Synthesis of analogs of amrinone: 4-(3,4-Disubstitutedphenyl)pyridines and derivatives thereof

4-(3,4-Dimethoxyphenyl)pyridine ( 5c ) prepared by the coupling of 3,4-dimethoxyphenyldiazonium chloride with pyridine was converted to 4-(4-pyridinyl)benzene-1,2-diol ( 6c ) by treating with hydrobromic acid. Diazotization of 4-(4-pyridinyl)benzeneamine ( 7 ) and 3-(4-pyridinyl)benzeneamine ( 12 ) gave the corresponding phenols 8 and 13 which were nitrated to give 2-nitro-4-(4-pyridinyl)phenol ( 9 ) and 2-nitro-5-(4-pyridinyl)-phenol ( 14 ), respectively. Reduction of these nitrophenols gave the corresponding aminophenols 10 and 16 which in turn were reacted with N,N'-carbonyldiimidazole to yield benzoxazolones 11 and 17 , respectively. Catalytic reduction of 2-nitro-4-(4-pyridinyl)benzeneamine ( 18 ) gave 4-(4-pyridinyl)benzene-1,2-diamine ( 19 ) which was reacted with orthoesters, urea, tetraethoxymethane, and N,N'-di(carbomethoxy)methylpseudothiourea to give the corresponding benzimidazole derivatives 20, 21, 22 , and 23 .     

Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

Two 2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4-chloropyridines. In addition, a number of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2c-h were obtained from 2-(4-pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1-alkylhydroxyisoindolones 6a-f which, in two cases 6a,b , were dehydrated and subjected to three separate reductions to give targets 2c,d . In three cases, the intermediate hydroxyisoindolones 6c-e were reduced in one step to the target compounds 2c-g with lithium aluminum hydride-aluminum chloride. When 6f , the product of the addition of phenyl Grignard to 5 , was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane-trifluoroacetic acid. The lithium aluminum hydride-aluminum chloride conditions were successfully applied to the synthesis of a 1-benzyl-4-piperidine derivative 21.     

Furopyridines. XVII . Cyanation,chlorination and nitration of furo[3,2-b]pyridine N-oxide

The N-oxide 2 of furo[3,2-b]pyridine ( 1 ) was cyanated by the Reissert-Henze reaction with potassium cyanide and benzoyl chloride to give 5-cyano derivative 3 , which was converted to the carboxamide 4 , carboxylic acid 5 , ethyl ester 6 and ethyl imidate 8 . Chlorination of 2 with phosphorus oxychloride yielded 2-9a , 3- 9b , 5- 9c and 7-chloro derivative 9d . Reaction of 9d with sodium methoxide, pyrrolidine, N,N-dimethylformamide and ethyl cyanoacetate afforded 7-methoxy- 10 , 7-(1-pyrrolidyl)- 11 and 7-dimethylaminofuro[3,2-b]pyridine ( 14 ) and 7-(1-cyano-1-ethoxy-carbonyl)methylene-4,7-dihydrofuro[3,2-b]pyridine ( 12 ). Nitration of 2 with a mixture of fuming nitric acid and sulfuric acid gave 2-nitrofuro[3,2-b]pyridine N-oxide ( 15 ).     

Pyridazine Derivatives and Related Compounds,Part 1. Some Reactions with 4-Cyano-5,6-Diphenyl-2,3-Dihydropyridazine-3-One

4-Cyano-5,6-diphenyl-2,3-dihydropyridazine-3-onc 1 reacts with phosphorous oxychloride to give 70% of the corresponding 3-chloro derivative 2. Treating 2 with anthranilic acid in butanol, 4-cyano-2,3-diphenyl-10H-pyridazino[6,1-b]quinoxaline-10-one, 3 was obtained. Compound 1 reacts with phosphorous pentasulphide to give 3-mercapto derivative 4, which was converted by acrylonitrile to S-(2-cyanoethyl)pyridazine derivative 5. Compound 4 reacts with ethyl bromoacetate and with phenacyl bromide gave the corresponding thieno[2,3-c] pyridazine derivatives 8, 9, Alkylation of 1 with ethyl chloroacetate afforded 3-0-carbethoxymethyl derivative 10. Compound 10 reacts with amines (aniline, hydrazine) to give the corresponding amide and acid hydrazide 13, 12 respectively. Hydrolysis of 10 with sodium hydroxide gave the corresponding acid derivative 11. Treating 1 with methyl iodide, 3-0-methyl derivative 14 was obtained, which was converted by ammonium acetate/acetic acid to 3-amino-4-cyano-5,6-diphenyl pyridazine 15. Compound 1 reacts with methyl magnesium iodide gave 4-acetyl derivative 16, which was reacted with hydrazine, phenyl hydrazine and with hydroxylamine to give the substituted I H pyrazolo [3,4-c] pyridazine 17 a,b and isoxazolo [5,4-c] pyridazine 18 derivatives respectively.     

Furopyridines. II. Bromination and nitration of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

In order to reveal the reactivities of furopyridines, we undertook bromination and nitration of four furopyridines ( 1, 2, 3 and 4 ) whose chemical properties had been almost unknown. Bromination of 1, 2, 3 and 4 gave the corresponding trans-2,3-dibromo-2,3-dihydro derivatives 6, 8, 10 and 12 , respectively, which were converted to 3-bromofuropyridines 7, 9, 11 and 13 by treatment with sodium hydroxide in aqueous methanol. Nitration of 1 with a mixture of fuming nitric acid and sulfuric acid afforded a mixture of addition products 14a, 14b and 14c and 2-nitro derivative 15 . Both 14a and 14b were easily converted to 15 by treatment with sodium bicarbonate. Compound 2 was nitrated to give a mixture of cis- and trans-2-nitro-3-hydroxy-2,3-dihydro derivative 16a and 16b and 2-nitro derivative 17 . The cis isomer 16a was transformed to the trans isomer 16b by refluxing on silica gel in ethyl acetate. Compound 16b was dehydrated with acetic anhydride to give 17 . Nitration of 3 gave a nitrolic acid derivative 20 . Nitration of 4 gave a mixture of 2-nitro derivative 22 and 3-(trinitromethyl)pyridin-4-ol ( 23 ). The structures of 20 and 23 were established by single crystal X-ray analysis. The differences of behavior observed in these reactions are discussed in connection with the results of the determination of pKa values and the relative reactivities of deuteriodeprotonation of these furopyridines.     

Synthesis of some N-substituted isonicotinamides

A one-pot transformation of some cyclic 1,3-dicarbonyls 1 with N-(isonicotinoyl)glycine 2 and one-carbon synthons in acetic anhydride to the corresponding N-substituted isonicotinamides (pyridine-4-carbox-amides) 7-9 containing a fused pyran-2-one ring is described. Compound 8 was further converted with some nitrogen-containing nucleophiles either to the corresponding quinoline- 2,5 -diones 10-11 or 5-hydra-zonobenzopyran-2-ones 14-15. Under more severe conditions the compound 8 gave with hydrazine 5-hydrazonoquinoline derivative 12 or even 13 . Hydrazoic acid transformed compound 8 to the pyrano-[3,2-c]azepine system 16 . Diazotization of 1-amino derivative 10 gave deaminated product 11.     

Stereospecific substitution of enantiomerically pure 1-(2-pyridinyl)ethyl methanesulfonate with beta-dicarbony compounds

The alkylation of the sodium salt of the malonic acid diester with (R)-1-(2-pyridinyl)ethyl methanesulfonate (2) gave the dimethyl (R)-[1-(2-pyridinyl)ethyl]malonate (3a), stereospecifically. The alkylation reaction of methyl acetoacetate gave the methyl (2'S,2R/2S)-3-oxo-2-[1-(2-pyridinyl)ethyl]butanoate (3d) along with the methyl (S)-3-[1-(2-pyridinyl)ethoxy]-2-butenoate (4d). The acid hydrolysis and decarboxylation of 3d under acidic conditions gave (R)-4-(2-pyridinyl)pentan-2-one (6), and the alkylation of methyl (R)-[1-(2-pyridinyl)ethyl]acetoacetate with benzyl bromide gave a mixture of C-benzylated and O-benzylated products 7 and 8.     

Synthesis and single-crystal X-ray diffraction analysis of 2-sulfamoyladenosine (6-amino-9-β-D-ribofuranosylpurine-2-sulfonamide)

2-Amino-9-β-D-ribofuranosylpurine-2-sulfonamide (2-sulfamoyladenosine, 4 ), a congener of sulfonosine ( 3 ), was synthesized by four different routes. Acid catalyzed fusion of 6-chloropurine-2-sulfonyl fluoride ( 5 ) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose ( 8 ) gave a good yield of 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine-2-sulfonyl fluoride ( 9 ). Ammonolysis of 9 furnished 4 . Lewis acid catalyzed glycosylation of the trimethylsilyl derivative of either 6-chloropurine-2-sulfonamide ( 6 ) or 6-aminopurine-2-sulfonamide ( 7 ) with 8 gave the corresponding N9-glycosylated products, 10 and 11 , respectively, which on ammonolysis gave 4 . Amination of 2-thioadenosine ( 12 ) with chloramine solution gave the sulfenamide derivative 13 , which on subsequent oxidation with m-chloroperoxybenzoic acid furnished an alternate route to 4 . The structure of 4 was established by single-crystal X-ray diffraction studies. 2-Sulfamoyladenosine ( 4 ) is devoid of significant inhibitory activity against L1210 leukemia in mice.     

Studies on imidazole derivatives and related compounds. I. Synthesis of novel antineoplastic derivatives of 4-carbamoylimidazolium-5-olate

Acylation of 4-carbamoylimidazolium-5-olate ( 2 ) with a variety of acid chlorides produced 4(5)-carbamoyl-1H-imidazol-5-(4)yl acid carboxylates ( 3a-j ). Treatment of esters 3a,c with sodium hydroxide gave imides, 4a,c . Methylation of 3a and 2 with diazomethane gave the N-3 methyl derivative ( 6 ) and a mixture of the N-3, O-dimethyl derivative ( 9 ), the N-1, N-3-dimethyl derivative ( 10 ) and the O-methyl derivative ( 11 ), respectively. 5-Carbamoyl-1-methylimidazolium-4-olate ( 7 ) and its 4-carbamoyl isomer ( 16 ) were prepared from 2-aminopropanediamides 8 and 15 , respectively. Treatment of the imidazolium compound ( 10 ) with aqueous potassium hydroxide gave the recyclized product, 1-methyl-5-methylcarbamoylimidazolium 4-olate ( 18 ). Methyl derivatives 6, 7 , and 9 except 16 demonstrated the complete lack of antitumor activity against Lewis lung carcinoma or sarcoma 180 in mice.     

Synthesis of 1,8-, 1,6- and 3,6-dichloro-9H-thioxanthen-9-ones

Cyclization of 2-chloro-6-[(3-chlorophenyl)thio]benzoic acid ( 2 ) gave a mixture of 1,8-, 3 , and 1,6-dichloro-9H-thioxanthen-9-ones 4 . The mixture was converted to 1,8-diamino- 7 , and 1-amino-6-chloro-9H-thioxanthen-9-ones 8 , from which 3 and 4 were prepared separately, respectively. From a mixture of 4 and 3,6-dichloro-9H-thioxanthen-9-one ( 11 ) obtained by cyclizing 4-chloro-2-[(3-chlorophenyl)thio]benzoic acid ( 10 ) was separated 11 by conversion of 4 to 8 .     

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.     

Synthese von zwei natürlich vorkommenden Lactonen mit 10gliedrigen Ringen: (±)-Phoracantholid J und I

Synthesis of Two Naturally Occurring 10-Membered Ring Lactones: (±)-Phoracantholide J and I Two 10-membered ring lactones 7 and 11 from the metasternal secretion of the eucalypt longicorn Phoracantha synonyma have been synthesized by the following method. Reaction of the dilithium derivative of 4-pentynoic acid ( 3 ) with 4-tetrahydropyranyloxy-1-pentylbromide ( 2 ), followed by removal of the protecting group and by esterification with diazomethane, gave methyl 9-hydroxy-4-decynoate ( 4 ; s. Scheme 1). Partial hydrogenation of the triple bond in 4 with Lindlar palladium catalyst, followed by saponification lead to cis-9-hydroxy-4-decenoic acid ( 6 ). The 9-hydroxydecanoic acid ( 9 ) was synthesized by addition of methyl magnesium iodide to methyl 8-formyloctanoate ( 8 ) followed by saponification (s. Scheme 2). The hydroxy acids 6 and 9 were converted into the S-(2-pyridyl) thioesters and cyclized in dilute benzene solution under the influence of silver ions to yield (±)-phoracantholide J ( 7 ) and I ( 11 ) in 74 and 71% yield, respectively.     

Furopyridines. VI. Preparation and reactions of 2- and 3-substituted furo[2,3-b]pyridines

This paper describes the synthesis and chemical properties of some 2- and 3-substituted furo[2,3-b]pyridines. Reaction of ethyl 2-chloronicotinate 1 with sodium ethoxycarbonylmethoxide or 1-ethoxycarbonyl-1-ethoxide gave β-keto ester 2 or ketone 5 , respectively. Ketonic hydrolysis of 2 afforded ketone 3, from which furo[2,3-b]pyridine 4 was obtained by the method of Sliwa. While, 2-methyl derivative 7 was prepared from 5 by reduction, O-acetylation and the subsequent pyrolysis. Reaction of ketone 3 with methyllithium gave tertiary alcohol 8 which was O-acetylated and pyrolyzed to give 3-methyl derivative 9 . Formylation of 4 , via lithio intermediate, with DMF yielded 2-formyl derivative 10 , from which 7 , was obtained by Wolff-Kishner reduction. Dehydration of the oxime 11 of 10 gave 2-cyano derivative 12 , which was hydrolyzed to give 2-carboxylic acid 13 . Reaction of 3-bromo compound 14 with copper(I) cyanide gave 3-cyano derivative 15 . Alkaline hydrolysis of 15 afforded compound 16 and 17 , while acidic hydrolysis gave carboxamide 18 . Reduction of 15 with DIBAL-H afforded 3-formyl derivative 19 . Wolff-Kishner reduction of 19 gave no reduction product 9 but hydrazone 20 . Reduction of tosylhydrazone 21 with sodium borohydride in methanol afforded 3-methoxymethylfuro[2,3-b]pyridine 22 .     

A convenient synthesis of 2-amino-4H-1,3,4-oxadiazino[5,6-b]-quinoxaline derivatives

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with a 2-fold molar amount of ethyl chloroglyoxalate gave ethyl 8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline-2-carboxylate 6 , whose reaction with hydrazine hydrate afforded the C₂-hydrazinocarbonyl derivative 7 . The reaction of compound 7 with nitrous acid provided the C₂-acylazide derivative 8 , which was converted into the C₂-amino 9 , C₂-carbamate 11a-c, 12a,b , and C₂-ureido 13a-c, 14 derivatives. The mass spectral fragmentation patterns were examined for compounds 10–14 , wherein the molecular ion peak did not appear in the mass spectra of compounds 10c, 11a-c, 12a,b, 13c , and 14.     

Synthesis of vinca alakaloids and realated compounds 98. Oxidation with dimethyldioxirane of compounds containing the aspidospermane and quebrachamine ring system. A simple synthesis of (7S,20S)‐(+)‐rhazidigenine and (2R,7S,20S)‐(+)‐rhazidine

The oxidation of (‐)‐tabersonine ( 1 ) with dimethyldioxirane (DMD) in neutral and acidic medium gave 16‐hydroxytabersonine‐N‐oxide ( 3 ) and the didehydrovincamine isomers 4 and 5 , respectively. (+)‐14,15‐Didehydro‐quebrachamine ( 7 ) furnished the hydroxyindolenine 9 , and the pentacyclic derivative 11 . (+)‐Quebrachamine ( 8 ) and DMD in neutral medium gave (7S,20S)‐(+)‐rhazidigenine ( 12 ) which was converted to (2R,7S,20S)‐(+)‐rhazidine ( 13b ) with hydrochloric acid.     

Chemical conversion of uridine to 8,5′-O-cyclo-3-deazaguanosine

Treatment of 1-(2,3-O-isopropy lidene-β-D-ribofuranosyl)-2-oxo-4-imidazoline-4-carboxylic acid methyl ester with formaldehyde gave the 5-hydroxymethyl derivative which, after aeetylalion, gave the 5-eyanomelhyl derivative by treatment with tetra-n-butylammonium cyanide. The 2,5′-O-cyclo derivative of the 5-cyanomethylimidazole-4-carboxylate was converted to the title compound by treatment with ammonia. The present sequence of reactions furnished the chemical conversion of uridine to a 3-deazaguanosine via the imidazole nucleoside as the intermediate.     

Synthesis of novel quinoxalines by ring transformation of 3-quinoxalinyl-l,5-benzodiazepine

Ring transformation of the 3-quinoxalinyl-l,5-benzodiazepine ( 2 ) gave 3-(benzimidazol-2-ylmethylene)-2-oxo-l,2,3,4-tetrahydroquinoxaline hydrochloride ( 4a ), whose treatment with 5% sodium hydroxide provided the free base 5a , while refluxing of the 3′-chloro-l-formyl derivative 3 in acetic acid and in 10% hydrochloric acid/acetic acid afforded 3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,2-dihydro-1-formyl-2-oxo-3H-1,5-benzodiazepine hydrochloride ( 7 ) and 3-methyl-2-oxo-l,2-dihydroquinoxaline ( 6 ), respectively. Compounds 4a and 5a were converted into 3-(α-hydroxyiminobenzimidazol-2-ylmethyl)-2-oxo-l,2-dihydroquinoxaline ( 8 ) and 3-(benzimidazol-2-ylcarbonyl)-2-oxo-l,2-dihydroquinoxaline ( 10 ), respectively, which were further transformed into 3-(benzimidazol-2-yl)isoxazolo[4,5-b]quinoxaline ( 9 ) and 12 -(benzimidazol-2-yl)-6H-quinoxalino[2,3-b I 1,5]benzodiazepine ( 11 ), respectively.     

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.     

Synthèse de l'évernine

Synthesis of Evernin Two syntheses of the depside evernin 6 are described. Condensation of methyl acetoacetate and methyl crotonate followed by aromatization and reduction with Raney-Ni led to methyl orsellinate (3) . The condensation of everninic acid (4) , obtained by partial methylation of 3 and saponification of the methyl ester, with methyl 2, 4-dihydroxy-3, 6-dimethylbenzoate (methyl β-orcin carboxylate) (5) in presence of cyclohexylcarbodiimide gave evernin ( 6 ). In a second syntheis methyl dihydroorsellinate (1) was regiospecifically converted into its 4-methyl enol ether and aromatized via the benzene selenenyl derivative to yield methyl evernate (7) . Benzylation followed by saponification gave the free acid 8 . Methyl β-orcin carboxylate (5) was synthesized in an analogous way from methyl 3,6-dimethyl-2,4-dioxocyclohexanecarboxylate. Condensation of 8 with the methyl ester 5 by treatment with trifluoroacetic anhydride in toluene yielded 9 , which could be converted into evernin ( 6 ) by hydrogenolysis of the benzyl ether.     

Furopyridines. V. A simple synthesis of furo[2,3-c]pyridine and its 2-and 3-methyl derivatives

A simple synthesis of furo[2,3-c]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxyisonicotinate ( 2 ) is described. The hydroxy ester 2 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 3a or 3b . Cyclization of compound 3a afforded ethyl 3-hydroxyfuro [2,3-c]pyridine-2-carboxylate ( 4 ) which was hydrolyzed and decarboxylated to give furo[2,3-c]pyridin-3(2H)-one ( 5a ). Cyclization of 3b gave the 2-methyl derivative 5b . Reduction of 5a and 5b with sodium borohydride yielded the corresponding hydroxy derivative 6a and 6b , respectively, which were dehydrated with phosphoric acid to give furo[2,3-c]pyridine ( 7a ) and its 2-methyl derivative 7b . 4-Acetylpyridin-3-ol ( 8 ) was O-alkylated with ethyl bromoacetate to give ethyl 2-(4-acetyl-3-pyridyloxy) acetate ( 9 ). Saponification of compound 9 , and the subsequent intramolecular Perkin reaction gave 3-methylfuro[2,3-c]pyridine ( 10 ). Cyclization of 9 with sodium ethoxide gave 3-methylfuro[2,3-c]pyridine-2-carboxylic acid, which in turn was decarboxylated to give compound 10 .