Tetrasubstituted Thiophenes Research Articles

Back Cover: Silver‐Catalyzed Coupling of Two CH Groups and One‐Pot Synthesis of Tetrasubstituted Furans, Thiophenes, and Pyrroles (Chem. Eur. J. 32/2015)

Back Cover: Silver‐Catalyzed Coupling of Two CH Groups and One‐Pot Synthesis of Tetrasubstituted Furans, Thiophenes, and Pyrroles (Chem. Eur. J. 32/2015)

ChemInform Abstract: Sequential One‐Pot Synthesis of Tri‐ and Tetrasubstituted Thiophenes and Fluorescent Push—Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push–pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

Highly mild approach towards synthesis of tetrasubstituted thiophenes by an organic salt afforded by cyclic thioureas and ketene dithioacetals

An organic salt generated by cyclic thioureas and 2-di(methylsulfanyl)methylenemalononitrile in reaction with primary and secondary α-haloketones leads to tetrasubstituted thiophenes without using additional base or catalyst at room temperature.

One pot synthesis of tetrasubstituted thiophenes: [3 + 2] annulation strategy

A simple, efficient and economical synthesis of dimethyl 3-amino-5-(2-oxo-2-arylethyl)thiophene-2,4-dicarboxylates has been reported by ring opening of methyl 3-amino-6-aryl-4-oxo-4H-thieno[3,2-c]pyran-2-carboxylates by alkoxide ions.

Sequential One-Pot Synthesis of Tri- and Tetrasubstituted Thiophenes and Fluorescent Push-Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push-pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

ChemInform Abstract: An Efficient One‐Pot Three‐Component Synthesis and Antimicrobial Evaluation of Tetra Substituted Thiophene Derivatives.

AbstractThe synthesized thiophene derivatives exhibit good to excellent activity against Gram‐negative microorganism (P.

Design, Synthesis, and Biological Evaluation of Tetra-Substituted Thiophenes as Inhibitors of p38α MAPK.

p38α mitogen-activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4-fluorophenyl/4-pyridyl rings connected to either a 5- or 6-membered heterocycle. In this study, a small library of substituted thiophene-based compounds bearing the vicinal 4-fluorophenyl/4-pyridyl rings was designed using computational docking as a visualisation tool. Compounds were synthesised and evaluated in a fluorescence polarisation binding assay. The synthesised analogues had a higher binding affinity to the active phosphorylated form of p38α MAPK than the inactive nonphosphorylated form of the protein. 4-(2-(4-fluorophenyl)thiophen-3-yl)pyridine had a Ki value of 0.6 μm to active p38α MAPK highlighting that substitution of the core ring to a thiophene retains affinity to the enzyme and can be utilised in p38α MAPK inhibitors. This compound was further elaborated using a substituted phenyl ring in order to probe the second hydrophobic pocket. Many of these analogues exhibited low micromolar affinity to active p38α MAPK. The suppression of neonatal rat fibroblast collagen synthesis was also observed suggesting that further development of these compounds may lead to potential therapeutics having cardioprotective properties.

ChemInform Abstract: [3 + 3] Annulation of Donor—Acceptor Cyclopropanes with Mercaptoacetaldehyde: Application to the Synthesis of Tetrasubstituted Thiophenes.

A conceptually new method for synthesis of tetrasubstituted thiophenes in two steps from trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol has been developed. It involves AlCl3-mediated [3+3] annulation of the cyclopropane-derived 1,3-zwitterionic intermediates with in situ generated mercaptoacetaldehyde, followed by DBU-induced rearrangement of the resulting tetrahydrothiopyranols. The target thiophenes are produced in 55–82% yields.

An efficient one-pot three-component synthesis and antimicrobial evaluation of tetra substituted thiophene derivatives

Abstract A convenient one-pot three-component method for the preparation of tetra-substituted thiophene derivatives has been developed. Reaction of acetyl acetone 1 , phenyl isothiocynate 2 and 2-chloromethyl derivatives 3a – 3c in the presence of potassium carbonate afforded the target compounds, namely ethyl 2-(4-acetyl-3-methyl-5-(phenylamino)thiophen-2-yl)-2-oxoacetate derivatives 4a – 4e , ethyl 3-(4-acetyl-3-methyl-5-(phenylamino)thiophen-2-yl)-3-oxopropanoate derivatives 4f – 4i , di((4-acetyl-3-methyl-5-phenylamino)thiophen-2-yl)ketone derivatives 4j – 4n in reasonable overall yields. The synthesized compounds were screened for antimicrobial activity. The detailed synthesis, spectroscopic data and antimicrobial activities of synthesized compounds were reported.

ChemInform Abstract: Three‐Component Cascade Annulation of β‐Ketothioamides Promoted by CF3CH2OH: A Regioselective Synthesis of Tetrasubstituted Thiophenes.

A rapid and highly efficient method for the regioselective synthesis of thiophene derivatives has been developed by annulation of β-ketothioamides with arylglyoxals and 5,5-dimethyl-1,3-cyclohexanedione in CF3CH2OH within 15 min. The present synthesis has several desirable features, such as high regioselectivity, a concise one-pot protocol, short reaction time, and easy purification. This methodology provides an alternative approach for easy access to tetrasubstituted thiophenes via a one-pot cascade reaction without other additives.

3+3] Annulation of donor–acceptor cyclopropanes with mercaptoacetaldehyde: application to the synthesis of tetrasubstituted thiophenes

A conceptually new method for synthesis of tetrasubstituted thiophenes in two steps from trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol has been developed. It involves AlCl3-mediated [3+3] annulation of the cyclopropane-derived 1,3-zwitterionic intermediates with in situ generated mercaptoacetaldehyde, followed by DBU-induced rearrangement of the resulting tetrahydrothiopyranols. The target thiophenes are produced in 55-82% yields.

Three-Component Cascade Annulation of β-Ketothioamides Promoted by CF3CH2OH: A Regioselective Synthesis of Tetrasubstituted Thiophenes

A rapid and highly efficient method for the regioselective synthesis of thiophene derivatives has been developed by annulation of β-ketothioamides with arylglyoxals and 5,5-dimethyl-1,3-cyclohexanedione in CF3CH2OH within 15 min. The present synthesis has several desirable features, such as high regioselectivity, a concise one-pot protocol, short reaction time, and easy purification. This methodology provides an alternative approach for easy access to tetrasubstituted thiophenes via a one-pot cascade reaction without other additives.

Introduction of methionine mimics on 3-arylthiophene: influence on protein farnesyltransferase inhibition and on antiparasitic activity

In the course of our search for new protein farnesyltransferase inhibitors with antiparasitic activity, we found that addition of a methionine residue at position 2 of 3-arylthiophenes greatly improved enzyme inhibition. To investigate the influence of this methionine residue on FTase and antiparasitic activities, 29 novel tetrasubstituted thiophenes bearing methionine or analogous moieties were synthesised. These new derivatives were evaluated on human and Trypanosoma brucei protein farnesyltransferases and on proliferation of 4 protozoan parasites: Plasmodium falciparum, Trypanosoma brucei brucei, Trypanosoma cruzi and Leishmania donovani. Some compounds showed promising low micromolar or submicromolar activities on T. b. brucei and L. donovani confirming the potential of this new class as antiparasitic agents.

ChemInform Abstract: The Reactivity of gem Cyanoester Ketene Dithiolates Towards the Development of Potent Antioxidant Heterocycles.

AbstractA variety of tetrasubstituted thiophene, thieno‐thiophene and tris‐heterocyclic compounds are synthesized by intra‐ or intermolecular cyclocondensation reactions of gem‐cyanoester ketene dithiolates (IV).

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity

Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

Cross-Conjugated Cruciform Fluorophores

In optoelectronic devices, chromophores can be designed at the molecular level to create materials with properties desired for advanced applications. Organic fluorophores in particular can be constructed with macroscopic properties that arise from two distinct contributions: (i) the collective impact of the molecular backbone and substituents and (ii) the connectivity within the molecule (that is, the spatial molecular architecture). Accordingly, the exploration of novel conjugated architectures is a productive area of current research. Different two-dimensional, "X-shaped" conjugated materials have been synthesized for a variety of applications. They include spiro compounds, paracyclophanes, swivel-type dimers, bisoxazole-derived cruciforms, tetraethynylethenes, and tetrasubstituted tolanes. A subset of these compounds are constructed from two "perpendicular" pi-conjugated linear arms connected through a central aromatic core; examples of these include tetrakis(arylethynyl)benzenes, tetrakis(styryl)benzenes, and tetrasubstituted thiophenes. In this Account, we evaluate 1,4-distyryl-2,5-bis(arylethynyl)benzenes or cruciforms (XFs). Electronic substitution of this "X-shaped" cross-conjugated scaffold tunes both the energy levels of the frontier molecular orbitals (FMOs) and their spatial distribution in XFs. The resulting fluorophores exhibit FMO separation, imbuing XFs with unusual yet desirable properties for sensory applications. Using model analytes, we examine how the underlying FMO arrangement and the nature of analyte interaction elicit observable responses. These studies provide a foundation for accessing functional responsive ratiometric cores, demonstrating the importance and unique potential of FMO-separated fluorophores. We also highlight the essential contribution of serendipity in materials development. Moving beyond one-dimensional molecular wire-type fluorophores to two-dimensional "X-shaped" materials provides access to materials with unexpected and exciting properties. XFs represent such novel conjugated architectures, and their successful development has frequently has hinged on inspiration from structural components and principles developed in diverse research areas.

One-pot synthesis of new tetrasubstituted thiophenes and selenophenes

In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene dithioacetals.

Design, synthesis and pharmacological evaluation of novel tetrasubstituted thiophene analogues as anti-inflammatory agents

A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL were performed using standard drug ascorbic acid.

Synthesis, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC50 value 31.59 μg/mL.

Efficient synthesis of tetrasubstituted thiophenes by reaction of benzoyl isothiocyanates, ethyl bromopyruvate and enaminones

An efficient synthesis of ethyl 2-(4-acetyl-5-benzoylamino-3-methyl-2-thienyl)-2-oxoacetates is described via reaction between benzoyl isothiocyanates and ethyl bromopyruvate in the presence of enaminones.