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.     

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.     

A novel one-pot and efficient procedure for the synthesis of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]-2′,3,4′,5′-tetraones

A novel and practical one-pot procedure is described for the preparation of several new of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]-2′,3,4′,5′-tetraones based on the addition reaction of ninhydrin and 6-aminouracils followed by oxidative cleavage of their corresponding dihydroxyindenopyrrolopyrimidines.     

Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2-vinyl-1H-pyrroles

The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to 2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied. Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole derivative.     

An efficient synthesis of new 1-H-4′-methyl-3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinoline] scaffolds

Efficient synthesis of new 3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinolines] by a four step synthetic route based on 1-benzyl-4-piperidone reactivity is reported.     

Domino reactions in water for the stereoselective synthesis of novel spiro dihydro-2′H-[indene-2,3′-thiophen]-1(3H)-ones with three contiguous stereocenters

The domino reactions of (E)-2-(aryl)-2,3-dihydro-1H-inden-1-ones and 1,4-dithiane-2,5-diol in the presence of triethylamine in water stereoselectively afforded a library of 2′-(aryl)-4′-hydroxy-4′,5′-dihydro-2′H-spiro[indene-2,3′-thiophen]-1(3H)-ones. This transformation presumably proceeds via the generation of 2-mercaptoacetaldehyde from 1,4-dithiane-2,5-diol followed by Michael addition–intramolecular aldol sequence with C–C and C–S bond formations and creation of three contiguous stereocenters in a one-pot operation.     

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 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.     

Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinolines)

Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinoline) derivatives as a mixture of (S^∗,S^∗)- and (S^∗,R^∗)-diastereomers. Mostly, the major diastereomer has the S^∗,S^∗-configuration. According to X-ray diffraction data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated with the structure of the Knoevenagel products whose conformation is fixed by the strong intramolecular C-H?π interaction.     

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes: a simple and efficient one-pot approach to the substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′(1′H,3H,3′H)-pentone framework

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes in the presence of bromine leads to the selective and efficient formation of substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′-(1′H,3H,3′H)-pentones in 70-88% yields via a complex cascade process. Spirobarbiturates containing the furo[2,3-d]pyrimidine framework are a class of compounds with interesting pharmacological and physiological activity.     

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.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

Preparation, spectroscopic properties of 1,4-di (N,N-diisopropylacetamido)-2,3(1H,4H)-quinoxalinedione (L) lanthanide complexes and the supramolecular structure of [Nd2L2(NO3)6(H2O)2]·H2O

The reaction of lanthanide nitrate with 1,4-di (N,N-diisopropylacetamido)-2,3(1H,4H)-quinoxalinedione (L) yields six novel Ln(III) complexes ([Ln₂L₂(NO₃)₆(H₂O)₂]·H₂O) which are characterized by elemental analysis, thermogravimetric analysis (TGA), conductivity measurements, IR, electronic and ¹H NMR spectroscopies. A new quinoxalinedione-based ligand is used as antenna ligand to sensitize the emission of lanthanide cations. The lowest triplet state energy level of the ligand in the nitrate complex matches better to the resonance level of Eu(III) and Sm(III) than Tb(III) and Dy(III) ion. The f-f fluorescence is induced in the Eu³⁺ and Sm³⁺ complexes by exciting into the π-π* absorptions of the ligand in the UV. Furthermore, the crystal structures of a novel binuclear complex [Nd₂L₂(NO₃)₆(H₂O)₂]·H₂O has been determined by single-crystal X-ray diffraction. The binuclear [Nd₂L₂(NO₃)₆(H₂O)₂]·H₂O complex units are linked by the intermolecular hydrogen bonds and π-π interactions to form a two-dimensional (2-D) layer supramolecule.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Catalytic photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine and carbon dioxide

Photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine (TMB) in MeCN under bubbling of CO₂ proceeded with high catalytic efficiency, giving 3,3-diphenylacrylic acid (DPA) and 3-hydroxy-3,3-diphenylpropionic acid (20). The turnover number (TON=(DPA+20)/TMB) reached 17. Similarly, 1-phenyl-1-cyclohexene yielded cis-2-acetamido-2-phenylcyclohexanecarboxylic acid with TON 5.9. As compared with related N,N-dimethylaniline derivatives, TMB is more resistant to photodecomposition, has the much larger absorbance in the S₀→S₁ transition, and has the lower quenching efficiency by CO₂. Probably these factors are partly responsible for the high TON observed for TMB.     

5′-Epimeric 3′-deoxy-3′,4′-didehydronucleoside-5′-C-phosphonates: synthesis and structural assignment by NMR and X-ray analyses

Epimeric 5′-(RS) dialkyl 3′-deoxy-3′,4′-didehydro-5′-C-phosphonates were prepared by nucleophilic addition of various dialkyl phosphites to 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes. Whereas direct NMR configuration assignment for the C5′ atom bearing the phosphoryl and hydroxy groups using the J (P,H4′) and J (H5′,H4′) coupling constants is impossible due to the absence of the H4′ atom, successful separation, crystallisation and X-ray crystallographic analysis of a pair of epimeric 5′-C-phosphonates, followed by correlation with a series of NMR parameters, led to efficacious configuration assignment of individual epimers in the mixtures.     

Synthesis,spectral characterization of the zinc(II) mixed-ligand complexes of N(4)-allyl thiosemicarbazones and N,N,N′,N′-tetramethylethylenediamine,and crystal structure of the novel [ZnL2(tmen)] compound

Mixed-ligand zinc complexes with N,N,N′,N′-tetramethylethylenediamine (tmen) and R-salicylaldehyde N(4)-allyl thiosemicarbazones (R: 3-OCH₃ (L₁), 5-Br(L₂)), [ZnL_1,2(tmen)], were synthesized and the complexes were characterized by elemental analysis, atomic absorption spectrometer, magnetic susceptibility, molar conductivity, electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) mass spectra and IR, UV–Vis, ¹H NMR and ¹⁵N spectroscopies. Crystal of [ZnL₂(tmen)] have a slightly distorted square pyramid involving O, N, S atoms of thiosemicarbazone and one N atom of tmen in basal plane and the other N atom of tmen in apex of the pyramid. The non-coordinated allyl group is disordered.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

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.