Thio-acids—V : Some reactions of 3-oxo-1,2-dithioles

Diphenyldiazomethane with compound (1) gave dibenzoyl, while 2 and 3 gave the corresponding 3-oxo(2H)thiophenes 5. With copper-bronze 1 gave 2,2′-di-(thiobenzoate) (4), while 2 gave 2,7-diphenylthiepin (6a) and 2,5-diphenylthiophene (7a), but 3 gave only 2,5-di-(p-methoxyphenyl)thiophene (7b). With Grignard reagents 1 gave the corresponding methanol derivative 14, while 2 gave the thiobenzoylethylenes 13a and b, but 3 gave 2,7-di-(p - methoxyphenyl) - 4,4,5,5- tetraphenyl(4H)thiepin (15). The reaction mechanisms are discussed.     

Bromination of 3-phenylindoles

Brominations of 3-phenylindole (1a) and its 1-methyl-(1b) and 1-acetyl-(1c) derivatives with NBS in AcOH and CCl₄ have been carried out. In AcOH 1 gave 2-bromo derivatives (2) in high yields and the relative reactivity was found to be NH > NMe ? NAc by competitive reactions. In boiling CCl₄1a and 1b gave 2 but bromination of 1c did not proceed. Bromination of 1a with 2 moles of NBS in AcOH gave 2,6-(major) and 2,5-dibromides (8 and 9). Reaction of 2a with thiourea gave 19. Selective reduction of the bromine atom at the 2-position in 2,6-dibromide (10) was achieved by Zn3CuNaOH, and irradiation of 8 in EtOH-alkali reduced 2,6-dibromide to 1a.     

Preparation and reaction of cyclopropyltriphenylphosphonium salt

Cyclopropyltriphenylphosphonium bromide (2a) was conveniently prepared from 3-bromopropyltriphenylphosphonium bromide (1a). The Wittig reaction of cyclopropyltriphenylphosphonium bromide (2a) with carbonyl compounds gave alkylidenecyclopropanes (4, 6 and 7). Successive treatment of 1a with two equivalents of base and carbonyl compounds gave alkylidenecyclopropanes (4 and 5) without isolation of intermediary 2a. 2-Methylcyclopropyltriphenylphosphonium bromide (2b) was prepared and allowed to react with carbonyl compounds.     

Synthesis of 4,6-(and 5,7-)dimethoxy-3,3-dimethyl-1-indanones

Grignard reaction of ethyl 3-(3,5-dimethoxyphenyl)-propionate (4) followed by cyclodehydration of the carbinol (5) with conc H₂SO₄ gave 4,6-dimethoxy-3,3-dimethylindane (6). Oxidation of the indane (6) with CrO₃-pyridine complex in methylene chloride gave 4,6-dimethoxy-3,3-dimethylindan-1- one (1) in high yield. Conjugate addition of methyl magnesium iodide to methyl α-cyano-β-methyl-3,5-dimethoxycinnamate (11), prepared from 3,5-dimethoxyacetophenone (10) by Knoevenagel condensation, resulted in methyl 2-cyano-3-(3,5-dimethoxyphenyl)-3,3-dimethylpropionate (12). Refluxing the ester (12) with aq DMSO containing sodium chloride gave the corresponding nitrile (15) which underwent Höesch reaction to yield 5,7-dimethoxy-3,3-dimethylindan-1-one (2).     

Reactions of bicyclobutylidene and 1,3-bis(trimethylene)propadiene : Synthesis of trispiro[3.0.3.0.2.0]undecane, 9-methylenedispiro[3.0.3.1]nonane,and bicyclobutylidene-2,2'- and 2,4'-dione

A number of reactions of bicyclobutylidene (1) and 1,3-bis(trimethylene)propadiene (2), directed towards the preparation of compounds in which conjugated and steric effects of the cyclobutane ring could be evaluated, are described. Trispiro[3.0.3.0.2.0] undecane (4) was prepared from 1, and 1-cyclobutylidenespiro[3.2]hexane (8b) from 2. Thermolysis of 8b gave 9-methylenedispiro[3.0.3.1]nonane (14). Oxidation of 1 with singlet oxygen gave the “ene” product 17, and an attempted two step conversion to the dioxetane via the bromohydroperoxide 19 also gave 17. Oxidation of 2 with peroxyacids gave products which probably arose from either the allene oxide or the bis-oxirane. The cyclobutane ring does not appear to afford any steric protection to allow the isolation of the dioxetane or allene oxide. Three unsucessful routes directed towards the synthesis of bicyclobutenyl (24) are described, and the syntheses of bicyclobutylidene-2,4'-dione (39) and -2,2'-dione (40) are reported.     

Incorporation of 5-substituted uracil derivatives into nucleic acids—III : Synthesis of 5-substituted uracils derived from 5-acetyluracil

5-Acetyluracil (1) has been converted into 5-(bromoacetyl)-uracil (2) by an established procedure. Reduction of 2 with sodium borohydride gave 5-(2-hydroxyethyl)uracil (4) in low yield. Treatment of 5-vinyluracil (7), obtained from 1 by published methods, with 1 molecular proportion of bromine followed by heating to 100°, gave E-5-(2-bromovinyl)uracil (8). Reaction of 8 with potassium t-butoxide gave 5(7)H-furanol[2,3,d]pyrimidin-6-one (10) and upon reduction with sodium in liquid ammonia, 8 gave 5-ethyluracil (11). Compound 2 showed low antibacterial activity against Staphylocuccus aureus, Streptococcus faecalis and Escherichia coli in nutrient broth and in a medium containing only inorganic salts, glucose and thymine, appreciable activity (～ 6 μg/ml) against E. coli. Compound 2 was not incorporated into the DNA of E. coli.     

Novel generation and cycloaddition reactivity of N-phenylsulfonylbenzonitrilimine via thermal decomposition of N-(phenylsulfonyl)benzohydrazonoyl chloride

Thermal decomposition of N(phenylsulfonyl)-benzohydrazonoyl chloride (1) in refluxing toluene generated N-phenylsulfonylbenzonitrilimine (2) which gave 1,3-dipolar cycloadducts with ethyl (4a) and methyl acrylate (4b), acrylonitrile (4c), styrene (4d), norbornene (4e), and norbornadiene (4f). The reactions with 4a–d, 2 afforded regiospecifically 5-R substituted pyrazolines 5a–d in lower yields. The raction of 2 with 4e gave only exo adduct 5e, while the reaction with 4f gave both exo- (5f_x) and endo adducts (5f_n) as well as their retro-Diels-Alder product 6.     

Synthesis of adamantane derivatives—38: Synthesis of 1,3-bishoadamantane via ring-expansion of homoadamantan-2-one and homoadamant-4-en-2-one

The ring expansion of homoadamant-4-en-2-one (7) via the corresponding aminomethyl alcohol (9) gave 1,3-bishomoadamant-7-en-4-one (10) as the major product which was converted to 1,3-bishomoadamant-4-ene (14) and 1,3-bishomoadamanta-4,7-diene (16) via the alcohols 13 and 15. Catalytic hydrogenation of 14 and 16 afforded 1,3-bishomoadamantane (2). The ring expansion of homoadamantan-2-one (17) via the aminomethyl alcohol (19) afforded a 9:1 mixture of 1,3-bishomoadamantan-4-one (12) and 5-one (20). The same mixture was also obtained directly from 17 on treatment with diazomethane. The Wolff-Kishner reduction of 12 and 20 gave also 2.     

Photo-Reimer-Tiemann reaction of phenols,anilines and indolines

The photo-reaction of phenol (1) with chloroform in the presence of diethylamine gave salicylaldehyde (2) and 4-hydroxybenzaldehyde (3) in fair yield. Dihydroxybenzenes, sensitive to alkali, under similar conditions without the base gave corresponding aldehydes and a cyclohexa-2,5-dienone (15). The photo-reaction was also applied to diethylaniline (18), indoline (21) and N-methylindoline (24). In carbon tetrachloride instead of chloroform in an alcohol solution the same type of reaction took place to give esters. The mechanism involving the coupling of a phenoxy radical or a radical cation with dichloromethyl radical and not involving dichlorocarbene is proposed.     

Synthesis of (S-(−)-wybutine,the fluorescent minor base from yeast phenylalanine transfer ribonucleic acids

The Wittig reaction of 1-benzyl-7-formylwye (12) with (R)-[2-carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (8) followed by successive methylation and reduction gave (-)-wybutine [(S)-1a].     

Flavanoid epoxides—XIII : Acid and base catalysed reactions of 2′-tosyloxychalcone epoxides. Mechanism of the algar-flynn-oyamada reaction

2′-Tosyloxychalcone epoxide (6a) on reaction with alkali gave flavonol (4a) while similar treatment of 6′-methoxy-2′-tosyloxychalcone epoxide (6b), both at room temperature and at the boiling point of the reaction medium, afforded 5-methoxyaurone (5b). The latter result indicates that an epoxide is not an intermediate in the production of flavanols from 2′-hydroxy-6′-methoxychalcone epoxides on treatment with alkaline hydrogen peroxide (AFO Reaction) at the higher temperature. Epoxide 6a on treatment with boron trifluoride etherate gave a mixture of flavanonol and flavonol while epoxide 6b gave formyldesoxybenzoin (9) under similar conditions.     

Diphenyl N-halosulfilimines : Preparation,decomposition, and reactions with nucleophiles

Diphenyl N chloro (l)-N bromo (2) and N-iodo-sulfilimines (3) were prepared by halogenation of diphenyl free sulfilimine. Compound 1 decomposed in benzene at room temperature. The decomposition of 1 is a chain reaction since the reaction was induced by chlorine or t-butyl hypochlorite affording diphenyl(diphenylsulfilimino) sulfonium chloride(4a) while it was inhibited by styrene or stilbene. Compound 4a was also obtained by the reaction of 1 with diphenyl sulfide in benzene. Decomposition of 1 in acetic acid proceeded smoothly affording various products. Compound 1 reacted with sulfides sulfoxides triarylphosphines and triethylamine affording the N-substituted iminosulfonium salts. Compounds 1 and 2 were hydrolyzed with sodium hydroxide affording diphenyl sulfoximine. The reaction of 1 with sodium cyanide gave diphenyl N cyanosulfilimine(17). The reaction of 1 with Grignard reagent gave diphenyl free sulfilimine. Compounds 2 and 3 are more stable than 1. Decomposition of 2 in benzene or acetic acid gave diphenyl(diphenylsulfilimino)sulfonium perbromide(4c)     

Controlling the photochemical reactions of alkenes by light-path length effects of a microchannel reactor

Photoirradiation of Me₂CO–H₂O solution of pent-4-en-1-ol (1a) with a high-pressure mercury lamp in a test tube gave 8-hydroxyoctan-2-one (3a) in 66 % yield along with oxetane (4a) and the isomer (4a′) in 10 % yield. Irradiation of the running Me₂CO–H₂O solution of 1a in the flow system of a microchannel reactor (MCR) gave mainly 4a. The photoreaction of 1,1-diphenylethene (2a) with triethylamine gave a Markovnikov-type adduct (5a) and an anti-Markovnikov-type adduct (6a). The use of the MCR enhanced the production of 5a. These phenomena were explained by the light-path length effects of the MCR.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Optically active α-hydroxy-α-(tetrahydroquinoxalin-3-on-2-yl)esters by ring transformation of (R,R)-diethyl oxirane-2,3-dicarboxylate

The reaction of (R,R)-diethyl oxirane-2,3-dicarboxylate 6 with o-phenylendiamines 7 and 1,8-diaminonaphthalene gave optically active (2R,2′S)-2-hydroxy-2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetates 8 or (2R,2′S)-2-hydroxy-2-(3-oxo-1,2,3,4-tetrahydronaphtho[1.8-ef][1.4]diazepin-2-yl)-acetate 9, respectively, in a regio and stereoselective manner. o-Phenylendiamines 7 with an electron-donating substituent gave other regioisomers to the electron-poor 7. Together with previous investigations in this field the present results demonstrate a dependence of the mode of the reaction of glycidates with o-phenylendiamines on the substituents at the glycidate.     

Nucleophilic subsitution at silicon: Synthesis of sterically-hindered bis(2,6-di-t-butylaryloxy)silanes

The reaction of the monomethylsilane (8a) with two equivalents of the 4-(carboalkoxy)-2,6-di-t-butyl-substituted phenol (7b) in toulene using triethylamine as an acid acceptor gave the bis(aryloxy) adduct (9a). The analogus reaction of the dimethylsilane (8b) with sodium 2,6-di-t-butyl-4-(methoxycarboxyl)-phenolate (7a) gave only the monosubstitution product (10a). The reaction of the corresponding phenolate (7e) with 8b gave a mixture of 7a, 10a, and bis-adduct (9b), whereas, in the presence of 15-crown-5, the bis-adduct 9b was obtained. The bis-adducts 9c–e were prepared in an analogous manner. The reaction of n-hexyl 3,5-di-t-butyl-4-hydoxylbenzoate (7h) with the diphenylsilane (8c) gave only the monosubstitution product 12, while forcing conditions gave, unexpectedly, the methyl ether 13. The reaction of 4-(carboalkoxyethyl)-2,6-di-t-butylphenol (16a) with 8a gave the bis adduct. The reaction of 16a with 8b in THF, without a crown ether, gave a low yield of the monosubstitution product. The bis-adducts 17b–c were obtained by the reaction of 8b with the corresponding phenolates (16a–b) in tetraglyme. Compound 17b was also obtained by the reaction of 8b with 16a in THF with a crown ether. These results are discussed in terms of charge dispersal in the phenolate ion and the corresponding effect upon both ion-pairing and aggregation in solution.     

Synthesis of 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil by selective elimination reactions

For the synthesis of y 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil (16), the precursor, 5′-O-benzoyl derivative (2),² was elaborated in a variety of ways. 1-(5′-O-Benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (4)² was benzoylated to N³-benzoyl-1-(2′,5′-di-O-benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (5), which directly yielded 2 on treatment with sodium benzoate. 1-(3′,5′-Di-O- benzoyl-2′-O-tosyl-β-D-lyxofuranosyl)uracil (8) and its 3′,5′-O-isopropylidene analog (10) resisted elimination reactions, thus proving absolute selectivity in the elimination of the derivatives of 1-β-D- lyxofuranosyl-uracil. Seeking a more economical path to 2, 1-(5′-O-benzoyl-β-D-lyxofuranosyl)uracil (11) was first benzoylated to give 2′,5′-di-O-benzoate (12), accompanied by 3′,5′-di- and 2′,3′,5′-tri-O- benzoate. Mesylation of the major product (12) gave 1-(2′,5′-di-O-benzoyl-3′-O-mesyl-β-D- lyxofuranosyl)uracil (15), which, on treatment with sodium benzoate, gave 2 in an highly improved yield. Basic hydrolysis on 2 gave compound 16.     

Synthesis of methylpyridine derivatives—XXXIIIChem. Pharm. Bull.25, 203 (1977).: Phosphonylation and chlorination of methylpyridine and 3-nitro-methylpyridine derivatives

Novel phosphonylation of the active Me group of pyridine derivatives is described.Reaction of 2 (and 4) -methylpyridine (3 and 5) with PCl₅ in POCl₃ gave 2 (and 4) -trichloromethylpyridine (4 and 6). Similarly, reaction of 4 (and 6) methyl-3-nitropyridine (7 and 9) afforded the corresponding trichloromethyl derivative (8 and 10). However, the similar reaction of 2-methyl-3-nitropyridine (11) gave dichloro-(3-nitro-2-pyridyl)-methylphosphonic dichloride (12).Mechanisms of the formation of these products are discussed.     

Stereoselective synthesis of fluoroalkenes via (Z)-2-fluoroalkenyliodonium salts

Stereoselective synthesis of fluoroalkenes is described. (Z)-2-Fluoro-1-alkenyl(phenyl)iodonium tetrafluoroborates (1) were synthesized stereoselectively in good yields by Michael-type addition of HF to 1-alkynyl(phenyl)iodonium tetrafluoroborates (2) with a commercially available HF reagent, hydrofluoric acid or Et₃N-3HF. Pd-catalyzed cross-coupling reactions using 1 gave (Z)-2-fluoro-1-alkene derivatives in moderate yields. The treatment of 1 with KI in the presence of a catalytic amount of CuI gave (Z)-2-fluoro-1-iodo-1-alkenes (3). Pd-catalyzed cross-coupling reactions of 3 gave better results than that of 1, and a variety of (Z)-2-fluoro-1-alkene derivatives were synthesized in good yields.     

Copper and palladium complexes with N-heterocyclic carbene ligands functionalised with carboxylate groups

The new imidazolium salts functionalised with the trimethylsilyl ester group 1a–c, were easily obtained by quaternisation of alkyl- or aryl-imidazoles with trimethylsilyl bromoacetate. Salt 1a was isolated and fully characterised. It reacted with mesityl copper (Cu₅Mes₅) under trimethylsilyl abstraction to form the complex 2. Methanolysis of 1a–c gave good yields of the carboxylic acid functionalised imidazolium salts 3a–c. Deprotonation of the latter in liquid ammonia led to the zwitterionic imidazolium carboxylates 4a–c. Reaction of 4a with (Cu₅Mes₅) gave solutions from which the insoluble polymeric 5a crystallised slowly. Generation of the carboxylate-functionalised NHC in situ followed by reaction with Pd(OOCCH₃)₂ gave the new complex 6a in which the NHC-carboxylate ligand is chelate bidentate.