The stereochemistry of 1,6,7,12b-Tetrahydro-2H,4H-[1,2] oxazino[3′,4′:1,2]-pyrido[3,4-b]indole and of 1,2,3,6,7,12b-Hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2]pyrido[3,4-6] indole

From an analysis of nmr spectral data, 1,6,7,12b-tetrahydro-2H,4H-[1,3 ]oxazino[3′, 4′ :1,2]-pyrido[ 3,4-b ]indole is shown to exist in solution at room temperature almost entirely in the cis-fused ring conformation with the nitrogen lone pair bisecting the C4 methylene group whereas under the same conditions 1,2,3,6,7,12b-hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2] pyrido-[3,4-b ]indole exists as an approximately 50:50 equilibrium mixture of the cis and trans-fused ring conformations.     

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.     

Synthesis of 2-amino-6,7-dihydrothieno-[3′,2′:5,6]pyrido[2,3-d]pyrimidin-4-one

2-Amino-6,7-dihydrothieno[3′,2′:5,6]pyrido[2,3-rf]pyrimidin-4-one ( 1 ) was prepared in three steps from S-(3-butynyl)thiosemicarbazide hydroiodide ( 3 ) and diethyl ketomalonate. The featured step in this synthetic sequence was an intramolecular Diels-Alder reaction of the in situ generated 3-(3-butynylthio)-6-carboethoxy-5-chloro-1,2,4-triazine ( 9 ) to provide the key intermediate 5-carboethoxy-6-chloro-2,3-dihydrothieno-[2,3-b]pyridine ( 6 ). In the course of studies directed toward the preparation of 1 , thermolysis of 3-(3-butynyl-thio)-6-carboethoxy-1,2,4-triazin-5(2H)-one ( 2 ) was found to involve competitive intramolecular Diels-Alder and intramolecular coplanar cycloamination processes, providing the 2,3-dihydrothieno[2,3-b]pyridin-6(7H)-one ( 4 ) and the 1,3-thiazino[3,2-b]-1,2,4-triazin-3-one (5) derivatives, respectively.     

Synthèse et propriétés photochromiques de 1, 3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4-f][1,4]benzoxazines] et de 1,3-dihydrospiro[2H-indole-2,7′-[7H]thiazolo[5,4-f][1,4]benzoxazines]

Synthesis and Photochrmic Characteristics of 1,3-Dihydrospiro[2H-indole-2,3′-[3H-]pyrimido[5,4-f][1,4]benzoxazines] and 1,3-Dihydrospiro[2H-indole-2,7′[7H]thiazolo[5,4-f][1,4]benzoxazines] Two new series of 1,3-dihydrospiro[2H-indole-ozazine] derivatives were synthesized, the 1,3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4]pyrimido[5,4-f][1,4]benzoxaines] 4-10 and the 1,3-dihydrospiro[2H-indole2,7′-[7H]thiazolo-[5,4-f][1,4]benzoxaines] 11–17 . These series extend the available range of photochromic properties (rate constant of thermal bleaching, UV/VIS spectrum of the opened coloured form, and photocoloration yield), an interesting feature of variable-transmission materials. The synthesis of these compounds (Scheme 1) required the preliminary synthesis of intermediate β-hydroxy-α-nitrosotherocycles 18 and 19 (Scheme 2). Important amounts of a coloured, non-photochromic, stable secondary product (See 20 ) were found in the condensation in the spiro[indole-thiazolobenzoxazine] series. The photochromic characteristics of the new derivatives were determined using a flash-photolysis apparatus coupled to a fast-scanning spectrometer. The role of the heteroatoms in the oxazine moiety and the role of substitutents in the indole moiety were investigated quantitatively through the study of the photochromic properties and the solvent effects. The presence of an S-atom gives rise to interesting properties which open up new prospects for synthesis and application.     

The synthesis of 5,6-dihydro-6-methylthiazolo-[2,3-b] [1,3] benzodiazepines, 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5] thiazolo[2,3-b] [1,3] benzodiazepine,and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b] [1,3]-benzodiazepine via 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione

Catalytic reductive scission of 4-methylcinnoline (V) with Raney nickel afforded o-amino-β-methylphenethylamine (IV) in 57% yield. Treatment of IV with carbon disulfide followed by thermal cyclization of the product furnished 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione (III). Reaction of III with ethyl chloroacetate, ethyl 2-bromohexanoate, ethyl 2-chloroacetoacetate, 2-bromo-2′-methoxyacetophenone, and 2-bromoacetophenone provided a series of substituted 5,6-dihydro-6-methylthiazolo[2,3-b][1,3]benzodiazepines. Condensation of III with 2-chlorocyclopentanone and 2-chlorocyclohexanone gave 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5]thiazolo[2,3-b][1,3]benzodiazepine and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b][1,3]benzodiazepine, respectively. Structure assignments are discussed. None of the compounds possessed appreciable biological activity.     

Synthesis and proton NMR stereochemical study of 7,8,9-substituted-7,8-dihydro-4H,9H-furo[2′,3′,4′:4,4a,5]-naphth[2,1-e][1,3]oxazin-4-ones

7,8,9-Substituted-7,8-dihydro-4H,9H-furo[2′,3′,4′:4,4a,5]naphth[2,1-e][1,3]oxazin-4-ones were stereospecifically obtained as a single pair of enantiomers. Their relative trans configuration and the conformation of the dihydro oxazine ring were established by ¹H nmr 2D NOESY experiments.     

The [4+2]-cycloaddition of ketene containing both acyl and imidoyl groups to aldehyde: Synthesis,crystal and molecular structure of 1-p-bromophenyl-4-p-toluoyl-1, 3-dihydro-5H-[1,3]oxazino[4,3-c][1,4]benzoxazine-3,5-dione

Thermal decarboxylation of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo[5,1-c][1,4]benzoxazine-1, 2,4-trione resulted in 2-oxo-2H-1,4-benzoxazin-3-yl(p-toluoyl)ketene; the latter under-goes [4+2]-cycloaddition withp-bromobenzaldehyde to form 1-p-bromophenyl-4-p-toluoyl-1, 3-dihydro-5H-[1,3]oxazino[4,3-c][1,4] benzoxazine-3,5-dione. The crystal and molecular structure of the latter has been studied by X-ray analysis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1633–1636, September, 1993.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

The synthesis and transformations of 2H-naphtho-[1,2-b]pyran-2-one derivatives. Naphtho[2′,1′:5,6]-pyrano[3,4-d][1,3]oxazines and naphtho[1′,2′:5,6]pyrano[3,4-d]-pyrimidines,derivatives of two new heterocyclic systems

1,4-Naphthoquinone ( 1 ) was transformed with alkyl 2-aminofumarates 2 into 2H-naphtho[1,2-b]pyran-2-ones 3 and 4 , which served as intermediates in the synthesis of 7, 8 and 13 , which are derivatives of two new heterocyclic systems: naphtho[2′,1′:5,6]pyrano[3,4-d][1,3]oxazine and naphtho[1′,2′:5,6]pyrano[3,4-d]pyrimidine.     

Synthesis of [3,3′(4H,4′H)‐Bi‐2H‐1,3‐oxazine]‐4,4′‐diones and Their Hydrolysis

The [3,3′(4H,4′H)‐bi‐2H‐1,3‐oxazine]‐4,4′‐diones 3a – 3i were obtained by [2+4] cycloaddition reactions of furan‐2,3‐diones 1a – 1c with aromatic aldazines 2a – 2d (Scheme 1). So, new derivatives of bi‐2H‐1,3‐oxazines and their hydrolysis products, 3,5‐diaryl‐1H‐pyrazoles 4a – 4c (Scheme 3), which are potential biologically active compounds, were synthesized for the first time.     

Spiro[1,3-benzoxathiepin-4(5H),1′-cyclohexa[2,4]diene]-2,2′-dione,a Novel Heterocyclic Ring System

The 4,4′,6,6′-tetrasubstituted 2,2′-alkylidenebis(phenols) 1 reacted with CISCOI to give spiro[1,3-benzoxathiepin-4(5H), 1′-cyclohexa[2,4]diene]-2,2′-diones 4 , together with cyclic carbonates 5 . The structures of the products were elucidated mainly by ¹³C-NMR and ¹H-NMR spectroscopy.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Synthesis of 4-[(1,3-diaminopyrrolo[3′,4′:4,5]pyrido[2,3-d]-pyrimidin-8-yl)benzoyl]-L-glutamic acid as a potential antifolate

This paper is dedicated to the memory of Professor Roland K. Robins The synthesis of 4-[(1,3-diaminopyrrolo[3′,4′:4,5]pyrido[2,3-d]pyrimidin-8-yl)benzoyl]-L-glutamic acid ( 18 ), a potential antifolate and anticancer agent, has been achieved starting from 1,4-dibromobutan-2-ol with alkyl p-aminobenzoic acids. Condensation of these two agents gave 1-(4-alkoxycarbonylphenyl)pyrrolidin-3-ols 7a,b , which were oxidized to the corresponding pyrrolidin-3-one derivatives 8a,b . Compounds 8a,b were converted into 1,3-diamino-8-(4-alkoxycarbonylphenyl)-7,8-dihydro-9H-pyrrolo[3′,4′:4,5]pyrido[2,3-d]pyrimidines 12a,b in 4 steps. Saponification of 12b the benzoate ester and coupling with di-tert-butyl glutamate afforded a mixture of 7,8-dihydro product 16 and its aromatized derivative 17 . Finally hydrolysis of esters 16 or 17 gave only the title compound 18 . The 7,8-dihydro tricyclic derivatives were easily air-oxidized to form their fully aromatized compounds. The title compound 18 was one tenth less active than MTX against HL-60 cells in culture.     

A convenient synthesis of 3-aryl-4H- Benzopyrano[3,4-d]isoxazol-4-ones

Regioselective 1,3-dipolar cycloaddition of nitrile oxides 5a-c to ethyl o-hydroxycinnamate (3) gave the corresponding ethyl trans-3-aryl-4,5-dihydro-5-(2-hydroxyphenyl)-4-isoxazolecarboxylates 6a-c . Their structure was confirmed by reductive cleavage to 1 and compounds 9a-c . Compounds 6a-c afforded upon heating in the presence of pyridine the 3-aryl-4H-[1]benzopyrano[3,4-d]isoxazol-4-ones 11a-c . Compound 10c was also isolated from 6c and transformed thermally into 11c .     

Synthesis, 1H- and 13C-NMR spectra,crystal structure and ring openings of 1-methyl-6,9-epoxy-9-aryl-5,6,9,10-tetrahydro-1H-imidazo [3,2-e] [2H-1,5] oxazocinium methanesulfonate

The methanesulfonic acid catalyzed reaction of 1-(4-chloro- and 2,4-dichlorophenyl)-2-(1-methyl-2-imida-zolyl)ethanones 1a and 1b with glycerol produced cis- and trans-{2-haloaryl-2-[(1-methyl-2-imidazolyl)methyl]-4-hydroxymethyl}-1,3-dioxolanes 2a and 2b with a 2:1 cis/trans ratio. Besides these five-membered ketals, the reaction of 1a with glycerol afforded a small amount of trans-{2-(4-chlorophenyl)-2-[(1-methyl-2-imidazolyl)methyl]-5-hydroxy}-1,3-dioxane ( 3a , 7%). The reaction of methanesulfonyl chloride with cis-1 formed the corresponding methanesulfonates, cis- 4 , which rapidly cyclized to the title compounds 5 . Base-catalyzed ring opening of 5 furnished 1-methyl-5,6-dihydro-6-hydroxymethyl-8-(4-chloro- and 2,4-dichlorophenyl)-1H-imidazo[3,2-d][1,4]oxazepinium methanesulfonates 7 . Acid-catalyzed hydrolyses of 5 or 7 provided 1-methyl-2-[(4-chloro- and 2,4-dichloro)phenacyl]-3-[(2,3-dihydroxy)-1-propyl]imidazolium salts 12 . Structure proofs were based on extensive ¹H and ¹³C chemical shifts and coupling constants and structures of 3a and 5a were confirmed by single crystal X-ray crystallography.     

Synthesis of imidazo[5,4-d] [1,3]thiazines: X-ray structure of N-methyl-N′-[5-(methylamino)-3-nonylimidazo[5,4-d] [1,3]thiazin-7(3H)-ylidene]thiourea

N-Alkyl-N′-[5-(alkylamino)-3-alkylimidazo[5,4-d] [1,3]thiazin-7(3H)-ylidene]thioureas were obtained by the reaction of 1-substituted 5-amino-4-cyanoimidazoles with alkyl isothiocyanates. The structure of this heterocyclic system was confirmed by single crystal X-ray diffraction analysis.     

New heterocyclic structures. [1,3]Thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine

Derivatives of two new molecular structures, namely, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d]-[1,3]thiazino[3,2-a]pyrimidine, were synthesized together with other heterocyclic compounds. Retrosynthetic analysis of their molecular skeletons suggested a simple way of obtaining 3,4-dihydro-7,8-diamino-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, which is a useful intermediate for their synthesis. This intermediate and the thiazole homologue were obtained directly by reaction of 5,6-diamino-2,3-dihydro-2-thioxo-4(lH)-pyrimidi-none with 1,3- or 1,2-dibromoalkane, respectively.     

Reactions of anthranilamide with isocyanates: A new facile synthesis of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2H,6H-[1,3]oxazino[2,3-b]quinazolin-6-one [1]

2,3-Dihydro-5H-oxazolo[2,3-b]quinazolin-5-one 5a was synthesized from anthranilamide 1 and 2-chloro-ethyl isocyanate either by a direct reflux in methanol, or by stirring at room temperature in acetonitrile leading to the intermediate, 2-(2-chloroethyl ureido)benzamide 6a which was subsequently cyclized on heating with an organic base. However, when compound 6a was refluxed with concentrated hydrochloric acid, it furnished 3-(2-chloroethyl)-2,4-dioxo-1H,3H-quinazoline 2a in good yields. 3,4-Dihydro-2H,6.H-[1,3]-oxazino[2,3-b]quinazolin-6-one 5b , 3-(3-chloropropyl)-2,4-dioxo-1H,3.H-quinazoline 2b and 2-(3-chloropropyl ureido)benzamide 6b were obtained similarly from 1 and 3-chloropropyl isocyanate.     

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 ).     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.