Synthesis and hydrolytic cleavage of 1-aryl-5-cyano-6-(2-dimethylaminovinyl)-4-oxo(thioxo)-1,4-dihydropyrimidines

1-Aryl-5-cyano-6-(2-dimethylaminovinyl)-4-oxo-1,4-dihydropyrimidines and their 4-thioxo analogs, which were prepared in three steps from cyanoacetamide and cyanothioacetamide, respectively, were subjected to hydrolysis. In aqueous AcOH, hydrolysis of N-(dimethylaminomethylene)-2-cyano-5-dimethylamino-2,4-pentadieneamide derivatives containing amino groups at position 3 afforded formylpyridones. The reaction of 2-cyano-3-dimethylaminothiocrotonamide with DMF dimethyl acetal gave rise to 3-cyano-4-dimethylamino-2-methylthiopyridine.     

1,3-Dipolar cycloaddition reaction of benzodiazinium and naphthyridinium N-imines with acetylenic esters

1,3-Dipolar cycloaddition of N-imines derived from mono-N-amino salts of phthalazines, 2-phenylquinoxaline, 1,5- and 1,8-naphthyridines with dimethyl acetylenedicarboxylate: and methyl propiolate resulted in the formation of new tricyclic: heterocyclic ring systems with bridgehead nitrogen.     

The synthesis of pyrazolo[1,2-a]pyrazoles. Regio- and stereo-selective 1,3-dipolar cycloadditions of (1Z)-rel-(4R,5R)-1-arylmethylene-4-benzoylamino-5-phenyl-3-pyrazolidinon-1 -azomethinimines

Reaction of rel-(4R,5R)-4-benzoylamino-5-phenyl-3-pyrazolidinone (4) with aromatic aldehydes 5a-f gave the corresponding (1Z)-rel-(4R,5R)-1-arylmethylene-4-benzoylamino-5-phenyl-3-pyrazolidinon-1-azomethinimines 6a-f . 1,3-Dipolar cycloadditions of azomethinimines 6a-f to various dipolarophiles, which were found to proceed regio- and stereo-selectively, afforded the corresponding pyrazolo[1,2-a]-pyrazoles 8a-f, 10 , and 13–16 . Reaction of azomethinimine 6a with hydrogen cyanide gave rel-(5R,6R)-6-benzoylamino-5,6-dihydro-3,5-diphenyl-1-oxo-1H,7H-pyrazolo[1,2-a][1,2,3]triazole (18) as a representative of a new ring system.     

A Double Mannich -type Reaction in the 1,4,5,6-Tetrahydropyridine-2-thiolate Series: A Convenient Approach to Functionalized 3,7-Diazabicyclo[3.3.1]nonane Derivatives

The reaction of N-methylmorpholinium 5-alkoxy-carbonyl-4-aryl-3-cyano-2-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with primary amines and formaldehyde under mild conditions afforded 7-substituted alkyl 9-aryl-5-cyano-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1-carboxylates in fair to good yields (52–74%).     

A synthesis of lumazine derivatives

Treatment of 6-amino-1,3-dimethyl-5-nitrosouracil (Ia) with dimethyl acetylenedicarboxylate (DMAD) in dimethylformamide (DMF) afforded 6,7-bis(dimethoxycarbonyl)-1,3-dimethyllumazine (II). Similarly, the reaction of 6-amino-1,3-dimethyl-5-phenylazouracil with DMAD gave also II. Hydrolysis of II with hydrochloric acid gave 1,3-dimethyllumazine-6-carboxylic acid (III). III was chlorinated with thionyl chloride and then aminated with ethanolic ammonia to give rise to 6-carbamoyl-1,3-dimethyllumazine (V). V was alternatively synthesized by the treatment of Ia with propiolamide in DMF.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

A Double <Emphasis Type="Italic">Mannich</Emphasis>-type Reaction in the 1,4,5,6-Tetrahydropyridine-2-thiolate Series: A Convenient Approach to Functionalized 3,7-Diazabicyclo[3.3.1]nonane Derivatives

Summary. The reaction of N-methylmorpholinium 5-alkoxy-carbonyl-4-aryl-3-cyano-2-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with primary amines and formaldehyde under mild conditions afforded 7-substituted alkyl 9-aryl-5-cyano-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1-carboxylates in fair to good yields (52–74%). Third author was Deceased on February 26, 2007     

Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization

The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with 3-(1,3-benzodioxol-5-yl)-2-methylpropanal (ocean propanal) and p-toluidine afforded 7-aryl-2-(1,3-benzodioxol-5-ylmethyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitriles in modest (25–46%) yields. The structure of the key compound was confirmed by X-ray crystal structure analysis.     

The Synthesis of Naphthosultine and Benzodisultines and Their Pyrolysis with Dienophiles: Studies on o‐Naphthoquinodimethane and Bis‐o‐Quinodimethane

Sealed tube reactions of the naphthosultine 8 with a series of electron‐deficient dienophiles (fumaronitrile, N‐phenylmaleimide, dimethyl fumarate, and dimethyl acetylenedicarboxylate) in toluene at 180 °C gave corresponding 1:1 cycloadducts 11–14 in various amounts along with rearranged naphthosulfolene 7 in 67–95% yields. The reaction of 1,2,4,5‐tetra(bromomethyl)benzene with Rongalite (sodium form aldehyde sulfoxylate) and tetrabutylammonium bromide in DMF gave benzodisultines 17 and 18 in a combined yield of 56%. Sealed tube reactions of benzodisultines 17 and 18 with a series of dienophiles in xylene at 200 °C gave corresponding 1:1 and 1:2 cycloadducts 20–27 . The results suggested that thermal extrusion of sulfurdioxide from these sultines led to either o‐naphthoquinodimethane 6 (from 8 ) or bis‐o‐quinodimethane 19 (from 17 and 18 ); sub sequent trapping of these reactive intermediates by dienophiles and SO₂ gave various 1:1 and 1:2 Diels‐Alder ad ducts in modest to excellent yields.     

Mono-N-amino salt of benzodiazines and naphthyridines

The mono-N-amino salts of 3-phenylcinnoline, phthalazine, 1-phenylphthalazine, 4-phenylquinazoline, 2-phenylquinoxaline, 1,5- and 1,8-naphthyridines are in high yields prepared by direct N-amination of the parent heterocycles with O-mesitylenesulfonylhydroxylamine. With the one expection of 3-phenylcinnoline, the site of N-amination was determined by mass and nmr spectral techniques. The results indicate that the N-amination occurs preferentially at the least sterically hindered nitrogen atom.     

Tetrakis(alkylthio)thieno[3,4-c]thiophene: Synthesis,stability, and reactivity

The synthesis of tetrakis(alkylthio)thieno[3,4-c]thiophenes la-e by the dimerization reaction of bis(alkylthio)cyclopropenethiones is described. The remarkable thermodynamic and kinetic stability suggests the significant electron-accepting conjugation of the alkylthio substituents to the carbanionic 1, 3, 4, and 6 carbons in the framework. The isopropylthio- and ethylthio-substituted thienothiophenes 1d and 1e undergo cycloaddition reactions with dienophiles such as N-phenylmaleimide and dimethyl acetylenedicarboxylate to give the cycloadducts in moderate yields.     

Heterocycles derived from the condensation of 1,3-propanediamine with phthalic acid derivatives

The condensation of phthalic anhydride with 1,3-propanediamine afforded N-(o-carboxybenzoyl)-1,3-propanediamine (I) which by intravolecular cyclization was transformed into 2,3,4,6-b-tetrahydropyrimido[2,1-a]isoindol-6-one (II) rather than the benzodiazonine (III). An intermediate in the condensation is proposed. The reaction of 1,3-propanediamine with dimethyl phthalate also did not afford III, but rather a more complex product, dibenzo[c,l]-1,6,10,15-tetraazacyclooctadecane-5,11,16,22-tetraone (IX). Reaction of 1,3-propanediamine with phthaloyl chloride gave 6,13-propanodibenz[c,h]-1,6-diazecine-5,7,12,14-tetrone (XII). Spectroscopic data of the heterocycles obtained and chemical properties of II are given.     

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.     

2-Benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxy-carbonylvinyl-1 as N-protecting groups in peptide synthesis. Their application in the synthesis of dehydropeptide derivatives containing N-terminal 3-heteroarylamino-2,3-dehydroalanine

Ethyl 2-benzoyl-3-dimethylaminopropenoate ( 6 ) and methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) were used as reagents for the protection of the amino group with 2-benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxycarbonylvinyl groups in the peptide synthesis. Reactions of ethyl 2-benzoyl-3-dimethylaminopropenoate (6) with α-amino acids gave N-(2-benzoyl-2-ethoxycarbonylvinyl-1)-α-amino acids 13–19. These were coupled with various amino acid esters to form N-(2-benzoyl-2-ethoxycar-bonylvinyl-1)-protected dipeptide esters 20–31. The removal of 2-benzoyl-2-ethoxycarbonylvinyl-1 group, which was achieved by hydrazine monohydrochloride or hydroxylamine hydrochloride, afforded hydrochlo-rides of dipeptide esters 32–41 in high yields. Similarly, the substitution of the dimethylamino group in methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) by glycine gave N-(2-benzoylamino-2-methoxycar-bonylvinyl-1)glycine ( 47 ), which was coupled with glycine ethyl ester to give N-[N-(2-benzoylamino-2-methoxycarbonylvinyl-1)glycyl]glycine ethyl ester ( 48 ). Treatment of 48 with 2-arnino-4,6-dirnethylpyrimi-dine afforded N-[glycyl]glycine ethyl ester hydrochloride (34) in high yield. Amino acid esters and dipeptide esters were employed in the preparation of tri- 58-70, tetra- 71–82, and pentapeptide esters 83–85 containing N-terminal 3-heteroarylamino-2,3-dehydroalanine. 2-Chloro-4,6-dimethoxy-1,3,5-triazine was employed as a coupling reagent for the preparation of peptides 58–85.     

Tetrahydroquinolizinium ylides: preparation and 1,3-dipolar cycloaddition

By the Cu(II)-catalyzed reaction of 2-(4-diazo-3-oxoalkyl)pyridines (2), 4-alkoxycarbonyl (or 4-acyl)-3-oxo-1,2,3,4-tetrahydroquinolizinium ylides (3) were obtained in high yields. From the cycloaddition reaction of 3 with acetylenic esters (propynoates or acetylenedicarboxylates) the labile [2 + 3] cycloadducts, 3-oxo-3H-2a,4,5,8a-tetrahydropyrrolo[2,1,5-de]quinolizine-2a-carboxylates (8 or 12), were identified, which further reacted with DMAD (dimethyl acetylenedicarboxylate) to afford azocine derivatives (15 or 16) and produced pyrrolodihydroquinolizines (9 or 20) by dealkoxycarbonylation.     

Oxidative ring-opening of rel-(2R,3R,5S)-5-aryl-2-benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-3-phenyl-1H,5H-pyrazolo[1,2-a]-pyrazoles. Synthesis of rel-(2R,3R)-3-phenyl-3-[5-aryl-3,4-bis(methoxycarbonyl)pyrazolyl-1]alanine esters

rel-(2R,3R)-N-Benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-1H,5H-pyrazolot[1,2-a]-pyrazoles 5 , accesible by cycloaddition of dimethyl acetylenedicarboxylate ( 3 ) to (1Z)-rel-(4R,5R)-1-aryl-methylidene-4-benzoylamino-5-phenyl-3-pyrazolidinone-1-azomethine imines 4 , undergo oxidative ring cleavage with methanolic bromine giving rel-(2R,3R)-N-benzoyl-3-phenyl-3-[5-aryl-3,4-bis(methoxy-carbonyl)pyrazolyl-1]alanine methyl esters 6 as products.     

Synthesis of [1,5-A]Pyrimidinone Ring Derivatives

Cyclodehydrogenation of the benzalhydrazino derivatives 5 and 6 gave 6-cyano-7-(4-methoxyphenyl)- 2-phenyl-5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (8) and 6-cyano-7-(4-methoxyphenyl)-4-methyl-2-phenyl- 5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (9) respectively. Melhylation, acetylation and benzylation of 8 gave the corresponding N-methyl, acetyl and benzyl derivatives 10-12 . Methylation of 5 with dimethylsulfate gave 2-benzalhydrazino-5-cyano-3-methyl-6-(4-methoxyphenyl)-3,4-dihydropyrimidin-4-one (6) , of which the reaction with acetic anhydride in pyridine afforded the N-acetylbenzalhydrazino derivative 15 . The latter was also prepared from acetylation of 5 followed by medthylation with iodomethane. Acetylation of 5 with boiling acetic anhydride afforded the diacetyl derivative 16 , whereas its benzylation gave the mono-N-benzyl derivative 14 .     

(1E)-1,3-dimethoxy-1,3-butadiene

Reaction of 1,1-dimethoxy-2-butyne (II) with sodium methoxide in dimethyl sulfoxide at 100° yields (1E)-1,3-dimethoxybutadiene (III) (20–30%). The diene III undergoes ready Diels-Alder reaction with maleic anhydride, N-phenyltriazolinedione and dimethyl acetylenedicarboxylate.     

The Synthesis of Cyclopenta[ c ]pyridine (2-Pyrindene) Derivatives

Ethyl 2-(N-morpholinyl)cyclopent-1-ene-1-carboxylate reacted smoothly with cyanothioacetamide to give morpholinium 4-cyano-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridine-3-thiolate; the former when treated with N-benzyl-α-chloroacetamide gave either a S-alkyl derivative or cyclopenta[d]thieno[2,3-b]pyridine, depending on the reaction conditions. Under Mannich-type aminomethylation with primary amines and formaldehyde the above thiolate afforded derivatives of the previously unknown heterocyclic system, cyclopenta[g]pyrido[2,1-b][1,3,5]thiadiazine in 81–90% yields.     

从容易制备的三氟甲基恶唑酮直接合成三氟甲基吡咯及其有关化合物

作者考察了三氟甲基恶唑酮与缺电子烯烃在不同条件下的反应, 发现了三氟甲基恶唑酮与α-氯代丙烯腈的串联Micheal加成-类Mannich反应-脱羧消除反应.提供了分别通过1,3-偶极环加成反应和串联的环合反应从三氟甲基恶唑酮直接合成三氟甲基吡咯及其有关三氟甲基杂环化合物的方法