Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

The structure of new cis and trans 3′-phenyl-3′,3a′,4′,5′,6′,7a′-hexahydro-2,1-benzisoxazole-7a′-spiro-2-(3-phenylaziridine)

The reaction of dibenzalcyclohexanone with hydroxylamine hydrochloride afforded three compounds 1–3 including the aziridine 3 showing a 3′,3a′-trans configuration. Now we report on the isolation of a new aziridine 4 , possessing a 3′,3a′-cis configuration. Its structure was deduced by 2D nmr and single crystal X-ray diffraction studies.     

Ortho effects of a nitro group in 2′,3′ and 4′monosubstituted-trans-2,4-dinitrostilbenes on electron impact. IV

The mass spectral fragmentation patterns of thirteen 2′,3′ and 4′-R-trans-2,4-dinitrostilbenes obtained by electron impact have been studied. The main routes of fragmentation involves loss from the molecular ion due to the ortho effects of the 2-nitro substituents. Substitution on positions 2′,3′ and 4′ of stilbene moiety does not influence the fragmentation patterns.     

2′,3′‐Dehydrosalannol

The title compound, methyl (2aS,3R,5R,5aS,6S,6aS,8R,9aS,10aR,10bR,10cS)‐8‐(3‐furyl)‐2a,4,5,5a,6,6a,8,9,9a,10a,10b,10c‐dodeca­hydro‐3‐hydroxy‐2a,5a,6a,7‐tetra­methyl‐5‐(3‐methylbut‐2‐enoyl­oxy)‐2H,3H‐cyclo­penta­[4′,5′]­furo­[2′,3′:6,5]benzo[cd]­isobenzo­furan‐6‐acetate, C₃₂H₄₂O₈, was isolated from uncrushed green leaves of Azadirachta indica A. Juss (neem) and has been found to possess antifeedant activity against Spodptera litura. The conformations of the functional groups are similar to those of 3‐des­acetyl­salannin, which was isolated from neem kernels. The mol­ecules are linked into chains by intermolecular O—H?O hydrogen bonds.     

Synthesis of 3‐substituted pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidines and related fused thiazolo derivatives

Convenient syntheses of 3‐substituted ethyl 4‐oxo‐2‐thioxo‐1,2,3,4,5,6,7,8‐octahydropyrid[4′,3′:4,5]thieno[2,3‐d]pyrimidine‐7‐carboxylates 3a, b, 6, 11–13 , ethyl 3‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5 H‐pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8‐7H‐carboxylate ( 4 ), and ethyl 2‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5H‐pyrido[4′,3′:4,5]thieno[2, 3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8[7H]carboxylate ( 8 ) from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahythieno[2,3‐c]pyridine‐3,6‐dicarboxylate ( 1 ) are reported. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:201–207, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10131     

Synthesis of novel pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidines,pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[l,6‐a]benzimidazoles and related fused systems

3‐Amino‐4‐aryl‐5‐ethoxycarbonyl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides 3a‐c were prepared from ethyl 4‐aryl‐3‐cyano‐6‐methyl‐2‐thioxo‐1,2‐dihydropyridine‐5‐carbonylates 1a‐c and reacted with some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a‐c, 7a‐c and 8a‐c , respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key compound, ethyl 2‐chloromethyl‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 9 . Also, 3‐amino‐2‐benzimidazolylthieno[2,3‐b]pyridine‐5‐carboxylate 5 and 2‐(3′‐aminothieno [2,3‐b]pyridin‐2′‐yl)‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 17 were prepared from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.     

Different nucleobase orientations in two cyclic 2′,3′‐phosphates of purine ribonucleosides: Et3NH(2′,3′‐cAMP) and Et3NH(2′,3′‐cGMP)·H2O

The crystal structures of triethyl­ammonium adenosine cyclic 2′,3′‐phosphate {systematic name: triethyl­ammonium 4‐(6‐amino­purin‐9‐yl)‐6‐hydroxy­methyl‐2‐oxido‐2‐oxoperhydro­furano[3,4‐c][1,3,2]dioxaphosphole}, Et₃NH(2′,3′‐cAMP) or C₆H₁₆N⁺·C₁₀H₁₁N₅O₆P⁻, (I), and guanosine cyclic 2′,3′‐phosphate monohydrate {systematic name: triethyl­ammonium 6‐hydroxy­methyl‐2‐oxido‐2‐oxo‐4‐(6‐oxo‐1,6‐dihydro­purin‐9‐yl)perhydro­furano[3,4‐c][1,3,2]dioxaphosphole monohydrate}, [Et₃NH(2′,3′‐cGMP)]·H₂O or C₆H₁₆N⁺·C₁₀H₁₁N₅O₇P⁻·H₂O, (II), reveal different nucleobase orientations, viz. anti in (I) and syn in (II). These are stabilized by different inter‐ and intra­molecular hydrogen bonds. The structures also exhibit different ribose ring puckering [₄E in (I) and ³T₂ in (II)] and slightly different 1,3,2‐dioxaphospho­lane ring conformations, viz. envelope in (I) and puckered in (II). Infinite ribbons of 2′,3′‐cAMP⁻ and helical chains of 2′,3′‐cGMP⁻ ions, both formed by O—H⋯O, N—H⋯X and C—H⋯X (X = O or N) hydrogen‐bond contacts, characterize (I) and (II), respectively.     

Flavylium Network of Chemical Reactions in Confined Media: Modulation of 3′,4′,7‐Trihydroxyflavilium Reactions by Host–Guest Interactions with Cucurbit[7]uril

In moderately acidic aqueous solutions, flavylium compounds undergo a pH‐, and in some cases, light‐dependent array of reversible chemical reactions. This network can be described as a single acid–base reaction involving a flavylium cation (acidic form) and a mixture of basic forms (quinoidal base, hemiketal and cis and trans chalcones). The apparent pK′_a of the system and the relative mole fractions of the basic forms can be modulated by the interaction with cucurbit[7]uril. The system is studied by using ¹H NMR spectroscopy, UV/Vis spectroscopy, flash photolysis, and steady‐state irradiation. Of all the network species, the flavylium cation possesses the highest affinity for cucurbit[7]uril. The rate of interconversion between flavylium cation and the basic species (where trans‐chalcone is dominant) is approximately nine times lower inside the cucurbit[7]uril.     

Synthesis of 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyrans] and 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro-[isobenzofuran-1,4′-pyrans]

The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyran] ring system ( 2a ) has been prepared from o-bromobenzoic acid. The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-pyran] ring system ( 3a ) has been prepared from 2-bromobenzhydrol methyl ether. Several 3-(dimethylaminoalkyl) derivatives of both 2a and 3a were prepared by lithiation followed by alkylation.     

Nucleic acid related compounds. 114. Synthesis of 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides and selected cytotoxic,anti‐hepatitis b,and adenosine deaminase substrate activities

Selected 2,6‐(disubstituted)purine 2′,3′‐didehydro‐2′,3′‐dideoxynucleosides and 2′,3′‐dideoxynucleosides were prepared and evaluated. Treatment of 5′‐protected ribonucleosides with phenoxythiocarbonyl chloride and 4‐(dimethylamino)pyridine, or under Schotten‐Baumann conditions, gave high yields of 2′,3′‐O‐thiono‐carbonates that underwent Corey‐Winter elimination. Treatment of unprotected ribonucleosides with α‐ace‐toxyisobutyryl bromide in “moist” acetonitrile gave trans 2′,3′‐bromohydrin acetate mixtures that underwent reductive elimination with zinc‐copper couple or zinc/acetic acid. Catalytic hydrogenation of the resulting 2′,3′‐enes gave 2′,3′‐dideoxynucleosides. Treatment of the 2‐amino‐6‐chloropurine and 6‐amino‐2‐fluoro‐purine derivatives with nucleophiles gave 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides. 2′,3′‐Dideoxyguanosine and the 2‐amino‐6‐[amino ( 16d ), methoxy ( 16b ), ethoxy ( 16c ), and methylamino ( 16j )]purine 2′,3′‐dideoxynucleosides showed good anti‐hepatitis B activity with infected primary duck hepatocytes. Cytotoxic effects with selected analogues were evaluated in human T‐lymphoblastic and promyelocytic leukemia cell lines. The 2‐amino‐6‐fluoro derivative 16m was the most cytotoxic of the 2‐amino‐6‐(substituted)purine 2′,3′‐dideoxynucleosides, and 2‐fluoro‐2′,3′‐dideoxyadenosine ( 21a ) was the most cytotoxic compound. The order of efficiency of hydrolysis of the 6‐substituent from 2‐amino‐6‐(sub‐stituted)purine 2′,3′‐dideoxynucleosides (V_max/K_m) with adenosine deaminase from calf intestine was: 2‐amino‐6‐[amino ( 16d ) > methoxy ( 16b ) > ethoxy ( 16c )], all of which were ≤3% of the efficiency with adenosine. The 6‐methylamino derivative 16j , as well as 16b , 16c , and 16d were readily converted into 2′,3′‐dideoxyguanosine by duck cell supernatants.     

Synthesis,structure and some reactions of 4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]‐quinazolines]

2′‐Substituted 5′,6′,7′,8′‐tetrahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 3a‐d were synthesized by condensation of 3‐substituted 5‐amino‐1,2,4‐triazoles 1a‐d with 2‐cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2′‐substituted cis‐4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 4a‐d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X‐ray analysis of 6 and 11b . The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1‐b]quinazolines.     

2′,3′‐Dide­hydro‐3′‐deoxy­thymidine N‐methyl‐2‐pyrrolidone solvate (D4T·NMPO)

The title compound, 1‐(2′,3′‐di­deoxy‐β‐d ‐glycero‐pent‐2‐eno­furan­osyl)­thymine 1‐methyl‐2‐pyrrolidone solvate, C₁₀H₁₂N₂O₄·­C₅H₉NO, is an NMPO solvate of the anti‐AIDS agent D4T. In its crystal structure, both the pyrimidine and the furan­ose rings are planar and approximately perpendicular [82.1 (4)°]. The value of the torsion angle defining the orientation of the thymine with respect to the joined furane, χ = ?100.8 (4)°, and that of the torsion angle giving the orientation of the hydroxyl group linked to the furane ring, γ = 52.9 (5)°, show that the gly­cosyl­ic link adopts the so‐called high‐anti conformation and the 5′‐hydroxyl group is in the +sc position. The NMPO solvate is linked to the nucleoside through a fairly strong hydrogen bond.     

An Efficient Synthesis of 1′,7′,8′,9′‐Tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione Derivatives in Aqueous Medium

An efficient and green reactions of isatins, 3‐amine‐1H‐pyrazole (5‐methyl‐1H‐pyrazol‐3‐amine) and 1,3‐diketone in aqueous medium for the synthesis of novel 1′,7′,8′,9′‐tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione derivatives were reported in this research. The advantages of this reaction are simple operation, mild‐reaction conditions, wide scope substrate, high yields, and friendly environment. The products were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS.     

Synthese von [16,16,16,16′,16′,16′-2H6] Lycopin

Synthesis of [16,16,16,16′,16′,16′ ²H₆]Lycopene Lycopene having at both ends the deuteriated methyl groups trans to the chain has been synthesized for further biochemical experiments aimed to elucidate the stereochemistry of the cyclization step. Incidentally a gas-chromatographic separation of the isotopisomers 1 and 2g has been observed.     

Synthesis and reduction of thieno[2′,3′(3′,2′ or 3′,4′):5,6]-azocino[2,1-a]isoindole-7, 13-diones

A synthesis of the thieno[2′,3′(3′,2′ or 3′,4′):5,6]azocino[2,1-a]isoindole-7,13-diones 6a-c was developed from N-thienylethylphthalimides 3a-c using a Wittig reaction followed by a Friedel-Crafts cyclization of acetic acid derivatives 5a-c . Reduction of ketones 6a-c into alcohols 7a-c was stereo specific.     

Synthetic approaches to 4,8‐dimethyl‐5′‐(N‐pyridiniummethyl)‐ 4′,5′‐dihydropsoralens and 4,8‐dimethyl‐5′‐ (N‐aminomethyl)‐ 4′,5′‐dihydropsoralens

New synthetic approaches to 4,8‐dimethyl‐5′‐(N‐pyridiniummethyl)‐4′,5′‐dihydropsoralens and 4,8‐dimemyl‐5′‐(N‐aminomethyl)‐4′,5′‐dihydropsoralens are described. The 5′‐halomethyl‐4′,5′‐dihydro‐psoralen precursors are formed by electrophilic ring closures of 4,8‐dimethyl‐6‐allyl‐7‐hydroxycoumarin. The ring‐closure reactions may also be applied to the synthesis of 5′‐halomethyl‐4‐methyl‐4′,5′‐dihydroangelicins. The compounds are potential therapeutic agents for improved psoralen ultraviolet A radiation treatment.     

Synthesis of 3′,5′‐Cyclic Phosphate and Thiophosphate Esters of 2′‐C‐Methyl Ribonucleosides

2′‐C‐Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5′‐triphosphates, dosing as appropriately protected 5′‐phosphates or 5′‐phosphorothioates appears attractive. For this purpose, four potential pro‐drugs of 2′‐C‐methylguanosine, i.e., 3′,5′‐cyclic phosphorothioate of 2′‐C‐methylguanosine and 2′‐C,O⁶‐dimethylguanosine, 1 and 2 , respectively, the S‐[(pivaloyloxy)methyl] ester of 2′‐C,O⁶‐dimethylguanosine 3′,5′‐cyclic phosphorothioate and the O‐methyl ester of 2′‐C,O⁶‐dimethylguanosine 3′,5′‐cyclic phosphate, 3 and 4 , respectively, have been prepared.     

Nonsymmetrical Dithienylethenes Bearing Dithieno[3,2‐b:2′,3′‐d]thiophene Units with Photochromic Performance in the Crystalline Phase

Four novel nonsymmetrical photochromic diarylethene compounds containing dithieno[3,2‐b:2′,3′‐d]thiophene units were designed and synthesized to investigate their photochromic properties. All these molecules adopt a photoactive antiparallel conformation in single crystals, as revealed by X‐ray crystallographic analysis, and exhibit excellent photochromism in solution as well as in the crystalline phase.