Synthesis of N-1 and ribose modified inosine analogues on solid support

Herein, we report the synthesis and the use of new N-1-dinitrophenyl-inosine based solid supports, in which the C-2 of the purine base is strongly activated toward the attack of N-nucleophiles. The synthesized supports, binding the nucleoside by a 5′-O-monomethoxytrityl function, have been used to accomplish the synthesis of a small library of N-1 alkylated inosine and AICAR derivatives. In addition, cleavage of the 2′-3′ ribose bond of N-1 alkylated inosine derivatives anchored to the supports allowed to prepare a new set of N-1 alkylated-2′,3′-secoinosine derivatives in high yields.     

Reactions of 1,4-bis(tetrazole)benzenes: formation of long chain alkyl halides

The reactions of 1,4-bis[2-(tributylstannyl)tetrazol-5-yl]benzene with α,ω-dibromoalkanes were carried out in order to synthesise pendant alkyl halide derivatives of the parent bis-tetrazole. This led to the formation of several alkyl halide derivatives, substituted variously at N1 or N2 on the tetrazole ring. The crystal structures of 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (2-N,2-N′), 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (1-N,2-N′) and 1,4-bis[(2-(8-bromooctyl)tetrazol-5-yl)]benzene (2-N,2-N′) are reported. Further discussion involves the structure of 1,4-bis[2-(6-bromohexyl)-2H-tetrazol-5-yl]benzene (2-N,2-N′) previously reported.     

A solid-phase approach to the synthesis of N-1-alkyl analogues of cyclic inosine-diphosphate-ribose (cIDPR)

We report here an efficient solid-phase synthesis of N-1-alkyl-substituted analogues of cyclic inosine-diphosphate-ribose (cIDPR), a mimic of cyclic ADP-ribose (cADPR). Our synthetic strategy makes use of a polystyrene support to which inosine was bonded through a 2′,3′-acetal linkage. Insertion of a ω-hydroxy-polymethylene chain of variable length on N-1, followed by conversion into N-1-alkylinosine-bis-phosphate derivatives and cyclization, allowed to obtain analogues of cIDPR of various ring size. The cyclization step was carried out both in solid-phase and in solution by pyrophosphate bond formation. The effect of the N-1-polymethylene chain length on the cyclization yields as well as the reaction conditions, which led to the solid-phase pyrophosphate bond formation, were thoroughly investigated.     

A convenient synthesis of the cytidyl 3′-terminal monomer for solid-phase synthesis of RNG oligonucleotides

Replacing the phosphodiester backbone of RNA with positively charged guanidinium linkages has been shown to enable RNA oligomers to overcome electrostatic repulsion and bind double-stranded DNA in a triplex with high affinity. Ribonucleotide monomers with the ability to form guanidinium linkages have been synthesized for the generation of ribooligonucleotides with guanidinium linkages (RNGs) through solid-phase synthesis. We report herein an efficient method for the synthesis of N⁴-benzoyl-2′-O-(tert-butyldimethylsilyl)-5′-N-(4-monomethoxytritylamino)-3′-O-succinyl-5′-deoxycytidine, a new monomer required for the solid-phase synthesis of cytidyl RNG oligonucleotides.     

New N-acyl, N-alkyl, and N-bridged derivatives of rac-6,6′,7,7′-tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-bisisoquinoline

The preparation of potential new ligand systems based on the rac-1,1′,2,2′,3,3′,4,4′-octahydro-6,6′,7,7′-tetramethoxy-1,1′-bisisoquinoline skeleton has been investigated. Syntheses of N-(2-bromobenzyl), N-(3-acetoxybenzyl), N-acetyl, N-chloroacetyl, N-chlorocarbonyl, N-ethoxycarbonyl and N-tert-butyloxycarbonyl derivatives and five macrocyclic, polyether containing derivatives are described.     

Novel chiral C1-1′,2′,3′,4′-tetrahydro-1,1′-bisisoquinolines: synthesis, resolution, and applications in catalytic enantioselective reactions

A straightforward synthesis of a structurally constrained C₁-1′,2′,3′,4′-tetrahydro-1,1′-bisisoquinoline 1 is described. Resolution of this compound has been achieved successfully. The preparation of chiral N-alkyl, urea, and thiourea derivatives as potential new chiral ligands, based on the parent compound 1, is reported. Chiral compound 1 induced very good selectivity and yield in the addition of either Et₂Zn (85% ee, 96% yield) or nitromethane (85% ee, 60% yield) to benzaldehyde.     

Reactions of bis(tetrazole)phenylenes. Surprising formation of vinyl compounds from alkyl halides

The reactions of 1,2-bis(tetrazol-5-yl)benzene (1), 1,3-bis(tetrazol-5-yl)benzene (2), 1,4-bis(tetrazol-5-yl)benzene (3), 1,2-(Bu₃SnN₄C)₂C₆H₄ (4), 1,3-(Bu₃SnN₄C)₂C₆H₄ (5) and 1,4-(Bu₃SnN₄C)₂C₆H₄ (6) with 1,2-dibromoethane were carried out by two different methods in order to synthesise pendant alkyl halide derivatives of the parent bis-tetrazoles. This lead to the formation of several alkyl halide derivatives, substituted at either N1 or N2 on the tetrazole ring, as well as the surprising formation of several vinyl derivatives. The crystal structures of both 1,2-[(2-vinyl)tetrazol-5-yl)]benzene (1-N,2-N′) (1b) and 1,3-bis[(2-bromoethyl)tetrazol-5-yl]benzene (2-N,2-N′) (5d) are discussed.     

Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.     

Synthesis, properties, and hepatic metabolism of strongly fluorescent fluorodipyrrinones

From non-fluorescent 8-H fluorophenyldipyrrinones, highly fluorescent (?_F 0.4-0.6) analogs have been synthesized by reaction with 1,1′-carbonyldiimidazole to bridge the dipyrrinone nitrogens and form an N,N′-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2′,1′-f]pyrimidine-3,5-dione). Amphiphilic, water-soluble 8-sulfonic acid derivatives are then obtained by reaction with concd H₂SO₄. The resulting fluorinated and sulfonated N,N′-carbonyl-bridged dipyrrinones, isolated as their sodium salts, are potential cholephilic fluorescence and ¹⁹F MRI imaging agents for use in probing liver and biliary metabolism. After intravenous injection in the rat they were excreted rapidly and largely unchanged in bile. ¹⁹F NMR spectroscopy of a pentafluorophenyl-tosylpyrrolinone synthetic precursor exhibited rarely seen diastereotopicity.     

Coupling and cycloaddition of ynamides: homo- and Negishi coupling of tosylynamides and intramolecular [4+2] cycloaddition of N-(o-ethynyl)phenyl ynamides and arylynamides

N,N′-aryl- and N,N′-alkyl-buta-1,3-diyne-1,4-ditosylamides have been synthesized for the first time, in good to excellent yields, by copper-catalyzed dimerization of the corresponding N-aryl or N-alkyl tosylynamides. Negishi coupling of N-ethynylzinc tosylamides derivatives with (hetero)aryl iodides in the presence of Pd₂dba₃ and triphenylphosphine affords N-aryl and N-alkyl arylynamides in yields of up to 90%. Intramolecular [4+2] cycloaddition reactions of N-ethynylphenyl ynamides and arylynamides allow the synthesis of carbazoles and benzannulated and heteroannulated carbazoles in moderate-to-good yields.     

Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides

A simple and efficient method for the preparation of eight phosphoramidite building blocks for incorporation of 2′-O-(2-aminoethoxymethyl)ribonucleosides and 2′-O-(3-aminopropoxymethyl)ribonucleosides into synthetic oligonucleotides has been developed. The synthetic routes are maximally convergent and provide sufficient amounts of phosphoramidites for several solid-phase synthesis coupling reactions. Using acyclic derivatives 17a,b the overall yields of phosphoramidites 2 and 3 were increased up to 50% for pyrimidine nucleosides and up to 30% for purine derivatives with substantial decrease of total reaction steps. The 2′-O-substituent was found to be stable during oligonucleotide synthesis. The resulting oligonucleotides are of particular interest for post-synthetic functionalization and conjugation.     

Synthesis of efficient blue and red light emitting phenanthroline derivatives containing both hole and electron transporting properties

Two phenanthroline derivatives containing a hole transporting triphenylamine and an electron transporting 1,3,4-oxadiazole unit have been prepared with high yield. UV-vis absorption and fluorescence measurement indicated they are high efficient light-emitting materials. The compounds are 6-(5-(4-N,N′-diphenylaminophenyl)-1,3,4-oxadiazol-2-yl) quinoxalino[2,3-f] phenanthroline (9, λ_max = 635 nm, 40% quantum yield), and 1-ethyl-2-(4-(5-(4-N,N′-diphenylaminophenyl)-1,3,4-oxadiazol-2-yl)phenyl)imidazo[4,5-f]phenanthroline (14, λ_max = 461 nm, 78% quantum yield). Preliminary study on electroluminescence for the two fluorescent dyes prepared from vacuum evaporation resulted in blue and red light emitting organic light emitting diodes (OLED).     

Intramolecular amidation: synthesis of novel imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole fused diazepinones

Novel heterocyclic systems 2-alkyl/aryl-9-(2-hydroxybenzylidene)-7,9-dihydro-8H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-d][1,2]diazepin-8-one and 9-(2-hydroxy-benzylidene)-3,3-dimethyl-3,4,7,9-tetrahydro-2H-11-thia-4b,6,7,10-tetraazaindeno[1,2-a]azulene-1,8-dione are synthesized via an intramolecular amidation reaction. An interesting ring opening and cyclization of 2-alkyl/aryl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde and 6,6-dimethyl-8-oxo-2-(2-oxo-2H-chromen-3-yl)-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-3-carbaldehyde are discussed.     

The Thorpe-Ziegler-type reaction of 3-cyanopyridine-2(1H)-thiones with Biginelli 6-bromomethyl-3,4-dihydropyrimidin-2(1H)-ones: cascade assembling of tetra- and pentacyclic heterocyclic scaffolds

3-Cyanopyridine-2(1H)-thiones have been shown to react with Biginelli-type ethyl 4-aryl-6-(bromomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates upon heating in DMF giving rise to ethyl 4-aryl-6-{[(3-cyanopyridin-2-yl)thio]methyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates. The latter upon treatment with an excess of NaH or t-BuOK in boiling DMF undergo a tandem Thorpe-Ziegler-type heterocyclization to give pyrido[3″,2″:4′,5′]thieno[2′,3′:5,6]pyrido[4,3-d]pyrimidine derivatives in good yields. Selected compounds were tested for antibacterial and antifungal activity.     

Helicity of N,N′-diaryl-trans-1,2-diaminocyclohexane derivatives. Implications for molecular helicity manipulations

Derivatives of trans-1,2-diaminocyclohexane (DACH), useful as chiral ligands, scaffolds and building blocks, differ in their conformation. The conformation of N,N′-diaryl-DACH derivatives was studied by the semiempirical and DFT computational methods and by exciton-coupled circular dichroism. It was found that, contrary to M-helical N,N′-diimine, N,N′-diimide and N,N′-diamide derivatives, the aromatic residues in N,N′-diphenyl derivatives are oriented to form a P-helix for the (R,R)-DACH absolute configuration. The helicity of the bis-aryl system is modified in the case of 1-naphthyl or 2-naphthyl derivatives. Further switching of helicity has been demonstrated by either protonation or mono-N-acetylation of N,N′-diaryl DACH derivatives.     

Synthesis, structure, and biological evaluation of C-2 sulfonamido pyrimidine nucleosides

The C-2 sulfonamido pyrimidine nucleosides were prepared by opening the 2,2′- or 2,3′-bond in anhydronucleosides under nucleophilic attack of sulfonamide anions. Reaction of the sodium salt of p-toluenesulfonamide or 2-(aminosulfonyl)-N,N-dimethylnicotinamide with 2,2′-anhydro-1-(β-d-arabinofuranosyl)cytosine gave the C-2 sulfonamido derivatives in excellent yields. Ring opening of the less reactive 2,2′-anhydrouridine and 2,3′-anhydrothymidine could be accomplished with DBU/CH₃CN activation of p-toluenesulfonamide, giving moderate yields for C-2 sulfonamido derivatives. The action of acetic acid or ZnBr₂/CH₂Cl₂ on 5-methyl-N²-tosyl-1-(2-deoxy-5-O-trityl-β-d-threo-pentofuranosyl)isocytosine led to the cleavage of both the protection group and the nucleoside bond, yielding 5-methyl-N²-tosylisocytosine as the major product. Structures of the prepared C-2 sulfonamido nucleosides were confirmed by the 1D and 2D NMR experiments, and X-ray structural analysis of 4-imino-N²-tosylamino-1-(β-d-arabinofuranosyl)pyrimidine. Both methods confirmed β-configuration and anti-conformation of the 2-sulfonamido nucleosides. The investigated compounds displayed moderate inhibition of tumor cell growth in vitro, as determined by the MTT assay using six different human tumor cell lines.     

Pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline, a novel tetracyclic ring system

Reaction of 2-chloro-3-(3-chloro-1H-pyrazol-5-yl)quinoxaline and aldehydes does not afford the corresponding N-(α-hydroxyalkylated) derivatives but results in a cyclisation reaction to give a derivative bearing the hitherto undescribed pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline system.     

Unexpected formation of 6,7-dihydrobenzo[4′,5′]imidazo-[1′,2′: 1,6]pyrimido[5,4-a]indolizine derivative in the alkylation of 2-amino-1-(benzimidazol-2-yl)-3-(4-methoxybenzoyl)indolizine

An attempt to effect exhaustive alkylation of 2-amino-1-(benzimidazol-2-yl)-3-(4-methoxybenzoyl) indolizine with alkyl iodides in boiling acetone led to the formation of 6,6-dimethyl-8-(4-methoxybenzoyl)-6,7-dihydrobenzo[4′,5′]imidazo[1′,2′: 1,6]pyrimido[5,4-a]indolizine instead of expected N-alkyl derivatives. The product structure was proved by X-ray analysis.     

Structural, spectral and thermal studies of substituted N-(2-pyridyl)-N′-phenylthioureas

N-2-(3-picolyl)-N′-phenylthiourea, 3PicTuPh, monoclinic, P2₁/n, a=7.617(2) b=7.197(5), c=22.889(5) Å, β=94.63(4)°, V=1250.7(1) Å³ and Z=4; N-2-(4-picolyl)-N′-phenylthiourea, 4PicTuPh, triclinic, P-1, a=7.3960(5), b=7.9660(12), c=21.600(3) Å, α=86.401(4), β=84.899(8), γ=77.769(8)°, V=1237.5(3) Å³ and Z=4; N-2-(5-picolyl)-N′-phenylthiourea, 5PicTuPh, monoclinic, P2₁/c, a=14.201(1), b=4.905(3), c=17.689(3) Å, β=91.38(1)°, V=1231.8(7) Å³ and Z=4; N-2-(6-picolyl)-N′-phenylthiourea, 6PicTuPh, monoclinic, C2/c2, a=14.713(1), b=9.367(1), c=18.227(1) Å, β=92.88(1)°, V=2515.5(1) Å³ and Z=8 and N-2-(4,6-lutidyl)-N′-phenylthiourea, 4,6LutTuPh, monoclinic, C2/c, a=11.107(2), b=11.793(2), c=20.084(4) Å, β=96.10(3)°, V=2616(1) Å³ and Z=8. Intramolecular hydrogen bonding between N′H and the pyridyl nitrogen and intermolecular hydrogen bonding involving the thione sulfur are affected by substitution of the pyridine ring, as is the planarity of the molecule. ¹H NMR studies in CDCl₃ show the NH′ hydrogen resonance considerably downfield from other resonances in the spectrum for each thiourea.     

N,N-Dimethylethylenediamine in direct and direct template syntheses of Cu(II)/Cr(III) complexes

Four new heterometallic Cu(II)/Cr(III) complexes with N,N-dimethylethylenediamine (dmen) and its novel Schiff-base derivatives, N′-[(1Z)-3-amino-1,3-dimethylbutylidene]-N,N-dimethylethane-1,2-diamine (dmenac) and N′-((1Z)-3-{[2-(dimethylamino)ethyl]amino}-1,3-dimethylbutylidene)-N,N-dimethylethane-1,2-diamine (dmen₂ac), have been easily prepared by self-assembly and characterized by spectroscopic methods and single crystal X-ray analysis. The structures of all the complexes are assisted by numerous hydrogen bonds that provide a web of interactions and mould the supramolecular architectures of the compounds. Variable-temperature (1.8–300 K) magnetic susceptibility measurements reveal Curie-Weiss paramagnetic behavior of all the compounds, supported by EPR studies.