ketoester by an one-pot two-step sequence is described. This two-step protocol consists of a catalytic enantioselective Michael reaction followed by base mediated nitrous acid elimination. The products, bearing an all-carbon quaternary stereocenter including a vinyl moiety, was synthesized in high yield with excellent er. β-Nitroenones containing substituted aryl or heteroaryl group produced the vinylated product with excellent enantioselectivity. Our protocol demonstrates the first use of β-nitroenones as an electrophilic component in an enantioselective reaction. This is also the first example of a catalytic umpolung vinylation reaction of β-ketoester. The reaction could be scaled up at least to 1.0 mmol scale without hampering the yield or enantioselectivity. A model based on the bifunctional nature of the catalyst was proposed to rationalize the observed stereochemical outcome of the reaction. References: Ray Choudhury, A.; Manna, M. S.; Mukherjee, S. manuscript under preparation. Chapter 4: Enantioselective Dearomatization of Isoquinolines by Anion-Binding Catalysis en Route to Cyclic α-Aminophosphonates α-Aminophosphonates and related α-aminophosphonic acid derivatives are used extensively in medicinal and pharmaceutical sciences as surrogates of α-amino acids. The strong correlation between the biological activities of compounds containing α-aminophosphonic acids and their absolute configuration renders the enantioselective synthesis of α-aminophosphonates imperative to such studies. Considerable advancement has taken place in the catalytic enantioselective synthesis of acyclic α-aminophosphonates using various strategies. In contrast, enantioselective synthesis of cyclic α-aminophosphonates remains elusive, despite their prominent abundance in biologically active molecules. In this chapter, the development of an enantioselective dearomatization of diversely substituted isoquinolines through acyl activation and nucleophilic addition of silyl phosphites is presented. Using a simple and easy to prepare tert-leucine derived thiourea as the anion-binding catalyst, this base-free protocol delivers cyclic α-aminophosphonates in excellent yields with moderate to high enantioselectivities. The reaction was found to be general with respect to different isoquinolines when applied to monosubstituted isoquinolines bearing substituent at nearly every position and even to disubstituted isoquinolines. Our protocol was also found to be suitable for dihydroisoquinolines. This is the first example of the use of silyl phosphites as the nucleophile in asymmetric dearomatization reactions driven by anion-binding catalysis. In fact, this is also the first time asymmetric anion-binding catalysis has been applied to the synthesis of α-aminophosphonates. A preliminary experiment with quinoline points toward potential applicability of this strategy to other nitrogenous heteroaromatics. References: Ray Choudhury, A.; Mukherjee, S. under revision.

碩士
國立臺灣師範大學
化學系
102
The dissertation is divided into two parts summarizing the results based on the experimental works performed during the course of study. The first part includes a convenient procedure for the synthesis of Benzothiopyran (thiochromene) derivatives via the Michael addition of sodium salt of (2-formylphenyl) ethanethioate and nitrostyrene in the presence of 4-Dimethylaminopyridine (DMAP) as catalyst one pot. Benzothiopyran (thiochromene) derivatives are important and ubiquitous motif structure which is present in wide variety of pharmaceuticals, synthetic intermediates, and functional materials. Besides that some of the Benzothiopyran (thiochromene) derivatives acts as dyes. Thus, Benzothiopyran derivatives have triggered sustainably increasing attention in the synthetic and medicinal chemistry communities. The second part describes a successful route for the one-pot two-step sequence involving a nucleophilic aromatic substitution (SNAr) of activated fluorobenzenes with azide nucleophile and in situ Huisgen cycloaddition of the resulting sodium azides with thiochromenes has been developed for a rapid access to 2,4,5-trisubstituted 1,2,3-(NH)-triazoles. Most of the 1,2,3-triazole derivatives shows anticancer activities, anti-inflammatory and antimicrobial, etc. Also often used as a backbone in the synthesis of natural products. Here, we provide an efficient and high yield method for the synthesis of triazole structure.

博士
國防醫學院
生命科學研究所
102
A series of novel thiochromeno[2,3-c]quinolin-12-ones with a potential side chains had been synthesized by a various synthetic route via Pfitzinger reaction, intramolecular cyclization, and nucleophilic substitution. The biological activity had been preliminarily studied for cell cytotoxicity, topoisomerases inhibition, and in vitro cytotoxicity against NCI’s 60 cell line human tumor screen. The results indicated that compounds N7, N14, N18 and N19 exhibited significant potent inhibitory effects in TOPs-mediated DNA by using TOP activity assays. Twenty-six compounds were selected by the NCI for one dose screening program and further studies on compounds N2, N7, N14, N19, and N25 where the curves cross these lines represent the interpolated values to cause 50% growth inhibition, total growth inhibition, and 50% cell killing, respectively. Among of them, compounds N7 and N14 not only showed the outstanding cytotoxic effects (Both values of GI50 were 1.66 M) but also exhibited dual inhibitions of TOP I/II (the range of IC50 values were between 1-10 M). Interestingly, compound N2 revealed poor cytotoxicity and mild TOPs inhibition but disclosed the high selective ratio (9.091) against breast cancer (GI50 from 0.04 M to 10.10 M). The exact mechanism of how this pharmacophore contributes to its activity is still unclear, however, the group in the extended arm of the novel tetracyclic thiochromenoquinolones might contribute to proper binding to the residues within the TOP-mediated DNA complexes.