Synthesis of new 5‐substitutedbenzo[b]thiophene derivatives

Previous works of our group have dealt with the synthesis of 1‐(aryl)‐3‐[4‐(aryl)piperazin‐1‐yl]propane derivatives in the search for new and efficient antidepressants with a dual mode of action: serotonin reuptake inhibition and 5‐HT_1A receptor afinity [1‐4]. From these studies we concluded that the 3‐[4‐(aryl)piperazin‐1‐yl]‐1‐(benzo[b]thiophen‐3‐yl)propane derivatives led to the best results. The continuation of this research project required the preparation of some new 3‐acyl‐5‐substituted benzo[b]thiophenes with a wide variety of substituents at the 5 position, ranging from nitro to hydroxyl derivatives. To obtain these derivatives we acylated the corresponding 5‐substituted benzo[b]thiophenes when it was possible.     

The psuedo‐michael reaction of 2‐aminoimidazolines 2. Part 1. Synthesis and structure assignment of isomeric 5(1H)‐Oxo and 7(1H)‐Oxo‐2,3‐dihydroimidazo[1,2‐a]pyrimidine‐6‐carboxylates

The pseudo‐Michael reaction of 1‐aryl‐2‐aminoimidazolines‐2 with diethyl ethoxymethylenemalonate (DEEM) was investigated. Extensive structural studies were performed to confirm the reaction course. For derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent. When the reaction temperature was held at ?10 °C only the formation of 1‐aryl‐7(1H)‐oxo‐2,3‐dihydroimi‐dazo[1,2‐a]pyrimidine‐6‐carboxylates ( 4 ) was observed in contrast to earlier suggestions. Under the room temperature conditions, the same reaction yielded mixtures, with varying ratio, of isomeric 1‐aryl‐7(1H)‐oxo‐ ( 4a‐4f ) and 1‐aryl‐5(1H)‐oxo‐2,3‐dihydroimidazo[1,2‐a]pyrimidine‐6‐carboxylates ( 5a‐5f ). The molecular structure of selected isomers, 4b and 5c , was confirmed by X‐ray crystallography. Frontal chro‐matography with delivery from the edge was applied for the separation of the isomeric esters. The isomer ratio of the reaction products depended on the character of the substituents on the phenyl ring. The 1‐aryl‐7(1H)‐oxo‐carboxylates ( 4a‐4f ) were preferably when the phenyl ring contained H, 4‐CH₃, 4‐OCH₃ and 3,4‐Cl₂ substituents. Chloro substitution at either position 3 or 4 in the phenyl ring favored the formation of isomers 5a‐5f . The isomer ratios were confirmed both by ¹H NMR and chromatography. The reaction of the respective hydrobromides of 1‐aryl‐2‐aminoimidazoline‐2 with DEEM, in the presence of triethylamine, gave selectively 5(1H)‐oxo‐esters ( 5a‐5f ).     

NH‐Heterocyclic Aryliodonium Salts and their Selective Conversion into N1‐Aryl‐5‐iodoimidazoles

The synthesis of N‐arylimidazoles substituted at the sterically encumbered 5‐position is a challenge for modern synthetic approaches. A new family of imidazolyl aryliodonium salts is reported, which serve as a stepping stone on the way to selective formation of N1‐aryl‐5‐iodoimidazoles. Iodine acts as a “universal” placeholder poised for replacement by aryl substituents. These new λ³‐iodanes are produced by treating the NH‐imidazole with ArI(OAc)₂, and are converted to N1‐aryl‐5‐iodoimidazoles by a selective copper‐catalyzed aryl migration. The method tolerates a variety of aryl fragments and is also applicable to substituted imidazoles.     

Non conventional syntheses of heterocyclic compounds. 2. Synthesis of 1H-4,5-dihydro-1,3,4-benzotriazepine derivatives

Arylazoanils carrying aromatic methyl or ethyl groups in the position ortho to the imine function thermally cyclize to give 1H-4,5-dihydro-1,3,4-benzotriazepine derivatives in fairly good yields. A study of the effect of the substituents on both the aryl rings is reported. The reaction is interpreted as an internal oxo-reduction process.     

Synthesis and Opto-electronic Properties of BODIPY o-OPhos Systems

Herein, we report the versatile synthetic strategy and opto-electronic properties for the phosphorylation of BODIPY derivatives 5aa - 5ak by substituting with an electron-donating/withdrawing group at the ortho position. Nevertheless, this new methodology relatively promotes the tolerance of the aldehyde moiety and the high yield for the synthesis of BODIPY o-OPhos derivatives. The photophysical studies suggest improved optical properties due to the inductive effect of various electron-donating/withdrawing groups. The UV-visible and the emission data suggest that BODIPY o-OPhos derivatives emphasize the property of the excited states with an increase in fluorescence intensity and high quantum yields due to the presence of bulky phospsho-triester at the meso- position which hinders the free rotation around the C-Ar bond and facilitates the development of OLEDs and various organophosphorus warfare agents. Electrochemical studies reveal 5ak depicts the ease of redox activity amongst the 5aa - 5ak derivatives. The density functional theory indicates the highest occupied molecular orbital on the BODIPY moiety whereas the lowest unoccupied molecular orbital delocalized on BODIPY and the phospho-triester moieties. Thus, the unique development of the novel BODIPY derivatives with improved optical and redox properties pave the way for fluorescent probes and bioimaging techniques.     

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.     

Synthesis of Acyclic Nucleosides with N‐[(Benzyloxy)(aryl)methyl] Substituents as Potential HEPT,EBPU, and TNK‐651 Analogues

The syntheses of the novel acyclic nucleosides 5a – 5m , carrying different N‐[(benzyloxy)(aryl)methyl] substituents, are described (Scheme). These compounds could be prepared in medium‐to‐good yields by either direct or silyl‐assisted coupling of the electrophiles 6 with either purine or pyrimidine nucleobases, or with different imidazole derivatives. The reactivity of the positively charged electrophilic intermediates derived from 6 upon Cl^? abstraction was rationalized by ab initio HF/6‐311G quantum‐mechanic calculations. The positive charge was found to be dispersed differently, depending on the electronic properties of the aryl substituents.     

Microwave‐Assisted One‐Pot Synthesis of 2‐(Substituted phenyl)‐1H‐benzimidazole Derivatives

A series of 2‐(substituted phenyl)‐1H‐benzimidazole derivatives with various 5‐and 6‐position substituents (‐H, ‐CH₃, ‐CF₃) were synthesized via microwave irradiation using a short synthetic route and Na₂S₂O₅ as oxidant. This simple, fast, and efficient preparation of benzimidazole derivatives has been developed using readily available and inexpensive reagents (aldehydes and 1,2‐phenylenediamines) under solvent‐free conditions.     

Asymmetric Mannich‐Type Synthesis of N‐Phosphinyl α‐Aminophosphonic Acid Monoesters

A convenient diastereoselective synthesis of diisopropyl (2R,3R)‐3‐{{{(R/S)‐aryl[(diethoxyphosphinyl)amino]methyl}hydroxyphosphinyl}oxy}‐2‐hydroxybutanedioate through Mannich‐type reactions is reported. The reactions take place under mild conditions in good yields, and this makes it possible to introduce various substituents at the α‐position to the P‐atom of α‐aminophosphonates. The chiral diisopropyl (4R,5R)‐2‐chloro‐1,3,2‐dioxaphospholane‐4,5‐dicarboxylate ( 3 ) was found to be a good phosphonylating agent in this stereoselective reaction.     

Reactions of 1,3-dihydrobenzo[<Emphasis Type="Italic">c</Emphasis>]thiophene 2,2-dioxides with electrophilic agents

Nitration, sulfonation, and iodination of 1,3-dihydrobenzo[c]thiophene 2,2-dioxide and its derivatives with electron-releasing and electron-withdrawing substituents were studied. Electrophilic substitution in 1,3-dihydrobenzo[c]thiophene 2,2-dioxide occurs at position 5. The presence of electron-withdrawing substituents in this position hinders further substitution, while electron-releasing substituents in positions 5 and 6 direct an electrophile to position 4.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 428–431, February, 2005.     

Reactions of Methyl 4-Aminofurazan-3-carboximidate with Nitrogen-Containing Nucleophiles

Methyl 4-aminofurazan-3-carboximidate reacts with aromatic amines and hydrazines to give the corresponding amidines and amidrazones. The reaction of the title compound with o-phenylenediamine yields 3-amino-4-(2-benzimidazolyl)furazan, and with acylhydrazines N²-acyl-4-aminofurazan-3-carbohydrazides are formed. The latter undergo thermal intramolecular cyclization with formation of 3-amino-4-(1,2,4-triazol-3-yl)furazan derivatives containing various substituents in position 5 of the triazole ring.     

Influence of substituents in the salicylaldehyde‐derived Schiff bases on vanadium‐catalyzed asymmetric oxidation of sulfides

A series of chiral Schiff bases ( L ¹ – L ⁵ ) with different substituents in the salicylidenyl unit were prepared from condensation of 3‐aryl‐5‐ tert ‐butylsalicylaldehyde derivatives and optically active amino alcohols. Bromination of 3‐phenyl‐5‐ tert ‐butylsalicylaldehyde gave an unexpected product 3‐(4‐bromophenyl)‐5‐bromosalicylaldehyde, from which the corresponding Schiff base ligands L ⁶ and L ⁷ , derived from (S)‐valinol and (S)‐ tert ‐leucinol, respectively, were prepared. Ligands L ¹ – L ⁷ were applied to the vanadium‐catalyzed asymmetric oxidation of aryl methyl sulfides. Under the optimal conditions, the oxidation of the thioanisole with H₂O₂ as oxidant in CH₂Cl₂ catalyzed by VO(acac)₂‐ L ¹ – L ⁷ gives good yields (74–83%) with moderate enantioselectivity (58–77% ee). Ligand L ⁷ , containing a 4‐bromophenyl group on the 3‐position and a Br atom on the 5‐position of the salicylidenyl moiety, displays an 80–90% ee for vanadium‐catalyzed oxidation of methyl 4‐bromophenyl sulfide and methyl 2‐naphthyl sulfide. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and tautomerism of 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles

The cyclocondensation of 1-methyl-2-phenacyl-1H-benzimidazole with aroylhydrazines yields 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles. The ¹H NMR spectra indicate that these products display tautomerism. The more stable tautomers have structures containing electron-donor aryl substituents at C-5 and electron-withdrawing aryl substituents at C-3 of the pyrazole ring.     

9,10‐Diarylanthracenes as Molecular Switches: Syntheses,Properties, Isomerisations and Their Reactions with Singlet Oxygen

A series of 9,10‐diarylanthracenes with various substituents at the ortho positions have been synthesised by palladium‐catalysed cross‐coupling reactions. Such compounds exhibit interesting physical properties and can be applied as molecular switches. Despite the high steric demand of the substituents, products were formed in moderate‐to‐good yields. In some cases, microwave conditions further improved yields. Bis‐coupling afforded two isomers (syn and anti) that do not interconvert at room temperature. These products were easily separated and their relative stereochemistries were unequivocally assigned by NMR spectroscopy and X‐ray analysis. The syn and anti isomers exhibit different physical properties (e.g., melting points and solubilities) and interconversion by rotation around the aryl–aryl axis commences at <100 °C for fluoro‐substituted diarylanthracenes and at >300 °C for alkyl‐ or alkoxy‐substituted diarylanthracenes. The reactions with singlet oxygen were studied separately and revealed different reactivities and reaction pathways. The yields and reactivities depend on the size and electronic nature of the substituents. The anti isomers form the same 9,10‐endoperoxides as the syn species, occasionally accompanied by unexpected 1,4‐endoperoxides as byproducts. Thermolysis of the endoperoxides exclusively yielded the syn isomers. The interesting rotation around the aryl–aryl axis allows the application of 9,10‐diarylanthracenes as molecular switches, which are triggered by light and air under mild conditions. Finally, the oxygenation and thermolysis sequence provides a simple, synthetic access to a single stereoisomer (syn) from an unselective coupling step.     

Binding of leucomycin and its derivatives to E. Coli ribosomes

Structure-activity relationships have been discussed for inhibition of [¹⁴C] erythromycin binding to Escherichia coli ribosomes by leucomycin and its acyl derivatives in the light of the Fujita-Ban de novo model. The group contributions of various substituents show that acylation at position 4″ of the mycarose moiety of leucomycin increases affinity for binding of leucomycins to ribosomes. It is also indicated that unlike at position 2' in mycaminose region a free hydroxyl at position 9 of the lactone ring is not important for binding to ribosomes.     

Perfluoroalkylation of 2-Thiopyrimidine Derivatives

The method of perfluoroalkylation of heterocyclic thiols and disulfides by thermolytic reaction with xenon(II) bisperfluoroalkylcarboxylates has been extended to sulfur-containing pyrimidines, including 2-mercaptopyrimidines, symmetrical disulfides, and S-trifluoroacetyl derivatives obtained from the corresponding thiols. The main reaction products are 2-SC_nF_2n+1 (n = 1, 2)-substituted pyrimidines. Their formation proceeds only via disulfides into which the initial thiols and S-trifluoroacetyl derivatives are converted in the reaction medium. Side reactions occurred in the case of trifluoromethylation linked with the perfluoroalkylation of the pyrimidine nucleus at the free 5 position (in the case of the 4,6-dimethyl derivative), or at position 4 or 4 and 5 (for unsubstituted pyrimidine). In addition, the introduction of the CF₃ group at one of the methyl substituents was confirmed by the formation of CH₂CF₃ fragment.     

Modular Synthesis of Phenanthro[9,10‐c]thiophenes by a Sequence of CH Activation,Suzuki Cross‐Coupling and Photocyclization Reactions

A total number of 15 different 3,4‐diarylthiophenes were synthesized, which bear a chlorine atom in ortho‐position of one of the aryl substituents. One aryl group was introduced by an oxidative cross‐coupling reaction, involving a C?H activation at C4(3) of the thiophene core. The other aryl group was in most cases introduced by a Suzuki cross‐coupling reaction, which succeeded the oxidative cross‐coupling step. Photocyclization reactions of the 3,4‐diarylthiophenes were performed in a solvent mixture of benzene and acetonitrile (50:50 v/v) at λ=254 nm and proceeded to the title compounds in yields of 60–82 %. The selectivity of the photocyclization was determined at the ortho‐chloro‐substituted aryl ring by the position of the chlorine substituent. At the other ring, a single regioisomer was observed for phenyl and para‐substituted phenyl groups. For 2‐naphthyl and ortho‐substituted phenyl rings a clear preference was observed in favor of a major regioisomer, while meta‐substitution in the phenyl ring led to a about 1:1 mixture of 5‐ and 7‐substituted phenanthro[9,10‐c]thiophenes. Mechanistically, the photocyclization is likely to occur as a photochemically allowed, conrotatory [(4n+2)π] process accompanied by elimination of HCl. It was shown for two phenanthro[9,10‐c]thiophene products that they can be readily brominated in positions C1 and C3 (74–77 %), which in turn allows for further functionalization at these positions, for example, in the course of halogen–metal exchange and polymerization reactions.     

Catalyst‐free Synthesis of 5‐Arylimidazo[1,2‐c]quinazoline Derivatives in Ionic Liquids

The reaction of 2‐(4,5‐diphenyl‐1H‐imidazol‐2‐yl)aniline and aromatic aldehyde was treated in ionic liquids under catalyst‐free condition and gave dehydrogenated 5‐aryl‐2,3‐diphenylimidazo[1,2‐c ]quinazolines. The same reaction gave un‐aromatized 5‐aryl‐2,3‐diphenyl‐5,6‐dihydroimidazo[1,2‐c ]quinazoline derivatives while it was controlled in an inert gas. This procedure approach to imidazo[1,2‐c ]quinazolines has the advantages of milder reaction conditions, one‐pot, catalyst free, high yields, and environmentally benign.     

New phosphonium molybdate-promoted green,fast and selective catalytic procedure for the synthesis of trisubstituted imidazoles

The compound 1,1′-(ethane,1,2-diyl)ditriphenylphosphonium hexamolybdate dimethylsulfoxide {C₂H₄[P(C₆H₅)₃]₂}{Mo₆O₁₉}·SO (CH₃)₂ ( I ) was prepared, and ¹H-NMR, ¹³C-NMR, Fourier transform-infrared, differential scanning calorimetry and single crystal X-ray diffraction analysis were used to characterize the titled compound. Crystallographic data showed that compound I crystallized in the monoclinic crystal system in C2/c space group. The compound ( I ) was used for selective synthesis of 2,4,5-tri aryl imidazole derivatives under solvent-free conditions efficiently. Because of hindrance of the catalyst, the yields of products for aldehydes bearing para substituents are higher than the aldehydes bearing ortho substituents, and for aromatic aldehydes with meta substituents are very low.     

Heck arylations of pent-4-enoates or allylmalonate using a palladium/tetraphosphine catalyst

The Heck reaction of aryl halides with functionalised alk-1-enes should be a powerful method for the synthesis of functionalised (E)-1-arylalk-1-ene derivatives. The major problem of this reaction is the palladium-catalysed migration of the carbon-carbon double bond along the alkyl chain when there are no substituents on the C3 carbon of the alk-1-enes. We observed that for the arylation of ethyl pent-4-enoate, ethyl 2-methylpent-4-enoate or dimethyl allylmalonate this migration could be partially or completely controlled using appropriate reaction conditions. The ramification on the alkyl chain and the substituents on the aryl halide have also an important influence on this migration. Moreover, the cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/1/2[PdCl(C₃H₅)]₂ system catalyses this reaction with a wide range of aryl bromides using very high ratio substrate/catalyst in good yields.