Pyrazolo [1,5-a]indole. 10. Mitteilung über metallogranische reaktionen und folgeprodukte

Pyrazolo[1,5- a ]indoles Treatment of 1-(2-heteroaroyl or aroyl-phenyl)-pyrazoles ( 3 ) with potassium hydroxide in 95% ethanol or with sodium ethanolate in ethanol produces a novel ring closure to new 4-hydroxy-4-(4-heteroaryl or aryl)-4H-pyrazolo [1,5-a]indoles 5 and 6 (Table 1). A 2, 3, or 4-pyridyl at position 4 is easily reduced yielding the 4-(2, 3, or 4-piperidyl)-derivatives 7 and 8 (Table 2). Water is split off from these piperidyl-derivatives 7 or 8 to give the piperidylidene derivatives 9 or 10 (Table 3) which may be considered as heterocyclic analogues to known tricyclic psychopharmaceuticals with antidepressant or neuroleptic activities.     

Benzimidazole condensed ring systems. 5. Studies on the Synthesis of Pyrimido[1,6-α]benzimidazole-1,3(2H,5H)-diones

The reaction of ethyl 1H-benzimidazole-2-acetate (1) with methyl or ethyl isocyantes 2a,b resulted in excellent yields of the respective 2-methyl- or 2-ethylpyrimido[1,6-a]benzimidazole-1,3(2H,5H)-diones 3a,b , while the reaction of 1 with phenyl isocyanate (2c) gave, unexpectedly, ethyl 2-(1-phenylcarbamoyl-1H,3H-benzimidazol-2-ylidene)-2-phenylcarbamoylacetate (4). Alkylation of 3 with trimethyl or triethyl phosphates 5a,b led to the 5-methyl or 5-ethyl derivatives 6a-d . Chlorination of 6 with sulfuryl chloride afforded the 4-chloro derivatives 7a-d.     

A new type of deoxygenation of quinoxaline N-oxides

The reaction of 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4-oxide 3a or 2-[2-(p-bromobenzylidene)-1-methylhydrazino]-6-chloroquinoxaline 4-oxide 3b with dimethyl acetylenedicarboxylate under reflux in N,N-dimethylformamide resulted in deoxygenation to give 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4a or 2-[2-(p-bromobenzilidene)-1-methylhydrazino]-6-chloroquinoxaline 4b , respectively, while the reaction of compound 3a or 3b with dimethyl acetylenedicarboxylate under reflux in dioxane precipitated dimethyl 8-chloro-4-[2-(p-chlorobenzyli-dene)-1-methylhydrazino]-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6a or dimethyl 4-[2-(p-bromobenzylidene)-1-methylhydrazino]-8-chloro-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6b , respectively. Further refluxing of compound 6a or 6b in N,N-dimethylformamide provided compound 4a or 4b , respectively.     

Syntheses,spectroscopy, and catalysis of (η 4-cod)Rh(I)-complexes with (R or S)-2-(salicylaldimine)-2-phenylethanol or (rac)-2-(salicylaldimine)-1-phenylethanol

Condensation of salicyldehyde with (R or S)-2-amino-2-phenylethanol or rac-2-amino-1-phenylethanol gives enantiopure (R or S)-2-(salicylaldimine)-2-phenylethanol (R- or S-H₂L1) or (rac)-2-(salicylaldimine)-1-phenylethanol (rac-H₂L2). The Schiff bases coordinate to [Rh(η ⁴-cod)(μ-O₂CCH₃)]₂ to afford mononuclear [Rh(η ⁴-cod){(R or S)-2-(salicylaldiminato)-2-phenylethanol-κ ² N,O}], [Rh(η ⁴-cod)(R- or S-HL1)] (1 or 2), or [Rh(η ⁴-cod){(rac)-2-(salicylaldiminato)-1-phenylethanol-κ ² N,O}], [Rh(η ⁴-cod)(rac-HL2)] (3). The Schiff base and complexes are characterized by IR-, UV/Vis-, ¹H/¹³C-NMR-, mass-spectroscopy, circular dichroism (CD), and polarimetry. The synthetic and spectroscopic results suggest that deprotonated Schiff base coordinates to [Rh(η ⁴-cod)] as a six-membered N,O-chelate with distorted square planar geometry at rhodium. CD and polarimetry measurements show the enantiopurity of the Schiff bases as well as the complexes in solution. The in situ system composed of [Rh(η ⁴-cod)Cl]₂ and S-H₂L1 has been used as a catalyst for the reduction of acetophenone into rac-1-phenylethanol with 85% conversion in diphenylsilane at 0–5°C.     

Synthèses de produits organofluorés VI Solvolyse de chlorofluorocyclopropanes

Fluoro-organic Syntheses VI: The Solvolysis of Chlorofluoro-cyclopropanes 2-Fluoro-allylic carbocations, generated from 1-chloro-1-fluoro-cyclopropanes or 2-fluoro-allyl p-toluene-sulfonates in water or acetic acid, undergo either proton loss or addition of hydroxyl or acetoxyl. In the latter case, an alkyl-substituted 2-fluoro-allyl ion leads predominantly to the more branched product (e.g. 3-fluoro-2-methyl-3-buten-2-ol) which may be converted into the less branched one (e.g. 2-fluoro-3-methyl-2-buten-2-ol) through reversible reactions.     

Synthesis of some 4H,10H[1]benzoxepino[3,4-c]pyrazol-4-one derivatives

1H(or 2H)4H10H[1]Benzoxepino[3,4-c]pyrazol-4-ones were prepared from phenoxymethylpyrazolecarboxylic acids which in turn were synthesized from simple starting materials. Different pathways to allow the predominant formation of the N-1 or N-2 substituted derivatives are described. The isomeric 1 or 2-substituted structures were supported by ¹³C-nmr.     

Comparison of A2E Cytotoxicity and Phototoxicity with all-trans-Retinal in Human Retinal Pigment Epithelial Cells†

All-trans-retinal is the precursor of A2E, a fluorophore within lipofuscin, which accumulates in human retinal pigment epithelial (hRPE) cells and contributes to age-related macular degeneration. Here we have compared the in vitro dark cytotoxicity and visible-light-mediated photoreactivity of all-trans-retinal and A2E in hRPE cells. All-trans-retinal caused distinct cytotoxicity in hRPE cells measured with cell metabolic activity (MTS) and lactate dehydrogenase release assays. Significant increases in intracellular oxidized glutathione (GSSG), extracellular GSH and GSSG levels and lipid hydroperoxide production were observed in cells incubated in the dark with 25 and 50 μm all-trans-retinal. Light modified all-trans-retinal’s harmful action and decreased extracellular glutathione and hydroperoxide levels. A2E (<25 μm ) did not affect cell metabolism or cytoplasmic membrane integrity in the dark or when irradiated. 25 μm A2E raised the intracellular GSSG level in hRPE cells to a much smaller extent than 25 μm all-trans-retinal. A2E did not induce glutathione efflux or hydroperoxide generation in the dark or after irradiation. These studies support our previous conclusions that although A2E may be harmful at high concentrations or when oxidized, its phototoxic properties are insignificant compared to those of all-trans-retinal. The endogenous production of A2E may serve as a protective mechanism to prevent damage to the retina by free all-trans-retinal.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

Camphor and Isocamphanone in the Synthesis of Disubstituted Acetylene Alcohols,Ethers, and Esters

By treating 1-octyne and phenylacetylene with butyllithium the corresponding lithium acetylides were obtained that with camphor and isocamphanone provided along streospecific process 2-exo-(1-octynyl or 2-phenyl-1-ethynyl)-2-endo-lithiumoxy-5,5,6-trimethylbicyclo[2.2.1]heptane and 2-endo-(1-octynyl or 2-phenyl-1-ethynyl)-2-exo-lithiumoxy-1,7,7-trimethylbicyclo[2.2.1]heptane. The hydrolysis of these lithium alcoholates occurred selectively and resulted in individual tertiary terpene alcohols containing exo-acetylene substituent in the case of camphor, endo-acetylene fragment in the case of isocamphanone. The alcohols reacted with methyl, ethyl, or butyl iodides in the presence of hexamethylphosphoramide to afford ethers, and with benzoyl chloride to furnish disubstituted esters of benzoic acid.     

Syntheses,spectroscopy, optical properties,and diastereoselectivity of copper(II)-complexes with chiral aminoalcohol based Schiff bases

Chiral aminoalcohol based Schiff bases (R or S)-2-{(E)-(2-hydroxy-1-phenylethylimino)methyl}phenol and (R/S)-2-{(E)-(2-hydroxy-2-phenylethylimino)methyl}phenol coordinate to copper(II)acetate to give enantiopure Λ/Δ- or Δ/Λ-bis[(R or S)-2-{(E)-(2-hydroxy-1-phenylethylimino)methyl}phenoxide-κ²N,O]copper(II), {Λ/Δ-Cu(R-L1)₂ (1) or Δ/Λ-Cu(S-L1)₂ (2)}, and racemic Δ/Λ- and Λ/Δ-bis[(R/S)-2-{(E)-(2-hydroxy-2-phenylethylimino)methyl}phenoxide-κ²N,O]copper(II), {Δ/Λ- and Λ/Δ-Cu(R/S-L2)₂ (3)}, respectively. The complexes are characterized by elemental analyzes, IR, UV–Vis, polarimetry, circular dichroism (CD), differential scanning calorimeter (DSC), and mass spectroscopy. Polarimetry shows the rotation to the left at ?113.6° (1) and to the right at +106.4^o (2). CD spectra show the expected mirror-image relationship with opposite sign of ellipticity maxima (Δε_max = +0.43 for 1 and ?0.42 M^?1 dm³ cm^?1 for 2 at 638 nm) due to the d-d transitions of the metal ion. CD spectral analyzes further reveal a diastereoselectivity or diastereomeric excess towards Λ-Cu(R-L1)₂ or Δ-Cu(S-L1)₂ configuration for 1 or 2 in solution. Similarly, the enantiomeric pair of Δ-Cu(R-L2)₂ and Λ-Cu(S-L2)₂ configurations (CD inactive) for 3 will be preferred in solution. Electronic spectra in different solvents reveal a negative solvatochromism by shifting absorption maxima of the MLCT band to higher energies in solvents of increasing polarity as well as acceptor number. DSC analyzes show an endothermic peak at 525.5 (1) or 528.7 K (2), corresponding to a thermally induced structural phase transformation from distorted square-planar to regular tetrahedral.     

Photochemisches Verhalten von 1- und 2-alkylierten 1, 2-Dihydronaphthalinen bei tiefen Temperaturen

The irradiations of 1, 1-dimethyl- (8), 1, 1-di-(tri-deuteriomethyl)- (d₆– 8 ), 1, 1, 2, 2-tetramethyl- ( 9 ) and cis- and trans-1, 2-dimethyl-1, 2-dihydronaphthalenes (cis- and trans- 10 ) were investigated in 2, 2-dimethylbutane/pentane at ?100° using a mercury high-pressure lamp, and with mercury high- and low-pressure lamps at room temperature. The results were compared with one another, and those of the individual compounds are collected in schemes 2 and 4–7. The most important results are the following: 1. The 1, 2-dihydronaphthalenes undergo a conrotatory ring opening to the o-quinodimethanes on irradiation with high- or low-pressure lamps at room temperature or at ?100°. Thermal reactions ([1, 7a]H-shifts, electrocyclisations) are suppressed at ?100°. The o-quinodimethanes formed from 8 (scheme 2), 9 (scheme 5) or cis- 10 (scheme 6) undergo on irradiation with the high-pressure lamp, [1, 5]H-shifts or photochemical Diels-Alder reactions after renewed photochemical excitation, to yield the benzobicyclo[3.1.0]hex-2-ene derivatives. These Diels-Alder reactions do not proceed stereospecifically, and therefore are not orbital symmetry controlled reactions. 2. If the 1, 2-dihydronaphthalenes are irradiated at room temperature with either a high- or a low-pressure lamp, then the initially formed o-quinodimethanes undergo thermal [1, 7a]H-shifts, in preference to all other reactions, as long as this is sterically possible; the resulting products can undergo secondary photochemical transformations. Such o-quinodimethanes are formed on irradiation of 8, 9 and cis- 10 . From trans- 10 , an o-quinodimethane mixture is formed, of which one component (cis, cis- 22 ) undergoes thermal [1, 7a] H-shifts, while the other (trans, trans- 22 ) suffers a thermal disrotatory electrocyclisation to give cis- 10 . If a high-pressure lamp is used in the last experiment, then the competing photochemical Diels-Alder cyclisation to bicyclic compounds of the type 23 (scheme 7) can result in the trans, trans- 22 . As was shown by Salisbury [3], and confirmed by ourselves in other cases [2], photochemical Diels-Alder reactions or [1, 5]H-shifts in the o-quinodimethanes require light of wavelength ? 400 nm (high-pressure lamp). The present photochemical investigations amplify and confirm our earlier conclusions concerning the photochemistry of the 1, 2-dihydronaphthalenes [2].     

Benzothiazoline derivatives. II. Preparation of N-substituted derivatives of 2-benzothiazolinethione by thiation of the 2-oxo analogs

Thuiation of the benzoate and acetate esters of 3-(2-hydroxyethyl)-2-benzothiazolinone (Ig) gave the corresponding thiones. The benzoate was then deblocked to yield 3-(2-hydroxyethyl)-2-benzothiazolinethione (Ik), a compound not accessible by direct addition or substitution. Attempts to introduce a chlorine (or bromine) atom in place of the hydroxy 1 group in the latter compound or its S-isomer, 2-(2-hydroxyethylthio)benzothiazole (11a), gave 2,3-dihydrothiazolo-[2,3-b ] benzothiazolium chloride (or bromide) (IIIa or b). The latter compound undergoes dihydrothiazolo ring opening when treated with sodium hydroxide or sodium sulfide to give bis[2-(2-benzolhiazolinon-,3-yl)ethyl]disulfide (IVc) or bis[2-(2-benzothiazolinethion-3-yl)ethyl] disulfide (lVb),respectively. 2-Benzothiazolinethione reacted with ethylenimine and with N-phenylethylenimine to give S-substituted derivatives. Addition to vinyl n-butyl ether gave the expected N-substituted derivative, which was found to undergo removal of the butyoxyethyl group when subjected to conventional conditions for ether cleavage.     

Alkylation of 4,5-dichloropyridazin-6-one with α,ω-dibromoalkanes or 4,5-dichloro-1-(ω-bromoalkyl)pyridazin-6-ones

Alkylations of 4,5-dichloropyridazin-6-one (1) with dibromoalkanes 2 or 3 in the presence of potassium carbonate or tetrabutylammonium bromide/potassium hydroxide were investigated under restricted condition. Reactions of 1 with 2 or 3, except for 2b and 3b , in the presence of potassium carbonate or tetrabutylammonium bromide/potassium hydroxide gave only the N-alkylation products 3 and/or 4. Alkylation of 1 with 2b or 3b in the presence of potassium carbonate yielded the N-alkylation products 3b and/or 4b and the O-alkylation product 5 as the main product, whereas treatment of 1 with 2b or 3b in the presence of tetrabutylammonium bromide/potassium hydroxide afforded selectively the N-alkylation products 3b and/or 4b.     

Synthesis of Chiral 12-Phenyl(2H)dodecanoic Acids: Useful metabolic probes for the biosynthesis of 1-alkenes from fatty acids

The synthesis of chiral 12-phenyi(²H)dodecanoic acids as metabolic probes for the evaluation of the stereo-chemical course of the biosynthesis of 1-alkerses from fatty acids in plants and insects is described. The diastereoisomeric (2R, 3R)- or (2S, 3S)-12-phenyl(2,3?²H₂)dodecanoic acids 11 are obtained in high chemical and optical yield (>97% e.e.) from the readily available (E)-12-phenyl(2,3-²H₂)dodec-2-enoic acid ( 10 ) or (E)-12-phenyldodec-2-enoic acid ( 10a ) by microbial reduction with wet packed cells of Clostridium tyrobutyricum in either ²H₂O or H₂O buffer. (2R)- and (2S)-12-phenyl(2?²H)dodecanoic acids 9 (>97% e.e.) are accessible from the allylic alcohol 6 via Sharpless epoxidation with (+)-L- or (?)-D-diethyl tartrate, Synthetic routes to the (E)- and (Z)-11-phenyl(1?²H) undec-1-enes 16 and 16a as reference compounds are also included.     

1,2-Benzothiazines VIII. A novel semmler-wolff type transformation of 2-methyl-2H-1,2-benzothiazin-4-one 1,1-dioxide oxime

Refluxing the oxime ( 1 ) of 2-methyl-2H-1,2-benzothiazin-4(3H)one 1,1-dioxide with tri-fluoroacetic acid or with boron trifluoride in acetic acid gives the corresponding N-acyl derivative ( 2 or 3) of 4-amino-2-methyl-2H-1,2-benzothiazin-3(4H)one 1,1-dioxide. This transformation appears to be related to the acid catalyzed conversion of α-tetralone oxime to α-naphthylamine.     

Réactions de Friedel et Crafts de dérivés aromatiques sur les composés dioxo-1,4,2,3-non saturés. IV. Réactions des hydroxy-5-ouchloro-5-diméthyl-3,5- ou diméthyl-4,5-dihydro-2,5-furannones-2

Friedel-Crafts reactions of aromatic derivatives with 1,4-dicarbonyls 2,3-éthylenic compounds. Part IV. Reactions of 5-hydroxy or 5-chloro 3,5-dimethyl or 4,5-dimethyl 2 (5 H) furanones We studied the Friedel-Crafts reactions of 2-(5H)-furanones. In the presence of sulfuric acid and of an aromatic derivative, 5-hydroxy- or 5-chloro-5-methyl-2-(5H)-furanones with one methyl group either in the 3 position, or in the 4 position generally give the corresponding 5-aryl-2-(5H)-furanones, while with aluminium chloride, it is possible to obtain, when a reaction takes place, isomeric 1H-indenecarboxylic acids. However, in a particular case, an addition to the substrate's double bond is observed. The 3-aryl-5-hydroxy-tetrahydrofuran-2-one obtained is methylated in two ways and gives either a cyclic product, or a linear one. In two cases tautomerism between 1H-1-indenecarboxylic acid and 1H-3-indenecarboxylic has been shown by ¹H-NMR.     

The preparation of quinolines and related fused-ring heterocycles from the dianions of benzoylacetone,certain cyclic ketone oximes,or certain substituted hydrazones

C(α),O-Dilithiooximes, C(α),N-dilithiobenzoylhydrazones, or C(α),N-dilithiocarboalkoxyhydrazones were prepared in an excess of lithium diisopropylamide (LDA) and condensed with 2-aminobenzophenones, or isatoic anhydrides to give intermediates that were treated with aqueous acid, which caused their hydrolysis, cyclodehydration and/or linear dehydration to give products which were substituted quinolines or related fused-ring heterocycles (e.g., cycloheptaquinolines). Dilithiobenzoylacetone was condensed with 2-aminobenzophenones, which was followed by acid cyclodehydration to substituted 2-phenacylquinolines.     

Azimine. VI. 1-Alkoxycarbony 1-2,3-dialkyl- und -2,3-diaryl-azimine

Azimines VI: 1-Alkoxycarbonyl-2,3-dialkyl- and -2,3-diarylazimines Alkoxycarbonyl-nitrenes 2 – generated in situ by α-elimination from N-[(4-nitrophenyl)-sulfonyloxy]carbamates 4 – were reacted with six aliphatic and aromatic azo compounds to yield 1-alkoxycarbonyl-azimines 11 (R′ = Alkyl). Thus, (2Z)- or (2E)- 1 -alkoxycarbonyl-2,3-diisopropyl-azimines ( 8 or 9 ) were obtained stereospecifically from (E)- or (Z)-1,1′-dimethylazoethane ( 5 or 6 ) and 1-alkoxycarbonyl -2,3-(cis-1,3-cyclopentylene)-azimines ( 10 ) resulted from 2,3-diazabicyclo[2.2.1]-2-heptene ( 7 ), always using both ethoxy- and methoxycarbonyl-nitrene ( 2a and 2b ). With 2a , (E)-azobenzene ( 14 ) was converted only to a single stereoisomer of 1-ethoxycarbonyl-2,3-diphenyl-azimine ( 17 ) and both stereoisomers of azo(p-toluene) ( 15 or 16 ) reacted to give the same stereoisomer of 1-ethoxycarbonyl-2,3-di(p-tolyl)-azimine ( 18 ).     

Conversion of 4-amino-4H-1,2,4-triazole to 1,3-bis(1H-azol-l-yl)-2-aryl-2-propanols and 1-phenacyl-4-[(benzoyl or 4-toluenesulfonyl)-imino]-(1H-1,2,4-triazolium) Ylides

A series of 1,3-bis(1H-azol-1-yl)-2-aryl-2-propanols 17 were synthesized in an one-pot procedure by reacting l-aryl-2-(1H-1,2,4-triazol-l-yl)- or l-aryl-2-(1H-imidazol-l-yl)ethanones with dimethylsulfoxonium methide in the presence of either 1,2,4-triazole or imidazole. The aromatic groups in 17 were either 4-bromo-, 4-chloro-, 2,4-dichloro- or 2,4-difluorophenyl. 4-Amino-4H-1,2,4-triazole was acylated with either benzoyl or 4-toluene-sulfonyl chloride to afford [4-(benzoyl or 4-toluenesulfonyl)amino]4H-1,2,4-triazole. Subsequent alkylations with 4-bromo- or 4-chlorophenacyl bromide produced 1-(4-bromo- or 4-chlorophenacyl)-4-[(benzoyl- or 4-toluenesulfonyl)amino]-1H-1,2,4-triazolium bromides. Neutralizations of these salts provided the corresponding ylides.     

Condensation of 2-Pyridylmethyllithium Nucleophiles and Pyridine Electrophiles as a Convenient Synthetic Route to Polydentate Chelating N-Donor Ligands

Condensation of 2-pyridylmethyllithium or (6-methyl-2-pyridyl)methyllithium nucleophiles and pyridine, 2-picoline, or 4-tert-butylpyridine as electrophiles leads to new polydentate N-donor ligands, methyl-, tert-butyl-substituted tripyridinedimethanes, or to tripyridinedimethane itself, in good or high yields. Depending on the reagent ratio, solvent used, and reaction conditions, the corresponding intermediate dipyridinemethanes can be minor by-product or major products of the condensation. In contrast to 2-pyridylmethyllithium, lithiated 2-isopropylpyridine does not react with pyridine electrophiles. Vice versa, nucleophilic substitution at the C(2)-pyridine carbon of 2,2-bis(2-pyridyl)propane with 2-pyridylmethyllithium takes place to produce products of condensation of 2-isopropylpyridine and dipyridylmethyllithium. DFT calculations of the Gibbs free energies of reactions combined with pK _a values of the CH-acids involved help to explain the reactivity observed.