Acetylenic amides. 2. The generation and reactions of dianions derived from 2-propynamides

The dianion of N-benzyl-2-propynamide can be generated by the treatment of 4 with two equivalents of LDA at ?65° or ethylmagnesium bromide at ?20°. The trilithio species 6 is readily formed using 3 equivalents of LDA. Reaction of 5 with aldehydes or ketones produce hydroxypropynamides 9 in good yields. Silation of 5a with chlorotrimethylsilane produces N-benzyl-3-trimethylsilyl-2-propynamide ( 13 ) in high yield. Reduction of 9 furnishes either fully saturated amides 15 or partially reduced cis-olefins 16 or 18 . Compounds 16 , on heating, rearrange to 4-ketoamides 17 . Carboxylation of 5a with carbon dioxide produces 3-benzyl-2,4-dioxo-5-oxazidinylacetic acid ( 11 ). Warming 11 in dimethyl sulfoxide results in the loss of carbon dioxide and the formation of N-benzylpyruvamide ( 21 ).     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical Münchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles

The unsymmetrical mesoionic münchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+13→19 in 74% yield.     

Synthesis and characterization of novel 2-(1-benzyl-3-[4-fluorophenyl]-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-one derivatives

Novel 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e were synthesized via Vilsmeier-Haack reaction of the appropriate 1-benzyl-2-(1-(4-fluorophenyl)ethylidene)hydrazines, derived from 4-fluoroacetophenone 1 with substituted 2-benzylhydrazines 2a to 2e . The base catalyzed condensation of 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e with 1-(4-fluoro-2-hydroxyphenyl)ethanone 4 gave (E)-3-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-ones 5a to 5e . On cyclization with dimethyl sulfoxide (DMSO)/I₂, compounds 5a to 5e gave 2-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-ones 6a to 6e . Structures of all novel compounds were confirmed by infrared (IR), proton nuclear magnetic resonance (¹H NMR), carbon nuclear magnetic resonance (¹³C NMR), and mass spectral data. All the synthesized compounds were screened for their antibacterial activities.     

Studies on the syntheses of azole derivatives. Part VIII. Photolysis of N-aryl-N-benzylearbamoyl azides [studies on the syntheses of heterocyclic compounds. Part CDXV

Photolysis of N-benzyl-N-phenylearbamoylazide (IVc) afforded 1-benzy 1-2-benzimidazolinone (Ic), 2-benzimidazolinone (IIe), 4-benzy 1-2-benzimidazolinone (IIe), and 5-benzy1-2-benzimidazo-linone (IIf)- The same reaction of N-benzyl-N-(4-chlorophenyl) carbamoyl azide (IVd) gave 3-benzyl-1-(phenylhydrazocarbonyl)-2-benzimidazolinone (VIb) besides the above four products. In the case of N-benzyl-4-(4-butoxyphenyl)carbamoyl azide (IVe), 1-benzy1-5-butoxy-2-benz-imidazolinone (1e), 5-butoxy-2-benzimidazolinone (IId), 5-benzy1-2-benzimidazolinone (IIf), and 4-benzy1-6-butoxy-2-benzimidazolinone (IIg).     

Displacement of Sugar Triflates with C-Nucleophiles: D-Glucopyranose and D-Ribofuranose Chain Extension and Functionalization

Treatment of methyl 4-O-benzyl-2,3-di-O-methoxymethyl-6-O-1-6-O-trifluoromethanesulfonyl-α -D-glucopyranoside 1 or 3-O-benzyl-1,2-O-isopropylidene-5-O-trifluoromethenesulfonyl-α-D-ribofuranoside 2 with a variety of functionalized C-nucleophiles in THF/HMPA leads to the corresponding chain-extended sugars in very good to excellent yields.     

The synthesis of the benzyltetrahydropyrans

The 2-benzyl-, 3-benzyl- and 4-benzyltetrahydropyrans have been prepared via the reaction of benzylsodium with 2-chloro-, 3-bromo- and 4-chlorotetrahydropyran in 49, 29 and 27% yields, respectively. The structures of these compounds were substantiated from their nmr, mass spectra and analytical data.     

Synthesis and photochromic and fluorescence properties of 3-(1-benzyl-5-methoxy-2-methylindolyl)-4-thienyl-substituted furan(pyrrole)-2,5-diones

New nonsymmetrical dihetarylethenes, 3-(1-benzyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)furan-2,5-dione and 1-alkyl- and (1-aryl)-3-(1-benzyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)-1H-pyrrole-2,5-dione, exhibiting photochromic properties in solutions were synthesized. Noncyclic isomers of dihetarylethenes show fluorescence with quantum yields up to 0.13.     

General preparative route to benzo[g]quinolines (1-azaanthracenes)

A convenient synthetic pathway to benzo[g]quinolines (1-azaanthracenes) has been developed. The nickel catalyzed coupling of methyl 2-chloronicotinate ( 3a ) with benzylic organo zinc reagents 2a-e led to the methyl 2-benzylic substituted nicotinates 4a-e. Treatment of methyl 2-chloro-6-methylnicotinate ( 3b )with 2a in a similar manner led to methyl 2-benzyl-6-methyInicotinate ( 4f ). The coupling of 2-chloro-3-acetylpyridine ( 5 ) with benzyl zinc bromide ( 2a ) led to 2-benzyl-3-acetylpyridine ( 4g ). The coupling of the 2,5-dichlorobenzylic organic zinc reagent ( 2f ) with methyl 2-choronicotinate ( 3a ) was unselective but readily coupled with methyl 2-bromonicotinate ( 6 ) to yield methyl 2-(2,5-dichlorobenzyl)nicotinate ( 4h ). The esters 4a-f,h on reduction with lithium aluminum hydride led to the corresponding alcohols 7a-f,h which were subsequently oxidized with manganese dioxide to the respective 2-benzylic substituted pyridine-3-carboxaldehydes 8a-f,h. In one case the coupling of benzy] zinc bromide ( 2a ) with 2-chloropyridine-3-carboxaldehyde ( 9 ) led directly to 2-benzylpyridine-3-carboxaldehyde ( 8a ), but in poor yield. Cyclizations of the aldehydes 8a-d,f,h or the ketone 4g with polyphosphoric acid afforded the benzo[g]quinolines 10a-d,f-h in high yields. Aldehyde 8e was cyclized to 10e using a solution of sulfuric acid in methanol. Several of the benzo[g]quinolines 10c,d could be readly converted into the benzo[q]quinoline-5,10-diones 11c,d on treatment with ammonium ceric nitrate.     

Studien zur Chemie von thienoanellierten O,N- und S,N-haltigen Heterocyclen, 10. Mitt.: Synthese von 2- substituierten Thieno-Diltiazemderivaten

Summary The syntheses of 2-acetyl-, 2-benzyl-, and 2-ethyl-thieno-diltiazem derivatives are described starting from the corresponding 5-substituted 3-nitro-2-thiophenthiolvia reaction with racemic methyltrans-3-(4-methoxyphenyl)-glycidate under different conditions (solvent, catalyst, temperature) to obtain purethreo orerythro products. The nitro groups of these products were reduced and the resulting amino esters cyclized. The thieno[2,3-b][1,4]thiazepin-5(4H)-ones were N-alkylated and acetylated in position 3. The desired 2-substituted 4-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-7-(4-methoxyphenyl)-5-oxothieno[2,3-b][1,4]thiazepin-6-yl acetates were isolated in good yields.

     

SYNTHESIS OF SIALYL-α-(2→3)-NEOLACTOTETRAOSE DERIVATIVES MODIFIED AT C-2 OF THE N-ACETYLGLUCOSAMINE RESIDUE: PROBES FOR INVESTIGATION OF ACCEPTOR SPECIFICITY OF HUMAN α-1,3-FUCOSYLTRANSFERASES,FUC-TVII,AND FUC-TVI *

A variety of sialyl-α-(2→3)-neolactotetraose (IV³NeuAcnLcOse₄ or IV³NeuGcnLcOse₄) derivatives (23, 31–37, 58–60) modified at C-2 of the GlcNAc residue have been synthesized. The phthalimido group at C-2 of GlcNAc in 2-(trimethylsilyl)ethyl (3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl)-(1→3)-(2,4,6-tri-O-benzyl-β-d-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-d-glucopyranoside (5) was systematically converted to a series of acylamino groups, to give the per-O-benzylated trisaccharide acceptors (6–11). On the other hand, modification of the hydroxyl group at C-2 of the terminal Glc residue in 2-(trimethylsilyl)ethyl (4,6-O-benzylidene-β-d-glucopyranosyl)-(1→3)-(2,4,6-tri-O-benzyl-β-d-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-d-glucopyranoside (42) gave three different kinds of trisaccharide acceptors containing D-glucose (49), N-acetyl-d-mannosamine (50), and D-mannose (51) instead of the GlcNAc residue. Totally ten trisaccharide acceptors (5–11 and 49–51) were each coupled with sialyl-α-(2→3)-galactose donor 12 to afford the corresponding pentasaccharides (14–21 and 52–54) in good yields, respectively, which were then transformed into the target compounds. Acceptor specificity of the synthetic sialyl-α-(2→3)-neolactotetraose probes for the human α-(1→3)-fucosyltransferases, Fuc-TVII and Fuc-TVI, was examined.     

An efficient synthesis of 6-benzyl-2-arylthieno[2,3-d]pyrimidin-4(3H)-ones catalyzed by HCl involving a Friedel-Crafts alkylation reaction

Aldehyde could undergo not only the subsequent condensation and cyclization with 2-aminothiophene-3-carboxamide to build a pyrimidine ring, but also a Friedel-Crafts alkylation reaction with thiophene moiety to give unexpected 6-benzyl-2-arylthieno[2,3-d]pyrimidin-4(3H)- ones in good yields catalyzed by concentrated HCl.     

The nucleophilic ring-opening of N-benzylquinuclidinium bromide

N-Benzylquinuclidinium bromide was ring opened by a series of heteronucleophiles, in the presence of cesium carbonate, to yield the corresponding N-benzyl-4-(2-hetero-ethyl)piperidines. The best yields were found with thiophenol (56%), phenol (55%), and benzimidazole (38%) as nucleophiles.     

Green chemistry design,innovation, solutions and a cohesive system

Abstract

The green, mild, and efficient synthesis of 2, 2-dimethyl-5-[(4-oxo-4H-chromen-3-yl) methylene]-1, 3-dioxane-4, 6-diones by Knoevenagel condensation of 4-oxo-4H-benzopyran-3-carbaldehydes with Meldrum's acid in presence of 1-benzyl-3-methylimidazolium chloride ((bnmim)(Cl)) ionic liquid at room temperature is reported. This method gives remarkable advantages such as a simple procedure, mild conditions, faster (10–20 min) reactions, and excellent yields. Additionally, the (bnmim)(Cl) was successfully recycled at least four times without significant loss of activity.     

Studies towards the synthesis of the fluorescent bases of phenylalanine transfer ribonucleic acids: synthesis of 7-methylwye isolated from extremely thermophilic archaebacteria

Acid- or base-catalyzed acylation of 1-benzylwye (7) provided the 7-substituted derivatives 9, 10, and 11 in poor yields. Although the reactions of lithiated 7 with electrophiles gave the 2-substituted derivatives 14, 15, 17, 20, 21, and 22, lithiation of 1-benzyl-7-bromo-2-chlorowye (23) followed by treatment with Me2CHCH2CHO (13) successfully introduced a side chain at the 7-position to afford 1-benzyl-2-chloro-7-(1-hydroxy-3-methylbutyl)wye (24). Cyclization of 1-benzyl-3-methylguanine (5) with 3-bromo-2-butanone followed by catalytic hydrogenolysis afforded 7-methylwye (2b), the hypermodified base isolated from archaebacterial transfer ribonucleic acids. A more efficient route for the synthesis of 2b has been developed via a series of reactions: the Vilsmeier-Haack reaction of 7, reduction with NaBH4, and catalytic hydrogenolysis over Pd-C.     

Indolo[3,3a,4-gh]chinoline und 10a, 6a-Iminopropano-indolo-[3,3a,4-gh]chinoline. Stereospezifische Synthesen und Umlagerungen. Teil II. 9. Mitteilung über synthetische Indolverbindungen

Alkaline hydrolysis of 1-benzyl-4, 4-dicyanoethyl-5-oxo-1,3,4,5-tetrahydro-benzo-[cd]indole under controlled conditions leads to 4-benzyl-4,6,7,8-tetrahydro-10a, 6a-iminopropanoindolo[3,3a,4-gh]quinoline-9(10H),12-dione ( 2a ), the first representative of such a ring system. Alkylation of this di-lactam affords the N-monoalkyl ( 2b ), the N, N'-dialkyl ( 3 ), and the N, O-dialkyl ( 4 ) derivatives according to the conditions employed. Treatment of compounds such as 2 with sodium in liquid ammonia results in the opening of one of the lactam rings by a stereoelectronically controlled reductive cleavage of the benzylamine bond; subsequent protonation proceeds stereospecifically to give trans-octahydroindolo[3,3a, 4-gh]quinolines (viz. 5 ). The NMR. spectra and the mechanism of the reductive ring opening are discussed.     

Selective base-promoted synthesis of substituted selenophenes by carbocyclization of (Z)-benzylselenoenynes

We herein described the synthesis of several 3-benzyl-2,5-diarylselenophene derivatives in moderate to good yields using (Z)-benzylselenoenynes as starting material in carbocyclization reactions. The reactions were carried out under mild conditions using only t-BuOK as base, in the complete absence of transition metals or additives. The cyclized 3-benzyl-2,5-diarylselenophenes obtained in the current protocol appear highly promising and attractive intermediates for the synthesis of polysubstituted selenophenes. For instance, 3-benzyl-2,5-diphenylselenophene was treated with Br(2) provided the corresponding 3-benzyl-4-bromo-2,5-diphenylselenophene in high yield. 4-Bromoselenophene derivative was applied as substrate in the palladium catalyzed cross-coupling reactions with boronic acids to give the Suzuki type products in excellent yields.     

Crystal structure and quantum chemical calculations of (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one

The known Schiff base compound, (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one, was prepared as before by reacting 1-benzyl-5-methylindoline-2,3-dione with 4-methoxyaniline. The product was unambiguously characterized using elemental analysis, ¹H and ¹³C-NMR spectroscopy, and its new single-crystal X-ray structural analysis. Molecular orbital calculations were conducted in order to investigate the structures and relative stabilities of the (E) and (Z) isomers of 1-benzyl-3-([4 methoxyphenyl]-imino)-5-methylindolin-2-one. Specific attention was paid to the (E) isomer. The available crystallographic experimental data for the latter ensured also validation of the model structures computationally derived at the theoretical B3LYP/6-31G(d,p) level.     

Synthesis of optically active 2-benzyldihydrobenzopyrans for the hypoglycemic agent englitazone

Two syntheses of some optically active 2-benzyl-2,3-dihydro-4H-benzopyrans and benzopyran-4-ones are presented. An asymmetric synthesis starting from D- and L-phenylalanine was used to provide both enantiomers of 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. Phenylalanine was diazotized in aqueous sulfuric acid to 2-hydroxy-3-phenylpropionic acid 6 which was converted in four steps to 1-bromo-2-(4-methoxycarbonylphenoxy)-3-phenylpropane 11. (4R,S)-Benzamido-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)-4H-1-benzopyran-4-carboxylic acid 16 was prepared from 11 by amidoalkylation with α-hydroxyhippuric acid in methanesulfonic acid solution followed by spiroalkylation to (4R,S)-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)spiro[4H-benzopyran-4,4′-2′-phenyloxazolidin]-5′-one 15. After the phenyloxazolidin-5-one 15 was hydrolyzed to the spirobenzamido carboxylic acid 16 , oxidative decarboxylation with sodium hypochlorite yielded optically active 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. The ketone in 19 was reduced by hydrogenation over palladium on carbon to a methylene group and the ester was converted to the aldehyde to give both isomers of the desired intermediate 2-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran 25. The second synthesis relied on an enzymatic hydrolysis of ethyl 2,3-dihydrobenzopyran-2-carboxylate 27 with the lipase from P. fluorescens to provide the desired 2R-ester. The ester group in (R)- 27 was converted to the triflate (R)- 29. Displacement of the triflate group with phenylmagnesium bromide and cuprous bromide as catalyst gave 2R-benzyl-2,3-dihydro-4H-benzopyran (R)- 30. Formylation of (R)- 30 provided 2R-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran (R)- 25 identical with that from the first synthesis. These optically active intermediates are used in the preparation of the hypoglycemic agent englitazone.     

Synthesis of certain metabolites and analogs of vitamin B6 and their ring-chain tautomerism

Pyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3-O-benzylpyridoxol (IV) and 3-O-benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide-pyridine-acetic acid complex gave 3-O-benzyl-4-pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4-pyridoxic acid. Treatment of VI with dimethylamine gave 2-methyl-3-benzyloxy-5-hydroxymethylpyridine-4-N,N-dimethylcarbox-amide (X) which oxidized to form the 5-formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylic acid (I). When reacted with liquid ammonia, VI gave 3-O-benzyl-4-pyridoxamide (VII) which was then oxidized to give 2-methyl-3-benzyloxypyridine-4,5-dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2-methyl-3-benzyloxy-5-carboxypyridine-4-N,N-dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2-methyl-3-hydroxy-4-formylpyridine-5-carboxylic acid (XVII) was synthesized starting from 3-O-benzyl-5-pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring-chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2-carboxy-4,5-dimethoxy)-phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine-d₅ the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine-d₅), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate-d₂, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0-d₆ both cyclic and open-chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C₆-H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open-chain form as observed by ir spectroscopy.