3-substituted Thiophene Research Articles

Transition Metal-catalyzed Bond-forming Reactions at the C-H Bond of Heteroaromatic Compounds

Recent progress in the C-H coupling reactions of heteroaromatic compounds in our group is summarized. Coupling of thiophene derivatives occurs in the presence of a nickel or palladium catalyst with a base as an additive. Lithium t-butoxide and several magnesium amides are effective for the coupling reaction of aryl chlorides, bromides, and iodides. Coupling at the C-H bond of thiophene with thienyl halides also occurs smoothly forming a thiophene-thiophene bond. The reaction is successfully applied to the polymerization of 2-halo-3-substituted thiophenes leading to highly regioregular head-to-tail-type poly(3-substituted thiophene)s. The reaction of thiazole at the C-H bond (2-position) with several secondary amines induces C-H, N-H coupling with a copper catalyst.

Metal-Free Regioselective Oxidative Biaryl Coupling Leading to Head-to-Tail Bithiophenes: Reactivity Switching, a Concept Based on the Iodonium(III) Intermediate

A new synthetic concept for obtaining unsymmetrical biaryl coupling products by an oxidative method is reported. Our synthetic strategy casts light on the reaction intermediate for switching the reactivity of 3-substituted thiophenes. On the basis of this strategy, a novel direct method for the synthesis of head-to-tail bithiophenes using hypervalent iodine(III) reagents has been developed.

ChemInform Abstract: Intermolecular Carbenoid Insertions: Reactions of 2-Substituted Thiophenes with Ethyl Diazoacetate in the Presence of Rhodium(II) Acetate.

Abstract The reactions of ethyl diazoacetate with a series of 2-substituted thiophenes in the presence of catalytic rhodium (II) acetate were examined. In the cases of 2-methylthiophene and 2-(trimethylsilyl)thiophene, cyclopropane and thiopyran products predominated while thiophene-2-thiol and 2-(methylthio)thiophene gave rise to thiopyrans and ethyl 2-(2-thienylsulfanyl)acetate. No reaction was apparent when 2-pyrrolidinothiophene was used. 2-Alkoxythiophenes, however, allowed for the production of a series of ethyl 6-alkoxy-6-thioxo-2, 4-hexadienoates. The mechanistic implications are discussed. The reactions of EDA with 2-substituted thiophenes and catalytic Rh2(OAc)4 produced cyclopropanes, thiopyrans and polyenes. Download : Download full-size image

ChemInform Abstract: Regioselective Electrophilic Formylation - 3-Substituted Thiophenes as a Case Study.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Electrochemical polymerization and characterization of new copolymers of 3-substituted thiophenes

This work presents the electrochemical synthesis and characterization of 3-substituted thiophene conducting copolymers suitable for applications in electrochromic displays. The 3-methoxythiophene (MOT), 3-thiophenemethanol (TM), 3-thiopheneethanol (TE) and 3-thiophenecarboxylic acid (TCA) monomers showed oxidation potentials at 1.1, 1.5, 1.5 and 1.8 V/SCE, respectively. Copolymers containing MOT (PMOT-co-TE, PMOT-co-TM and PMOT-co-TCA) were synthesized by oxidative electropolymerization and characterized by GPC, FTIR, UV–vis and cyclic voltammetry. The copolymers were found to be soluble in acetonitrile, N,N-dimethylformamide and N,N-dimethylsulfoxide. PMOT, PMOT-co-TE and PMOT-co-TCA showed a dependence of the anodic potential on the scan rate and a quasi-reversible profile. PMOT-co-TM showed an irreversible electrochemical profile. PMOT and PMOT-co-TE were the most electroactive polymers. The oxidation potentials vs. SCE of PMOT, PMOT-co-TE, PMOT-co-TM and PMOT-co-TCA were 0.22, 0.30, 1.16 and 0.20 V/SCE at 50 mV s −1, respectively. The copolymers deposited on ITO showed reversible color variation between blue in the oxidized state to orange when reduced, demonstrating their potential for electrochromic applications.

Highly Enantioselective Friedel−Crafts Reaction of Thiophenes with Glyoxylates: Formal Synthesis of Duloxetine

An efficient Friedel-Crafts reaction of a series of 2-substituted thiophenes with alkyl glyoxylates has been developed using a catalytic amount of an easy accessible 6,6'-dibromo-BINOL/Ti(IV) complex. A variety of hydroxy(thiophene-2-yl)acetates can be synthesized in high enantioselectivites (92-98% ee) and good yields. This is the first report on the efficient asymmetric F-C reaction of thiophenes with alkyl glyoxylates. Starting from simple thiophene and n-butyl glyoxylate, we demonstrated the formal synthesis of duloxetine.

Crystal Structures and Luminescence Properties of Pd(II) and Pt(II) Complexes with 2,5-Bis(thiophene)-1-nonyl-3,4-bis(methylthio)pyrrole

oto the pyrrole frame. The luminescence properties of the free ligand and the complexes were investigated in solution and solid states. The luminescence of the compounds were not favored by substituting thiophene moieties to the pyrrole frame, compared to the unsubstituted nbmptp (nbmptp = 1-nonyl-3,4-bis(methylthio)pyrrole). In particular, thiophene substitution quenched the emission from the complexes dissolved in CH2Cl2 and reduced the charge transfer transitions from S atoms of the thio moieties to Pt in crystalline state, which was very characteristic of Pt(nbmptp)Cl2.

Iron(III) Chloride Catalyzed Nazarov Cyclization of 3-Substituted Thiophene Derivatives

The Nazarov cyclization of silicon-free 3-substituted thiophene derivatives was effectively catalyzed by 10 mol% FeCl 3 , which provided the desired cyclized TRANS product in good yield.

Reactivity of cyclometallated platinum complexes with chiral ligands

The reaction of [Pt 2Me 4(μ-SMe 2) 2] with 3-substituted iminic thiophenes and 2-phenylpyridine gives platinum (II) [C,N] cyclometallated complexes which contain a labile ligand (SMe 2 or CH 3CN). Several platinum (II) complexes have been synthesized by substitution reactions with phosphine or sulfoxide ligands to introduce, in most cases, a second chiral center. The new complexes’ reactions with methyl iodide were subsequently studied and showed results that are dependent on the steric and electronic effects of both the cyclometallated ligand and the ancillary phosphine or sulfoxide ligand. The structure of [PtMe(( R)-C 10H 7CHMeNCHC 4H 2S)(CH 3CN)], a synthetic precursor, is also reported.

Synthesis of 3′,4′-disubstituted terthiophenes. Characterization and electropolymerization. I. 3′,4′-dibromo-2,2′:5′,2″-terthiophene in photovoltaic display

Recent studies on conducting polymers have demonstrated that polymers of 3-substituted thiophene produce very stable compounds. Although this kind of substitution improves the regularity, structural defects still exist. To overcome this drawback, the polymerization of 3,4-disubstituted thiophene is proposed as a convenient way of synthesizing regular, highly conjugated conductive polymers. Our interest is thus focused on the synthesis of tetra-substituted thiophene derivatives, their polymerization, electrochemical properties, spectral characteristics, oxidizing potential, and the feasibility of photocells development. In this article, we report the synthesis and characterization of 3′,4′-dibromo-2,2′:5′,2″-terthiophene which, as such or modified, may be a good starting product for obtaining new monomers of 3′,4′-disubstituted terthiophenes, that would allow the effect of the substituents on the properties of the respective polymers to be studied. In addition, the monomer was electropolymerized and the resulting deposit was electrochemically and morphologically characterized. Two conclusions were drawn: first, more uniform and homogeneous layers than those of polythiophene are obtained; second, the thin layers of the polymer, electron acceptors, absorb in the visible. Finally, photocells were assembled to investigate their photovoltaic effect. Although the so prepared solar cells showed some photovoltaic effect, the yield was low.© 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 5314–5321, 2006

Synthesis and characterisation of functionalised thiophene copolymers with electron donor and acceptor substituents

The synthesis of new donor/acceptor 3-substituted thiophene copolymers with two different alkyl substituents is presented. The new alternating (3-alkyl/3-cyano)thiophene copolymers were prepared via the Stille coupling reaction involving 2,5-bis-tri( n-butyl)tin-3-cyanothiophene and 2,5-dibromo-3-alkylthiophenes in the presence of catalytic amounts of palladium tetrakistriphenylphosphine. The new materials were characterised by NMR and UV–Vis spectroscopy and their molecular weights determined by gel permeation chromatography. The physical properties of the different copolymers are discussed in relation with their different alkyl group substituents (R = n-decyl and cyclohexyl).

The Synthesis of Head‐to‐Tail (H—T) Dimers of 3‐Substituted Thiophenes by the Hypervalent Iodine(III)‐Induced Oxidative Biaryl Coupling Reaction.

The head-to-tail (H–T) dimers could be obtained selectively by the oxidative coupling reaction of 3-substituted thiophenes using a combination of hypervalent iodine(III) reagents and trimethylsilyl trifluoromethanesulfonate.

Electrochemical copolymerization of 2-substituted thiophene derivative linked by polyether bridge with thiophene

New conducting copolymers have been synthesized via electrochemical oxidation of thiophene (Th) in the presence of monomer bis(2-thienyl)ethyl ( I). Cyclic voltammetry (CV) studies showed that the presence of monomer I in the electrolytic solution greatly changes the CV behaviour of the formation of the polythiophene films. It is found that the increasing ratio of I was found to decrease electroactivity of copoly( I-Th). Electrochemical synthesis of copolymer films was achieved via constant potential electrolysis (CPE) in an electrolytic solution containing 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF 6) dissolved in CH 3CN. Spectroelectrochemical (SPEL) properties of the films were investigated using UV–vis spectroscopic technique.

The synthesis of head-to-tail (H–T) dimers of 3-substituted thiophenes by the hypervalent iodine(iii)-induced oxidative biaryl coupling reaction

The head-to-tail (H-T) dimers could be obtained selectively by the oxidative coupling reaction of 3-substituted thiophenes using a combination of hypervalent iodine(III) reagents and trimethylsilyl trifluoromethanesulfonate.

Structure and electronic properties of alkylthiophenes coupled by Head-to-Tail and Head-to-Head regioselectivity

In the present paper a theoretical analysis of alkylthiophenes with Head-Tail-Head-Tail (HT-HT) and Head-Head-Tail-Tail (HH-TT) regioselectivities up to 6 monomeric units was carried out. Structure and electronic properties for the syn and anti forms were calculated by ab initio Hartree-Fock (HF) and Density Functional Theory (DFT) approaches. The energy gap between the conduction and valence bands was obtained at HF and DFT levels and also calculated with the semiempirical ZINDO/S-CI method. The results showed that the isomer with HH-TT regioselectivity presents lower energy gap for longer oligomers and the substitution of thiophene by alkyl groups does not change significantly the energy gap. This is important in the sense that more processable polymers can be obtained through alkylation without decrease the energy gap that is a molecular properties related to the electronic conductivity. Regarding to the conformational equilibrium, the syn form was found to be stable only for the HT-HT isomer and in this case the energy gap was found to be lower than those calculated for the anti form.

Synthesis and polymerization of 2- and 3-substituted thiophene derivatives linked by polyether bridges

New compounds consisting of 2- and 3-thienyl units linked by polyether bridges have been synthesized and their electrochemical polymerization was performed via constant potential electrolysis (CPE) in an electrolytic solution containing 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF6) dissolved in CH3CN. 2-Thienyl monomers (I and II), but not 3-thienyl monomers (III and IV), were also polymerized via chemical oxidation, which yielded broken π-conjugated polymer products. The polymers were characterized using 1H NMR and FT-IR spectroscopic techniques. It was found that both chemical and electrochemical oxidation of 2-thienyl monomers gave mainly poly(2,2′-bithiophenemethylene) due to elimination of polyether chains during the polymerization reaction. On the other hand, electrochemical oxidation of 3-thienyl monomers resulted in corresponding polymers without any cleavage of polyether bridges. Spectroelectrochemical (SPEL) properties of the products were investigated using UV–Vis spectroscopic techniques.

Synthesis and polymerization of 2- and 3-substituted thiophene derivatives linked by polyether bridges

New compounds consisting of 2- and 3-thienyl units linked by polyether bridges have been synthesized and their electrochemical polymerization was performed via constant potential electrolysis (CPE) in an electrolytic solution containing 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF 6) dissolved in CH 3CN. 2-Thienyl monomers ( I and II), but not 3-thienyl monomers ( III and IV), were also polymerized via chemical oxidation, which yielded broken π-conjugated polymer products. The polymers were characterized using 1H NMR and FT-IR spectroscopic techniques. It was found that both chemical and electrochemical oxidation of 2-thienyl monomers gave mainly poly(2,2′-bithiophenemethylene) due to elimination of polyether chains during the polymerization reaction. On the other hand, electrochemical oxidation of 3-thienyl monomers resulted in corresponding polymers without any cleavage of polyether bridges. Spectroelectrochemical (SPEL) properties of the products were investigated using UV–Vis spectroscopic techniques.

Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors

Prior reports from our laboratories have identified the nonpeptidic inhibitor 2 as a potent and selective Cathepsin K (Cat K) inhibitor. Modelling studies suggested that the introduction of a NH linker between the P3 aryl and P2 leucinamide moieties would allow the formation of a H-bond with the Gly66 residue of Cat K, hopefully increasing potency. Aniline 4 was thus synthesized and showed improved potency over its predecessor 2. Further modelling concluded that a 2-substituted five membered ring could more adequately place the P3 moiety of 4 into the S3 pocket of Cat K. The synthesis of the 2-substituted thiophene 5 confirmed this hypothesis by displaying a slight increase in potency against Cat K (>10-fold increase in potency vs 2) and a good selectivity profile against Cathepsins B, L, and S. This rationally designed inhibitor 5 also displayed increased potency in a functional bone resorption assay (10 nM) versus 2 (95 nM).

Iridium‐Catalyzed Direct Borylation of Five‐Membered Heteroarenes by Bis(pinacolato)diboron: Regioselective, Stoichiometric, and Room Temperature Reactions.

An iridium(I) complex generated from 1/2[Ir(OMe)(COD)]2 and 4,4′-di-tert-butyl-2,2′-bipyridine catalyzed the direct borylation of 2-substituted thiophenes, furans and pyrroles in stoichiometric amounts relative to bis(pinacolato)diboron in hexane at room temperature. The heteroarylboronates from regioselective CH activation at the 5-position were formed in high yields. Similar borylations of unsubstituted heteroarenes with an equimolar amount of the diboron regioselectively provided 2,5-bis(boryl)heteroarenes.

Dioxygenase-catalysed oxidation of monosubstituted thiophenes: sulfoxidation versus dihydrodiol formation.

Toluene dioxygenase (TDO)-catalysed sulfoxidation, using Pseudomonas putida UV4, was observed for the thiophene substrates 1A-1N. The unstable thiophene oxide metabolites, 6A-6G, 6K-6N, spontaneously dimerised yielding the corresponding racemic disulfoxide cycloadducts 7A-7G, 7K-7N. Dimeric or crossed [4 + 2] cycloaddition products, derived from the thiophene oxide intermediates 6A and 6D or 6B and 6D, were found when mixtures of thiophene substrates 1A and 1D or 1B and 1D were biotransformed. The thiophene sulfoxide metabolite 6B was also trapped as cycloadducts 17 or 18 using stable dienophiles. Preferential dioxygenase-catalysed oxidation of the substituent on the thiophene ring, including exocyclic sulfoxidation (1H-1J) and cis-dihydroxylation of a phenyl substituent (1G and 1N), was also observed. An enzyme-catalysed deoxygenation of a sulfoxide in P. putida UV4 was noticed when racemic disulfoxide cyclo-adducts 7A, 7B and 7K were converted to the corresponding enantioenriched monosulfoxides 8A, 8B and 8K via a kinetic resolution process. The parent thiophene 1A and the 3-substituted thiophenes 1K-1N were also found to undergo ring dihydroxylation yielding the cis/trans-dihydrodiol metabolites 9A and 9K-9N. Evidence is provided for a dehydrogenase-catalysed desaturation of a heterocyclic dihydrodiol (9Kcis/9Ktrans) to yield the corresponding 2,3-dihydroxythiophene (24) as its preferred thiolactone tautomer (23). A simple model to allow prediction of the structure of metabolites, formed from TDO-catalysed bacterial oxidation of thiophene substrates 1, is presented.