The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Optical response of phenantroimidazole-dyes covalently linked to a polynorbornene-backbone to acid and base

Two norbornene derivatives bearing phenantroimidazole dyes, namely endo/exo-11-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy) undecylbicyclo[2.2.1] hept-5-ene-2-carboxylat (5) and 11-(4-(1-Methyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy) undecylbicyclo[2.2.1]hept-5-ene-2-carboxylate (6) were synthesized. 5 and 6 were used to prepare statistical copolymers with endo,exo-bicyclo[2.2.1.]hept-2-ene-5,6-dicarboxylic acid dimethylester (7) via ring opening metathesis polymerization. The photophysical properties of the monomers and polymers and to what extent polymerization and substitution patterns influence the photophysical properties were investigated. Furthermore, the optical response upon addition of acid was investigated. The emission of monomer 5 shows a small bathochromic shift of 13 nm upon protonation while the emission of the resultant polymer poly5/7 exhibits a large red shift of 62 nm. In contrast, the according methylated monomer 6 and the resulting polymer poly6/7 gave similar absorption and emission characteristics. The differences were attributed to an increased tendency of the non-methylated dyes to interact when brought in close proximity in the polymer.     

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.     

Microwave-assisted Hantzsch thiazole synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and thioureas

N-Phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a-q) have been synthesized by the Hantzsch thiazole reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a-e) with suitably substituted thioureas using microwave heating. The ethanones (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with chloroacetylchloride 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.     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile-nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile (3, 27%) and 4-isocyano-2-(1-TIPS-1H-pyrrol-3-yl)but-2-enenitrile (7, 20%), in addition to our previously reported pyrido[3,4-b]thienopyrrole (2, 29%) and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (6, 71%) products. Minor amounts of 2-(thien-3-yl)-1H-pyrrole-3-carbonitrile (4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.     

An efficient controlled synthesis of bent-core oligoarenes and heteroarenes through ring transformation of 2H-pyran-2-ones

A general controlled synthesis of oligoarenes and heteroarenes through base-catalyzed ring transformation of 6-aryl-4-(pyrrolidin-1-yl)-2H-pyran-2-one-3-carbonitriles (1a-d) and methyl 6-aryl-4-methylthio-2H-pyran-2-one-3-carboxylates (1e-h) is described. This procedure offers flexibility in the fabrication of diverse oligoarene ring systems in a controlled fashion.     

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.     

Synthesis and characterization of aluminum and zinc complexes supported by pyrrole-based ligands and catalysis of the aluminum complexes toward the ring-opening polymerization of ?-caprolactone

Reaction of quinolin-8-amine with 1H-pyrrole-2-carbaldehyde or 5-tert-butyl-1H-pyrrole-2-carbaldehyde catalyzed by HCO₂H forms N-((1H-pyrrol-2-yl)methylene)quinolin-8-amine (≡ HL, 3a) or N-((5-tert-butyl-1H-pyrrol-2-yl)methylene)quinolin-8-amine (≡ HL′, 3b). Treatment of 3a and 3b respectively with AlMe₃ or AlEt₃ in toluene affords corresponding aluminum complexes LAlMe₂ (4a), L′AlMe₂ (4b) and LAlEt₂ (4c). Reaction of 3a and 3b with an equivalent of ZnEt₂ in toluene generates L₂Zn and L′₂Zn, respectively. A related compound N-((1H-pyrrol-2-yl)methylene)-2-(3,5-dimethyl-1H-pyrazol-1-yl)benzenamine (≡ HL″, 7) was prepared by reaction of 2-(3,5-dimethyl-1H-pyrazol-1-yl)benzenamine with 1H-pyrrole-2-carbaldehyde in the presence of HCO₂H. Reaction of 7 with AlMe₃ gives L″₂AlMe (8), and with ZnEt₂ yields L″₂Zn (9). All new compounds were characterized by NMR spectroscopy and elemental analysis. The structures of complexes 4b, 5b and 8 were additionally characterized by single crystal X-ray diffraction analyses. Complexes 4a-4c, and 8 were proved to be active catalysts for the ring-opening polymerization (ROP) of ?-caprolactone (?-CL) in the presence of BnOH. The kinetic study of the polymerization reactions catalyzed by 4a and 8 was performed.     

Design and synthesis of boron containing 2,4-disubstituted-phthalazin-1(2H)-one and 3,7-disubstituted-2H-benzo[b][1,4] oxazine derivatives as potential HGF-mimetic agents

We synthesized boron containing 2-(4-methoxybenzyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioaborolan-2-yl)phenyl) phthalazin-1(2H)-one 3 and 7-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-benzo[b][1,4] oxazine 8. The reaction of compound 2 with B₂pin₂ using potassium acetate as the base and Pd(PPh₃)₂Cl₂ as the catalyst, produced the corresponding boron-containing derivative 3 as a white solid in 65% yield. Alternatively, we have synthesized compound 8 as a yellow solid in 59% yield using the Miyaura borylation reaction. The potassium trifluoro(4-(-methyl-2H-benzo[b][1,4]oxazine-3-yl)phenylborate 9 was then obtained after treatment of 8 with aqueous solution of KF₂H in methanol as white solid product in 60% yield. The biological activities of the synthetic compounds are currently being evaluated.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.     

Micelles catalyzed one pot regio- and chemoselective synthesis of benzo[a]phenazines and naphtho[2,3-d]imidazoles ‘in H2O’

An efficient, novel, and concise one pot regio- and chemoselective synthesis of benzo[a]phenazines (4) and naphtho[2,3-d]imidazoles (8) has been accomplished in excellent yields by nucleophilic substitution reaction of 2,3-dichloro-1,4-naphthoquinone (1) with o-phenylenediamine (2) and benzamidines (7) respectively ‘in H₂O’ using base and micelles (SDS) as catalyst. Analog reaction of 2,3-dichloro-1,4-naphthoquinone (1) with 2-aminobenzenethiol (9) under identical conditions led to formation of a mixture of benzo[b]phenothiazine (10), benzo[a]phenothiazine (11), and benzo[a]-1,4-benzothiazino-3,2-phenothiazine (12) in 17%, 23%, and 57% yields, respectively.     

Photophysical properties and computational investigations of tricarbonylrhenium(I)[2-(4-methylpyridin-2-yl)benzo[d]-X-azole]L and tricarbonylrhenium(I)[2-(benzo[d]-X-azol-2-yl)-4-methylquinoline]L derivatives (X = N-CH3, O, or S; L = Cl, pyridine)

We report a combined experimental and computational study of new rhenium tricarbonyl complexes based on the bidentate heterocyclic N-N ligands 2-(4-methylpyridin-2-yl)benzo[d]-X-azole (X = N-CH₃, O, or S) and 2-(benzo[d]-X-azol-2-yl)-4-methylquinoline (X = N-CH₃, O, or S). Two sets of complexes are reported. Chloro complexes, described by the general formula Re(CO)₃[2-(4-methylpyridin-2-yl)benzo[d]-X-azole]Cl (X = N-CH₃, 1; X = O, 2; X = S, 3) and Re(CO)₃[2-(benzo[d]-X-azol-2-yl)-4-methylquinoline]Cl (X = N-CH₃, 4; X = O, 5; X = S, 6) were synthesized heating at reflux Re(CO)₅Cl with the appropriate N-N ligand in toluene. The corresponding pyridine set {Re(CO)₃[2-(4-methylpyridin-2-yl)benzo-X-azole]py}PF₆ (X = N-CH₃, 7; X = O, 8; X = S, 9) and {Re(CO)₃[2-(benzo[d]-X-azol-2-yl)-4-methylquinoline]py}PF₆ (X = N-CH₃, 10; X = O, 11; X = S, 12) was synthesized by halide abstraction with silver nitrate of 1-6 followed by heating in pyridine and isolated as their hexafluorophosphate salts. All complexes have been fully characterized by IR, NMR, electrochemical techniques and luminescence. The crystal structures of 1 and 7 were obtained by X-ray diffraction. DFT and time-dependent (TD) DFT calculations were carried out for investigating the effect of the organic ligand on the optical properties and electronic structure of the reported complexes.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

Efficient synthesis of new 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones

The synthesis of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones 5, 6a-d from 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d is reported. The 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d were obtained from regiospecific bromination of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 1, 2a-d with molecular bromine. The NMR and X-ray diffraction data showed that 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones were brominated at 4-position in the pyrrolidin-2-one ring.     

Synthesis and properties of a novel nucleoside derivative possessing a 2,3,5,6-tetraazabenzo[cd]azulene skeleton

We describe herein the synthesis and properties of the novel nucleoside derivative, 4,7-diamino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene (1). The palladium catalyzed cross-coupling reaction of 2,4-diamino-5-iodo-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (9) with acrylonitrile afforded 2,4-diamino-5-[(E)-1-cyano-2-ethenyl]-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (10) in 77% yield, which was treated with NaOMe in MeOH in the presence of NaSPh to give the desired 1 in 64% yield. Whereas 1 was stable in concentrated ammonia at room temperature, it was gradually hydrolyzed in water to give 4-amino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulen-7-one (12). Density functional calculations indicated that 12 was 20 kcal/mol more thermodynamically stable than 1 in a model study.     

Efficient stepwise and one pot three-component synthesis of 2-amino-4-(2-oxo-2H-chromen-3-yl)thiophene-3-carbonitriles

Environmentally benign conditions have been developed for the synthesis of 2-amino-4-(2-oxo-2H-chromen-3-yl)thiophene-3-carbonitriles (3) starting from 3-acetyl-2H-chromen-2-one (1) through the intermediacy of 2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)malononitrile (2) using the Knoevenagel condensation followed by the Gewald reaction. Alternatively, 3 could also be prepared in a one pot method by treating equimolar amounts of 1, malononitrile, and elemental sulfur. The merits of this preparation are mild reaction conditions, easy work-up procedure, and good yields.     

Pyrrolo-dC and pyrrolo-C: fluorescent analogs of cytidine and 2-deoxycytidine for the study of oligonucleotides

Pyrrolo-dC (1a, 6-methyl-3-(2-deoxy-β-d-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one) and its cyanoethyl phosphoramidite 2a were synthesized. The latter was incorporated into oligodeoxyribonucleotides by standard automated synthesis techniques, where pyrrolo-dC was found to serve as a fluorescent analog of deoxycytidine. The cyanoethylphosphoramidite (2b) of pyrrolo-C (2a, 6-methyl-3-(β-d-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one) was also synthesized and may find use for the site-specific incorporation of a fluorescent cytidine analog into oligoribonucleotides.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.