Reactions of Acylpyruvic Acids and 2,3-Dihydrofuran-2,3-diones with 2,3-Diaminopyridine

Acylpyruvic acids readily react with 2,3-diaminopyridine to form (Z)-3-acylmethylene-1H-3,4-di- hydropyrido[2,3-b]pyrazin-2-ones. 5-Aryl-2,3-dihydrofuran-2,3-diones which can be regarded as lactones derived from -enolized aroylpyruvic acids react with 2,3-diaminopyridine under mild conditions, yielding regioisomeric (Z)-2-aroylmethylene-4H-1,2-dihydropyrido[2,3-b]pyrazin-3-ones. The structure of the products and reaction chemoselectivity are discussed.     

Synthesis of 2,3-dihydro-5H-oxazolo[2,3-B]quinazolin-5-ones

Iodide-catalyzed ring expansion of 2-[(1-aziridinylcarbonyl)amino]benzoic acid methyl ester (2) gave 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one (3) in quantitative yield. Treatment of the dimethyl analog of 2 (9) with sodium iodide in acetone gave a mixture of the 2,3-dihydro-2,2-dimethyl- (10) and 2,3-dihydro-3,3-dimethyl-5H-oxazolo[2,3-b]quinazolin-5-ones (11). However, rearrangement of 9 with sulfuric acid produced only 10. Synthesis of 11 by another route for comparison is described, and the known syntheses of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-ones are reviewed.     

Azimine. VI. 1-Alkoxycarbony 1-2,3-dialkyl- und -2,3-diaryl-azimine

Azimines VI: 1-Alkoxycarbonyl-2,3-dialkyl- and -2,3-diarylazimines Alkoxycarbonyl-nitrenes 2 – generated in situ by α-elimination from N-[(4-nitrophenyl)-sulfonyloxy]carbamates 4 – were reacted with six aliphatic and aromatic azo compounds to yield 1-alkoxycarbonyl-azimines 11 (R′ = Alkyl). Thus, (2Z)- or (2E)- 1 -alkoxycarbonyl-2,3-diisopropyl-azimines ( 8 or 9 ) were obtained stereospecifically from (E)- or (Z)-1,1′-dimethylazoethane ( 5 or 6 ) and 1-alkoxycarbonyl -2,3-(cis-1,3-cyclopentylene)-azimines ( 10 ) resulted from 2,3-diazabicyclo[2.2.1]-2-heptene ( 7 ), always using both ethoxy- and methoxycarbonyl-nitrene ( 2a and 2b ). With 2a , (E)-azobenzene ( 14 ) was converted only to a single stereoisomer of 1-ethoxycarbonyl-2,3-diphenyl-azimine ( 17 ) and both stereoisomers of azo(p-toluene) ( 15 or 16 ) reacted to give the same stereoisomer of 1-ethoxycarbonyl-2,3-di(p-tolyl)-azimine ( 18 ).     

Five-Membered 2,3-Dioxo Heterocycles: XLVII. Reaction of 5-Aryl-4-phenyl-2,3-dihydrofuran-2,3-diones with Compounds Containing C = N and C≡N Bonds

Thermal decarbonylation of 5-aryl-4-phenyl-2,3-dihydrofuran-2,3-diones gives rise to intermediate aroyl(phenyl)ketenes which react with nonactivated Schiff bases, N,N'-dicyclohexylcarbodiimide, and p-di-methylaminobenzonitrile according to the [4 + 2]-cycloaddition pattern with formation of 6-aryl-5-phenyl-4H-1,3-oxazin-4-ones. Reactions of 5-aryl-4-phenyl-2,3-dihydrofuran-2,3-diones with activated Schiff bases at a temperature below the thermolysis temperature lead to 4-aroyl-4-phenyltetrahydropyrrole-2,3-diones.     

A Method for the Synthesis of 2,3-Disubstituted 2,3-Dihydrobenzofurans

Summary.  The synthesis of 2,3-disubstituted 2,3-dihydrobenzofuran diastereomers is described. The key step in the reaction sequence is the chemoselective reduction of a tert. alcohole with tert.-butylamine-borane/AlCl₃. The relative configuration of the substituents on the dihydrofurane moiety was assigned via NMR spectroscopy. Received September 7, 1999. Accepted November 9, 1999     

Pyrrolidine-2,3-dione, 1-allylpyrrolidine-2,3-dione and 1-ethoxypyrrolidine-2,3-dione

Authentic pyrrolidine-2,3-dione has been prepared by two different routes. It is shown that the material previously reported is actually a hydrolysis product, 4-amino-2-oxobutyric acid. 1-Allyl- and 1-ethoxypyrroli-dine-2,3-dione have been prepared as N-protected pyrrolidine-2,3-diones potentially useful in synthesis.     

Studies on quinazolinones. 2. Synthesis of 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3–6]quinazolin-5-one and -2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one

To search for novel antihypertensive heterocycles in the condensed quinazoline series, two representative compounds were synthesized via a suitable reaction sequences. Treating anthranilonitrile with allyl isocyanate gave 2-(allylureido)benzonitrile ( 10 ) in a quantitative yield. Compound 10 was cyclized to 3-allylquinazoline-2(1H, 4(3H)-dione ( 11 ). Bromination of 11 in carbon tetrachloride converted it into the corresponding 3-(2,3-dibromopropyl) derivative ( 12 ) in 92% yield. Ring closure of 12 was effected by the action of alkali to afford 2-bromomethyl-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 13 ). The title compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 7 ) could be obtained by a reaction of either 12 or 13 with 1-benzylpiperazine respectively. Starting from the readily available 3-allyl-2H-thioxoquinazolin-4(3H)-one ( 16 ) via the analogous reactions gave the 2-bromomethyl-2,3-dihydro-5H-thiazolo[2,3-b]-quinazolin-5-one ( 19 ) in good yield. However, the reaction of 19 with 1-benzylpiperazine provided another target compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 8 ) only in poor yield (8%). As major product, the dehydrobrominated compound, 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 22 ) was isolated. A preliminary pharmacological evaluation revealed that both compounds 7 and 8 are devoid of the antihypertensive activity.     

Synthesis of 2,3-dihydropyrido- and 2,3-dihydropyrimido-[1,4]diazepines from triaminopyridine and triaminopyrimidine

The reaction of 2,3,6-triaminopyridine 1 and 4,5,6-triaminopyrimidine 2 with one equivalent of the chal-cones 3, in acetic acid, leads to the formation of the 8-amino-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepine and 6-amino-2,3-dihydro-1H-pyrimido[4,5-b][1,4]diazepine derivatives 4 and 5 . The products were characterized by NMR techniques such as ¹³C, ¹H, and DEPT including selective ¹³C{¹H} decoupling experiments.     

Research on 2,3-polymethylenequinolines

The ionization constants of 4-chloro-6-R-2,3-polymethylenequinolines in 98% methanol were found and it was established that they correlate with the _epi substituent constants for quinoline. It is shown that the pK _a values of 2,3-tetra- and 2,3-pentamethylenequinolines are close to one another, whereas the pK _a values of 2,3-trimethylenequinolines are one order of magnitude lower; this is a result of the angular strain in the ring system of the latter.See [1] for communication XX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 506–507, April, 1977.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

2-substituted 2,3-dihydro-5H-thiazolo[2,3-b]quinazoline derivatives

The synthesis of a series of 2-substituted 2,3-dihydro-5H-thiazolo[2,3-b]quinazoline derivatives is described. Some of the title compounds exerted antiinflammatory and immunomodulating activities in laboratory animal models.     

Decyclization of 5-Aryl-4-methyl-2,3-dihydrofuran-2,3-diones by the Action of Nucleophiles

Ring cleavage in 4-methyl-5-phenyl-2,3-dihydrofuran-2,3-dione by the action of methanol and in 5-aryl-4-methyl-2,3-dihydrofuran-2,3-diones by the action of aniline and N-methylaniline results in formation of, respectively, methyl 3-methyl-4-phenyl-2,4-dioxobutanoate and 4-aryl-3-methyl-2,4-dioxobutananilides. The reaction mechanism was studied by ¹H NMR spectroscopy.     

Pyrrolo[2,3-d] pyrimidines. I. 5-hydroxypyrrolo[2,3-d] pyrimidines

5-Hydroxy-7-alkyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriles (VIIb-d) and 5-hydroxy-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, ethyl ester (VIIa) were prepared from 5-carbethoxy-4-chloro-2-phenylpyrimidine (IV) via 4-[(cyanomethyl)alkylamino[-2-phenyl-5-pyrimidinecarboxylic acid, ethyl esters (Vb-d) and 4-[(carboxymethyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid, diethyl ester (Va), respectively. The hydroxy group of the pyrrolo-[2,3-d]pyrimidines could be methylated, acetylated and tosylated. Hydrolysis of 5-methoxy-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (IX) afforded the corresponding amide (X).     

A new one-step synthesis of 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2h,6h[1,3]thiazino[2,3-b] quinazolin-6-one

2,3-Dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2H,6H[1,3] thiazino[2,3-b]-quinazolin-6-one have been synthesized in one step by the reaction of methyl anthranilate with ehloroalkyl isothiocyanates.     

Five-Membered 2,3-Dioxo Heterocycles: XLV. Thermolysis of 5-Aryl-4-phenyl-2,3-dihydrofuran-2,3-diones in the Absence of Other Partners and in the Presence of Carbonyl Compounds

Aroyl(phenyl)ketenes generated by thermolysis of 5-aryl-4-phenyl-2,3-dihydrofuran-2,3-diones undergo [4+2]-cyclodimerization to 3-aroyl-6-aryl-3,5-diphenyl-3,4-dihydro-2H-pyran-2,4-diones. Heating of the latter leads to rearrangement with formation of 4-aroyloxy-6-aryl-3,5-diphenyl-2H-pyran-2-ones. Thermolysis of 5-aryl-4-phenyl-2,3-dihydrofuran-2,3-diones in the presence of carbonyl compounds yields 6-aryl-5-phenyl-4H-1,3-dioxin-4-ones.     

Heterocyclizations in the pyrido[2,3-b]pyrazine series

In this paper, we report the results of heterocyclizations in the pyrido[2,3-b]pyrazine series to give the pyrido[2,3-e] or [3,2-e]pyrrolo[1,2-a]pyrazine. The Clauson-Kaas reaction on 2,3-diaminopyridine is investigated; regioselectivity on the 3-amino group is shown by ¹H- and ¹³C-nmr. Synthesis and reactivity of the original pyrazino[2,3-g]indolizine series is also reported.     

A new synthetic route to 2-substituted naphtho[2,3-b]furan-4,9-dione2-Substituted Naphtho[2,3-b]furan-4,9-dione

4,9-Dimethoxynaphtho[2,3-b]furan 9 was obtained in 91% yield via the reductive methylation of naphtho[2,3-b]furan-4,9-dione 2 . After treatment of 9 with butyllithium, the mixture was allowed to react with N,N-dimethylacetamide, followed by oxidization with cerium(IV) diammonium nitrate to give 2-acetylnaphtho[2,3-b]furan-4,9-dione 1 . 2-Formylnaphtho[2,3-b]furan-4,9-dione 13 and 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione 14 were also obtained from 9 by a similar method. The halodesilylations of 14 easily gave 2-iodonaphtho[2,3-b]furan-4,9-dione 16 , 2-bromonaphtho[2,3-b]furan-4,9-dione 17 , and 2-chloronaphtho[2,3-b]furan-4,9-dione 18 in 82%, and 93% and 83% yield, respectively. Furthermore, the nitrodesilylation of 14 gave 2-nitronaphtho[2,3-b]furan-4,9-dione 3 in 77% yield.     

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.     

X-ray crystallographic and NMR structural studies of trans-2,3-dichloro-5-ethyl-2,3-dihydrothieno[2 3-b]pyridine syn-1-oxide reactions of thiophene rings with hypochlorite reagents

X-ray analysis of a crystalline product obtained by treatment of 5-ethylthieno[2,3-b]pyridine with excess acidified hypochlorite establishes its stereochemistry as trans-2,3-dichloro-5-ethyl-2,3-dihydrothieno-[2,3-b]pyridine syn-1-oxide (5), wherein the pyridine ring is planar and the dihydrothiophene ring is non-planar with a C2-S-C7a angle of 86.6°. The trans geometry is corroborated by a proton-proton coupling constant J_2,3 of 6.8 Hz. Comparison of ¹H and ¹³C nmr data for 5 with analogous crystalline 2,3-dichloro-1-oxide addenda isolated in the isosteric benzo[b]thiophene and thieno[2,3-b]pyridine parent systems indicates that some proposed stereochemical assignments are questionable.     

Reaction of 5-phenyl-2,3-dihydrofuran-2,3-dione with 6,7-dimethoxy-3,4-dihydroisoquinoline. Crystal structure of 1-benzoyl-8,9-dimethoxy-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione

The reaction of 5-phenyl-2,3-dihydrofuran-2,3-dione with 6,7-dimethoxy-3,4-dihydroisoquinoline gave 1-benzoyl-2-hydroxy-8,9-dimethoxy-3,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3-one and its oxidation product,viz., 1-benzoyl-8,9-dimethoxy-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione. The last-mentioned compound was studied by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1845–1848, October, 1997.