Synthesis of 1,4-Dihydropyridines by Regioselective Additions of Benzylic Zinc Bromides to Pyridinium Salts and Their Aromatizations to 4-Benzylpyridines

Benzylic zinc reagents add with high regioselectivity to 1-(phenoxycarbonyl) salts of methyl nicotinate to yield methyl-1-(phenoxylcarbonyl)-4-benzyl-1,4-dihydronicotinates. The dihydronicotinates on heating with sulfur in decalin afford methyl 4-benzylnicotinates.     

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.     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

Nucleophilic additions of arylzinc compounds to aldehydes mediated by CrCl(3): efficient and facile synthesis of functionalized benzhydrols, 1(3H)-isobenzofuranones, benzyl alcohols, or diaryl ketones

In the presence of a stoichiometric amount of CrCl(3) and trimethylchlorosilane (TMSCl), nucleophilic addition of arylzinc compounds 1c-h to arylaldehydes 2a,b,g smoothly proceeded at room temperature to yield corresponding benzhydrols 4a-f in good yields. From arylzinc compounds 1a,b, 3-aryl-1(3H)-isobenzofuranones 3a-f were given by the CrCl(3)-mediated reaction with arylaldehydes 2a-f. Diaryl ketones 5a-e were obtained in good yields by the addition of excess amount of benzaldehyde as an oxidant to the resulting solution after the CrCl(3)-mediated reaction between arylzinc compounds 1c-g and arylaldehydes 2b,g was completed. In the nucleophilic additions of arylzinc compounds 1a,d,f to alkyladehydes 6b-f, the treatment of arylzinc compounds with CrCl(3) was required prior to the addition of the aldehydes in order to prevent the fast protodezincation of arylzinc compounds by the enolizable aldehydes. In these CrCl(3)-mediated nucleophilic additions of arylzinc compounds to aldehydes, arylchromium(III) species are probably reactive intermediates.     

Synthesis and comparative study of reactivities of δ-lactone,estor group and oxazinone ring in coumarin derivatives towards carbon or nitrogen nucleophiles

Condensation of methyl 7-methylcoumarin-4-acetate ( 2 ) with primary amines and with anthranilic acid gave 7-methyl-2-oxo-N-aryl-2H-[1]-benzopyran-4-acetamide ( 4a—d ) and (7), respectively. Compound 7 underwent cyclization to give 2-(7-methyl-2-oxo-2H-[1]-benzopyran-4-yl)-methyl-4H-3,1-benzoxazin-4-one ( 3 ). The reaction of 3 with aromatic amines gave the corresponding quinazolone derivatives 5 which tautomerises to the thermodynamically more stable isomer 6 , whereas its reaction with Grignard reagents and aromatic aldehydes gave 8a, 8b , and 9a, 9b , respectively.     

An improved chemo-enzymatic synthesis of 1-beta-O-acyl glucuronides: highly chemoselective enzymatic removal of protecting groups from corresponding methyl acetyl derivatives

An improved and widely applicable chemo-enzymatic method for the synthesis of a series of 1-beta-O-acyl glucuronides 5a-f has been developed from the corresponding methyl acetyl derivatives 3a-f, which were stereospecifically synthesized from cesium salts of carboxylic acids 1a-f and methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate (2). Chemoselectivity of lipase AS Amano (LAS) in the hydrolytic removal of O-acetyl groups of 3a-f to provide methyl esters 4a-f was influenced by the nature of their 1-beta-O-acyl groups; high selectivity was evident only for 3b and 3f. Carboxylesterase from Streptomyces rochei (CSR), newly screened as an alternative to LAS, showed much greater chemoselectivity toward the O-acetyl groups than LAS; 3a, 3d, and 3e were chemoselectively hydrolyzed only by CSR. The combination of CSR with LAS yielded better results in the hydrolysis of 3c and 3f than did single usage of CSR. Final deprotection of the methyl ester groups of 4a-f to provide 5a-f was chemoselectively achieved by using lipase from Candida antarctica type B (CAL-B) as well as esterase from porcine liver (PLE), although CAL-B possessed higher chemoselectivity and catalytic efficiency than did PLE. CSR also exhibited high chemoselectivity in the synthesis of (S)-naproxen 1-beta-O-acyl glucopyranoside (7) from its 2,3,4,6-tetra-O-acetyl derivative 6.     

Reactions of substituted (1,3-butadiene-1,4-diyl)magnesium, 1,4-bis(bromomagnesio)butadienes and 1,4-dilithiobutadienes with ketones, aldehydes and PhNO to yield cyclopentadiene derivatives and N-Ph pyrroles by cyclodialkenylation

1,4-Dilithiobutadiene derivatives 1, 1,4-bis(bromomagnesio)butadiene derivatives 2 and metallacyclic (1,3-butadiene-1,4-diyl)magnesium reagents 3 were prepared and their reactions with ketones, aldehydes, and PhNO were investigated. Multiply substituted cyclopentadienes and N-Ph pyrroles were formed by unprecedented reaction conditions. The carbonyl group of aldehydes and ketones was deoxygenated during the reaction and behaved formally as a one-carbon unit; the N==O moiety of PhNO was cleaved to afford N-Ph pyrrole derivatives. Furthermore, different reactivities among these three types of reagents 1, 2 and 3 were revealed. The 1,4-dilithium reagents 1 readily reacted with both aldehydes and ketones; the 1,4-dimagnesium reagents 2 reacted with aldehydes, but not ketones; the metallacyclopentadiene reagents of magnesium 3 showed higher reactivity and did react with ketones.     

Synthesis of substituted methyl 5,5-polymethylene-2,4-dioxotetrahydropyran-3-carboxylates

Dimethyl 2-(1-bromocyclohexylcarbonyl)-, 2-(1-bromocyclopentylcarbonyl)-, and 2-(1-bromocyclobutylcarbonyl)-2-methylmalonates reacted with zinc and aromatic aldehydes to give the corresponding methyl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro[5.5]undecane-4-, 6-aryl-9-methyl-8,10-dioxo-7-oxaspiro[4.5]-decane-9-, and 5-aryl-8-methyl-7,9-dioxo-6-oxaspiro[3.5]nonane-8-carboxylates.     

Benzannulation of 3-substituted pyrroles to indoles

In a new general indole synthesis, the anion derived from benzotriazolyl derivative 5b underwent regioselective 1,4-addition to various alpha,beta-unsaturated ketones; subsequent acid-catalyzed cyclization formed the corresponding indoles 1a-f.     

General and efficient insertion of carbons carrying benzotriazole

Anions formed from the lithiation of 1-(1-benzotriazolylalkyl)benzotriazoles (1, 6) and 1-(1-methylthioalkyl)benzotriazoles (10 and 10a) with n-BuLi underwent additions to cyclic and acyclic ketones giving intermediates 3a-f, 7b-f, and 11b-d, respectively, in excellent yields. Thermal rearrangements of intermediates 3a,b,d-f and 7b-d,f in the presence of zinc bromide provided one-carbon chain-extended or ring-expanded alpha-benzotriazolyl ketones 4a,b,d-f and 8b-d,f in moderate yields with excellent regioselectivity. By contrast, intermediates 11b-d on treatment with zinc bromide loose a molecule of benzotriazole followed by intramolecular cyclization of the resulting intermediates 12b-d to provide the 2,3- and 1,2,3-substituted indenes 13b-d in good yields.     

Preparation of New Wittig Reagents and Their Application to the Synthesis of alpha,beta-Unsaturated Phosphonates

The Wittig reagent [(diethoxyphosphinyl)methylidene]triphenylphosphorane (1b) has been successfully synthesized for the first time via its phosphonium triflate salt (4a), by treating (diethoxyphosphinyl)methyl triflate with triphenylphosphine. The procedure has been applied to the synthesis of other phosphoranes and phosphonium salts. The new Wittig reagents thus synthesized were treated with various aldehydes and an activated ketone, affording the corresponding alpha,beta-unsaturated phosphonates. Triphenylphosphorane 1b and triphenylphosphonium 4a led to both cis and trans isomers with the latter being predominant, while trans isomers were almost exclusively formed when tributyl reagents (1c and 4d) were used.     

Facile preparation of Hexahydropyrrolo

Chlorolactames 2a-f reacted with sodium azide to give the cyclopropylketimines 3a-f (75-89%), and acid hydrolysis of 3c,d yielded the cyclopropylketones 6c,d (61-67%). Compounds 3a-f and 6c, d were transformed by heating (170-240 degrees C, sublimation) to the air-sensitive dihydropyrroles 4a-f (51-71%) and dihydrofurans 7c, d (85-91%). Oxidation of the dihydro derivatives 4a-f and 7c,d with DDQ led to novel types of pyrrolo[3,2-e][1,4]diazepinedione derivatives 5a-f (75-84%) and furo[1H][3,2-e][1,4]diazepinediones 8c, d (91-93%).     

Bridged tetraquaternary salts from N,N'-polyfluoroalkyl-4,4'-bipyridine

4,4'-Bipyridine (1) with excess of polyfluoroalkyl bromide or iodides 2a-d at 100-110 degrees C without solvent gave the monoquaternary salts 3a-d in >90% yields. However, 1 with 2.5 equiv of 2a-c in DMF at 110 degrees C resulted in the diquaternary salts 5a-c in >85% yields. In DMF, 5a-c were obtained in comparable yields when a molar excess of 2a-c reacted with 3a-c. 1,4-Dibromobutane with 3a,b in DMF at 100 degrees C led to the tetraquaternary salts 7a,b in approximately 85% yields. In water or acetone/water as a solvent, salts 3a-d and 5a-c were metathesized with LiN(SO(2)CF(3))(2) and KSO(3)CF(3) to produce monoquaternary ionic liquids 4a-h in >88% yields and diquaternary ionic liquids 6a-f in >86% yields, respectively. Tetraquaternary ionic liquids 8a,b were obtained when LiN(SO(2)CF(3))(2) was reacted with salts 7a,b. These compounds were stable to 340 degrees C as determined by DSC. They are the first N-mono-, N,N'-di-, and N,N,N',N'-tetra-4,4'-polyfluoroalkylbipyridinium quaternary salts and ionic liquids.     

A novel approach to substituted 2H-azirines

2-(Benzotriazol-1-yl)-2H-azirines 4a-c, obtained by treatment of oximes 2a-c with tosyl chloride and aqueous KOH, were reacted with benzylmagnesium bromide or 4-methylbenzylmagnesium bromide in the presence of zinc chloride to give 2-benzyl-2H-azirines 5a-f. Potassium phthalimide and sodium salt of benzenethiol converted 2-(benzotriazol-1-yl)-2H-azirines 4a-c into novel 2H-azirines 6a-c and 7 in good yields.     

Asymmetric synthesis of 2 degrees- and 3 degrees-Carbinols via B-methallyl-10-(TMS and Ph)-9-borabicyclo[3.3.2]decanes

Simple Grignard procedures provide methallylboranes 1a and 1b in enantiomerically pure form from air-stable precursors in 98% and 95% yields, respectively. These reagents add smoothly to aldehydes and methyl ketones, respectively, providing branched 2 degrees- (6, 69-89%, 94-99% ee) and 3 degrees- (10, 71-87%, 74-96% ee) homoallylic alcohols.     

Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

Two 2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4-chloropyridines. In addition, a number of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2c-h were obtained from 2-(4-pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1-alkylhydroxyisoindolones 6a-f which, in two cases 6a,b , were dehydrated and subjected to three separate reductions to give targets 2c,d . In three cases, the intermediate hydroxyisoindolones 6c-e were reduced in one step to the target compounds 2c-g with lithium aluminum hydride-aluminum chloride. When 6f , the product of the addition of phenyl Grignard to 5 , was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane-trifluoroacetic acid. The lithium aluminum hydride-aluminum chloride conditions were successfully applied to the synthesis of a 1-benzyl-4-piperidine derivative 21.     

Reactions of β-Sulfinyl α,β-Unsaturated Ketones with Dienes

β-Sulfinyl α,β-unsaturated ketones (2a-f) reacted in a regioselective manner with dienes such as butadiene (3a) and 1,3-pentadiene (3b) to give 1,4-cyclohexadiene derivatives (4-8) with the concomitant elimination of sulfenic acid, while the ketones (2a-c) reacted with cyclopentadiene (3c) to yield the norbornenes (9).     

Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a-e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a-f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a-e and 10a-f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.     

Synthesis of 6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine

Five variants (methods A—E) of a synthetic route to 6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (3b) using N-benzyl-N'-methylethylenediamine (8a) are described. The reaction of 8a with 1-benzenesulfonyl-2-bromomethylaziridine (7) , 2-phenyl-4-(p-toluenesulfonyloxymethyl)oxazoline (13) , and β, β-dibromoisobutyric acid (15) resulted in the direct cyclization to give the precursor of 3b , 6-substituted 1,4-diazepine derivatives 9, 14 , and 16 , respectively (methods A—C). These compounds were transformed into the desired 3b , The preparation of 1,4-diazepine ring from methyl 2-tert-butoxycarbonyl-aminopropenate (18) was alternatively achieved by the intramolecular amidation of the intermediate 19a (method D) or reductive cyclization of the aminoaldehyde 23a (method E). Method E was found to efficiently produce the 6-amino-1,4-diazepine 3b.     

Synthesis of Some New Polyfused Thienothiophenes Part 4: Synthesis of Thienopyrimidine,Thienotriazine, Thienoimidazotriazine,Thienotriazolotriazine, and Thienotetrazolotriazine Derivatives

3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene 1 was allowed to react with CS 2 , carbonyl compounds, ethyl chloroformate, S,S-acetals, and oxallyl chloride to give thienopyrimidines 2-6 and thieno-1,4-diazepine 7 . Treatment of compound 1 with nitrous acid afforded compound 8 , which converted into the corresponding chloro derivative 9 by using PCl 5 . Compound 9 was reacted with amino reagents to afford the corresponding thienoimidazotriazines 10 and 11 , thienotriazolotriazines 12 and 13 and 4-hydrazinothienotriazine 14 . Treatment of compound 14 with aldehydes, triethyl orthoformate, CS 2 , nitrous acid and ylidenemalononitriles, afforded thienotriazolotriazine 16-18 , thienotetrazolotriazine 19 , and 4-pyrazolyl-thienotriazine 20-22 derivatives respectively.