An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Efficient syntheses of thiadiazoline and thiadiazole derivatives by the cyclization of 3-aryl-4-formylsydnone thiosemicarbazones with acetic anhydride and ferric chloride

3-Aryl-4-formylsydnone 4′-phenylthiosemicarbazones 3a-d and 3-aryl-4-formylsydnone thiosemicarbazones 3e-h are effective precursors of sydnonyl-substituted heterocycles. The thiosemicarbazones 3a-d reacted with acetic anhydride (4a) to give 4-acetyl-2-phenylamino-5-(3-arylsydnon-4-yl)-4,5-dihydro-[1,3,4]thiadiazoles 5a-d and 4-acetyl-2-(N-phenylacetamido)-5-(3-arylsydnon-4-yl)-4,5-dihydro-[1,3,4]thiadiazoles 6a-d. However, under similar method, thiosemicarbazones 3e-h produced only 4-acetyl-2-acetamido-5-(3-arylsydnon-4-yl)-4,5-dihydro-[1,3,4]thiadiazoles 6e-h in high yield. The sydnonyl-substituted thiadiazole derivatives 7a-h were also obtained successfully by the cyclization of 3-aryl-4-formylsydnone thiosemicarbazones 3a-h with ferric chloride (4b). In the cyclization, the thiosemicarbazones 3a-d are more reactive than the thiosemicarbazones 3e-h.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Unusual conversion of substituted-3-formylchromones to 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones: a facile and efficient route to novel 1,2,4-dithiazoles

Substituted 3-formylchromones react with 2-phenyl-4-dimethylamino-1-thia-3-azabuta-1,3-diene (4) or thio-benzamide (7) by heating their toluene solution in a sealed tube to give novel substituted 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones (6a-e) in high yields.     

Facile access to stereodefined dienoates and cyclopropylenoates containing a trifluoromethyl group

Ethyl (2E,4E)-3-trifluoromethyl-2,4-dienoates 1a-e and ethyl (E)-3-trans-alkylcyclopropyl-4,4,4-trifluoro-2-butenoates 2a-e were prepared from the trans-alkenylboronic acids 3a-e and the trans-cyclopropylboronic acids 4a-e with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate (5) by the Suzuki cross-coupling reaction in high yields (88-95%). The configurations of both 3a-e or 4a-e and 5 were retained in the reaction.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Simple preparation of phenylpropenoid β-d-glucopyranoside congeners by Mizoroki-Heck type reaction using organoboron reagents

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and arylboronic acid congeners gave the corresponding cinnamyl 2,3,4,6-tetra-O-acetyl- β-d-glucopyranosides (4a-m) in good yield. Among them, coupling products 4a-m were converted to not only the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-e) but also the unnaturally ones (1f-m).     

Synthesis and conformational analysis of 1,3,2-diazaphosphorino[6,1-a]isoquinolines, a new ring system

Through ring-closure reactions of N- or 1′-substituted 1-(2′-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (5a-e) with phenylphosphonyl dichloride, 1- or 3-substituted 4-phenyl-1,3,4,6,7,11b-tetrahydro-2H-1,3,2-diazaphosphorino[6,1-a]isoquinolin-4-one diastereomers (7a-e and 8a-c,e), the first representatives of a new ring system, were prepared. The diastereomeric ratios in the cyclizations and the conformer (A-E) populations of the nitrogen-bridged tricyclic systems (7 and 8) were strongly influenced by the N- and 1′-substituents of the starting diamines. The conformational analysis of compounds 7 and 8 was performed by ¹H, ¹³C and ³¹P NMR methods.     

An efficient route for the synthesis of 2-arylthiazino[5,6-b]indole derivatives

Substituted 2-thiobenzamidomethylindole derivatives (14a-e) were prepared by the reaction of 2-aminomethylindole (9) with substituted benzoyl chlorides, followed by sulfurization using Lawesson's reagent. Alternatively, these thioamides were obtained from the amine in one step in an efficient manner by using substituted benzaldehydes in the presence of sulfur, or at room temperature with the aid of substituted methyl dithiobenzoates. The Hugerschoff reactions of thiobenzamides (14a-e) with phenyltrimethylammonium tribromide provided the rare title 2-arylthiazino[5,6-b]indoles (15a-e) in good yields. A convenient one-pot approach for the synthesis of 2-phenyl-1,3-thiazino[5,6-b]indole (15a) from 2-aminomethylindole (9) is also described.     

A highly stereoselective preparation of CF3-substituted 1-aryl-1,2-diphenylethenes: application to the synthesis of panomifene

β-CF₃-α,β-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be crystallized in a mixture of CH₂Cl₂ and hexane. The addition-elimination reaction of (E)-4a with phenyllithium having substituents on the benzene ring provided 5a-j in 51-82% yields stereospecifically. Similarly, the treatment of (E)-4a with p-chloroethoxyphenyllithium in the presence of 12-crown-4 (20 mol %) at −10 °C, followed by slowly warming to room temperature, resulted in the formation of the corresponding panomifene precursor 6 in 82% yield.     

Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes

Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2S, 5R)-3a-6a and (2R, 5R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G^∗ level of conformational inter-conversion for (2S, 5R)-D5a and (2R, 5R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2S, 5R)-D5a while conformer K2 is more stable in the case of (2R, 5R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (−) and (+) epoxides in the case of ketones 3e-6e.     

A facile synthesis and thio-Claisen rearrangement of 3-aryl-2-phenyl-5-prop-2-ynylsulfanyl-3H-pyrimidin-4-ones: regioselective transformation to thieno[3,2-d]pyrimidin-4-ones

The synthesis and transformation of previously unknown 3-aryl-2-phenyl-5-prop-2-ynylsulfanyl-3H-pyrimidin-4-ones 3a-e to novel thieno[3,2-d]pyrimidin-4-ones 4a-e are reported.     

Rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates to pyrrolo[1,2-e]imidazol-6-ols, precursors of 2,5-dihydro-1H-pyrrole derivatives

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD rearrange in the presence of methoxide to give cis-3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olates 3 with 100% de. The acidic hydrolysis of 3 led to kinetically controlled formation of methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((arylamino)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylates 6a-e. The intramolecular transformylations of the latter to the corresponding (E)- and (Z)-methyl 4-hydroxy-2-((N-(aryl)formamido)methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 7a-e were shown to be substituent dependent (correlate with σ) and characterized by Hammett type equations. The effect of temperature was investigated and the ρ constants determined for the same reaction series at 50, 60 and 70 °C. The amide diastereomeric ratio [(E)-7]/[(Z)-7] is substituent dependent and can be described by the equation log[(E)]/[(Z)]_x=−ρσ_I+log[(E)]/[(Z)]_x=H.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Solvent-free reaction on KF-alumina under microwave: serendipitous one-pot domino synthesis of new isobenzofuran-1(3H)-ones from alpha-hydroxyketones

The reaction of four α-hydroxyketones 1a-d with a double equivalent of t-butyl acetylacetonate in the presence of KF-alumina under microwave irradiation afforded 6-acetyl-5-hydroxy-3,3-dialkyl-7-methyl isobenzofuran-1(3H)-ones 3a-d.     

Chemistry of cyclopropenones: synthesis of new pyrrolo[2,1-b]-1,3,4-oxadiazoles

2,3-Diphenylcyclopropenone (1) reacts with ylidene-N-phenylhydrazine-carbothioamides 2a-e to form the pyrrolo[2,1-b]-1,3,4-oxadiazoles 5a-e.     

Microwave-assisted manganese(III) acetate based oxidative cyclizations of alkenes with β-ketosulfones

The microwave-assisted synthesis of 5-(4-nitrophenyl)-2-phenyl-4-(phenylsulfonyl)-2,3-dihydrofuran (5a) was performed via manganese(III) acetate based oxidative cyclization of 1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone (3a) with vinylbenzene (4a). This new protocol was applied to four sulfone derivatives (3a-d), using vinylbenzene (4a) and diphenylethene (4b), affording a series of 2,3-dihydrofurans (5a-d, 6a-d) in moderate to good yields (26-55%). Similar methodology, applied on allylbenzene (4c), surprisingly, led to dehydronaphthalene derivatives (7a-d) in moderate yields. The unexpected mechanism and the role of allylbenzene (4c) are herein discussed.     

A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines

The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a-e) afforded rapid access to a family of α,β-unsaturated nitriles (3a-e) in good yields (67-78%). Flow hydrogenation (ThalesNano H-cube™) at 60 °C, 50 bar H₂ pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a-e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H₂ pressure and flow rates of 0.5-1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a-e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors.     

Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors

A series of triazepane derivatives such as (R)-3-amino-1-(1,2,5-triazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (7, 13a-p) and (R)-3-amino-1-(1,2,5-triazepan-5-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (17a-e) was synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV (DPP-IV) enzyme. Compounds with the acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. Among them, compound 13p ((R)-4-[1-acetyl-2-{3-amino-4-(2,4,5-trifluorophenyl)butanoyl-1,2,5-triazepan-5-carbonyl}benzoic acid]) showed a good in vitro activity without inhibiting CYP.     

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f subjected to hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a-6e or 7. Direct ring-closure of 6a-6e with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a-9e.