Application and details of photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones and related compounds

As novel methodology for synthesizing the furan ring, a photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones (7a-c) and related compounds 9a-c was accomplished to give 5,10-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1,3H)-dionylium tetrafluoroborates (8a-c⁺·BF₄⁻) and related compounds 2a-c⁺·BF₄⁻, respectively. In the photoinduced oxidative cyclization, the molecular oxygen in air is used as oxidant and the reaction proceeds under mild conditions to give desired products without byproducts, and thus, it is interesting from the viewpoint of the green chemistry. On the reactions of the mono-substituted derivatives 7d,e and 9e,f, the selectivity of the photoinduced cyclizations were reversed as compared with those of the DDQ-promoted oxidative cyclizations. By the NMR monitoring of the reactions of 7a and deuterated compound 7a-D₂ under degassed conditions, the details of the reaction pathway were clarified and rationalized on the basis of the MO calculation by the 6-31G^∗ basis set of the MP2 levels as well.     

New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.     

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.     

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.     

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.     

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.     

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.     

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.     

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 of (±)-5′-methoxyhydnocarpin-D, an inhibitor of the Staphylococcus aureus multidrug resistance pump

The total synthesis of regioisomerically pure (±)-5′-methoxyhydnocarpin-D (6) from commercially available vanillin (7), methyl gallate (9) and 2′,4′,6′-trihydroxyaceophenone (10) is achieved.     

Synthesis of a solvent-sensitive highly fluorescent derivative of perfluorocyclopentene

A solvent-sensitive highly fluorescent compound, N-[2-(1′,3′,4′,4′,5′,5′-hexafluorocyclopentenyl)]-4-(5-methoxy-thiazolyl)pyridine (1D) was synthesized as an unexpected product of the reaction of 4-bromo-5-methoxy-2-(4-pyridyl)thiazole (1B) with perfluorocyclopentene in the presence of n-BuLi. Primary mechanism of this reaction was proposed, and the photophysical properties of 1D in different solvents were studied.     

Synthesis of 4′-benzoyloxycordycepin from adenosine

With an aim to synthesize 4′-substituted cordycepins, the 4′-benzoyloxy precursor (9) was prepared from adenosine through an electrophilic addition (iodo-benzoyloxylation) to the 4′,5′-unsaturated derivative (5) and subsequent radical-mediated removal of the 3′-iodine atom of the resulting adducts (6). Usefulness of 9 was briefly verified by synthesizing the 4′-allyl (12) and 4′-cyano (13) analogues of cordycepin.     

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.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

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.     

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.     

Synthesis, structural characterization, and reactivity of organolanthanides derived from a new chiral ligand (S)-2-(pyrrol-2-ylmethyleneamino)-2′-hydroxy-1,1′-binaphthyl

Condensation of (S)-2-amino-2′-hydroxy-1,1′-binaphthyl with 1 equiv. of pyrrole-2-carboxaldehyde in toluene in the presence of molecular sieves at 70 °C gives (S)-2-(pyrrol-2-ylmethyleneamino)-2′-hydroxy-1,1′-binaphthyl (1H₂) in 90% yield. Deprotonation of 1H₂ with NaH in THF, followed by reaction with LnCl₃ in THF gives, after recrystallization from a toluene or benzene solution, dinuclear complexes (1)₃Y₂(thf)₂ · 3C₇H₈ (3 · 3C₇H₈) and (1)₃Yb₂(thf)₂ · 3C₆H₆ (4 · 3C₆H₆), respectively, in good yields. Treatment of 1H₂ with Ln[N(SiMe₃)₂]₃ in toluene under reflux, followed by recrystallization from a benzene solution gives the dimeric amido complexes {1-LnN(SiMe₃)₂}₂ · 2C₆H₆ (Ln = Y (5 · 2C₆H₆), Yb (6 · 2C₆H₆)) in good yields. All compounds have been characterized by various spectroscopic techniques, elemental analyses and X-ray diffraction analyses. Complexes 5 and 6 are active catalysts for the polymerization of methyl methacrylate (MMA) in toluene, affording syn-rich poly-(MMA)s.     

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.     

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.     

Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides

Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of potent A_2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.