Synthesis of tricyclic and tetracyclic thieno[3,2-f]-1,4-thiazepines

Treatment of 5-methylthio-2,3-dihydrothieno[3,2-f]-1,4-thiazepine ( 9 ) with acylhydrazines gave 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepines 10, 11 , and that of 9 with ethyl anthranilate gave 5,6-dihydrothieno[3′,2′:6,7][1,4]thiazepino[5,4-b]quinazolin-8-one ( 14 ). Reaction of 9 with hydrazine hydrate or 4-chlorophenylhydrazine afforded 5-hydrazino compounds 12, 15 , which were subsequently cyclized to ethyl 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepine-3-carboxylate ( 13 ), 2-(4-chlorophenyl)-5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepin-3(2H)-one ( 16 ) and 2-(4-chlorophenyl)-6,7-dihydro-2H-thieno[3,2-f][1,2,4]triazino[4,3-d][1,4]thiazepine-3,4-dione ( 17 ). New thieno-anellated heterocycles were prepared with the aim of studying their affinity for the benzodiazepine receptors.     

Synthesis of 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine

4-Methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 3 ) was synthetized from 2-acetylfuro[3,2-f]benzo[b]furan ( 4 ) or from 2-acetyl-5,6-dihydrofuro[3,2-f]benzo[b]furan ( 10 ). The key step involves a rearrangement-cyclization of azides 6 and 12 to form 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridin-1(2H) one ( 7 ) and 8,9-dihydro-4-methylfuro[3′,2′:5,6]benzofuro[3,2c]pyridin-1(2H)-one ( 13 ). Introduction of an aminoalkyl chain on carbon 1 was effected by substitution of 1-chloro-4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 8 ).     

Cyclization reactions of 1,3-dibromopropan-2-ol, 2,3-dibromopropan-1-ol and 1-bromomethyloxirane with 6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone

The cyclization reactions, carried out in strongly- or weakly-basic media, are described. Sometimes, 7-amino-2,3-dihydro-3-hydroxymethyl-5H-thiazolo[3,2-a]pyrimidin-5-one is separated out, together with 8-amino-3,4-dihydro-3-hydroxy-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, as the principal product. A mechanism of reaction, during which the cyclizating agents are changed into oxirane derivatives, is proposed. The results of single-crystal X-ray investigations on 8-amino-3,4-dihydro-3-hydroxy-7-nitroso-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (R = 0.035 for 1013 reflections), and on 7-hydroxymethyl-6,7-dihydrothiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one (R = 0.027 for 1607 reflections) are reported.     

Regioselective Heterocyclization of 3-(Cyclohex-2′-enyl)-4-hydroxy-6-methylpyran-2-one

Summary.  Regioselective heterocyclization of 3-(cyclohex-2′-enyl)-4-hydroxy-6-methyl pyran-2-one with various reagents afforded different heterocycles. With N-iodosuccinimide in acetonitrile at 0–5°C it gave 6-methyl-9′-iodo-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one, with C₅H₅NHBr₃ or C₆H₁₂N₄HBr₃ in CHCl₃ at 0–5°C it furnished 6-methyl-9′-bromo-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one. Cold concentrated H₂SO₄ lead to 6-methyl-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one, whereas PdCl₂(PhCN)₂ in C₆H₆ at 80°C afforded 9-methyl benzofuro[3,2-c]pyran-2-one. Corresponding author. E-mail: kcm@klyuniv.ernet.in Received December 27, 2001. Accepted (revised) March 1, 2002     

2,2′-Bifurylidene-5,5′-diones,Coumarins, 3a, 7a-dihydro-1H-inden-1-ones,and 5H-furo[3,2-b]pyran-5-ones from propyne and carbon monoxide

The [Co₂ (CO)₈]-catalyzed reaction between propyne and CO in acetone at 110° and 170 bar was re-investigated. There are five major products: (E)-3,4′-dimethyl-2,2′-bifurylidene-5,5′-dione ( 4 ), 3,5,8-trimethylcoumarin ( 8 ), 3a, 7a-dihydro-2,4,7,7a-tetramethyl-1H-inden-1-one ( 9 ), 2,6-dimethyl-5H-furo [3,2, -b]- pyran-5-one ( 11 ), and 2,7-dimethyl-5H-furo 3,2-b-pyran-5-one ( 12 ); of these, only one, 4 . had previously been recognized. In parallel experiments were obtained 2,6-dipentyl-5 H-furo[3,2-b]pyran-5-one ( 13 ), 2,7-dipentyl–5H-furo[3,2-b]pyran-5-one ( 14 ), 3a, 7a-dihydro-2,4,7,7a-tetrapentyl-1H-inden-1-one ( 15 ). And 3a, 7a-dihydro-2,4,6,7a-tetrapentyl-1H-inden-1-one ( 16 ) from hept-1-yne, and two further types of products from two atypical 1-alkynes: 3,6,9-tri(tert-butyl)-1-oxaspiro[4.4]nona-3,6,8-trien-2-one ( 20 ) from (tert-butyl)acetylene and the exo-dimer 21 of 2,5-bis(trimethylsilyl)cyclopenta-2,4-dien-1-one ( 22 ) from (trimethylsilyl)acetylene. Compounds 11,12 , and 20 were identified by X-ray analysis.     

9-Deazapurine nucleosides. The synthesis of certain N-5-β-d-ribofuranosylpyrrolo[3,2-d]pyrimidines

Several N-5 ribofuranosyl-2,4-disubstituted pyrrolo[3,2-d]pyrimidine (9-deazapurine) nucleosides were prepared by the single phase sodium salt glycosylation of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine ( 3 ) using 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dirnethylsilyl-α-D-ribofuranose ( 2 ). Use of 2 for the glycosylation avoided the formation of “orthoamide” products 1 and provided an excellent yield of the β nucleoside, 2,4-dichloro-5-[2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-β-D-ribofuranosyl]-5H-pyrrolo[3,2-d]pyrimidine ( 4 ), along with a small amount of the corresponding α anomer, 5 . Compound 4 served as the versatile intermediate from which the N-7 ribofuranosyl analogs of the naturally-occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, controlled amination of 4 followed by sugar deprotection and dehalogenation yielded the adenosine analog, 4-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidine ( 8 ) as the hydrochloride salt. Base hydrolysis of 4 followed by deprotection gave the 2-chloroinosine analog, 10 , and subsequent dehalogenation provided the inosine analog, 5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]-pyrimidin-4(3H)-one ( 11 ). Amination of 10 furnished the guanosine analog, 2-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one ( 12 ). Finally, the α anomer in the guanosine series, 16 , was prepared from 5 by the same procedure as that used to prepare 12 . The structural assignments were made on the basis of ultraviolet and proton nmr spectroscopy. In particular, the isopropylidene intermediates 9 and 14 were used to assign the proper configuration as β and α, respectively, according to Imbach's rule.     

Synthesis of a novel series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives

A series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives has been synthesized as possible antileukemic agents by condensation of methyl 3-(ethoxymethylene)amino-2-benzothiophene carboxylate (II) with a variety of amines to afford the corresponding 3-aryl and 3-alkyl [I]benzothieno[3,2-d]pyrimidin-4(3H)-ones, Ill and IV, respectively. In addition, Mannich reactions of [I]benzothieno[3,2-d]pyrimidin-4(3H)-one (VIII) with formaldehyde and secondary amines gave the expected derivatives, IX. 3-Amino[I]benzothieno[3,2-d]-pyrimidin-4(3H)-one (VI) reacted with substituted aromatic aldehydes in the presence of boron trifluoride to yield the corresponding imines VII.     

Synthesis of pyrido[2,3-d]pyrimidin-4-one derivatives

This paper describes one-pot synthesis of 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one 4 , 5H-dipyri-do[1,2-a:3′,2′-e]pyrimidin-5-one 10 and 5H-pyrido[3,2-e]pyrimido[1,2-a]pyrimidin-5-one 15 and some of their derivatives, starting with 2-chloro-3-pyridine carboxilic acid 1. Compounds 4 and 10 reacted with phosphorus pentasulfide to give the respective 5-thione analogues, 5 from 4 and 11 from 10 . Boiling the 5-thione derivatives with hydrazine hydrate, the respective 5-hydrazono derivatives 6 from 5 and 12 from 11 were obtained. The 5-acetyl hydrazono, 7 , and the 5-isopropylidenehydrazono, 8 , derivatives were also prepared from 6 , and the 5-propionylhydrazono derivatives, 13 , from 12 . Compound 4 reacted with hydrazine to give an adduct with two molecules of hydrazine and the probable structure 16 . Treating this adduct with acetone a monohydrazone 17 was obtained. Boiling a suspension of this adduct in DMF, it gave 6,10-dihydro-6H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-5-one 20 .     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

Synthesis of substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones and their sulfinyl and sulfonyl derivatives

A method for the synthesis of previously unknown pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones was suggested, which includes a condensation reaction of substituted 3-cyanopyridine-2(1H)-thiones with methyl 2-(chloromethyl)benzoate and subsequent treatment of the condensation products with potassium tert-butoxide. The oxidation of the condensation products to sulfoxides or sulfones and subsequent treatment of these compounds with potassium tert-butoxide led to substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11-oxides or substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11,11-dioxides.

     

Quinazolincs and 1,4-benzodiazepines. LXXXVI. The synthesis of imidazothienodiazepines and imidazopyrazolodiazepines

The thieno[3,2-e][1,4]diazepin-2-one ( 1a ), the thieno[2,3-e] [ 1,4] diazepin-2-one ( 1b ), the pyrazolo[3,4-e][1,4]diazepin-2-one ( 1c ) and a chloro analog of 1b , compound 1d , were each converted to derivatives of the novel tricyclic ring systems 4H-imidazo[1,5-a]thieno[2,3-f] [1,4]-diazepine, 4Himidazo[1,5a]thieno[2,3f][1,4]diazepine and 4H-imidazo[ 1,5-a]pyrazolo[4,3-f]-[1,4]diazepine. Depending on the substituents desired on the imidazo ring, two different synthetic pathways were employed.     

[1]Benzothienopyrimidines. I. Etude de la 3H-benzothieno[3,2-d]pyrimidone-4

3H-benzothieno[3,2-d]pyrimidin-4-one (3) was synthesized by bimolecular cyclising the 3-amino-2-carbethoxybenzothiophene (1) with formamide. The electrophilic substituion of 3 afforded N-methylated lactam derivavtives, the structure of which was assigned by 'H nmr and unequivocal synthesis. The sysnthesis of benzothieno[3,2-d]pyrimidine (7) was achieved by desulphurization of the 3H-benzothieno[3,2-d]-[3,2-d]pyrimisine-4-thione (6) or by oxydation of the 4-hydrazinobenzothieno[3,2-d]primidine (5).     

Oxidation of 3-hydroxykynurenine. A reexamination

The oxidation mixture of 3-hydroxykynurenine ( 1 ), treated with aqueous acetic anhydride and, subsequently, with acidic methanol, yields the 1-hydroxy-3-carbomethoxy-5-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 5 ), the 1-hydroxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5.H-pyrido[3,2-a]-phenoxazin-5-one ( 6 ), the 1-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5H-pyrido[3,2-a]phenoxazin-5-one ( 6a ), the l,5-dimethoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 7 ) and the 1-methyl-1(1′-[11-(β-aspartoyl-methyl esterimino)]ethenyl)ketal-1H,5H-pyrido[3,2-a]phenoxazin-5-one ( 8 ). A probable scheme, for the compound formation, is reported.     

Tetrahydropyridoazepines and tetrahydropyridoazepinones from the corresponding dihydroquinolones

The p-toluenesulfonate of 7,8-dihydro-5(6H)quinoloneoxime( 3 ) was subjected of a Beckmann rearràngement. The resulting 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one ( 4 ) was reduced with lithium aluminum hydride affording 2,3,4,5-tetrahydro-1H-pyrido[3,2-b] azepine ( 5 ). 5,6-l)ihydro-8(7H)quinolone ( 7 ), obtained by oxidation of 5,6,7,8-tetrahydro-8-quinolinol ( 6 ), was converted into the p-toluenesulfonate of 5,6-dihydro-8(7H)quinolone oxitne ( 9 ). Similarly the latter compound could be rearranged into 2,3,4,5-letrahydro-1H-pyrido [2,3-b] azepin-2-one ( 10 ) which on reduction produced 2,3,4,5-tetrahydro-1H-pyrido [2,3-b] azepine ( 11 ).     

Synthesis of new arylbenzofurodiazepin-6-ones

Two new tetracyclic structures, containing the diazepine ring, were synthesized: 5,6-dihydro-12H-benzofuro[3,2-b][1,5]benzodiazepin-6-one and 5,6-dihydro-12H-benzofuro[3,2-b]pyrido[3,2-f][1,5]diazepin-6-one. Thus N-(2-haloaryl)-2-[(2-cyanophenyl)oxy]acetamides were cyclized to the corresponding N-(2-haloaryl)-3-amino-2-benzofurancarboxamides and then, through the formation of the central diazepine ring, to the title compounds. Formation of the diazepine ring took place only when an electron-withdrawing group was present in the molecule to facilitate the nucleophilic attack of an amine in the benzofuran intermediate.     

Synthesis of a rotenone-like benzopyranobenzopyranone

The synthesis of a novel rotenone-like molecule, 9-methoxy-8-methyl-6,6a,12,12a-tetrahydro[1]benzopyrano-[3,4-b][1]benzopyran-12-one ( 2 ) is described. Efficient syntheses of 3,4-dihydro-2H-[1]benzopyran-3-one ( 9 ) from ethyl 3-hydroxy-2H-[1]benzopyran-4-carboxylate ( 6 ), an intermediate in the synthesis of 2 , were developed. Thermolysis of 6 and 9 in decalin yielded 6,8-dihydro-14H-bis[1]benzopyrano[3,4-b:4′,3′-e]pyran-14-one ( 8 ), which has previously been described. Also produced in the thermolysis was the isomeric 1H-bis[1]-benzopyrano[3,4-b:3′,4′-á]pyran-7-(9H)one ( 10 ), the first member of a novel, pentacyclic ring system.     

Temperature-dependent reaction of 1,4,6-triaminopyrimidine-2(1H)-thiones with vilsmeier reagent. formation of [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones

5,7-Diamino[1,3,4]thiadiazolo[3,2-a]pyrirnidinium chloride 2 , 7-amino[1,2,4]triazolo[1,5-c]pyrimidine-5(6H)-thiones 3 and the 5(6H)-one derivative 4a were synthesized by the reaction of 1,4,6-triaminopyrimidine-2(1H)-thione 1 with phosphoryl chloride and N,N-dimethylacylamides. Further, compounds 4 were prepared from 2, 3 or 1,4,6-triaminopyrimidin-2(1H)-one 6 by the treatment with the above reagents. Compounds 3 and 4 were converted to 7-amino[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones 5 .     

Methyl and Phenylmethyl 2-Acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate in the Synthesis of heterocyclic systems: Preparation of 3-amino-4H-pyrido-[1,2-a]pyrimidin-4-ones

Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 4 ) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 5 ) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N³-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10 – 12 , 5H-thiazolo[3,2-a]pyrimidin-5-one 13 , 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20 – 23 . Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24 – 26 were prepared from 10 – 12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.     

New heterocyclic structures. [1,2,5]Thiadiazolo[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazine and thiazolo[3,2a][1,2,5]thiadiazolo[3,4-d]pyrimidine

Derivatives of two new molecular structures, namely, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one and 6,7-dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo[3,4-d][pyrimidin-9-one, and derivatives of N-substituted sulfamic acid, namely, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl)sulfamic acid and (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, were separated out as by-products in the reduction reaction of 8-amino-3,4-dihydro-7-nitroso-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one and 7-amino-2,3-dihydro-6-nitroso-5H-thiazolo[3,2-a]pyrimidin-5-one derivatives, respectively, with sodium hydrosulfite. A mechanism of reaction, which hypothesizes the action of sodium hydrosulfite in an asymmetic form, is proposed. The results of single-crystal X-ray investigation on 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one (R = 0.032 for 863 reflections) and (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b]- [1,3]thiazin-6-on-7-yl)sulfamic acid, sodium salt (R = 0.028 for 3507 reflections) are reported.     

Fused pyrimidine systems: XIII. Synthesis and some transformations of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines

2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]-pyrimidin-4-one results in a linear pyrido[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazin-6-one. The iodocyclization of the same substrates affords the corresponding 9-(iodomethyl)(iodomethylidene)pyrido[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-5-ones and 3-iodopyrido[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure. 9-(Iodomethyl)-8,9-dihydro-5H-pyrido[4,3-e][1,3]thiazolo[3,2-a]pyrimidin-5-one treated with sodium azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper compounds provided pyrido [4,3-e][1,3]thiazolo[3,2-a]pyrimidinylmethyltriazoles.