SYNTHESIS OF ARYL(OR BENZYL)- (Z)-N-[2-AMINO-1,2-DICYANOVINYL]FORMAMIDINES

ABSTRACT

Starting from readily available ethyl(Z)-N-(2-amino-1,2-dicyanovinyl)formimidate (1), the N-aryl (or benzyl)-N′(-(2-amino-1,2-dicyanovinyl)formamidines (2) can be prepared in good yields by reaction with aromatic amines at room temperature in the presence of a catalytic amount of aniline hydrochloride.     

Reaction of dichloroketene and sulfene with N,N-disubstituted 6-amino-methylene-b,7,8,9 -tetrahydro-5H-benzocyclohepten-5-ones. Synthesis of 6-(2,2-Dichloroethylidene)-b,7,8,9-tetrahydro-5H-benzocyclohepten-5-one and of 5H-benzo[3,4]cyclohepta[2,l-b]pyran and 5H-Benzo[3,4]cyclo-hepta[1,2-e]-1,2-oxathiin derivatives

The 1,4-cycloaddition of dichloroketene to N,N-disubstituted 6-aminomethylene-b,7,8,9-tetra-hydro-5H-benzocyclohepten-5-ones afforded N,N-disubstituted 4-amino-3,3-dichloro-3,4,6,7-tetrahydro-5H-benzo[3,4]cyclohepta[2,l-b]pyran-2-ones only in the case of aromatic or strong hindering aliphatic N-substitution. The adducts gave N,N-disubstituted 4-amino-3-chloro-b,7-dihydro-5H-benzo[3,4]cyclohepta[2,l-b]pyran-2-ones by dehydrochlorination with collidine. Upon chromatography on neutral alumina, two products were instead isolated in the case of usual aliphatic N-substitution (diethylamine, piperidine), namely 6-(2,2-dichloroethylidene)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one and the dehydrochlorinated 2-pyrone; this latter was the sole product in the case of pyrrolidine substitution. The 1,4-cycloaddition of sulfene occurred readily to give N,N-disubstituted 4-amino-3,4,6,7-tetrahydro-5H-benzo[3,4]cyclohepta-[1,2-e]-1,2-oxathiin 2,2-dioxidesin the case of both aliphatic and partially aromatic N-substitution.     

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.     

DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3, 6-dihydropyrimidin-1[2H]-yl)-N-(4-(1, 3-dioxo-1H-benzo [de]isoquinolin-2[3H]-yl) aryl) acetamides as antimicrobial agents

We report herein DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3,6-dihydropyrimidin-1[2H]-yl)-N-(4-(1,3-dioxo-1H-benzo[de]isoquinolin-2[3H]-yl) aryl) acetamides ( 4a-j ). The silent features of this new one pot synthesis include the shorter reaction time, high yields, simple workup, and simultaneous formation of N-Amide and N-benzyl bonds in the one pot. The newly synthesized compounds ( 4a-j ) were characterized by different spectral techniques such as IR, ¹H-NMR, ¹³C-NMR, HRMS. All the synthesized compounds were evaluated for their anti-bacterial and anti-fungal activities. The anti-bacterial activities results reveal that the compounds 4a , 4g , 4i , and 4j are most active against S. aureus. In the case of B. subtilis the compounds 4a , 4i , and 4j are found to be most active. The compounds 4c , 4e , 4i , and 4j are most active against E. coli. In the case of P. aeruginosa 4a , 4i & 4j are found to be more active. On the other hand, the anti-fungal activity result shows that the compounds 4d , 4f , 4i , and 4j are more active against A. niger. The compounds 4a , 4d , 4i , and 4j are found to be more active against C. albicans.     

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 modified bischler-napieralski reaction. Synthesis of 2,3,4,9- tetrahydro-1H-pyrido[3,4-B]indole derivatives and their base-catalyzed transformation to N-acetyl-N-[2-[1 -acetyl-2-[1 -(acetyloxy)-1-propenyl]- 1H-indol-3-yl]ethyl]acetamides

The treatment of N-[2-(1H-indol-3-yl)ethyl]alkanamide, 1 (1), with phosphorus oxychloride under controlled conditions gave l-alkyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-ol, 2 . The reaction of 2 with acetic anhydride or with methyl isocyanate at room temperature resulted in the formation of amido carbinol 3 and urea carbinol 7, respectively. The former was transformed into amido ester 4 by boiling acetic anhydride. When the reaction of 3 with acetic anhydride was carried out in the presence of excess triethylamine at 105°, C-N bond cleavage of the tetrahydropyridine ring took place with concurrent bis(N-acetylation) to give the enol ester derivative 5 . The structures of all compounds are consistent with chemical and spectral evidence.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

Rearrangements of 5-acetyl-3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-2H-pyran-2-one and 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one into 1-aminopyridine,pyrano[2,3-b]pyridine and isoxazole derivatives

Rearrangements of 5-acetyl-3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-2H-pyran-2-one ( 1 ) and 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one ( 7 ) in the presence of N-nucleophiles, such as ammonia, hydrazine, and hydroxylamine, into 1-aminopyridine, pyrano[2,3-b]-pyridine, and isoxazole derivatives 5, 11 , and 15 is described. In the reaction of compounds 1 and 7 with C-nucleophiles, such as 5,5-dimethyl-1,3-cyclohexanedione and barbituric acid, only substitution of the dimethylamino group is taking place to give the compounds 17, 18 , and 20 .     

Facile Preparation of (S)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxy-5-(tributyltin)benzamide from Isoremoxipride: The Precursor of [125I]- and [123I]Epidepride

Abstract

[¹²⁵I]Epidepride, (S)-(?)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[¹²⁵I]iodo-2,3-dimethoxybenzamide ([¹²⁵I]NCQ 219), is a new, extremly potent radioligand, useful in the study of the distribution of the dopamine D-2 receptors in the brain. Its synthesis requires radioiodination of the corresponding 5-(tributyltin) derivative. The aryltin precursor (TDP 526) can be conveniently prepared in high yield from isoremoxipride (FLB 457) by tetrakis(triphenylphosphine)palladium(0)-catalyzed stannylation using bis(tri-n-butyltin) in triethylamine. An improved method for the preparation of isoremoxipride from o-vanillin was developed.     

Synthesis of 5H-Triazolo[1,5-d]- and 5H- Tetrazolo- [1,5-d]thieno[3,2-f]-1,4-diazepin-6(7H)-ones

5H-Triazolo[1,5-d]- and 5H-tetrazolo[1,5-d]thieno[3,2-f]-1,4-diazepin-6(7H)-ones have been obtained by the base catalysed ring expansion reaction of 5-chloromethyl-1,2,4-triazolo[1,5-c]- and 5-chloromethyltetrazolo- [1,5-c]thieno[3,2-e]pyrimidines. The required thienopyrimidine derivatives were synthesized from 2-amino-3-triazolyl- and 2-amino-3-tetrazolylthiophenes by acylation, followed by dehydrative cyclization.     

Synthesis of the penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-propyl]amino]benzoyl]-L-glutamic acid (5-DACTHF). An acyclic analogue of tetrahydrofolic acid

The penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]-benzoyl)-L-glutamic acid (1, 5-DACTHF, 543U76) was synthesized by a convergent route. L-γ-Glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis t-butyl ester ( 20 ) was prepared in ten steps from L-glutamic acid di-t-butyl ester and N-(benzyloxycarbonyl)-L-glutamic acid α-t-butyl ester. 4-[N-[3-(2,4-Diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]trifluoroacetamido]benzoic acid ( 6 ), which was synthesized from pyrimidinylpropionaldehyde 3 in three steps, was condensed with 20 , followed by deprotection to provide N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl]-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid ( 2 ). Hexaglutamate 2 is a potent inhibitor of glycinamide ribonucleotide transformylase.     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Synthesis of 1-arylacenaphtho[1,2-d]pyrazoles and 5,7-Dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes

2-Benzoyl- 5 and 2-acetylacenaphthenone 6 , prepared from the corresponding 1-acyl-2-(1-pyrrolidinyl)-acenaphthylenes 2 and 3 , reacted with arylhydrazines 8 under acidic conditions to give the corresponding 1-arylacenaphtho[1,2-d]pyrazoles 9 and 10 . Novel heteropentalene mesomeric betaines, 5,7-dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes 13 and 14 were prepared by reductive cyclization of 1-(o-nitrophenyl)acenaphtho[1,2-d]pyrazoles 9d and 10d , respectively.     

Synthesis of (2-hydroxy-5-nitrophenyl)di[1-(2-hydroxynaphthyl)]methane and 12-[1-(2-hydroxynaphthyl)]-10-nitro-12H-benzo[α]xanthene from of 5-nitrosalicylaldehyde derivatives and β-naphthol

The reaction of the morpholinal or anil of 5-nitrosalicylaldehyde with β-naphthol yielded (2-hydroxy-5-nitrophenyl)di[1-(2-hydroxynaphthyl)]methane. Condensation of the latter compound in boiling nitromethane gave 12-[1-(2-hydroxynaphthyl)]-10-nitro-12H-benzo[α]xanthene. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1336–1339, July, 1997.     

Synthesis and anticonvulsant activity of 3-[3-[(dimethylamino)-methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine

Wolff-Kishner reduction of 3-amino-4-(o-chlorobenzoyl)pyridine ( 3 ) afforded 3-amino-4-(o-chlorobenzyl)pyridine ( 5 ), which on subsequent reaction with triethyl orthoformate and then acetyl hydrazide yielded 1-acetyl-2-[N-[4-(o-chlorobenzyl)pyridin-3-yl]formimidoyl]hydrazone ( 7 ). Cyclization of hydrazone 7 gave 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 8 ), which on Jones oxidation yielded 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ). The Mannick reaction of 3-(3-methyl-4H-l,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ) with aqueous formalin and dimethylamine hydrochloride afforded 3-[3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)-pyridine ( 10 ). 3-[3-[(Dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine ( 10 ) exhibited good anticonvulsant activity in the subcutaneous pentylenetetrazole anticonvulsant screen indi cating that an appropriately substituted-pyridine ring moiety can serve as a bioisostere of a chlorobenzene ring with respect to anticonvulsant activity.     

Simple synthesis of 6-alkyl-5H-benzo[a]phenoxazin-5-ones

6-Alkyl-5H-benzo[a]phenoxazin-5-ones were prepared by the reaction of 5H-benzo[a]phenoxazin-5-one with carboxylic acid in the presence of silver ion and peroxydisulfate.

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Eine einfache Synthese von 6-Alkyl-5H-benzo[a]phenoxazin-5-onen (Kurze Mitteilung)

Zusammenfassung 6-Alkyl-5H-benzo[a]phenoxazin-5-one wurden mittels Reaktion von 5H-Benzo[a]phenoxazin-5-onen mit Carbonsäuren in Gegenwart von Silberionen und Peroxydisulfat dargestellt.

     

Synthesis of 6-(4-methyl-1-piperazinyl)-7H-indeno[2,1-c]-quinoline derivatives as potential 5-HT receptor ligands

Two synthetic pathways for the achievement of the title compounds are reported. The key intermediate, namely 3-carboxy-4-phenyl-2(1H)-quinolinone 9 , was directly cyclized into the corresponding 6-chloro-7H-indeno[2,1-c]quinolin-7-one 10 or alternatively it was esterified, reduced to the alcohol, chlorinated and cyclized into the 6-chloro-7H-indeno[2,1-c]quinoline 8 . Further reaction of the chloroindenoquinoline derivatives with N-methylpiperazine afforded the piperazinyl derivatives 4a-c .     

The synthesis of 7-(substituted-amino)-3-azabicyclo[3.2.0] heptanes

1,2-Cycloaddition reactions of several enamines with N-substituted maleimides and 4-phenyl-1,2,4-triazoline-3,5-dione have been carried out. The adducts were transformed into 7-(substituted-amino)-3-azabicyclo[3.2.0]heptanes and a 1,2,4-triazolidine-1-acetaldehyde, respectively. These are the first reported examples of 3-azabicyclo[3.2.0]heptanes substituted in any position other than the 3-position. The reaction of an ynamine with N-benzylmaleimide afforded a bicyclic intermediate which upon hydrolysis gave a 2,5-dioxo-3-pyrrolidineacetic acid.