S-Transalkylation/ring closing metathesis as a route to azathiamacrocycles incorporating 2,2′-bipyridine subunits

A new route to cyclophanes 6a,b incorporating 2,2′-bipyridine subunits has been elaborated using as the key steps (1) S-transalkylation of 6,6′-bis(methylsulfanyl)-2,2′-bipyridines 2a,b with ethyl bromoacetate resulting in the formation of 6,6′-bis[(ethoxycarbonyl)methylsulfanyl]-2,2′-bipyridines 3a,b and (2) ring-closing metathesis of the corresponding alkenyl ethers 5a,b.     

Syntheses of extreme sterically hindered 4-methoxyboronic acids

4-Iodoanisoles 3a,b, 3d and 4-bromoanisoles 4a-d were readily obtained. An extreme steric hindrance precluded obtaining 3c. Catalytic borylation of 3a,b, 3d followed by hydrolysis of boronic ester 26a,b, 26d easily provided the boronic acids 5a,b, 5d. Compounds 5a and 5d were also synthesised, starting from 4a and 4d, by halogen/metal exchange. Because of a too important steric hindrance, this last reaction failed with 4c and 4b led to the unexpected but stable boronic ester 6. The final obtaining of 5b required a strongly basic hydrolysis with heating.     

Rearrangement of the carbon skeleton in the intramolecular photoadduct of anthracene and benzene rings

The effectivity of optical switching between anthracene derivatives 3a,b and their intramolecular photocycloadducts 4a,b is impaired by traces of acid. The systematic treatment of 4a,b with an increasing excess of formic acid revealed that—apart from the normal enolether cleavage 4a,b→6a,b→7a,b—a cleavage with rearrangement of the carbon skeleton can occur: 5b→6b′. The driving force is a stability enhancement of the involved carbenium ions 5b→5b′. A further increased excess of formic acid leads finally to a competitive ether cleavage in the tetrahydrofuran ring 5b→8.     

Reactivity of 1-boraadamantanes towards bis(trialkylstannyl)ethynes. First examples of 3-boratricyclo[5.3.1.1]dodecanes, and the molecular structure of a tetraalkyldiboroxane

1-Boraadamantane (1) and 2-ethyl-1-boraadamantane (1(2-Et)) react with bis(trialkylstannyl)ethynes (3), R₃Sn-CC-SnR₃ with R=Me (a), Et (b), in a 1:1 molar ratio by 1,1-organoboration under very mild conditions to give the 4-methylene-3-borahomoadamantane derivatives 4a,b and 7a,b, respectively, which are dynamic at room temperature with respect to deorganoboration. The compounds 4a,b react further with 3a,b by 1,1-organoboration to the tricyclic butadiene derivatives 5a,b. Attempts to crystallise 4a afforded the product of hydrolysis, the diboroxane 6a which was characterised by X-ray structural analysis. All products were characterised in solution by ¹H-, ¹¹B-, ¹³C- and ¹¹⁹Sn-NMR spectroscopy.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

Synthesis, antitumor and DNA photocleaving activities of novel naphthalene carboxamides: effects of different thio-heterocyclic rings and aminoalkyl side chains

Two kinds of thio-heterocyclic fused naphthalene carboxamides, 3a-b, 4a-b, were designed, synthesized and quantitatively evaluated as efficient antitumor and DNA photocleaving agents. Compound 3a or 3b, having the thiophene ring, intercalated into DNA more strongly than compound 4a or 4b, having the thioxanthene ring. Compound 4a or 4b, photocleaved DNA more efficiently than 3a or 3b via superoxide anion. Compound 4a was the strongest inhibitor for P388 (murine leukemia cell), while 3a was the most cytotoxic one against A549 (human lung cancer cell). Each new compound showed stronger DNA photocleaving activity than corresponding naphthalimide.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Synthesis and binding ability of bile acid-based receptors for recognition of flavin analogues

Novel cholaphanes 6a,b, based on lithocholic and deoxycholic acids, were synthesised through 3a,b by a sequence of reactions involving Cs-salt methodology of macrocyclisation. Cholaphanes 6a,b and acyclic steroidal receptors 3a,b bind flavin analogues via three hydrogen bonds in CHCl₃.     

New possibilities of 1,2,4-triazines functionalization: first examples of synthesis and structure of boron-containing 1,2,4-triazines

By oxidation of 3-thioderivatives of 1,2,4-triazine 1a,b 3-alkylsulfonic derivatives 2a,b were obtained. Interaction of the sulfonic derivative 2a with indole leads to 3-oxo-5-indolyl-5-phenyl-as-triazine 4. The sulfone 2a reacts with 1-ethyl-2,6-dimethylquinolinium iodide to give 3-(1-ethyl-6-methyl-1,2-dihydroquinoline-2-methylene)-5-phenyl-1,2,4-triazine 5. The 3-morpholino- 3 and 3-thioderivatives 6, 7a,b of as-triazine were obtained by interaction of the sulfone 2 with morpholine and organic boron-containing thiols. The crystal structure of boron-containing derivative of as-triazine 7b was investigated by X-ray analysis.     

Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15→16 and 22→23+24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b, which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).     

Stereocontrolled conversion of some optically active (4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Optically active (4S,5R)-dihydroisoxazoles 5a-c (90-91% ee) have been prepared by reaction of the epoxyketones 4a-c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b.     

Synthesis of (−)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b. Intermediates 6a and 6b were efficiently converted to (−)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.     

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).     

Synthesis and characterization of half-sandwich Rh, Ir complexes containing mono-thiolate-ortho-carborane ligand

Two binuclear complexes [Cp^∗M(Cl)Carb^S]₂ (Cp^∗ = η⁵-C₅Me₅, M = Rh (1a), Carb^S = SC₂(H)B₁₀H₁₀, Ir (1b)) were synthesized by the reaction of LiCarb^S with the dimeric metal complexes [Cp^∗MCl(μ-Cl)]₂ (M = Rh, Ir). Four mononuclear complexes Cp^∗M(Cl)(L)Carb^S (L = BuⁿPPh₂, M = Rh (2a), Ir (2b); L = PPh₃, M = Rh (4a), Ir (4b)) were synthesized by reactions of 1a or 1b with L (L = BuⁿPPh₂ (2); PPh₃ (4)) in moderate yields, respectively. Complexes 3a, 3b, 5a, 5b were obtained by treatment of 2a, 2b, 4a, 4b with AgPF₆ in high yields, respectively. All of these compounds were fully characterized by IR, NMR, and elemental analysis, and the crystal structures of 1a, 1b, 2a, 2b, 4a, 4b were also confirmed by X-ray crystallography. Their structures showed 3a, 3b and 5a, 5b could be expected as good candidates for heterolytic dihydrogen activation. Preliminary experiments on the dihydrogen activation driven by these half-sandwich Rh, Ir complexes were done under mild conditions.     

Synthesis, characterization, and derivatization of some novel types of fluorinated mono- and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities

A series of thirty eight novel imidazolidineiminothiones (6a-g, 10a-h, 13a,b, 15a-d, and 16a), 5-thioxoimidazolidine-2,4-diones (7a-d, 11a-e, 14a,b, and 16b), and bis-imidazolidineiminothiones (17-20) with various fluorinated aromatic substituents at N-(1) and N-(3) were prepared in 75-85% yields. The imidazolidineiminothiones were synthesized from fluorinated N-arylcyanothioformanilides and substituted aromatic isocyanates, and by the reactions of fluorinated aromatic isocyanates with fluorinated and non-fluorinated aromatic N-arylcyanothioformanilides. Subsequent hydrolysis of selected products produced the corresponding 5-thioxoimidazolidine-2,4-diones. Preliminary screening of several compounds against Ehrlich ascites carcinoma (EAC) cells indicated that 6f and 16a were the most active (90% and 80% inhibition, respectively). Further evaluation for cytotoxicity against other tumor cell lines gave IC₅₀ values ranging from 0.67 to 3.83 μg/mL, where compounds 15a and 16a were markedly active against all cell lines. This highlights the synergistic effect of the suitably positioned fluorinated substituents on N-(1) and N-(3) of the imidazolidineiminothiones. Compounds 6a,e-g, 10a-c, 13b, 15a-d, and 17-20 were tested against microbial organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Sarcina lutea), and fungal strains (Candida albicans, Aspergillus niger, and Aspergillus flavus). Whereas compound 6a exhibited the highest antibacterial activity against Gram positive and Gram negative bacteria, 13b displayed the strongest antifungal activity against all fungal strains, reaching as high as 30 mm. Finally, 15a,b,d were subjected to in vitro testing of antiviral activity against hepatitis A virus (HAV), human herpes simplex virus 1 (HSV1), and Coxsackie B4 (COxB4) viral strain, where 15b was the most effective, reducing virus plaque count of HSV1 and COxB4 by 50% and 60%, respectively.     

A convenient synthesis of substituted 2,2′:6′,2″-terpyridines

The 2,2′:6′,2″-terpyridines 7a-c were prepared in good yield by reacting α-acetoxy-α-chloro-β-keto-esters 3a-c with bis-amidrazone 4 and 2,5-norbornadiene 6 in ethanol at reflux. Compounds 3a and 3b gave the 2,2′:6′,2″-terpyridines 9a and 9b, respectively, in moderate yield when treated with compound 4 and enamine 8.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Synthesis of novel lariat azathia crown macrocycles containing two triazole rings and bis crown macrocycles containing four triazole rings

The 13-hydroxy macrocycles 7a-d were prepared in 40-50% yields by the condensation of 1,ω-bis(4-amino-1,2,4-triazol-3-ylsulfany)alkanes 2a-d with 1,3-bis(2-formyphenoxy)-2-propanol (9). Acylation of 7a-d with 2-chloroacetylchloride gave the corresponding esters 11a,b. Amination of 11a,b with different amines in acetone furnished exclusively the target lariat macrocycles 12a,b and 13 in 60-70% yields. Reaction of 2 equiv. of the macrocycles 11a,b with 1 equiv. of piperazine afforded the novel bis macrocyles 14a,b in 50-60% yields. Reduction of 7a-d with NaBH₄ afforded the corresponding 13-hydroxyazathia crown ethers 15a-d in 65-70% yields.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Protonation and rearrangement of the tricyclo[4.2.2.2]dodeca-3,7,9,11-tetraene scaffold

The biplanemers 2a,b contain enol ether substructures, which permit facile protonations of the π electron system. The subsequent ether cleavage is characterized by rearrangements of the polycyclic scaffold of the carbenium ions or the electroneutral primary products. Apart from the expected products 3a and 5a, a series of unexpected ketones and diketones (4a′, 9b, 10b, 11b, and 12b) were obtained.