Studies on pyridonecarboxylic acids . 2. Synthesis and antibacterial activity of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids

A series of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids was prepared and evaluated for antibacterial activity. These compounds were synthesized from ethyl 2-mercaptoquinoline-3-carboxylates 17 which were obtained from anilines 11 by a route involving an intramolecular cyclization reaction.     

A NOVEL SYNTHESIS OF 2-SUBSTITUTED-4H-THIENO [2,3-d][1,3] OXAZIN-4-ONE AND 2,3-DISUBSTITUTED THIENO [2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Abstract

The synthesis of acetic 2-{[1-methyl-2-(4-oxo-5,6,7,8-tetrahydro-4H-benzo [4,5]-thieno [2,3-d] [1,3-oxazin-2-yl)ethylidene]amino}-4,5,6,7-tetrahydrohenzo[b]thiophene ?3-carboxylic acid anhydride 5 and 2-(oxopropyl)-5,6,7,8-tetrahydro-4H-benzo-[4,5] thieno[2,3-d][1,3]oxazin-4-one 7, has been achieved in three steps from ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b]thiophene-3-carboxlate 1 via the reaction with ethyl acetoacetate followed by hydrolysis and acetic anhydride-induced cyclization. The 2-substituent in compound 5 has two functional groups i.e. active methylene and acid anhydride which are suitably located for intramolecular transformation. Thermal and/or base catalyzed intramolecular cyclization of 5 afforded 2-(4-acetoxy-(hydroxyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-b]pyridin-3-yl)-5,6,7,8- tetrahydro-4H-benzo[4,5]thieno[2,3-d] [1,3]oxazin-4-one 10 and 9 respectively. Treatment of 5 with hydrazine hydrate, aromatic and/or heterocyclic amines induced the same intramolecular cyclization with a concomitant oxazine-pyrimidine interconversion to give 3-amino(aryl or heteryl)-2-(4-hydroxy-5,6,7,8-tetrdhydrobenzo-[4,5]thieno[2,3-b]pyridin-3-yl)-3,4,5,6,7,8-hexahydrobenzo[4,5] thieno[2,3-d] pyrimid in-4-one 11–14 respectively.     

Synthesis of 4-oxo-4H-quino[2,3,4-i,j][1,4]-benoxazine-5-carboxylic acid derivatives

The synthesis and antibacterial activity of 1-substituted amino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benox-azine-5-carboxylic acid derivatives is described. Key steps in the synthesis include carbon homologation and two intramolecular nucleophilic displacement cyclization reactions to generate the 4-oxo-4H-quino[2,3,4-i,j]-[1,4]benoxazine-5-carboxylic acid nucleus.     

Synthesis of indeno-fused derivatives of quinolizinium salts, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole, and 4h-quinolizin-4-one via benzannulated enyne-allenes

The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate 9 followed by treatment with 4-substituted pyridines 10 then furnished the benzannulated enediynes 11. On exposure of 11 to triethylamine, the indeno-fused quinolizinium salts 15 were produced in quantitative yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to form the benzannulated enyne-allenes 12, which then underwent either a concerted Diels-Alder reaction or a two-step process involving a Schmittel cyclization reaction to form biradical 13 followed by an intramolecular radical-radical coupling to afford 14. A subsequent prototropic rearrangement then produced 15. Similarly, 21a and 21b were produced from 19a and 19b, respectively. The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene (7) and 1-(2-propynyl)-1H-imidazole (25) followed by treatment of the resulting adduct with potassium tert-butoxide gave the indeno-fused imidazo[1,2-a]pyridine 24 in 98% yield. Similarly, the indeno-fused pyrido[1,2-a]indole 32 and 4H-quinolizin-4-one 35 were obtained by starting from 7 for cross-coupling with 1-(2-propynyl)-1H-indole (30) and 1-(2-propynyl)-2(1H)-pyridinone (33), respectively, followed by treatment with potassium tert-butoxide.     

Synthesis of 4H-1,3,4-oxadiazino[5,6-b]quinoxalines from 2-substituted quinoxaline 4-oxides

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a , while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9 , effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b , respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11 , whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12 .     

二苯并[b,f][1,5]二氮杂芳辛四烯衍生物的合成及拆分

以邻氨基二苯甲酮为原料,经自身缩合环化合成了3种二苯并[1,5]二氮杂芳辛四烯衍生物(1a~1c);以邻苯二甲酸酐和溴苯为原料经傅-克反应制得中间体2-(4-溴苯甲酰溴)苯甲酸(M1);M1经叠氮化后自缩合制得6,12-二(4-溴苯基)二苯并[b,f][1,5]二氮杂环辛四烯(1d);以邻氨基苯甲酸甲酯为原料,经自身缩合环化制得中间体二苯并[b,f][1,5]二氮杂环辛四烯-6,12(5H,11H)-二酮(M2);M2经氯化合成6,12-二氯二苯并[b,f][1,5]二氮杂环辛四烯(1e),化合物1a~1e的结构经~1H NMR,~(13)C NMR和ESI-MS表征,其中化合物1c为新化合物。利用超临界色谱(SFC)技术对化合物1a~1e实现了手性拆分,获得5对具有高旋光度的光学活性异构体(ee99%)。     

New synthetic approach to substituted isoindolo[2,1-a]quinoline carboxylic acids via intramolecular Diels-Alder reaction of 4-(N-furyl-2)-4-arylaminobutenes-1 with maleic anhydride

Acylation of substituted 4-(furyl-2)-4-arylaminobut-1-enes with maleic anhydride provided 2-allyl-6-carboxy-4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-enes in high yield under mild reaction conditions. The Diels-Alder adducts are formed via an initial amide formation followed by a stereoselective intramolecular [4+2] exo-cycloaddition reaction. Treatment of the tricyclic compounds with phosphoric acid at high temperatures (70-120 °C) promoted cyclic ether opening, intramolecular cyclization and aromatization to give the corresponding tetracyclic compounds, 5,6,6a,11-tetrahydro-10-carboxyisoindolo[2,1-a]quinolines, in moderate yields. The influence of the acid and the reaction temperature on the cyclization reactions are also discussed.     

Construction of mononitrogen heterocycles with a combined system of 1-azaspiro[4.n]alkene and 3-benzazocine fragments through the intramolecular eight-membered Heck cyclization

Amides, obtained from 1-azaspiro[4.n]alkenes (n = 3, 4, 5) and 2-(6-bromo-1,3-benzo-dioxol-5-yl)acetyl chloride, upon heating with a Herrmann—Beller palladium catalyst undergo intramolecular cyclization by the Heck reaction to form pentacyclic compounds (up to 94% yield) including an 1-azaspiro[4.n]alkene (n = 4, 5) fragment and a new eight-membered 3-benzazocine ring. The structure of the thus obtained pentacycles with the 1-azaspiro[4.4]non-7-ene fragment is isomeric to the structure of the main core of alkaloid cephalotaxine. In the case of 1-azaspiro[4.5]dec-2-ene derivative, the reaction is accompanied by the reduction of bromo amide, with the yield of the cyclization product being 34%. The starting 1-azaspiro-[4.n]alkenes (n = 3, 4, 5) were synthesized by the reductive diallylboration of 3-chloropropion-itrile or the corresponding lactams (piperidin-2-one, (2S)-2-hydroxymethyl-and 5,5-di-methylpyrrolidin-2-one) with subsequent intramolecular metathesis upon the action of Grubbs catalyst.     

Biradicals from benzoenyne-allenes. Application in the synthesis of 11H-benzo[b]fluoren-11-ols, 1H-cyclobut[a]indenes, and related compounds

New synthetic pathways to 11H-benzo[b]fluoren-11-ols, 1H-cyclobut[a]indenes, and related compounds via biradicals generated from benzoenyne-allenes were developed. Treatment of the diacetylenic propargylic alcohols 13, derived from condensation between benzophenones and the lithium acetylide of 1-(2-ethynylphenyl)-2-phenylethyne, with thionyl chloride produced the 11-chloro-11H-benzo[b]fluorene 14 and, after hydrolysis, the corresponding 11H-benzo[b]fluoren-11-ols 15. The transformation involved a sequence of reactions, including a biradical-forming C2-C6 cyclization (Schmittel cyclization) reaction of the chlorinated benzoenyne-allene intermediates followed by an intramolecular radical-radical coupling to form the formal Diels-Alder adducts. Interestingly, in the case of the diacetylenic propargylic alcohol 26, obtained from dibenzosuberenone (25), an intramolecular [2 + 2] cycloaddition reaction of the chlorinated benzoenyne-allene intermediate occurred, furnishing the 1H-cyclobut[a]indene 27 exclusively. The dramatic change of the reaction pathway could be attributed to the emergence of a steric strain due to the nonbonded interactions with the chloro substituent along the pathway toward the formal Diels-Alder adduct 31. On the other hand, the non-chlorinated benzoenyne-allene, derived from prototropic isomerization of the diacetylenic hydrocarbon 60, underwent a formal Diels-Alder reaction to furnish the 11H-benzo[b]fluorene-type hydrocarbon 61 exclusively.     

Synthesis of isoxazolopyrroloisoquinolines by intramolecular cyclizations of 5-(2-arylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones

5,8a,11a,11b-Tetrahydroisoxazolo[5′,4′:3,4]pyrrolo[2,1-a]isoquinolin-8(6H)-ones were prepared by intramolecular cyclization of 5-(2-arylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones in the presence of boron trifluoride diethyl etherate.     

Chemotherapeutic agents. IX. Synthesis and pesticidal activities of bis[4-aryl/alkyl-1, 2, 4-triazoline-5-thione-3-yl]alkanes and 1 -Aryl/alkyl-3-[4-(4-aryl/alkyl-1, 2, 4-triazoline-5-thione-3-yl)phenyl]thiourea and related compounds

Various bis[4-aryl/alkyl-1, 2, 4-triazoline-5-thione-3-yl]alkanes ( 3 ) were prepared from base cyclization of bis thiosemicarbazide 2 and transformed into sulphides by reaction with different alkyl halides in alkaline medium. These compounds were further oxidised to sulphones 5 with acidic potassium permanganate. 1-Aryl-3-[4-(4-aryl/alkyl-1, 2, 4-triazoline-3-thione-5-yl)phenyl]thioureas ( 8 ) were prepared in two steps from p-aminophenylhydrazide ( 6 ) and aryl/alkylisothiocyanates. Alkylation of 8 with different alkyl halides yielded exclusively sulphides 9 . Some sulphides 12 and Mannich bases 13 from 5-(p-fluorophenyl)-1, 3, 4-oxadiazol-2-thione ( 11 ) were also prepared to evaluate their pesticidal activities. All the prepared compounds were screened for pesticidal activities but none of them exhibited any significant activity.     

Heterocycles with a Benzothiadiazeypine Moiety. I. Synthesis of Pyrrolo[1,2-b]-s-triazolo[3,4-d] [1,2,5]benzothiadiazepine 5,5-Dioxide

Condensation of 2-nitrobenzenesulfonyl chloride with 2-ethoxycarbonyl-1H-pyrrole in the presence of potassium tert-butoxide and 18-crown-6 furnished 2-ethoxycarbonyl-1-(2-nitrobenzenesulfonyl)-1H-pyrrole. Reduction of nitro group to amino and subsequent cyclization by heating the aminoester in the presence of 2-hydroxypyridine as a bifuctional catalyst led to 11-oxo(10H)-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5,5-dioxide. Treatment of the latter compound with di-4-morpholinylphosphinic chloride gave the corresponding phosphinyloxyimine, which on reacting with formylhydrazine underwent intramolecular cyclization to afford the title tetracyclic ring.     

Intramolecular ipso-halocyclization of 4-(p-unsubstituted-aryl)-1-alkynes leading to spiro[4,5]trienones: scope, application, and mechanistic investigations

A new, general method for the synthesis of spiro[4,5]trienones is described by the intramolecular ipso-halocyclization of 4-(p-unsubstituted-aryl)-1-alkynes. In the presence of halide electrophiles, a variety of 4-(p-unsubstituted-aryl)-1-alkynes underwent the intramolecular ipso-halocyclization with water smoothly, affording the corresponding halo-substituted spiro[4,5]trienones in moderate to good yields. The obtained spiro[4,5]trienones can be applied in constructing the azaquaternary tricyclic skeleton via Pd-catalyzed Heck reaction. Notably, the prepared spiro[4,5]trienones and azaquaternary tricycles are of importance in the areas of pharmaceuticals and agrochemicals. The mechanism of the intramolecular ipso-halocyclization reaction is also discussed according to the (18)O-labeling experiments and DFT calculations.     

Synthesis of 4-(2-chloroethyl)-2,3-dihydro[1,4]oxazino[2,3-b]quinoline and 4-(2-chloroethyl)2,3-dihydropyrido[2,3-b][1,4]oxazine

The title compounds were synthesized from 3-[bis(2-hydroxyethyl)amino]quinolin-2(1H)-one 11a and 3-[bis(2-hydroxyethyl)amino]pyridin-2(1H)-one 18 respectively. The preparation involved a tandem chlorination/cyclization reaction.     

含双-三唑并噻二唑环的庚烷类衍生物的合成及抗菌活性

The aroylhydrazides were prepared by esterification and hydrazinolysis of corresponding aromatic carboxylic acids.The reaction of aroylhydrazides with CS2/KOH in absolute ethanol gave potassium aroyldithiocarbazates and then hydrazinolysis of potassium aroyldithiocarbazates with hydrazine hydrate afforded 3-aryl-4-amino-5-mercapto-1,2,4-triazoles(1a～1g).New seven compounds of bis[(3-aryl)-s-triazolo[3,4-b]-[1,3,4]thiadiazole derivatives(2a～2g) were synthesized in high yields by cyclization of nonanedioic ac...     

Polycondensed heterocycles. IV. synthesis of 1,4-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazine

A method for the synthesis of the title compound 3 consisted of an intramolecular cyclization in a stannic chloride catalyzed Friedel-Crafts reaction of N-(2-methylthiophenyl)-5-oxoproline chloride 10 , prepared by chlorination of the corresponding acid 9 obtained by hydrolysis of its ethyl ester 8 . Condensation of 2-methylthioaniline 4 with diethyl bromomalonate 5 afforded diethyl 2-methylthioanilinomalonate 6 which gave 8 either directly by reaction with ethyl acrylate or by alkylation with ethyl β-bromopropionate or ethyl acrylate and cyclization of resulting triethyl 2-(2-methylthio)anilino-2-carboxyglutarate 7 . This method was not convenient because of the poor yield of 3 (14%). On the other hand, cyclization of N-(2-mercaptophenyl)-5-oxoproline 14 with DCC and DMAP provided 3 in 45% yield. Oxidation with m-CPBA of the esters 11 and 8 , demethylation via the Pummerer rearrangement of the respective sulphoxides 12 and 17 with TFAA and oxidation with iodine of resulting N-(2-mercap-tophenyl)-5-oxoproline esters 13 and 18 gave the corresponding disulphides 16 and 19 . Hydrolysis of these latter compounds and reduction of the resulting bis[2-[2-(hydroxycarbonyl)-5-oxo-1-pyrrolidinyl]phenyl] disulphide 15 with sodium dithionite afforded the required 14 . Deprotection of t-butyl ester 13 with TFA at 55° to obtain 14 led to 3 in 42% yield. Finally the Pummerer rearrangement of N-(2-methylsulphinylphenyl)-5-oxo-proline 20 yielded the mixture of 14 and 15 .     

Synthesis under microwave irradiation of [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles and other diazoles bearing indole moieties and their antimicrobial evaluation

Microwave-assisted synthesis of some novel compounds, namely, 3-(2-methyl-1H-indol-3-yl)-6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a,b was accomplished via bromination of 2-methyl-3-[4-(arylideneamino)-5-mercapto-4H-[1,2,4]triazol-3-yl]-1H-indoles 3a,b. Also, new [1,3,4]thiadiazoles 12a,b, [1,2,4]triazoles 15a,b and [1,3,4]oxadiazoles 19a,b, with indole moieties, were prepared by cyclization of 1-[(2-methyl-1H-indole)-3-carbonyl]thiosemicarbazides 8a,b under microwave irradiation using different reaction conditions. Moreover, reaction of acid hydrazide 7 with ethyl 2-(N-phenylhydrazono)-3-oxobutanoate (20) gave the respective phenylhydrazonopyrazole derivative 21 under the reaction conditions employed. The structures of the synthesized compounds were assigned based on elemental analyses and spectral data (IR, (1)H-NMR, (13)C-NMR, MS). The antifungal and antibacterial activities of the new products were also evaluated.     

Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4, 3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4, 3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.     

Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.     

Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.