C?H Bond Activation/Borylation of Furans and Thiophenes Catalyzed by a Half‐Sandwich Iron N‐Heterocyclic Carbene Complex

A coordinatively unsaturated iron‐methyl complex having an N‐heterocyclic carbene ligand, [Cp*Fe(L^Me)Me] ( 1 ; Cp*=η⁵‐C₅Me₅, L^Me=1,3,4,5‐tetramethyl‐imidazol‐2‐ylidene), is synthesized from the reaction of [Cp*Fe(TMEDA)Cl] (TMEDA=N,N,N′,N′‐tetramethylethylenediamine) with methyllithium and L^Me. Complex 1 is found to activate the C? H bonds of furan, thiophene, and benzene, giving rise to aryl complexes, [Cp*Fe(L^Me)(aryl)] (aryl=2‐furyl ( 2 ), 2‐thienyl ( 3 ), phenyl ( 4 )). The C? H bond cleavage reactions are applied to the dehydrogenative coupling of furans or thiophenes with pinacolborane (HBpin) in the presence of tert‐butylethylene and a catalytic amount of 1 (10 mol % to HBpin). The borylation of the furan/thiophene or 2‐substituted furans/thiophenes occurs exclusively at the 2‐ or 5‐positions, respectively, whereas that of 3‐substituted furans/thiophenes takes place mainly at the 5‐position and gives a mixture of regioisomers. Treatment of 2 with 2 equiv of HBpin results in the quantitative formation of 2‐boryl‐furan and the borohydride complex [Cp*Fe(L^Me)(H₂Bpin)] ( 5 ). Heating a solution of 5 in the presence of tert‐butylethylene led to the formation of an alkyl complex [Cp*Fe(L^Me)CH₂CH₂tBu] ( 6 ), which was found to cleave the C? H bond of furan to produce 2 . On the basis of these results, a possible catalytic cycle is proposed.     

The ambident electrophilic behavior of 5‐nitro‐3‐X‐thiophenes in σ‐complexation processes

Kinetics of the reactions of 3,5‐dinitrothiophene 1 and 3‐cyano‐5‐nitrothiophene 2 with a series of parasubstituted phenoxide anions 3a–c have been investigated in aqueous solution at 20°C. Two unsubstituted electrophilic centers (C(2) and C(4)) of the two thiophenes have been identified. The Fukui functions correctly predict the C(2) and C(4) atoms as the most electrophilic centers of these electron‐deficient thiophenes 1 and 2 . Analysis of the experimental data in terms of Brønsted relationships reveals that the reaction mechanism likely involves a single‐electron transfer (SET) process. The excellent correlations upon plotting the rate constants versus the oxidation potentials E^o values is an additional evidence that reactions between thiophenes and phenoxide anions are proceeding through an initial electron transfer. It is of particular interest to note that the systems studied in this paper provide a rare example of a SET mechanism in σ‐complexation reactions. According to the free energy relationship log k = s(N + E) (Angew. Chem., Int. Ed. Engl., 1994, 33, 938–957), the electrophilicity parameters E of the C‐4 and C‐2 positions of the thiophenes have been determined and compared with the reactivities of other ambident electrophiles. On the other hand, the second‐order rate constants for the reactions of these thiophenes with the hydroxide ion has been measured in water and 50% water–50% acetonitrile and found to agree with those calculated theoretically using Mayr's equation from the E values determined in this work and from the previously published N and s parameters of OH⁻.     

Synthesis of new methylated thieno[2,3‐a] and [3,2‐b]carbazoles by reductive cyclization of 6‐(2′‐Nitrophenyl)benzo[b]thiophenes obtained by palladium‐catalyzed cross‐coupling isabel

The synthesis of new methylated thieno[2,3‐a] and [3,2‐b]carbazoles (5) (R=H) was achieved by a palladium‐catalyzed cross‐coupling, intramolecular reductive cyclization sequence of reactions. The cyclization precursors 6‐(2′‐nitrophenyl)benzo[b]thiophenes (3) were obtained by Suzuki cross‐coupling of 6‐boronated methylbenzo[b]thiophenes intermediates (2) with 2‐bromo or iodonitrobenzene. The boronated intermediates (2) were prepared via bromine‐lithium exchange followed by boron transmetalation and coupled in situ using Pd(OAc)₂ giving thus a “one‐pot” three steps reaction from the 6‐bromobenzo[b]thio‐phenes (1) to the cyclization precursors (3) . In the reductive cyclization step, N‐ethylthienocarbazoles (5) (R=Et) were also obtained. Several experiments have been made varying the amount of triethylphosphite and the time of reaction, to avoid their formation.     

Theoretical Study of 13C Chemical Shifts Structures of Some ortho-Substituted 3-Anilino-2-nitrobenzo[b]thiophenes and 2-Anilino-3-nitrobenzo[b]thiophenes and Comparison with Experimental

¹³C NMR chemical shifts have been calculated for structures of some substituted 3‐anilino‐2‐nitrobenzo‐[b]thiophenes ( 2 o) and 2‐anilino‐3‐nitrobenzo[b]thiophenes ( 3 o) derivatives containing OH, NH₂, OMe, Me, Et, H, F, Cl and Br. The molecular structures were fully optimized using B3LYP/6‐31G(d,p). The calculation of the ¹³C shielding tensors employed the GAUSSIAN 03 implementation of the gauge‐including atomic orbital (GIAO) and continuous set of gauge transformations (CSGT) by using 6‐311++G(d,p) basis set at density functional levels of theories (DFT). The isotropic and the anisotropy parameters of chemical shielding for all compounds are calculated. The predicted ¹³C chemical shifts are derived from equation δ=δ₀+δ where δ is the chemical shift, δ is the absolute shielding, and δ₀ is the absolute shielding of the standard TMS. Excellent linear relationships have been observed between experimental and calculated ¹³C NMR chemical shifts for all derivatives     

Programmed Site‐Selective Palladium‐Catalyzed Arylation of Thieno[3,2‐b]thiophene

Mono‐, di‐, tri‐, and tetraarylated thieno[3,2‐b ]thiophenes were synthesized by direct site‐selective Pd‐catalyzed C−H activation reactions with various aryl bromides in the presence of a phosphine‐free Pd(OAc)₂/KOAc catalyst system in N ,N ‐dimethylacetamide (DMAc). The arylation of 2‐arylthieno[3,2‐b ]thiophene took place at the C3 position if the 2‐aryl substituents possessed electron‐withdrawing groups and at the C5 position if they were bulky and possessed electron‐donating groups.     

Iridium‐Catalyzed Annulation Reactions of Thiophenes with Carboxylic Acids: Direct Evidence for a Heck‐type Pathway

The functionalization of thiophenes is a fundamental and important reaction. Herein, we disclose iridium‐catalyzed one‐pot annulation reactions of (benzo)thiophenes with (hetero)aromatic or α,β‐unsaturated carboxylic acids, which afford thiophene‐fused coumarin‐type frameworks. Dearomatization reactions of 2‐substituted thiophenes with α,β‐unsaturated carboxylic acids deliver various thiophene‐containing spirocyclic products. The occurrence of two interconnected reactions provides direct evidence for a Heck‐type pathway. The mechanistic scenario described herein is distinctly different from the S_EAr and concerted metalation–protodemetalation (CMD) pathways encountered in the well‐described oxidative C?H/C?H cross‐coupling reactions of thiophenes with other heteroarenes.     

Difunctionalisation of arenes and heteroarenes by directed metallation and sulfoxide-magnesium exchange

The aryl sulfoxide moiety allows an expedient two‐step difunctionalisation of readily available diaryl sulfoxides. Highly functionalised 1,2,4‐trisubstituted arenes and difunctionalised heteroarenes (furans, thiophenes, benzofurans and pyridines) were prepared in a two‐step sequence, triggered by an aryl sulfoxide group. In the first step, the sulfoxide moiety acts as a metallation‐directing group, allowing smooth ortho‐magnesiation with TMPMgCl ? LiCl (TMP=tetramethylpiperidine). After a quenching reaction with an electrophile, the resulting sulfoxide is converted into a second magnesium reagent with iPrMgCl ? LiCl (sulfoxide–magnesium exchange), which can be trapped with various electrophiles. Highly chemoselective TMPMgCl ? LiCl and iPrMgCl ? LiCl are compatible with a broad range of functional groups (e.g., F, Cl, CF₃, CN, CO₂tBu, alkynyl, ethers, thioethers). Large‐scale reactions (25–40 mmol) and the preparation of fully functionalised furans and thiophenes are also reported.     

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium‐catalyzed intramolecular oxidative C?H functionalization–arylthiolation of enethiolate salts of α‐aryl‐β‐(het)aryl/alkyl‐β‐mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one‐pot, two‐step process in which enethiolate salts [generated in situ through base‐mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C?H functionalization–arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N‐dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two‐step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)₂ (or PdCl₂) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2‐ and 3‐positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno‐fused heterocycles such as thieno[2,3‐b]thiophenes, thieno[2,3‐b]indoles, thieno[3,2‐c]pyrazole, and thieno[2,3‐b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd‐S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.     

Al(H_2PO_4)_3 as an Efficient and Reusable Catalyst for One-pot Three-component Synthesis of α-Amino Phosphonates under Solvent-free Conditions

Synthesis of α‐amino phosphonates is described under solvent‐free conditions at 100°C from reaction between aldehydes and amines in the presence of trialkyl phosphites using Al(H₂PO₄)₃ as an efficient and reusable heterogeneous catalyst. The advantages of this procedure are short reaction time, flexibility and having high to excellent yields.     

Metal‐Induced Thiophene Ring Opening and CC Bond Formation To Produce Unique Hexa‐1,3,5‐trienediyl‐Coupled Non‐Innocent Ligand Chelates

Ring opening of thiophenes containing an azo function in 2‐position and subsequent dimerization through C?C coupling were observed on reaction with [Ru(acac)₂(CH₃CN)₂] (acac=acetylacetonate) to produce two 1,3,5‐hexatriene‐linked redox‐active azothiocarbonyl chelate systems. Interaction of the non‐innocent chelate ligands and of the metals at a nanoscale distance of 1.45 nm via the conjugated hexatriene bridge was studied by magnetic and electron spectroscopic measurements in conjunction with DFT calculations, revealing four‐center magnetic interactions of this unique setting and weak intervalence coupling after reduction.     

Synthesis of Chiral 2,5—Bis（oxazolinyl） thiophenes and Their Application as Chiral Shift Reagents for 1,1′—Bi—2—naphthol

A series of C2-symmetrical chiral 2,5-bis (4′-alkyloxazolin-2-yl) thiophenes (thiobox) have been synthesized from thiophene-2,5-dicarboxylic acid by sequential amidation with a chiral ethanolamine,conversion of hydroxyl to chloro group, and base-promoted oxazoline ring formation.As demonstrated by (-)-2,5-bis[4′-(S)-isopropyloxazolin-2′-yl] thiophene,these thiobox systems exhibited remarkable chirality recognition of 1,1′-bi-2-naphthol giving rise to pronounced shifts in the ^1H NMR signals of the latter axial chiral compound at the positions of C-3,C-4,C-5,and C-8.     

Direct C?H Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct C? H functionalization of various enamides and enecarbamates was realized through visible‐light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)₂(dtbbpy)PF₆] as photocatalyst in combination with Na₂HPO₄, enamides such as N‐vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2‐bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C?C double bond in the E configuration could not be alkylated. Alkylation of N‐vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N‐vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron‐deficient bromides such as 3‐bromoacetyl acetate with N‐vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C?C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.     

A new method for the synthesis of dinaphtho[1,2‐b;2′,1′‐d]thiophenes and selenophenes

Naphthalene‐1‐sulfonic acid dimethylamides were treated with n‐BuLi and elemental sulfur or selenium to afford dinaphtho[1,2‐b:2′,1′‐d]thiophenes and selenophenes, respectively. This is the first example of making two C S/Se bonds and a C C bond in a single step at room temperature and also demonstrates a useful method for the synthesis of both thiophenes and selenophenes on naphthalene. In the case of the reactions of elemental selenium, diselenides were also obtained along with dinaphtho[1,2‐b:2′,1′‐d]selenophenes. The structure of dinaphtho[1,2‐b:′,1′‐d]thiophene was characterized by X‐ray crystallography as a representative molecule. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:239–248, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20291     

Synthesis of 1H‐quinazoline‐2,4‐diones from 2‐aminobenzonitriles by fixation of carbon dioxide with amidine moiety supported polymer at atmospheric pressure

1H‐Quinazoline‐2,4‐diones, which are key intermediates in the synthesis of medicines, were successfully synthesized from 2‐aminobenzonitriles by the fixation of CO₂ in the presence of a polystyrene derivative bearing amidine moiety [poly(amidine)]. A model reaction, that is, the reaction of 2‐aminobenzonitrile ( 1a ) with CO₂ in the presence of N‐methyltetrahydropyrimidine ( MTHP ) revealed that a catalytic amount of MTHP afforded 1H‐quinazoline‐2,4‐dione ( 2a ) quantitatively at atmospheric pressure. Several 1H‐quinazoline‐2,4‐diones ( 2a ‐ 2c ) were successfully synthesized from the corresponding 2‐aminobenzonitriles ( 1a ‐ 1c ) in the presence of poly(amidine). The poly(amidine) could easily be separated from the reaction mixture by filtration and reused in subsequent reactions owing to the heterogeneous system. These demonstrated that poly(amidine) is a useful heterogeneous polymer‐supported reagent for the synthesis of 1H‐quinazoline‐2,4‐diones from CO₂. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 653–657, 2009     

Palladium chloride anchored on organic functionalized MCM‐41 as a catalyst for the Heck reaction

Palladium chloride was grafted to amino‐functionalized MCM‐41 to prepare heterogeneous catalysts. XRD, N₂ adsorption–desorption isotherms, IR, ¹³C and ²⁹Si cross‐polarization magic‐angle spinning NMR spectroscopy and XPS techniques were employed to characterize the catalytic materials. The heterogeneous palladium catalyst exhibited excellent catalytic activity for the Heck vinylation of iodobenzene with methyl acrylate, giving 92% yield of methyl cinnamate in the presence of N‐methylpyrrolidone (NMP) and triethylamine (Et₃N). The stability of the heterogeneous catalyst was also studied in detail. The catalytic tests showed that the palladium leaching correlated to solvent, base and palladium loading. The heterogeneous catalyst exhibited excellent stability towards loss of activity and palladium leaching was not observed during six recycles in the presence of toluene and Na₂CO₃. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of classical and nonclassical 2‐amino‐4‐oxo‐6‐benzylthieno‐[2,3‐d]pyrimidines as potential thymidylate synthase inhibitors

A series of seven nonclassical 2‐amino‐4‐oxo‐6‐substituted thieno[2,3‐d]pyrimidines 2‐8 and one classical N‐[4‐(2‐amino‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidin‐6‐ylmethyl)benzoyl]‐L‐glutamic acid 9 (Table I) were designed as the first in a series of 6‐substituted 6‐5 fused ring analogs as potential thymidylate synthase (TS) inhibitors and as antitumor agents. The target compounds were synthesized via a Heck coupling of appropriately substituted iodobenzenes and allyl alcohol followed by cyclization using cyanoacetate and sulfur powder to afford substituted thiophenes. The resulting thiophenes were then cyclocondensed with chloroformamidine hydrochloride to afford 2‐amino‐4‐oxo‐6‐substituted thieno[2,3‐d]pyrimidines 2‐8 and 26 . Hydrolysis of 26 followed by coupling with diethyl L‐glutamate afforded 28 . The classical analog 9 was obtained by hydrolysis of 28 . None of the target compounds inhibited human recombinant thymidylate synthase at 23 μm except 9 for which the IC₅₀ value was 100 μm.     

A Straightforward Route to Potent Phenolic Chain‐Breaking Antioxidants by Acid‐Promoted Transposition of 1,4‐Benzo[b]oxathiines to Dihydrobenzo[b]thiophenes

The transformation of simple phenols with limited antioxidant activity into potent chain‐breaking antioxidants was achieved by a three‐step protocol, consisting of the conversion of phenols into 1,4‐benzo[b]oxathiines followed by an unprecedented acid‐promoted transposition to o‐hydroxydihydrobenzo[b]thiophenes, or dihydrobenzo[de]thiochromenes, starting from phenols or naphthols, respectively. These derivatives, bearing a benzo‐fused heterocycle with a sulfide sulfur ortho to the phenolic OH, have a rate constant of reaction with alkylperoxyl radicals (k_inh) comparable to that of α‐tocopherol. A solid rationale for the transposition mechanism as well as for the structure‐antioxidant activity relationship is presented.     

The Design and Synthesis of Novel 2,3‐Dihydrobenzo[f]isoquinolin‐4(1H)‐ones via Sequential Ugi–Heck Reactions by Using an Efficient Heterogeneous Palladium Nanocatalyst

A facile and efficient synthesis of N‐alkyl‐2‐(1, 2 dihydro‐1‐methylene‐4‐oxobenzo[f] isoquinoline‐3(4H)‐yl)‐2‐phenylacetamides is performed by the consecutive, two‐step procedure that consists of Ugi and Heck reactions. The Heck reaction was performed both by homogenous and a designed heterogeneous catalyst. The heterogeneous catalyst is a coordinated palladium to 1, 10‐phenanthroline attached to chitosan@Fe3O4 magnetite nanoparticles, which was shown to be more efficient than the homogenous Pd(OAc)₂/PPh₃ catalyst with good to excellent yields.     

Palladium nanoparticles immobilized on amphiphilic and hyperbranched polymer‐functionalized magnetic nanoparticles: An efficient semi‐heterogeneous catalyst for Heck reaction

To address the obstacles facing the use of palladium‐based homogeneous and heterogeneous catalysts in C─C cross‐coupling reactions, a novel semi‐heterogeneous support was developed based on hyperbranched poly(ethylene glycol)‐block ‐poly(citric acid)‐functionalized Fe₃O₄ magnetic nanoparticles (Fe₃O₄@PCA‐b ‐PEG). Because of the surface modification of the Fe₃O₄ nanoparticles with amphiphilic and hyperbranched polymers (PCA‐b ‐PEG), these hybrid materials are not only soluble in a wide range of solvents (e.g. water, ethanol and dimethylformamide) but also are able to trap Pd²⁺ ions via complex formation of free carboxyl groups of the PCA dendrimer with metal ions. The reduction of trapped palladium ions in the dendritic shell of Fe₃O₄@PCA‐b ‐PEG leads to immobilized palladium nanoparticles. The morphology and structural features of the catalyst were characterized using various microscopic and spectroscopic techniques. The catalyst was effectively used in the palladium‐catalysed Mizoroki–Heck coupling reaction in water as a green solvent. In addition, the catalyst can be easily recovered from the reaction mixture by applying an external magnetic field and reused for more than ten consecutive cycles without much loss in activity, exhibiting an example of a sustainable and green methodology.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).