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

α-(Aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate, 3 and 8 , have been synthesized by catalytic hydrogenation of 6-cyanomethylene-9-methoxymethylpurine derivatives 2 and 7 which were obtained by the substitution of 6-chloro-9-(methoxymethyl)purine ( 1 ) with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of 3 and 8 with amines gave the corresponding N-substituted α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate 4 and 10 . Reaction of 3 with piperidine gave 9-(methoxymethyl)-9H-purine-6-acetamide ( 5 ).     

The synthesis of 6-C-substituted 9-methoxymethylpurine derivatives

6-Cyanomethylene ( 2 ), which was prepared via 1 by substitution with malononitrile, has been catalytically hydrogenated to the α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetonitrile ( 3 ) in good yield using N,N-dimethylformamide-benzene as solvent over Pd-C under medium pressure. Intermediate 3 was derived to aldehyde 5 by hydrolysis with acid or base. Substitution of 3 with amines gave the corresponding alkylamines 6 and 7 . Reaction of 3 with hydrazine and acetamidine hydrochloride gave pyrazole derivative 8 and pyrimidine derivative 9 , respectively.     

Synthesis and comparative study of reactivities of δ-lactone,estor group and oxazinone ring in coumarin derivatives towards carbon or nitrogen nucleophiles

Condensation of methyl 7-methylcoumarin-4-acetate ( 2 ) with primary amines and with anthranilic acid gave 7-methyl-2-oxo-N-aryl-2H-[1]-benzopyran-4-acetamide ( 4a—d ) and (7), respectively. Compound 7 underwent cyclization to give 2-(7-methyl-2-oxo-2H-[1]-benzopyran-4-yl)-methyl-4H-3,1-benzoxazin-4-one ( 3 ). The reaction of 3 with aromatic amines gave the corresponding quinazolone derivatives 5 which tautomerises to the thermodynamically more stable isomer 6 , whereas its reaction with Grignard reagents and aromatic aldehydes gave 8a, 8b , and 9a, 9b , respectively.     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

Synthesis of 1-(2-hydroxyphenyl)-2,4-imidazolidinedione derivatives through cyclic transformations of ethyl 2-oxo-3(2H)-benzoxazoleacetate derivatives

A series of ethyl 2-oxo-3(2H)-benzoxazoleacetate derivatives 2 have been synthesized. By reaction with ammonia, primary amines or hydrazine, these compounds 2 were transformed into 1-(2-hydroxyphenyl)-2,4-imidazolidinedione derivatives 4, 5 and 6 , respectively. Some of these new hydantoins 4 , treated with phosphorus oxychloride, gave 3H-2-oxoimidazo[2,1-b]benzoxazole derivatives 9 . Ethyl 2-oxo-3(2H)-benzoxazolepropionate ( 10 ) was prepared by a Michaël reaction of ethyl acrylate with 2-benzoxazolone ( 1a ). With 10 , no cyclic transformation was observed in the presence of ammonia or alkylamine.     

4-Substituted-3-alkyl-3,4-dihydro-2H-1,3-benzoxazin-2-ones. IV (2-4). Keto-Enol tautomerism of β-keto ester derivatives. Reaction of β-dicarbonyl compounds with diamines

A series of α-[3-alkyl-3,4-dihydro-2-oxo-2H-1,3-benzoxazin-4-yl]-β-keto ester derivatives 1 (Table I) were synthesized by the condensation of 3-alkyl-3,4-dihydro-4-hydroxy-2H-1,3-benzoxazine-2-ones 3 (2) with β-keto esters 4 in the presence of traces of mineral acids under azeotropic conditions. Condensation of 1 with hydrazines 5 gave pyrazolone derivatives 2 (Table II). Condensation of β-diketone derivatives 6 with hydrazines 5 and with 1,2-benzenediamine ( 8 ) resulted in the formation of pyrazoles ( 7a-c ) and diazepine derivatives 12 (Table III) and 13 , respectively.     

The reactions of 4-dicyanomethylene-2-phenyl-4H-1-benzopyran and some benzologs with nucleophiles

4-Dicyanomethylene-2-phenyl-4H-1-benzopyran (1) reacts with primary amines under mild conditions to give 4-imino-3-alkyl-5-alkylimino-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]-pyridine derivatives which, in turn, are hydrolyzed with acid to 4-imino-3-alkyl-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones. When more vigorous conditions are employed for the reactions of 1 with primary amines, Dimroth rearrangements take place and the products are derivatives of 4-alkyl- (or aryl)amino-5-alkyl- (or aryl)imino-2-phenyl-5H-[1]benzopyrano-[3,4-c]pyridine. The latter compounds are hydrolyzed by acid to the corresponding 5-pyridone derivatives. The reaction of 1 with piperidine gives 2-phenyl-4-piperidyl-5H-[1]benzopyrano-[3,4-c]pyridin-5-one. Sodium methoxide reacts with 1 to give 3-cyano-2-methoxy-4-(2-hydroxyphenyl)-6-phenylpyridine. Two benzologs of 1 have been allowed to react with primary and secondary amines and the products are analogous to those obtained from 1 .     

Furopyridines. XXVII. Reactions of 2-methyl and 2-cyano derivatives of furo[2,3-b]-, -[3,2-b]-, - [2,3-c]- and -[3,2-c]pyridine

Bromination of 2-methylfuropyridines 1a-d-Me gave the 3-bromo derivatives 2a-d , while the 2-cyano compounds 1a-d-CN resulted in the recovery of the starting compounds. Nitration of 1a-d-Me and 1a-d-CN did not yield the corresponding nitro derivative, except for 1-c-CN giving 3-nitro derivative 3c in 7% yield. N-Oxidation of 1a-d-Me and 1b-d-CN with m-chloroperbenzoic acid yielded the N-oxides 4a-d-Me and 4b-d-CN , whereas 1a-CN did not afford the N-oxide. Cyanation of N-oxides 4a-d-Me and 4b-d-CN with trimethylsilyl cyanide gave the corresponding α-cyanopyridine compounds 5a-d-Me and 5b-d-CN . Chlorination of 4a-d-Me and 4b-d-CN with phosphorus oxychloride also gave the α-chloropyridine compounds 6b-d-Me and 6b-d-CN , accompanying formation of γ-chloropyridine 6a-Me, 6′b-Me and 6′b-CN , β-chloropyridine 6′b-CN , and α'-chloropyridine derivatives 6′c-Me and 6′c-CN . Acetoxylation of 4a-d-Me and 4b-d-CN with acetic anhydride yielded α-acetoxypyridine compounds 7a-Me and 7b-CN , pyridone compounds 11d-Me, 11c-CN and 11d-CN , 3-acetoxy compounds 8, 9b, 9c , and 2-acetoxymethyl derivatives 10b and 10c.     

Reactions of 4-dicyanomethylenepyrans with hindered primary amines

The reaction of 2,6-dimethyl- and 2,6-diphenyl-4-dicyanomethylene-4H-pyran with hindered primary amines such as isopropylamine and cyclohexylamine gave 1-alkyl-2-amino-3-cyano-6-rnethyl(or phenyl)-4-acetonylidene (or phenacylidene)-1,4-dihydropyridine derivatives. The 6-methyl-4-acetonylidene examples underwent a facile thermal rearrangement to give 1-alkyl-2,6-dimethyl-4-dicy anomethy lene-1,4-dihydropy ridines. Several reactions of the acylidene derivatives are described.     

Nucleosides CV. Synthesis of the 8-((β-D-ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine isosteres of adenosine and inosine

Reaction of ethyl N-cyanoformimidate ( 3 ) and of ethyl N-carbelhoxyformimidate ( 5 ) with 3-aminopyrazole ( 2 ) gave 4-amino- and 4-oxo-3H-pyrazolo[1,5-a]-1,3,5-triazine ( 4 and 7 ), respectively. Reaction of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole ( 8 ) with the same reagents similarly gave the blocked 4-amino-8-ribosyl- and 4-oxo-3H-8-ribosyl-pyrazolo[ 1,5-a]-1,3,5-triazine ( 9 and 15 ), respectively. Deblocking in acid finally afforded the unblocked products 10 (an isostere of adenosine and formycin) and 16 (an isostere of inosine and formycin B). The corresponding derivatives in the a series were made by identical procedures for confirming all structural assignments. Preliminary in vitro testing results of 10 are included.     

Synthesis of ethyl 2-[(1-aryl-1H-1,2,4-triazol-3-yl)oxy]propionates and related derivatives

Alkylation of 1-aryl-1H-1,2,4-triazol-3-ols with ethyl 2-bromopropionate under basic conditions resulted in the formation of 2-[(1-aryl-1H-1,2,4-triazol-3-yl)oxy]propionic acid, ethyl esters. No N-alkylated products were detected. Similar alkylation of 2-oxo-5-phenyl-1,3,4-thiazole and the corresponding 1,3,4-oxadiazole gave only N-alkylated derivatives. With 4-hydroxy-6-phenylpyrimidine and 2-oxo-4-phenylthiazole, both O- and N-alkylation occurred. Structure assignments were based on ir and ¹³C nmr spectral data.     

Von der basenkatalysierten Ringöffnung von 2H-Azirinen zu einer α-Alkylierungsmethode von primären Aminen

From a Base Catalyzed Ring Opening of 2H-Azirines to an α-Alkylation Method of Primary Amines It is shown that fluorene-9′-spiro-2-(3-phenyl-2H-azirine) ( 1 ) on treatment with various alcohols in the presence of the corresponding alkoxide ions yields N-(9′-fluorenyl)benzimidates 2a-d (Scheme 1). 2,2,3-Triphenyl-2H-azirine ( 3 ) reacts with methanol in a similar manner (Scheme 2). Benzimidates 2a (Scheme 3), 8 (Scheme 4) and and 10 (Scheme 5) can easily be deprotonated by butyllithium (BuLi) or lithium diisopropylamide (LDA) in tetrahydrofuran (THF) to 1-methoxy-2-aza-allylanions, that can be alkylated, at C(3), exclusively, by various electrophiles (e.g. R-X(X = I, Br), RCHO or methyl acrylate (see also Scheme 6)). As the acidic hydrolyses (1N HCl) of benzimidates 9 and 11 leads to the corresponding α-alkylated free amines 15 and 18 (Scheme 7 and 8), benzoyl derivatives 16 and 19 are obtained from the hydrolysis under basic conditions. On the other hand, it is observed that a catalyzed Chapman rearrangement of 9 and 11 results in the formation of N-benzoyl-N-methyl derivatives 17 and 20 (Scheme 7 and 8). The described reactions offer a simple method for the α-alkylation of activated primary amines.     

The synthesis of 5-substituted 3-benzoylamino-6-(2-substituted amino-1-ethenyl)-2H-pyran-2-ones and their transformations into 2H-pyrano[3,2-c]pyridine derivatives

A new approach to the 2H-pyrano[3,2-c]pyridine system is described. 5,6-Disubstituted 3-benzoylamino-2H-pyran-2-ones 3a,b , prepared from the corresponding 1,3-dicarbonyl compounds 1a,b and methyl (Z)-2-benzoylamino-3-dimethylaminopropenoate ( 2 ), were converted into 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one ( 4a ) and 5-acetyl derivative 4b . The exchange of the dimethylamino group in 4a,b with aromatic amines 5a-f,m , héteroaromatic amines 5g-i , and benzylamines 5j-l produced 5-ethoxycarbonyl-3-benzoylamino-6-(2-arylamino- or heteroarylamino-or benzylamino-1-ethenyl)-2H-pyran-2-ones 6a-l , and its 5-acetyl analog 6m . The compounds 6 were cyclized in basic media into 2H-pyrano[3,2-c]pyridine derivatives 7a-h . Analogously react also α-amino acid derivatives 8a-c and 11 as nitrogen nucleophiles producing 9a-c, 10 and 12 .     

Synthesis of new phosphorylated analogs of nucleotides containing adenine and ethylidene-1,1-bisphosphoryl moieties

Reaction of adenine and 9-[2-(1,3-dioxolan-2-yl)ethyl]-9H-purine-6-amine with ethylidene-1,1-bisphosphonates resulted in the formation of new purine bases containing ethylidene-1,1-bisphosphoryl groups.

     

The mannich reaction in the synthesis of N,S-containing heterocycles 4. Aminomethylation of 6-amino-3,5-dicyano-1,4-dihydropyridine-2-thiolates: A convenient regioselective route to 3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene derivatives

Treatment of N-methylmorpholinium 4-R-6-amino-3,5-dicyano-1,4-dihydropyridine-2-thiolates (R = 2-ClC₆H₄ and 2-MeOC₆H₄) with primary amines in the presence of an excess of formaldehyde gave 13-R-8-thioxo-3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-1,9-dicarbonitrile derivatives in high yields (66–95%). In a similar way, aminomethylation of 3-R-10-amino-7,11-dicyano-9-aza-3-azoniaspiro[5.5]undeca-7,10-diene-8-thiolates (R = Me and Et) afforded 1′-alkyl-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-13,4′-piperidine]-1,9-dicarbonitriles in 43–91% yields. Alternatively, these compounds were obtained by multicomponent cyclocondensation of N-alkylpiperidin-4-ones, cyanothioacetamide, primary amines, and aqueous formaldehyde. The starting 3-R-10-amino-7,11-dicyano-9-aza-3-azoniaspiro[5.5]undeca-7,10-diene-8-thiolates were prepared by a new method from N-alkylpiperidin-4-ones and cyanothioacetamide. The structure of 5,11-bis(4-ethoxyphenyl)-13-(2-methoxyphenyl)-8-thioxo-3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-1,9-dicarbonitrile was examined by X-ray diffraction analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1014–1022, May, 2007.     

A New General Approach to Enantiomerically Pure Cyclic and Open-Chain (R)- and (S)-α,α-Disubstituted α-Amino Acids

A wide range of cyclic and open-chain α,α-disubstituted α-amino acids 1a-p were prepared. The racemic N-acylated α,α-disubstituted amino acids were resolved by coupling to chiral amines 15-18 derived from (S)-phenylalanine to form diastereoisomers 19/20 or 21/22 that could be separated by crystallization and/or flash chromatography on silica gel (Scheme 3). Selective cleavage via the 1,3-oxazol-5(4H)-ones 10a-p gave the corresponding optically pure α,α-disubstituted amino-acid derivatives 11 or 12 in high yield (Scheme 3). The absolute configurations of the α,α-disubstituted amino acids were determined from X-ray structures of the diastereoisomers 20, 21g′, 22d .     

The synthesis and transformations of ethyl (Z)-2-[2,2-bis(ethoxycarbonyl)vinyl]amino-3-dimethylaminopropenoate,a new reagent in the synthesis of heterocyclic compounds

Ethyl (Z)-2-[2,2-bis(ethoxycarbonyl)vinyl]amino-3-dimethylaminopropenoate (5) , a new reagent in the synthesis of heteroaryl substituted β-amino- α,β- -dehydro—amino acid derivatives and some fused hetero-cyclic systems, was prepared from ethyl N-2,2-bis(ethoxycarbonyl)vinylglycinate (3) and N,N-dimethyl-formamide dimethyl acetal (4) . The substitution of the dimethylamino group in the compound 5 with heterocyclic amines produced ethyl 2-[2,2-bis(ethoxycarbonyl)vinyl]amino-3-heteroarylaminopropenoates 7a-f and, in some instances, [2,2-bis-(ethoxycarbonyl)vinyl]aminoazolo- or -azinopyrimidine derivatives 8g-k.     

Reactions of some pyranylidene esters with amines

The reactions of 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2,6-diphenyl-4H-pyran ( 1 ) with primary amines gave the corresponding 1-substituted 1,4-dihydropyridine derivatives. The related benzo derivative of 1 (12) and primary amines gave 3-substituted 3,4-dihydro-2-phenyl-5H-[1]benzopyrano[3,4-c] pyridine-4,5-dione derivatives. With secondary amines, 12 gave 2-phenyl-4H,5H-pyrano[3,4-c] [1]benzopyrane-4,5-dione, and with isopropylamine, N,N-dimethylhydra-zine, and methanolic potassium hydroxide, 12 gave 4-phenacylcoumarin. Some reaction intermediates were isolated which indicate probable reaction paths. The reactions with amines were extended to a naphtho derivative of 1 (19) and to a thia homolog of 12 (24).     

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 ).     

Synthése,stéréochimie,et réactivité thermique de (N-méthylidenealkylamino)-2 aziridines

1-Alkyl-2-(N-methylidenealkylamino)aziridines are obtained by the reaction of primary amines with either α-chloroacraldehyde or α-chlorocrotonaldehyde. Structural assignments are made by nmr spectroscopy. The thermal rearrangement of 1-alkyl-2-(N-methylidenealkylamino)-3-methylaziridines to pyrroles is described.