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 of 4-substituted 1,4-benzodiazepine-3,5-diones

Synthetic routes leading to the preparation of 4-substituted 1,4-benzodiazepine-3,5-diones are described. Thus, 2-carbobenzoxyaminobenzoic acid was converted to its p-nitrobenzyl ester (I) and the decarbobenzoxylated product (II) gave, with ethyl α-bromoacetate, N-(2-carboxy p-nitrobenzylate)phenylglycine ethyl ester (III). The latter was hydrogenolyzed to N-(2-car-boxy)phenylglycine ethyl ester (IV), which was coupled with benzylamine to give N-(2-carboxy-benzylamido)phenylglycine ethyl ester (VIa). Saponification of VIa afforded N-(2-carboxy-benzylamido)phenylglycine (VIIa) which was cyclized with DCCI to produce 4-benzyl-2H-1,4-benzodiazepine-3,5(lH,4H)dione (VIIIa). Alternatively, 2-nitro-N-phenylbenzamide (Xb) was reduced to 2-amino-N-phenylbenzamide (XIb) which was converted to N-(2-carboxanih'do)-phenylglycine ethyl ester (VIb). The latter was converted to 4-phenyl-2H-1,4-benzodiazepine-3,5(1H,4H)dione (VIIIb) in an analogous fashion described for VIIIa.     

Organic Phosphorus Compounds 61. Esterification and chlorination of nitrilo-tri(methylene-phosphonic acid), N(CH2PO3H2)3, and hydroxyethylidenediphosphonic acid,H2O3PC(OH)(CH3)PO3H2, and the corresponding esters

Nitrilo-tri(methylenephosphonic acid) and hydroxyethylidenediphosphonic acid are esterified in high yield when treated with excess orthoformic acid ester under reflux. Because of the high temperature necessary to effect esterification a partial isomerization of hydroxyethylidenediphosphonate to the phosphate-phosphonate isomer V takes place. Chlorination of N(CH₂PO₃H₂)₃ or a mixture of the ester and the acid with PCl₅ yields tris(chloromethyl)amine, N(CH₂Cl)₃. Interaction of N(CH₂Cl)₃ and (EtO)₃P yields nitrilo-tri(methylenephosphonate), which on hydrolysis with HCl conc. produces N(CH₂PO₃H₂)₃. Chlorination of a mixture of hydroxyethylidene-diphosphonic acid and the corresponding ethyl ester IV which contained the phosphate-phosphonate isomer V gave the products VII to XI. Chlorination of the acid III with PCl₅ gave 4 products, i.e., VIII, IX, XI and Cl₂(O)POP(O)Cl₂. The ¹H- and ³¹P-NMR. spectra of the products are discussed.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 10. Reactions with ester enolates. Synthesis of 4-hydroxy-1-methyl-3-prenyl-2(1H)-quinolinones,Crucial intermediates in the synthesis of quinoline alkaloids

N-Methylisatoic anhydride reacts with the lithium enolates of esters to produce β-ketoesters 4 in nearly quantitative yield. Thermal cyclization of these relatively unstable intermediates afford the corresponding 3-substituted-4-hydroxy-1-methyl-2(1H)-quinolinones (5) in good yields. The reaction of the lithium enolate of 5-methyl-4-hexenoic acid ethyl ester ( 14 ) with various nuclear substituted isatoic anhydrides gives 4-hydroxyl-methyl-3-prenyl-2(1H)-quinolinones 8, 9 , and 18 which are highly desirable intermediates in the synthesis of a variety of quinoline alkaloids. Treatment of 18 with DDQ furnishes oricine in 73% yield.     

Reactions of 3-chloro-6-hydrazinopyridazine with michael-retro-michael reagents

Although pyrazole formation results from treatment of 3-chloro-6-hydrazinopyridazine ( 2 ) with both ethoxymethylenemalononitrile and ethyl (ethoxymethylene)cyanoacetate, 6-chlorotriazolo[4,3-b]pyridazine ( 5 ) was produced (75% yield) when 2 was treated with diethyl ethoxymethylenemalonate. Treatment of 2 with diethyl acetylmalonate ( 8 ) gave both 6-chloro-3-methyltriazolo[4,3-b]pyridazine ( 10 ) and 5-hydroxy-3-methyl-1-(6-chloro-3-pyridazinyl)-1H-pyrazole-4-carboxylic acid ethyl ester ( 12 ). Pyrazole 12 was initially isolated as a salt of triazolopyridazine 10 .     

Reactions of o-aminonitriles with isocyanates. 2. A facile synthesis of imidazo[1,2-c]quinazoline-2,5-(3H,6H)dione

Anthranilonitrile reacts with ethyl isocyanatoacetate to form 2-(3-ethoxycarbonylmethylureido)benzonitrile (3b) which, upon heating, or treatment with a base, undergoes a double cyclization to yield imidazo[1,2-c]-quinazoline-2,5-(3H,6H)dione ( 5 ) in excellent yield. In the presence of acid, 3b is converted into 1,4-dihydro-2,4-dioxo-3-(2H)quinazolineacetic acid ( 11 ), or its ethyl ester ( 10 ). The action of concentrated sulfuric acid converts the adduct 13 of anthranilic acid and ethyl isocyanatoacetate into 2-ethoxycarbonyl-methylamino-4H-3,1 -benzoxazin-4-one ( 14 ).     

Rearrangements of 4-(2-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester

The treatment of 4-(2-aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylic acid diethyl ester (III) with refluxing toluene or pyridine afforded 1,2,3,6-tetrahydro-2,4-dimethyl-2,6-methano-1,3-benzodiazocine-5,11-dicarboxylic acid diethyl ester (IV) as the major product. In addition, the following minor products were isolated: 2-methyl-3-quinolinecarboxylic acid ethyl ester (V), 3-(2-aminophenyl)-5-methyl-6-azabicyclo[3,3,1]-hept-1-ene-2,4-dicarboxylic acid diethyl ester (VI), and 5,6-dihydro-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid ethyl ester (VII). In contrast, acidic conditions caused the conversion of III into V in a 95% yield. The formation of the latter appears to involve IV as an intermediate, since IV degraded rapidly in acid to give V in a quantitative yield.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

Synthesis and reactions of 3-carbethoxy and 3-aroyl-3,4-dihydro-1h-2,3-benzoxazin-1-ones

A series of 3-substituted 3,4-dihydro-1H-2,3-benzoxazin-1-ones (IV) (Scheme I) was prepared by reaction of 2-bromomethylbenzoyl chlorides (II) with N-hydroxyethylcarbamate (III) or with benzohydroxamic acids. Acid hydrolysis of 3-carbethoxy (IVa) and 3-benzoyl derivatives (IVb) afforded a mixture of 2-(hydroxyaminomethyl)benzoic acid (V) and 2,3-dihydro-2-hydroxy-1H-1-isoindolinone (VII). Compound IVa reacted with ethanol, amines or hydrazine to yield the ethyl ester X, amides XIV (Scheme II) and the hydrazide XII of 2-(N-carbethoxy-N-hydroxy-aminomethyl)benzoic acid. Diazotization of the hydrazide XII afforded the unstable azide XIII which did not undergo the Curtius reaction but gave the benzoxazinone IVa by loss of hydrazoic acid.     

Synthesis of 3-acetyl-4-amino-6-arylpyran-2-ones and ethyl 7-aryl-4,5(1H,5H )-dioxopyrano[4,3-b]pyridine-2-carboxylates

The reactions of aroylacetonitriles with the nickel chelate of ethyl acetoacetate afforded new block heterocyclic reagents, viz., 3-acetyl-4-amino-6-arylpyran-2-ones. The reactions of the latter with diethyl oxalate gave rise to ethyl 7-aryl-4,5(1H,5H)-dioxopyrano[4,3-b]pyridine-2-carboxylates.     

Cyclocondensation of 2-hydrazinoperimidine with diethyl oxalate and ethyl pyruvate

Refluxing 2-hydrazinoperimidine (1) with excess amount of diethyl oxalate (2a) gave ethyl 1H-1,2,4-triazolo[4,3-a]perimidine-3-carboxylate (4a) in 84% yield. On the other hand, heating 1 with ethyl pyruvate (2b) in glacial acetic acid afforded 3-methyl-1,2,4-triazino[4,3-a]perimidin-4(1H)-one (6b) in 92% yield. Structures of the products were investigated by spectral and elemental analysis.     

New atropoisomeric alkenylphenylglycine derivatives: Synthesis of (5R*)- and (5S*)-isomers of (1R*,3aR*,4S*,11S*)-3a,5,9,11-tetramethyl-4,5-dihydro-3aH-1,4-methano[1,3]oxazolo[3,2-a]quinolin-2-one

We synthesized methyl ester of N-(1-methylbut-2-en-1-yl)-N-phenylglycine which underwent acid catalyzed aromatic amino Claisen rearrangement to provide methyl-N-[2-(1-methylbut-2-en-1-yl)phenyl]glycinate. A mixture of syn- and anti-atropisomeric methyl-N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycinates was obtained either by the reaction of this ester with acetyl bromide or by the reaction of the sodium salt of N-acetyl-2-(1-methylbut-2-en-1-yl)-4-methylaniline with methyl bromoacetate. Upon saponification of the synthesized ester mixture the syn-atropisomer of N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycine was isolated by fractional crystallization. Treatment of the obtained acids with acetic anhydride, ethyl chloroformate, dicyclohexylcarbodiimide or isopropenylacetate leads to compounds of 4,5-dihydro-3aH-methano[1,3]oxazolo[3,2-a]quinolin-2-one structure.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

Synthesis of polynucleotide analogs by grafting optically active adenine,cytosine, and hypoxanthine derivatives onto polytrimethylenimine

A new family of polynucleotide analogs were prepared by grafting nucleic acid base derivatives onto polytrimethylenimine. Several new optically pure α-nucleic acid base substituted propanoic acids were prepared as pendant groups. The (R)-ethyl adeninylpropanoate was obtained from adenine and (S)-ethyl lactate by utilizing a diethyl azodicarboxylate-triphenyl phosphine method. Subsequent hydrolysis of the ester in aqueous acid gave the (R)-adeninylpropanoic acid without racemization. The reaction of cytosine sodium salt with (S)-ethyl 2-[(methylsulfonyl)oxy] propanoate produced the 20% racemized (R)-ethyl 2-(cytosin-1-yl)propanoate. The optically pure ester was obtained by recrystallization from ethyl alcohol, which was hydrolyzed in aqueous acid to give the (R)-acid with 66% enantiomeric excess. The (R)-2-(hypoxanthin-9-yl)propanoic acid was prepared by reaction of (R)-2-(adenin-9-yl)propanoic acid with sodium nitrite. The pendant groups were allowed to react with N-hydroxy compounds in the presence of dicyclohexylcarbodiimide to give the active esters. These active esters underwent reaction with N,N-dipropylamine to provide monomer model compounds. The pendant groups were grafted onto polytrimethylenimine by using the active ester method. The racemization reactions were observed in the grafting reactions. The resulting polymers showed a range of percent grafting from 60 to 80%.     

1,6- and 1,7-naphthyridines. II. Synthesis from acyclic precursors

A number of 8-hydroxy-6-methyl-1,6-naphthyridin-5(6H)-one-7-carboxylic acid alkyl esters 3 and the isomeric 5-hydroxy-7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid alkyl esters 4 were synthesized from acyclic precursors obtained starting from quinolinic anhydride 5. Thus, methanolysis of 5 afforded the hemiester 6 which treated with oxalyl chloride and sarcosine ethyl ester gave 3-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-2-carboxylic acid methyl ester 8. Compound 8 was cyclized to naphthyridines 3a-e with sodium alkoxides. The isomeric naphthyridines 4a-c were obtained by cyclization of the open intermediary 2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-3-carboxylic acid methyl ester 9 obtained by a route that involves treatment of 5 with sarcosine ethyl ester and esterification with diazomethane. Spectroscopic properties (¹H nmr, uv, ir) of compounds 3 and 4 are discussed and confirmed the proposed structures.     

Synthesis and Some Properties of 2-(5-Methyl-2-Phenyl-2H-1,2,3-Diazaphosphol-4-yl)-4H-Benzo[d]-1,3,2-Dioxaphosphorin-4-One

Abstract

2-(5-Methyl-2-phenyl-2Н-1,2,3-diazaphosphol-4-yl)-4H-benzo[d]-1,3,2-dioxaphosphorin-4-one 1 readily reacts with hexafluoroacetone, mesoxalic acid diethyl ester, trifluoropyruvic acid ethyl ester and chloral to give 2-(5-methyl-2-phenyl-2H-1,2,3-dizaphosphole-4-yl)-derivatives of 1,3,2- and 1,4,2-dioxaphosphepines.     

β-Carbolines derived from β-methyltryptophan and a stereoselective synthesis of (2RS,3SR)-β-methyltryptophan methyl ester

The methyl ester of isomer A of β-methyltryptophan (2SR,3RS; 2A ) was stereoselectively prepared by an efficient modified method through the reaction of a-methyl-N-(1-Methylethyl)-1H-indole-3-methanamine ( 3 ) with methyl nitroacetate to give the desired nitro compound as a mixture of two racemates 5A , and 5B. During the recrystallization process epimerization occurred and only racemate 5A crystallized out. Catalytic hydrogenation of 5A in the presence of acid stereoselectively yielded the desired amino acid ester 2A. Pictet-Spengler condensation of 2A with aldehydes under aprotic conditions followed by dehydrogenation gave excellent yields of β-carbolines 7a-i , (R = methyl, ethyl, acetyl, phenyl, pyridine-2-yl, furan-2-yl, quinoline-2-yl, styryl, phenethyl). Also β-carbolines 7a,b,i were synthesized by the Pictet-Spengler condensation of (3-meth-yltryptophan under acidic aqueous conditions followed by esterification and dehydrogenation.     

Synthesis of α-(aminomethylene)-9H-purine-6-acetic acid derivatives

α-(Aminornethylene)-9H-purine-6-acetamide ( 3a ) and the corresponding ethyl acetate 9 have been synthesized by catalytic hydrogenation of 6-cyanomethylenepurine derivatives 2 and 7 which were obtained by the substitution of 6-chloropurine derivatives with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of α-(aminomethylene)-9-(tetrahydrofuran)-9H-purine-6-acetamide ( 3b ) with amines gave the corresponding N-alkyl- and N-arylamines 5 , which were treated with acid to give N-substituted α-(aminomethylene)-9H-purine-6-acetamides 6 . Substitution of 9 with amines gave the corresponding N-alkyl- and N-aryl substituted amines 10 .     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 12. Synthesis of araliopsine and isoplatydesmine

N-Methylisatoic anhydride reacts with the lithium enolate derived from 3,3-dimethyloxiranepropanoic acid ethyl ester (7) to initially produce the acyclic β-ketoester 8 . Under neutral conditions, 8 spontaneously cyclizes to the alkaloid araliopsine ( 1a ). In the presence of acid, 8 cyclizes to a mixture of 1a and its leanear isomer isoplatydesmine (2a).     

Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.