Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Regioselective monobromination of (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-aryl-2-propen-1-ones using bromodimethylsulfonium bromide and synthesis of 8-bromoflavones and 7-bromoaurones

A wide variety of monobrominated compounds 2a-l have been prepared in good yields from (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-aryl-2-propen-1-ones (1a-l) through regioselective ring bromination using 1.5 equiv of bromodimethylsulfonium bromide (BDMS) at room temperature. Similarly, some of the 2′-hydroxychalcones can be converted directly into tribromides 3 or dibromides 4 by employing 4.0 equiv of BDMS under different reaction conditions which in turn can be transformed into 8-bromoflavones and 7-bromoaurones on treatment with 0.2 M ethanolic KOH solution. Mild reaction conditions, good yields and no chromatographic separation are some of the salient features of the present protocol.     

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.     

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.     

Interaction of 2-(2′,6′-dialkylphenylazo)-4-methylphenols with iridium. C-H activation and migration of alkyl group

Reaction of 2-(2′,6′-diethylphenylazo)-4-methylphenol (L²) with [Ir(PPh₃)₃Cl] afforded two organoiridium complexes 3 and 4 via C-H bond activation of an ethyl group in the arylazo fragment of the L² ligand. In both the complexes the azo ligand binds to iridium as a dianionic tridentate C,N,O-donor. Two triphenylphosphines and a hydride (in the case of complex 3) or chloride (in the case of complex 4) are also coordinated to the metal center. A similar reaction of [Ir(PPh₃)₃Cl] with 2-(2′,6′-diisopropylphenylazo)-4-methylphenol (L³) yielded another organoiridium complex 5, where migration of one iso-propyl group from its original location (say, the 2′ position) to the corresponding third position (say, the 4′ position) took place through C-C bond activation. In this complex the modified azo ligand binds to iridium as a dianionic tridentate C,N,O-donor. Two triphenylphosphines and a hydride are also coordinated to the metal center. The structures of complexes 3 and 4 have been optimized through DFT calculations. The structure of complex 5 has been determined by X-ray crystallography. All the complexes show characteristic ¹H NMR signals and intense transitions in the visible region. Cyclic voltammetry on all the complexes shows an oxidation within 0.66-1.10 V vs SCE, followed by a second oxidation within 1.15-1.33 V vs SCE and a reduction within −0.96 to −1.07 V vs SCE.     

A simple and stereodivergent strategy for the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides exploiting (Z)-but-2-en-1,4-diol and (R)-2,3-cyclohexylideneglyceraldehyde

Barbier type additions of allylic bromide 4, derived from (Z)-but-2-en-1,4-diol 2 to (R)-2,3-cyclohexylideneglyceraldehyde 1 were performed through mediation with Zn employing Luche’s procedure and also with low valent Cu, Co, and Fe which were produced via bimetal redox strategy in THF to afford 5c,d as the major products. From these, 5a,b were prepared following an oxidation-reduction protocol. Compound 5c was exploited as a representative starting material to develop a simple and inexpensive strategy toward the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides having stereodiversity at 3′- and 4′-positions.     

Photoactive building blocks for coordination complexes: Gilding 2,2′:6′,2″-terpyridine

The alkyne unit of 4′-ethynyl-2,2′:6′,2″-terpyridine has been functionalized with Ph₃PAu, (2-tolyl)₃PAu or Au(dppe)Au units to produce compounds 1-3, respectively. These derivatives have been characterized by electrospray mass spectrometry, solution ¹H and ¹³C NMR, UV-Vis and emission spectroscopies, and single crystal X-ray diffraction. In the solid state, molecules of 1 or 2 pack with separated domains of tpy and R₃PAu units; the tpy units in 2 (but not 1) exhibit face-to-face π-stacking. Compound 3 crystallizes as 2(3)^.CHCl₃, and the folded conformation of the dppe backbone results in a short (2.9470(8) Å) aurophilic interaction. Folded molecule 3 captures CHCl₃, preventing intramolecular face-to-face π-interactions between the tpy units. In CH₂Cl₂ solution, 1-3 are emissive when excited between 230 and 300 nm, but over minutes when λ_ex = 230 nm, the emission bands decay as the compounds photodegrade.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

Synthesis of a series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides

A series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides 1a-d, analogues of 3TC that has high biological activities against HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis featured the construction of thiofuranose skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group in compounds 13a,b.     

A pyrazolyl-terminated 2,2′:6′,2″-terpyridine ligand: Iron(II), ruthenium(II) and palladium(II) complexes of 4′-(3,5-dimethylpyrazol-1-yl)-2,2′:6′,2″-terpyridine

The preparation of 4′-(3,5-dimethylpyrazol-1-yl)-2,2′:6′,2″-terpyridine (2) under acidic conditions results in the formation of the salts [H₂2][MeOSO₃]₂ and [H₂2][EtOSO₃]₂, treatment of which with base leads to neutral 2. The structure of [H₂2][EtOSO₃]₂ · H₂O has been established by single crystal X-ray diffraction. The complexes [Fe(2)₂][PF₆]₂ and [Ru(2)₂][PF₆]₂ have been prepared and characterized, and the single crystal structure determination of [Ru(2)₂][PF₆]₂ is reported; [Fe(2)₂][PF₆]₂ is isostructural with [Ru(2)₂][PF₆]₂. Treatment of [Fe(2)₂]²⁺ with PdCl₂ produces [Pd(2)Cl]⁺, isolated and structurally characterized as the hexafluoridophosphate salt, illustrating that metal exchange within the tpy-binding domain occurs in preference to palladium(II) coordination by the N-donor atom of the pendant 3,5-dimethylpyrazol-1-yl unit in 2. [Pd(2)Cl]²⁺ can also be prepared from PdCl₂ and [H₂2][MeOSO₃]₂ in refluxing methanol.     

Synthesis of procyanidins by stepwise- and self-condensation using 3,4-cis-4-acetoxy-3-O-acetyl-4-dehydro-5,7,3′,4′-tetra-O-benzyl-(+)-catechin and (−)-epicatechin as a key building monomer

3,4-cis-4-Acetoxy-3-O-acetyl-4-dehydro-5,7,3′,4′-tetra-O-benzyl-(+)-catechin (1a) or (−)-epicatechin (1b) reacted high regio- and stereo-selectively with 1.5 equiv of the 5,7,3′,4′-tetra-O-benzyloxyflavan-3-ol (4a or 4b) in the presence of 1 equiv of TMSOTf to give the corresponding procyanidins. On the other hand, the self-condensation of 1a in the presence of a catalytic amount of B(C₆F₅)₃ afforded wide-range procyanidins from dimer to 15-mer like a biomass.     

Synthesis and tautomeric structure of 6-arylhydrazono 1H-pyrazolo[3′,4′:4,5]pyrimido[1,6-b][1,2,4]triazepines

A simple synthetic strategy is described for synthesis of the hitherto unreported 6-arylhydrazono-1,3-diphenyl-7-methyl-1H-pyrazolo[3′,4′:4,5]pyrimido[1,6-b][1,2,4]triazepin-5(6H)-ones 5a-j. The acid dissociation constants were determined for the series prepared and were correlated by the Hammett equation using the enhanced substituent constants. The results of such a correlation together with the spectral data indicated that the studied compounds exist predominantly in the hydrazone tautomeric form.     

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

The 2,2′:6′,2″-terpyridines 8a and 8b were prepared in good yield by reacting α-acetoxy-α-chloro-β-keto-esters 1 (R¹ = ⁿPr and Ph) with the bis-amidrazone 7 and 2,5-norbornadiene 5 in ethanol at reflux.     

Synthesis and crystal structure of 2′-deoxy-2′-fluoro-4′-thioribonucleosides: substrates for the synthesis of novel modified RNAs

We report herein the synthesis of appropriately protected 2′-deoxy-2′-fluoro-4′-thiouridine (5), -thiocytidine (7), and -thioadenosine (35) derivatives, substrates for the synthesis of novel modified RNAs. The synthesis of 5 and 7 was achieved via the reaction of 2,2′-O-anhydro-4′-thiouridine (3) with HF/pyridine in a manner similar to that of its 4′-O-congener whereas the synthesis of 35 from 4′-thioadenosine derivatives was unsuccessful. Accordingly, 35 was synthesized via the glycosylation of the fluorinated 4-thiosugar 25 with 6-chloropurine. The X-ray crystal structural analysis revealed that 2′-deoxy-2′-fluoro-4′-thiocytidine (8) adopted predominately the same C3′-endo conformation as 2′-deoxy-2′-fluorocytidine.     

A new protecting group ‘3,5-O-sulfinyl’ for xylo-nucleosides. A simple and efficient synthesis of 3-amino-3-deoxyadenosine (a puromycin intermediate), 2,2-anhydro-pyrimidine nucleosides and 2,3-anhydro-adenosine

We developed a new protecting group, the cyclic sulfite for the protection of the 3^′,5^′-dihydroxy group of nucleosides. Seven cyclic sulfites, 4a-c, 5a-b, and 6a-b were prepared in high yields from the corresponding xylo-uridines 1 and 2, and xylo-adenosines 3 with thionyl chloride, respectively. Synthesis of the puromycin intermediate 8 was carried out by deprotection of the sulfite moiety through an intramolecular cyclization of the 2^′-α-carbamate 7.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Further studies of tetrakis(N,N′-dialkylbenzamidinato)diruthenium(III) chloro and alkynyl compounds: molecular engineering of metallayne monomers

Three diruthenium(III) compounds Ru₂(L)₄Cl₂, where L is mMeODMBA (N,N′-dimethyl-3-methoxybenzamidinate, 1a), DiMeODMBA (N,N′-dimethyl-3,5-dimethoxy benzamidinate, 1b), or DEBA (N,N′-diethylbenzamidinate, 1c), were prepared from the reactions between Ru₂(OAc)₄Cl and respective HL under reflux conditions. Metathesis reactions between 1 and LiC₂Y resulted in bis-alkynyl derivatives Ru₂(L)₄(C₂Y)₂ [Y=Ph (2), SiMe₃ (3), SiⁱPr₃ (4) and C₂SiMe₃ (5)]. The parent compounds 1 are paramagnetic (S=1), while bis-alkynyl derivatives 2-5 are diamagnetic and display well-solved ¹H- and ¹³C-NMR spectra. Molecular structures of compounds 1b, 1c, 2c, 3c and 4b were established through single crystal X-ray diffraction studies, which revealed RuRu bond lengths of ca. 2.32 Å for parent compounds 1 and 2.45 Å for bis-alkynyl derivatives. Cyclic voltammograms of all compounds feature three one-electron couples: an oxidation and two reductions, while the reversibility of observed couples depends on the nature of axial ligands.