Synthesis and pharmacological evaluation of 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles

A fast access to novel 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles 4 was developed using the readily available preclinical candidate BYK 405879 (1) as starting material. The 5-amino function was installed by the Curtius rearrangement of carboxylic acid 2 or by the Hofmann rearrangement of carboxamide 8 furnishing benzimidazole 3 as key intermediate. In the Ghosh Schild rat, some of the target compounds 10-14 showed noteworthy activity as potassium-competitive acid blockers.     

A general method for the synthesis of the most powerful naturally occurring Maillard flavors

The natural flavors 2-acetyl-1-pyrroline 1a, 2-propionyl-1-pyrroline 1b, 2-acetyl-3,4,5,6-tetrahydropyridine 1c, 2-acetyl-2-thiazoline 1d, 2-propionyl-2-thiazoline 1e, and the artificial flavor 2-acetyl-5,6-dihydro-4H-1,3-thiazine 1f have been prepared by catalytic SeO₂ oxidation of the corresponding cyclic imines 6a-c and sulfur cyclic imines 7a-c using TBHP as co-oxidant. The oxidation of the pyrrolines 1a and b is completely regioselective. Professional olfactory evaluation together with the odor threshold of the new flavor 1f is reported.     

Oxidative synthesis of azacyclic derivatives through the nitrenium ion: application of a hypervalent iodine species electrochemically generated from iodobenzene

Oxidation of the methoxyamide derivatives 1, 4, and 7 has been examined to elaborate efficient synthetic methodology of the azacyclic derivatives 2, 3, 5, 6, and 8, which would be applicable as synthetic intermediates of complicated bioactive substances. In addition to direct anodic and PIFA [phenyliodine(III) bis(trifluoroacetate)] oxidations, an active species derived from iodobenzene generated under electrolytic conditions was examined as an oxidant, and its synthetic efficacy was demonstrated in comparison of the reaction outcomes with other oxidation methods. In the oxidation, the methoxy substitution of substrates modulated the cyclization mode to provide the azaspiro- (2, 8) or quinolinone-type (3, 5, 6) products.     

Synthesis of a regioisomeric analogue of the 3C-protease inhibitor thysanone via a Hauser annulation strategy

Hauser annulation of 3-cyano-5,7-dimethoxy-(3H)-isobenzofuran-1-one 4 with ethyl acrylate as a method to access activated naphthoquinone 3, a key intermediate for the synthesis of thysanone 1, proved unreliable. In contrast to this, Hauser annulation of regioisomeric 3-cyano-4,6-dimethoxy-(3H)-isobenzofuran-1-one 13 with ethyl acrylate proceeded readily affording ethyl 5,7-dimethoxy-1,4-naphthoquinone 12, after oxidation of the initial dihydroxynaphthalene 16. Allylation of naphthoquinone 12 followed by reductive methylation and Wacker oxidation afforded ketone 11 that underwent CBS reduction to (2′S)-alcohol 19 followed by cyclisation to lactone 20. Reduction of the lactone followed by oxidative demethylation afforded (1S,3S)-6,8-dimethoxy-1-hydroxy-3-methylpyrano[2,3-c]-1,4-naphthoquinone 22, a regioisomeric analogue of the 3C-protease inhibitor thysanone 1.     

Electrooxidation of activated α,ω-diols to cyclic tetramethylene acetals of the corresponding dials

Activated α,ω-diols such as ethylene glycol 1a, 1,3-propanediol 1b, but-2-ene-1,4-diol 1c and hexa-2,4-diyne-1,6-diol 1d can be converted into cyclic tetramethylene acetals of the corresponding α,ω-dials (2a-d) in 70% yield by a simple anodic oxidation in dry tetrahydrofuran on a glassy carbon anode. Glycerol 3 when subjected to similar anodic oxidation gave a structure 4 containing three seven-membered 1,3-dioxepane rings.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).     

New possibilities of 1,2,4-triazines functionalization: first examples of synthesis and structure of boron-containing 1,2,4-triazines

By oxidation of 3-thioderivatives of 1,2,4-triazine 1a,b 3-alkylsulfonic derivatives 2a,b were obtained. Interaction of the sulfonic derivative 2a with indole leads to 3-oxo-5-indolyl-5-phenyl-as-triazine 4. The sulfone 2a reacts with 1-ethyl-2,6-dimethylquinolinium iodide to give 3-(1-ethyl-6-methyl-1,2-dihydroquinoline-2-methylene)-5-phenyl-1,2,4-triazine 5. The 3-morpholino- 3 and 3-thioderivatives 6, 7a,b of as-triazine were obtained by interaction of the sulfone 2 with morpholine and organic boron-containing thiols. The crystal structure of boron-containing derivative of as-triazine 7b was investigated by X-ray analysis.     

Osmium assisted C-H activation and CN cleavage of N-(2′-hydroxyphenyl) benzaldimines. Synthesis, structure and electrochemical properties of some organoosmium complexes

Reaction of N-(2′-hydroxyphenyl)-4-R-benzaldimines (L-R, R = OCH₃, CH₃, H, Cl and NO₂) with [Os(PPh₃)₃Br₂] in refluxing 2-methoxyethanol in the presence of triethylamine affords two families of organoosmium complexes (1-R and 2-R). In both 1-R and 2-R complexes a benzaldimine ligand is coordinated to the metal center as tridentate C,N,O-donor. In the 1-R complexes, a bidentate N,O-donor imionsemiquinonate ligand, derived from the hydrolysis of another benzaldimine, and a PPh₃ ligand are also coordinated to osmium. In the 2-R complexes, a carbonyl, derived from decarbonylation of 4-R-benzaldehyde (derived from the same hydrolysis stated above), and two PPh₃ ligands take up the remaining coordination sites on osmium. Structures of the 1-Cl and 2-OCH₃ complexes have been determined by X-ray crystallography. All the 1-R and 2-R complexes are diamagnetic, and show characteristic ¹H NMR signals and intense MLCT transitions in the visible region. Cyclic voltammetry on the 1-R complexes shows a reversible Os(III)-Os(IV) oxidation within 0.47-0.67 V (vs SCE), followed by an irreversible oxidation of the imionsemiquinonate ligand within 1.10-1.36 V. An irreversible Os(III)-Os(II) reduction is also displayed by the 1-R complexes within −1.02 to −1.14 V. Cyclic voltammetry on the 2-R complexes shows a reversible Os(II)-Os(III) oxidation within 0.29-0.51 V, followed by a quasi-reversible oxidation within 1.04-1.29 V, and an irreversible reduction of the coordinated benzaldimine ligand within −1.16 to −1.31 V.     

Structures of enzymatic oxidation products of epigallocatechin

To understand the structures of uncharacterized black tea polyphenols, the oxidation products of (−)-epigallocatechin were investigated. Enzymatic oxidation and subsequent heating of the reaction mixture afforded four new oxidation products (6, and 9–11) along with theasinensins C (4) and E (5), dehydrotheasinensin E (12), epitheaflagallin, hydroxytheaflavin, and desgalloyl oolongtheanin. The structures of the new compounds were determined chemically and spectroscopically. Isotheasinensin E (6) is a C-2 epimer of 5, and compounds 9 and 10 are oxidation products of 12. Another new compound, 11, is a yellow pigment and presumed to be a degradation product of proepitheaflagallin. The results disclosed new oxidation mechanisms that occur during black tea production.     

Amphiphilic perfluoroalkylated sulfones and sulfonate betaines

Two types of perfluoro alkyl-containing amphiphilic sulfones 7-9 and 13-15, respectively, and sulfonate betaines 23-32 were prepared using 2-[(perfluoroalkyl)methyl]oxiranes (1-3, R_F = C₄F₉, C₆F₁₃, C₈F₁₇) or 3-(perfluoroalkyl)propyl iodides (16 and 17, R_F = C₆F₁₃, C₈F₁₇) as the starting compounds. The overall yields of two-step syntheses were above 90%. The compounds 7-9 were prepared by the reaction of oxiranes 1-3 with 2-sulfanylethan-l-ol and subsequent oxidation of intermediate sulfides. Similarly, the amphiphiles 13-15 were obtained by analogous reaction of oxiranes 1-3 with thiomorpholine and subsequent oxidation of the sulfur atom in the morpholine ring. In the syntheses of betaines 23-32, the starting compounds 1-3 or 16 and 17 were first reacted with dimethylamine followed by the ring-opening reaction of the intermediate fluoroalkyl(dimethyl)amines with propane-1,3- or butane-1,4-sultones.     

Total synthesis of eurypamides, marine cyclic-isodityrosines from the Palauan sponge Microciona eurypa

Total synthesis of eurypamides A, B, and D, 1, 2, and 4, has been successfully accomplished. The Tl(NO₃)₃ (TTN) oxidation of the halogenated bisphenols, 14a, 14b, 24, and 43, effected regio-controlled cyclization to provide the corresponding diaryl ethers, 15a, 15b, 25, and 46. This investigation revealed a structural revision of eurypamide A as to possess (2″S,3″R,4″S)-configuration (47), along with the spectral data of pure 2 and 4, which were previously characterized in a mixture.     

Synthesis of perfluoroalkyl-containing multifunctional groups compounds for textile finishing

A new kind of perfluoroalkyl-containing multifunctional groups compound was designed. Treatment of 1H,1H,2H,2H-perfluorooctyltrichlorosilane (4) with allylmagnesium bromide provided key intermediate 1H,1H,2H,2H-perfluorooctyltriallylsilane (2). Hydroboration followed by oxidation, epoxidation and dihydroxylation of 2 gave perfluoroalkyl-containing multifunctional groups compound 1a, 1b and 1c, respectively.     

Novel reactions of lycoctonine analogs: unusual pyrolysis of C4-COOH and hydrogenolysis of N-C6 bond

Pyrolysis of carboxylic acid group at C-4 of 2, an oxidation product from the C₁₉-diterpenoid alkaloid lycoctonine 1, generated an unexpected but novel rearranged product 13 (37%). The structure of 13 was confirmed by its 2D NMR data and its single crystal X-ray crystallographic analysis. In addition, hydrogenolysis of 13 in the presence of acetic acid yielded the N-C6 bond fission products 16 and 17, which represents the first hydrogenolysis involving the breakage of the N-C6 bond of the diterpenoid alkaloids. Some new observations on the oxidation of lycoctonine 1 were described as well.     

Synthesis of the marine furanoditerpene (−)-marginatone

A synthesis of the marine labdane furanoditerpene (−)-marginatone 1 has been accomplished by a short sequence of reactions starting from (+)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (+)-dihydrocoronarin E 6, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (+)-coronarin E 5 was previously synthesized from (−)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (−)-marginatone 1, by which its absolute configuration has been confirmed.     

Total synthesis of the mushroom metabolite (+)-calopin

A synthesis of (+)-calopin (1a) was achieved employing a highly stereoselective ene reaction between 8-phenylmenthyl glyoxylate (3) and the β,β-dimethylstyrene 4c. Transesterification of the resulting homoallylic alcohol 5c, followed by allylic oxidation and hydrogenation yielded the δ-lactone 13 which was deprotected to the natural product 1a.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Synthesis and structural revision of eurypamides isolated from the Palauan sponge Microciona eurypa

Eurypamides A and B, 1 and 2, were successfully synthesized by employing Tl(NO₃)₃ (TTN) oxidation of the corresponding halogenated phenols, 9, 16, and 26. This investigation revealed that the dihydroxyarginine residue of 1 should be revised to possess (2S,3R,4S)-configuration. In addition, the synthesis of 2 provided a pure sample, which was previously characterized in a mixture.     

Calix[4]quinones. Part 4: The ClO2 oxidation of calix[4]arene dialkyl ethers

Except for the special case of calix[4]arene diethyl ether 1, the chlorine dioxide oxidation of dialkyl ethers 2-5 yielded only the corresponding calix[4]diquinone dialkyl ethers 8-11. Chlorine dioxide oxidation of calix[4]arene diethyl ether 1 produced two isomeric products 6 and 7, which were stable enough to be isolated by column chromatography. However, a slow conformational interconversion between isomeric pair 6 and 7 was observed at room temperature, and the equilibrium was reached after 400 h at 18 °C with an amount of 5:3 in favor of syn-isomer.     

Quinoxaline-annelated Z-shaped quadruple-bridged orthocyclophanes: synthesis and crystal structures

A three-step synthesis of nineteen Z-shaped quadruple-bridged [6,6] and [6,4]orthocyclophanes comprising two quinoxaline-based sidewalls are described. The synthesis began from the bis-Diels−Alder adducts B1-B3 followed by ruthenium-promoted oxidation of dichloroetheno-bridges in the adducts to generate a bis-α-diketones, which were then condensed with various arene-1,2-diamines (9a-g) to construct sidewalls (phane parts) of Z-shaped quadruple-bridged orthocyclophanes D1-3, D2g, and D3g. Single-crystal structures of six orthocyclophanes (D1a, D2a, D2f, D3f, D2g-α, and D3g-α) were obtained and revealed that the C_Ar−H?π and π?π stacking interactions between N-containing arene rings are the major driving force for molecular assembly and crystal packing, in addition to the interactions involving the polar OCH₃ groups and the solvate molecules.     

[4+2] Cycloaddition of 1-phosphono-1,3-butadiene with azo- and nitroso-heterodienophiles

Under microwave activation, diethyl 1-phosphono-1,3-butadiene (1) reacted with t-butyl azodicarboxylate (2) and o-nitrosotoluene (5) to furnish quantitatively [4+2] cycloadducts, 3-phosphono-3,6-dihydro-1,2-pyridazine (3) and 6-phosphono-3,6-dihydro-1,2-oxazine (6), respectively. Selective oxidation and/or reduction of 6 led to functionalized δ-aminophosphonic derivatives in cyclic (7, 8) and aliphatic series (9, 10). Intermediate 10 may be cyclized into 2-phosphono-2,5-dihydro-1-pyrrole (12).