Ethyl 3,3-diamino-2-(2-p-tolylpyrimidin-4-yl)acrylate,a new representative of hetarylketene aminals

A new representative of hetarylketene aminals, ethyl 3,3-diamino-2-(2-p-tolylpyrimidin-4-yl)acrylate, was synthesized by the reaction ofp-toluamidine with the condensation product of dimethylformamide dimethyl acetal and the difluoroboron chelate of acetyl(ethoxycarbonyl)ketene (N-benzoyl)aminal. This synthesis is an example of pyrimidine ring assembly using the methodology based on transformations of chelate complexes.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1638–1640, September, 1994.This research was partially supported by the International Science Foundation (Grant No. M5QOOO).     

Stereoselective Synthesis and Diels-Alder Reactions of (Z)- and (E)-1,2-bis(Phenylthio)-1,3-Butadiene

Bromination of 3-phenylthio-2-sulfolene (2) with N-bromosuccinimide gave 2-bromo-3-phenylthio-2-sulfolene (3) which was converted mainly to 2,3-bis(phenylthio)-2-sulfolene (4) by treatment with sodium phenylthiolate. Thermal desulfonylation of 4 at different temperatures in the presence of a base (DBU) yielded stereoselectively the (Z)- and (E)-1,2-bis(phenylthio)-1,3-butadiene (6). These two geometric isomers could be thermally interconverted. The Diels-Alder reactions of 6 were also investigated. Only the (Z)-diene 6a could undergo the Diels-Alder reaction; the (E)-diene 6b was in situ converted to the Z isomer before undergoing (he Diels-Alder reaction. The reaction of 6a with N-phenylmaleimide gave the cycloaddition product 7 with complete endo selectivity, but under daylight or during chromatography it readily underwent a thioallylic rearrangement to yield 8 with inversion of configuration. The cycloaddition of 6a with methyl acrylate proceeded regiospecifically, but generating a mixture of endo and exo isomers. The endo/exo ratio could be increased by using ZnCl₂ as the catalyst.     

Heterocycles with a Bridged Nitrogen Atom. 13. An Anomalous Example of the Sulfonating Action of Dimethyl Sulfate During an Attempt at the Methylation of 5-Aminoindolizine. Crystal Structure of Methyl 5-Morpholyl-2-(p-nitrophenyl)indolizine-1-sulfonate

The reaction of 5-morpholino-2-(p-nitrophenyl)indolizine with dimethyl sulfate gives the sulfonation product - methyl 5-morpholyl-2-(p-nitrophenyl)indolizine-1-sulfonate. Its structure was proved by X-ray crystallographic analysis.     

Preparation, crystal structure, and spectroscopic, chemical, and electrochemical properties of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1,3-butadiene compared with those of (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene

Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (4) in ethanol containing NaOEt at 25 °C for 24 h under argon gives the title (2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spectroscopic properties, crystal structure, and electrochemical behavior of the obtained new extended π-electron system 6E, compared with those of the previously reported (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene (12), are documented. Furthermore, reaction of 6E with 1,1,2,2-tetracyanoethylene (TCNE) in benzene at 25 °C for 24 h under argon affords a new Diels-Alder adduct 8 in 59% isolated yield. Along with spectroscopic properties of the [π4+π2] cycloaddition product 8, the crystal structure, possessing a cis-3,6-substituted 1,1,2,2-tetracyano-4-cyclohexene unit, is shown. Moreover, reaction of 6E with (E)-1,2-dicyanoethylene (DCNE) under the same reaction conditions as the above gives no product; however, this reaction in p-xylene at reflux temperature (138 °C) for four days under argon affords a new Diels-Alder adduct 9 in 54% isolated yield. Although reaction of 6E with DCNE in toluene at reflux temperature (110 °C) for four days under argon provides 9 very slightly, reaction of 6E with dimethyl acetylenedicarboxylate (DMAD) in toluene at reflux temperature for two days under argon yields a new Diels-Alder adduct 10, in 58% isolated yield, which upon oxidation with MnO₂ in CH₂Cl₂ at 25 °C for 1 h gives 11, converting a (CH₃)₂N-4″ into CH₃NH-4″ group, in 37% isolated yield. The crystal structure of 11 supports the molecular structure 10 possessing a partial structure cis-3,6-substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene. The title basic studies on the above are reported in detail.     

Ringerweiterungsreaktionen von N-(2-Aminoäthyl)-, N-(4-Aminobutyl)-, N-(6-Amino-4-aza-hexyl)- und N-(8-Amino-4-aza-octyl)-lactamen. 7. Mitteilung über Umamidierungsreaktionen

Ring Enlargement Reactions of N -(2-Aminoethyl)- , N -(4-Aminobutyl)- , N -(6-Amino-4-aza-hexyl)- and N -(8-Amino-4-aza-octyl)-lactames The N-aminoalkyl-lactams 1 , 3 , 4 , 10 (Scheme 2) and 13 (Scheme 3) have been synthesized. In the presence of KAPA (potassium 3-aminopropylamide in 1,3-propanediamine) 1 is stable, whereas 3 , 4 and 10 rearrange under ring enlargement to 5 , 8 and 11 , respectively. The 4-aminobutyl derivate 13 rearranges in a fast reaction to 14 ; after a longer reaction time the 22membered ring 16 and the ring opened product 18 are formed. Hence it may be concluded that the 7membered lactam ring is more stable than the 10membered one, and the 11membered lactam ring is more stable than the 8 membered one. Moreover, the 5- and 6 membered ring intermediates of these transamidation reactions are prefered to the 7membered ring intermediates (cf. [10]).     

Diels-alder reaction of (E)-4-(2-nitroethenyl)-1H-imidazoles and methyl (E)-3-(1-imidazol-4-yl)propenoates

Diels-Alder reaction of methyl (E)-3-(1H-imidazol-4-yl)propenoates 2, 3a-c and (E)4-(2-nitroethenyl)-1H-imidazoles 3d,e with 2,3-dimethyl-1,3-butadiene, cyclopentadiene, and cyclohexa-1,3-diene gave the corresponding cycloadducts 6–9 .     

Heterocycles from carbohydrate precursors. Part XIX. The X-ray crystal structure determination of the reaction product of 4-(2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutyro-1,4-lactone-2-(p-bromophenylhydrazone) with methylhydrazine

X-ray crystallographic data show that the product obtained in the reaction of 4-(2-acetoxy-ethylidene)-4-hydroxy-2,3-dioxobutyro-1,4-lactone-2-(p-bromophenylhydrazone) with methyl-hydrazine is the bicyclic compound 2,6-dimethyl-3,4-dioxo-2,3,4,6,7,8-hexahydropyridazino-[4,3-c]pyridazine 4-(p-bromophenylhydrazone) ( 10 ) and not as originally suggested 1-methyl-3-(1-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(p-bromophenylhydrazone) ( 8 ).     

4-Substituted-4H-pyrrolo[2,1-c] [1,4]benzoxazines

The condensations of 1-(2-hydroxyphenyl) pyrroles with a variety of carbonyl compounds are shown to give new 4-substituted-4H-4-methylpyrrolo[2,1-c][1,4]benzoxazines. Some of the products were further functionalized. The ir, uv, and pmr spectra of the title heterocyclic system are discussed. Reaction of 1-(2-hydroxyphenyl) pyrrole with dimethyl acetylenedicarboxylate yielded dimethyl 3-(2-hydroxyanilino) phthalale; a mechanistic rationale which accounts for the result involves a rearrangement of the hypothetical Diels-Alder adduct.     

Synthese der diastereomeren 4-Amino- und 4-Hydroxy-3-(p-chlorphenyl)-valeriansäuren. Kristallstruktur von cis-4-(p-bromphenyl)-5-methyl-2-pyrrolidinon

Synthesis of 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids. X-ray structure of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone The syntheses of diastereomeric 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids and of their ring closure products (lactones and lactams), starting from 3-(p-chlorophenyl)-4-oxo-valeric acid, are described. A single-crystal X-ray structure analysis of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone is given. Some aspects of the biochemistry of threo-3-(p-chlorophenyl)-4-amino-valeric acid are presented.     

Reaction of 2-chloro-3-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone with cyclic amines (piperidine,morpholine, and pyrrolidine)

It was shown that the reaction of 2-chloro-3-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone with piperidine in the absence of a solvent gives not only a product of replacement of the chlorine atom by a piperidino group, 3-(4-N,N-dimethylaminoanilino)-2-piperidino-1,4-naphthoquinone, but also 2-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone and 2-(4-N,N-dimethylaminoanilino-2-piperidino)-1,4-naphthoquinone. The latter compounds are the only reaction products formed in dimethyl sulfoxide. The reaction with morpholine occurs in a similar way, whereas that with pyrrolidine gives only a product of replacement of the chlorine atom by hydrogen.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2451–2454, December, 1995.     

The crystal and molecular structures of 1-(P-bromophenyl)-5-bromopyridazine-3,6-dione and 1-(p-bromophenyl)-4-diethylaminopyridazine-3,6-dione

The structure of 1-(p-bromophenyI)-5-bromopyridazine-3,6-dione was unequivocally established by means of an X-ray crystal structure determination. By the same means its reaction product with diethylamine was proved to be 1-(p-bromophenyl)-4-diethylaminopyridazine-3,6-dione.     

Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds

Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds had been developed by introducing an iodo atom at the C-5 position of the imidazole ring of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds. Specifically, 5-iodo-1-(4-iodophenyl)imidazole-4-carbonitrile compound had shown double Sonogashira coupling reactions with two differently substituted iodine along with the formation of two other compounds where an unusual coupling product with self-aggregation property was obtained. In other cases, monocoupling had been observed together with another compound where iodine atom present at C5 position of imidazole was replaced by hydrogen atom.     

Synthesis and study of (2S,4S)-4-arylamino-2-carboxy-5-pyrrolidones

(2S,4S)-4-Arylamino-2-carboxy-5-pyrrolidones were prepared by hydrolysis of dimethyl (2S,4S)-4-arylamino-N-phthaloylglutamates. The protonation constants of the arylamino group in the synthesized compounds were determined. The pyrrolidone ring is stable in acidic or neutral solutions. The relative stability of the pyrrolidone ring in alkaline solutions was studied by IR spectroscopy.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2087–2090, December, 1993.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Asymmetric synthesis of (R)-6-amino-1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepine from L-asparagine

An efficient asymmetric synthesis of (R)-6-amino-1-methyl-4-(3-rnethylbenzyl)hexahydro-1H-1,4-diazepine [(R)-2] which serves as the amine part of (R)-1, a potent and selective 5-HT₃ receptor antagonist, is described. Formation of the hexahydro-1H-1,4-diazepine ring was achieved by the intramolecular ami-dation of the optically active aminocarboxylic acid 18 or reductive cyclization of the optically active aminoaldehyde 25. Compounds 18 and 25 were prepared from L-asparagine via the key aziridine derivatives 15 and 22 , respectively, with retention of the configuration. The intramolecular aziridine ring opening reaction of 29 gave the C₂? N bond cleavage product of the aziridine ring, the piperazin-5-one 30 , as the main product along with the desired 7-membered ring, the hexahydro-1H-1,4-diazepine product 19 .     

Synthesis and stereochemistry of rac.-trans-tetrahydro-6-hydroxy-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one

The base catalyzed reaction of 2-aminoethanethiol ( 3 ) with trans-3-(p-methoxyphenyl)glycidate ( 4 ) gave a mixture of isomeric lactams 5 and 6 , and in addition, a by-product 7 . The structures of these isomers were proven by X-ray crystallography. The data revealed that both isomers adopt the chair conformation in the solid state and the size of the heterocyclic ring in compound 5 is a six- and in compound 6 is a seven-membered ring.     

A new type of deoxygenation of quinoxaline N-oxides

The reaction of 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4-oxide 3a or 2-[2-(p-bromobenzylidene)-1-methylhydrazino]-6-chloroquinoxaline 4-oxide 3b with dimethyl acetylenedicarboxylate under reflux in N,N-dimethylformamide resulted in deoxygenation to give 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4a or 2-[2-(p-bromobenzilidene)-1-methylhydrazino]-6-chloroquinoxaline 4b , respectively, while the reaction of compound 3a or 3b with dimethyl acetylenedicarboxylate under reflux in dioxane precipitated dimethyl 8-chloro-4-[2-(p-chlorobenzyli-dene)-1-methylhydrazino]-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6a or dimethyl 4-[2-(p-bromobenzylidene)-1-methylhydrazino]-8-chloro-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6b , respectively. Further refluxing of compound 6a or 6b in N,N-dimethylformamide provided compound 4a or 4b , respectively.     

Synthesis of stereoisomeric 4-(2-methylindolin-1-yl)- and 4-(2-methylindol-1-yl) derivatives of glutamic acid

The reaction of dimethyl (2S,4RS)-N-phthaloyl-4-bromoglutamate with 2-methylindoline afforded diastereomeric 4-(2-methylindolin-1-yl)-(S)-glutamic acid derivatives, whose oxidation gave rise to 4-(2-methylindol-1-yl)-(S)-glutamic acid derivatives.     

Nitropyrazoles 17. Synthesis of 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole and the study of its chemical transformations

A new one-step method for the synthesis of 4-methyl-3(5)-nitropyrazole by nitration of 4-methylpyrazole is developed. Arylation of 4-methyl-3(5)-nitropyrazole with 1,3,5-trinitrobenzene gives 1-(3,5-dinitrophenyl)-4-methyl-3-nitropyrazole, nitration of which leads to 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole. The action of 1 equiv. of an O- or S-nucleophile (phenolate, p-chlorobenzenethiolate and ethoxide ions; anions of glycolanilide and thioglycolanilide) on 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole led to the substitution of the 5-NO₂ group of the pyrazole ring; under the action of one more equivalent of a nucleophile the NO₂ group of the benzene ring was substituted. The substitution product of the anion of thioglycolanilide for the 5-NO₂ group undergoes the intramolecular cyclization — oxidative nucleophilic hydrogen substitution in the benzene ring under the action of K₂CO₃.     

Saturated heterocycles. 254 . synthesis and stereochemistry of saturated or partially saturated pyridazino-[6,1-b]- and phthalazino[1,2-b]quinazolinones

By the reaction of anthranilic hydrazide 1 with cis-2-(p-methylbenzoyl)-1-cyclohexanecarboxylic acid 2a or diendo-3-(p-methylbenzoyl)bicyclo[2.2.1]heptane-2-carboxylic acid 2b , fused tetra- and pentacyclic ring systems 3a, b were prepared, trans-2-Amino-1-cyclohexanecar-bohydrazide 4b was reacted with 3-(p-chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1-b]quinazolinone 6 . From the reaction of cis-2-amino-1-cyclohexanecarbohydrazide 4a with 2a , three isomeric partially saturated 8H-phthalazino[1,2-b]quinazolin-8-ones 7a-c were formed. The reaction of diexo-2-aminobicyclo[2.2.1]heptane-3-carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3-aryl-4,5-dihydropyridazine or 3-arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by ¹H and ¹³C nmr methods, including DEPT, DNOE and 2D-HSC measurements.