Chinolizine und Indolizine,XIV Umlagerungen von Heterocyclen,X Ringumwandlungen von 1-Acyl-2-hydroxy-4-chinolizinonen

By heating with ammonia or aniline 1-acyl-2-hydroxy-4-quinolizinones (1 a–e) are transformed to 4-hydroxy-5-(2-pyridyl)-2-pyridones (3 a–f), with4 a–d as minor sideproducts. The structure of the rearranged compound3 f was established by an independent synthesis starting with6 and7. The reaction of1 a, d with ethyl β-aminocrotonate (β-ACE) yields pyrono-quinolizinones8 a, b and pyronopyridones9 a, b as byproducts; the latter are obtained in high yield by reaction of3 a, b with β-ACE. The ringtransformation reaction cannot be extended to 1-methoxycarbonyl-quinolizinones, such as10; in this case 2-amino-4-quinolizinone11 is the main product of the reaction with ammonia.     

Pyrindinchemie, 1. Mitt.: Über die Synthese des 3-Hydroxy-1-methyl-4-oxo-1,4-dihydropyrrolo[2′,3′:3,4]cyclopenta[1,2—b]pyridin-2-carbonsäureäthylesters (Ein Vertreter eines neuen heterocyclischen Ringsystems)

4 is synthesized starting from1 over the chloride3 and then cyclized byDieckmann condensation to the title compound8. The structure of4 is confirmed by chemical proof. By means of¹H-NMR-spectral analysis it could be determined that1 exists as internal salt (2a) of ethyl 5-hydroxy-7-oxo-7H-1-pyrindin-6-carboxylate.     

1,2,4,5-Tetrahydro-3,2,4-benzothiadiazepin-3,3-dioxide und 1,2,3,5,6,7-Hexahydro-4,3,5-benzothiadiazonin-4,4-dioxide

1.2.4.5-Tetrahydro-3.2.4-benzothiadiazepine-3.3-dioxide (3a) (1 a) was prepared both by treating o-xylylene dibromide with sulfamide and by reaction of o-xylylene diamine (1 c) with SO₂Cl₂ or sulfamide. 4-Chloro-o-xylylene-diamine (2 c) and 1.2-bis(β-aminoethyl)benzene (8), resp., yield 7-chloro-1.2.4.5-tetrahydro-3.2.4-benzothiadiazepine-3.3-dioxide (4 a) and 1.2.3.5.6.7-hexahydro-4.3.5-benzothiadiazonine-4.4-dioxide (9), resp., on treatment with sulfamide. 3 a, 4 a, and9 yield the corresponding N,N′-dialkyl derivatives on treatment of their Na-salts with alkyl halides. Several dialkyl derivatives of3 a were prepared also by reaction of1 a with N,N′-dialkyl sulfamides.     

Synthesis of 2,5-bis(piperidinomethyl)piperidine and 1,5-bis(aminomethyl)-3-azabicyclo[3.2.1]octanones

Schmidt reaction of mono- and bis-Mannich bases1 and2 c derived from cyclopentanone gave the corresponding basically substituted 2-piperidones3 and4, respectively. Reduction of the latter afforded5. DoubleMannich reaction of2 a–c with primary amines gave 3-azabicyclo[3.2.1]octanone derivatives6 a–e and7. The transamination of2 a was investigated.     

Synthese von (5,10)-(7,8)-Bisepoxiden aus α- und β-4-Phenyl-1,2,4-triazolin-3,5-dion-Addukten von Vitamin D3 und Röntgenstrukturanalyse eines der Benzoylderivate

Oxidation of the α- and β-4-phenyl-1,2,4-triazolin-3,5-dione adducts of vitamin D₃ (2 and1) withMCPBA yields two diastereomeric mixtures of the (5,10)-(7,8)-dioxiranes3 a,3 b,3 c and4 a,4 b respectively. The corresponding benzoates5 a,5 b,6 a and6 b were prepared and the X-ray crystal structure of5 b was determined. This analysis proved5 b to be the (5R, 1 OS)-(7R, 8R)-dioxirane of the β-resp. (6S)-4-phenyl-1,2,4-triazolin-3,5-dione adduct1 of vitamin D₃.     

Über die Bromierung von substituierten 3,4-Dihydro- und 6-Hydroxy- bzw. 6-Äthoxy-3,4,5,6-tetrahydro-2(1H)-pyrimidinonen

Bromination of 1-benzyl-4-methyl-3.4-dihydro-2(1H)-pyrimidinone (9 a) with 1 mole Br₂ in CHCl₃ yields 1-benzyl-5-bromo-6-hydroxy-4-methyltetrahydro-2(1H)-pyrimidinone,12 a, or the 6-ethoxypyrimidinone13 a, according to whether H₂O orEtOH is used in working up. With 2 moles Br₂,9 a analogously affords the 5.5-dibromopyrimidinnes14 a or15 a. Bromination of the 6-hydroxypyrimidinone10 a yields the same products,12 a and13 a, or14 a and15 a respectively, while the 4-phenyl-pyrimidinones9 b and11 b yield the corresponding 5-bromo-and 5.5-dibromopyrimidinones13 b and15 b. The structures of the compounds12 a-15 b are confirmed by their NMR data and chemical properties: the oxopyrimidinylmethylureas16 a and17 a are formed by the action of methylurea on12 a and13 a, or on14 a and15 a respectively; with hexamethylenetetramine,12 a reacts to give the 5.6-dihydroxypyrimidinone18 a, while13 b is transformed to the 4-phenylpyrimidinone19 b. 13 b was also synthesized from α-bromocinnamaldehyde. The mechanism of bromination is discussed.     

Synthese von Pyridonen aus Enaminen und Cyanessigsäuren

Reaction of enamines1 a–e with cyanoacetic acids2 a,b in acetic anhydride at about 100°C yields the α-cyanoacetylated enamines3 a–g. Under the same conditions methyl 4-cyano-2-(2-pyridyl)-acetoacetate3 h is obtained from methyl 2-pyridylacetate and2 a. Compounds3 are cyclized in hydrochloric acid yielding the 4-hydroxy-2-pyridones4; on the other hand in ethanolic sodium ethoxide solution the 2-amino-4-pyridones are obtained. The esters5 a,b andd are saponified to give the acids7 a–c which decarboxylate at 250°C to8 a–c.     

Formation of highly caged compounds through Diels—Alder cycloaddition of 3-bromo-7-(bromomethyl)tetracyclo[5.3.1.02,6.04,8]undeca-10(12)-ene-9,11-dione with itself and with cyclopentadiene

Diels–Alder reaction of the cage compound2 with itself, leading to the highly caged compound3, as well as with cyclopentadiene, leading to compounds 4 and5, is described.     

Pyrindinchemie, 3. Mitt.: Über die Synthese des 3-Hydroxy-1-methyl-4-oxo-1,4-dihydro-pyrrolo[2′,3′:3,4]cyclopenta[1,2-c]pyridin-2-carbonsäureäthylesters. Ein Vertreter eines neuen heterocyclischen Ringsystems

1 is synthesized by reaction of cinchomeronic anhydride with ethyl acetoacetate and triethylamine in acetic anhydride. Its structure is discussed by means of IR- and¹H-NMR-spectrum. By reaction of1 with SOCl₂ 3 is formed, which is converted with ethyl sarcosinate to4. The structure of4 is confirmed by chemical proof.Dieckmann cyclisation of4 gives the title compound7.     

Über substituierte 2-Amino-3,4,5,6-tetrahydro-1H-pyrimidinium-und 1,2,3,4,6,7,8,9-Octahydropyrimido-[1,2—a]pyrimidiniumchloride

Crotonaldehyde resp. cinnamaldehyde react with guanidiniumchloride to give 2-amino-6-guanidinio-4-methyl-3.4.5.6-tetrahydro-1H-pyrimidiniumdichloride (4 a) resp. 6-hydroxy-4-phenylpyrimidiniumchloride3 b and the 4.6-dihydroxy-2.8-dimethyl (resp. 2.8-diphenyl)octahydropyrimido[1.2?a]pyrimidiniumchlorides6 a and6 b, resp. Action of 2.4-(or 2.6-)xylenol on4 a resp.3 b yields 2-amino-6-[2(or 4)-hydroxy-3.5-dimethylphenyl]-4-methyl-(resp. 4-phenyl)-3.4.5.6-tetrahydro-1H-pyrimidiniumchlorides (8 a resp.8 b or9 a resp.9 b), which are transformed to the zwitterionic compounds10 a–11 b by aqu. NaOH.6 a reacts with 2.4-xylenol to give the triazaoxabenzanthraceniumchlorid12 a·HCl (prove for the structure given for6 a). The chemical properties and the NMR-, UV-, mass- and IR-spectra of the compounds are discussed.     

Zur Chemie der 5-Alkylamino-4H-thiopyrano[2,3-b]pyridin-4-one

4-Alkylaminopyridinethiones · HCl (1 · HCl) react with bis-trichlorethylmalonate (3) predominantly to 5-alkylamino-4H-thiopyrano [2,3-b]pyridine-4-ones (6). With alcohols in the presence of acids at 25°C6 undergoes an alcoholysis to the corresponding alkyl-3-(2-thioxo-3-pyridyl)propionates (9). On heating in dilute alkali6 is hydrolysed via 4-alkylamino-2-thioxopyridyl-propylketones (11) to the tautomers, 4-hydroxy-2-thioxopyridylpropylketone (12 A) and 2-thioxo-3-(1-hydroxybutenyl)-4-piperidon (12 B), resp. On refluxing with alkali the ethyl-pyridylpropionate9 a is cyclisized to the 1-alkyl-1,6-naphthyridine-2(1H)-one (4 a), but boiling in ethanolic acid hydrolyses9 a via the pyridylpropionic acid10 to 4-alkyl-aminopyridylpropylketone (11 a). The latter can be transformed via the tautomers12 A,B and 2-methylthio-3-pyridylpropylketone (13) to the 4-hydroxy-3-butyrylpyridone (14 A) and its tautomer, 3-(1-hydroxy-butenyl)-piperidine-2,4-diones (14 B) resp. The structure of14 A,B is established by reaction of 4-isopropylamino-2(1H)-pyridone (2) with butanoylchloride to the 4-isopropylamino-3-butyrypyridone (15) and hydrolysis of15 to the tautomers14 A,B.     

7,14-Cyclo-dihydro-codeinon

(5α,9α,13β,14β)-4,5-Epoxy-9-hydroxy-3-methoxy-17-methyl-hasubanan-6-one-hydrochloride (6 a·HCl) reacts with dimethyl sulfate to give the sulfate7 which yields the cyclopropane derivate10 on treatment with aqueous NaOH. The structure of 7,14-cyclo-dihydrocodeinone (10) was established on the basis of¹H- and¹³C-NMR-spectroscopy.     

Über die Synthese von 1,3-Dihydro-3-(2-dimethylaminoäthyl)-1-(3-thienyl)-benzimidazol-2-onen

The synthesis of 1-(3-thienyl)-benzimidazol-2-ones (3 a and4), described in an earlier paper¹, has been further investigated. The Na-salt of3 a is converted to a benzimidazolone substituted in position 3 (3 b). Dehydrogenation of the thiophene nucleus of3 a with chloranil yields5 a, which undergoes substitution in position 3 with Cl(CH₂)₂N(CH₃)₂ to give5 b. Monochlorination of5 a yields5 c, the structure of which is confirmed by¹H-NMR-spectroscopy.5 d is obtained by reaction of the Na-salt of5 c with Cl(CH₂)₂N(CH₃)₂.      

Über substituierte 1,6-Dihydro-1,3,5-triazin-2,4-diamine, 1′,5′,6′,7′-Tetrahydrospiro[cyclopentan-1,4′-cyclopentapyrimidin]-2′(3′ H)-imine und das 6-Phenyl-2,4-pyrimidindiamin

Guanidine reacts with cyclohexanone, cycloheptanone, acetone and 3-pentanone, resp., in a molar ratio 2∶1 to give the 1,3,5-triazaspiro[5.5]undeca-and [5.6]dodeca-1,3-dien-2,4-diamines3 a and3 b resp. and the 6,6-dimethylresp. diethyl-1,6-dihydro-1,3,5-triazin-2,4-diamines3 d and3 e resp. On the contrary, action of guanidine on cyclopentanone yields not3 c, but the 1′,5′,7′-tetrahydrospiro[cyclopentane-1,4′-cyclopentapyrimidine]-2′(3′H)-imines2 c, 5 c and6 c resp., which are 1∶2- and 1∶3-condensates. Phenylacetone is transformed by guanidine (1∶2) to give 6-phenyl-2,4-pyrimidindiamine (8 f). The structure of the compounds cited is proved by NMR-, IR-, and (partially) mass spectra. The different courses of the formation of3 a, b, d, e, 2 c, 5 c and6 c resp. and8 f are also discussed. The structural formulae of some additional bases, which were synthesized from guanidine and cyclopentanone, 3-pentanone and phenylacetone resp. could not be established.     

The first example of asymmetric Michael reaction catalyzed by chiral alkali metal alkoxides

Some chiral sodium alkoxides can be used as catalysts in the asymmetric Michael reaction as exemplified by the 1,4-addition of an achiral Ni^II complex of the Schiff base derived from glycine andN-(2-pyridylcarbonyl)-o-aminobenzophenone (1) to methyl methacrylate (2) or methyl acrylate (14). The products of the reaction of1 with2,viz., the corresponding diastereomeric complexes of 4-methylglutamic acid, are formed in dissimilar amounts (de 26–85%); theee value for the major diastereomer (2S,4R)-3a is 28%. After recrystallization, the enantiomeric purity of complex3a increases toee>85%. Acidcatalyzed hydrolysis of the enantiomerically enriched complex3a affords (2S,4R)-4-methylglutamic acid (ee>85%). The complex of glutamic acid15 resulting from the reaction of1 with14 is formed with anee of 45%. After recrystallization, the enantiomeric purities of complex15 and glutamic acid increase toee>90%.     

Stereochemie von α,ω-Diphenyl-alkan-α,ω-diolen

Reduction (both catalytically and with complex hydrides) of the diphenyl diketones1 (a, b, c andd withn=0, 2, 3 and 4) was investigated mainly with regard to the diastereomeric ratio of the diols2. For2 a and2 b exact results were obtained by NMR spectroscopy (without or with shift reagents) of the diol mixture (2 a) or after stereoselective cyclization to the cyclic ethers (3 b). AlsoGC andLLC were employed for the analysis of2 a (GC of the trimethylsilyl derivatives) and for the ethers3, resp. (GC for3 a and3 d;LLC for3 b and3 c). The reduction of1 a, 1 b (and in part1 c) proceeds with high stereoselectivity; themeso-diol preponderates in the case of2 a, therac.-diol for2 b and2 c; with increasingn the diastereomeric ratio approaches the statistical ratio of 1∶1. Preparations of the stereoisomeric diols (2 b, c andd via acetylenic precursors) and of the cyclic diphenyl ethers (by stereoselective cyclization and/or chromatographic separation;3 c and3 d for the first time) as well as the determination of their configurations are described. The latter was achieved by NMR and for the ethers3 also by hydrogenation of the corresponding heteroaromatics.     

Autoassembly of cage structures

Thed,l-(1a) andmeso-forms (1b) of α,α'-dihydroxy-α,α'-dimethyladipic acid, dilactone (3), diiminodilactone (4), and lactonolactam (5) were obtained by the reaction of acetonylacetone with KCN and HCl. The transformations of1 to the esters2, dilactone3 to la, and diiminodilactone4 to dilactone3 were studied. It was shown that3 can be readily obtained from la by thermolysis, acid catalysis, and DCC action as well as by acid catalyzed cyclization of2a, while dilactone3 can be obtained from1b and2b in negligible yield only under drastic conditions, obviously, due to the partial epimirization of themeso-forms. The mild thermolysis of1b leads totrans-lactonoacid (6), from which the ester7 has been obtained. The effective acid catalyzed cyclization of amides8 and9 to3, lactamoamide12 to5, and amide14 to model lactone13 was found. The NMR spectra of the products were studied, and a¹H NMR test was suggested for identification ofd,l- andmeso-forms1 and2. The stereochemistry of monolactones6, 7, 9, 10a, 10b, 11, and dilactone3 was established. The differences in the chemical behavior of α,α'-dihydroxyglutaric and adipic acids were explained by the significant reduction of the non-bonded interactions of the substituents in the corresponding monolactones during the transfer from 1,3- to 1,4-substituted systems.     

Strukturelle Abwandlungen an Nukleotiden,Nukleosiden und Nukleosidbasen mit β-Acylvinylphosphoniumsalzen

β-Acetylvinyl-triphenylphosphonium bromide1 reacts with CMP to form the 3,N⁴-etheno-derivative {[6-(5′-phosphoribofuranosyl)-2-methyl-5-oxo-imidazo [1.2-c]pyrimidin-3-yl]-methyl}triphenyl-phosphonium bromide (2). Guanine affords mainly the lin. condensation product [(6-methyl-9-oxo-imidazo[1.2-a]-purin-7-yl)-methyl]triphenylphosphonium bromide (3) and the angular tricyclic product [(6-methyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]-triphenylphosphonium bromide (4). For comparison we synthesized the angular condensed heterocycle5, (6.8-dimethyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]triphenylphosphonium bromide, by reaction of 1-methylguanine with1, and the corresponding linear derivative6 [(4.6-dimethyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methyl]-triphenylphosphoniumbromide from 3-methylguanine and1. AHofmann-type degradation of3 with the anion of diethyl malonate led to7, diethyl (6-methyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methylmalonate, a compound whose structure resembles some Y-bases in t-RNA.Wittig reaction of the silylated nucleoside derivative8 a {[2-methyl-5-oxo-6-(2′.3′.5′-tris-trimethylsilyl)-ribofuranosyl-imidazo[1.2-c]pyrimidin-3-yl]methyl}-triphenylphosphonium bromide, with C₆H₅CHO resulted in the 2-methyl-3(ω-styryl)-6[2′.3′.5′-tris-(trimethylsilyl)]ribofuranosyl-imidazo[1.2-c] pyrimidin-5-one (9).     

Über die Reaktionen von Guanidin bzw. Harnstoff mit Cyanhydrinen

Action of guanidine or urea on cyclohexanone-, cyclopentanone-, cycloheptanone-and acetonecyanohydrine3 a?3 d generates very different products: 3 a reacts with guanidine inDMF to yield 1,3-diazaspiro[4.5]decane-2,4-diimine (5 a). Heating the components without solvent affords 7,14-diazadispiro[5.1.5.2]pentadecan-15-one(7)^15–17, the guanidine not participating in the reaction; similarly3 b is transformed by guanidine to a pentacyclic dispirocompound (possible formulae19 and20), whereas3 d reacts to give 3,3,5,5-tetramethylpiperazine-2,6-dione(21)¹⁹. In 3-pentanone guanidine-cyanide condensates itself to give 2,4-diamino-triazine (22)^{21, 22}. Action of urea on3 a?3 d yields the 4-imino-1,3-diazaspiroalkan-2-ones6 a?6 c and the 4-imino-5,5-dimethylimidazolidin-2-one6 d ^6–8 resp. If the reaction of urea and3 d is carried out inDMF, however, 5,5-dimethyl-4-ureido-3-imidazolin-2-one (28) (or the tautomeric carbamoyliminoimidazolidinone27) is produced. The structures of the compounds prepared are proved by NMR-, IR- and mass spectra.     

Two efficient methods for the synthesis of novel indole-based chalcone derivatives

Two powerful methods for the synthesis of indole-based chalcone derivatives, namely (E)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl)-3-aryl(hetaryl)prop-2-en-1-ones (3a–l), are described, involving the ultrasound-assisted or solvent-free Claisen–Schmidt condensation reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl)indole (1) and various aromatic aldehydes (2a–l). The ultrasound-assisted Claisen–Schmidt condensation reaction was carried out using 1,4-dioxane as solvent and KOH as base at room temperature to give the corresponding products (3a–l) in yields ranging from 75 to 88 %. Alternatively, the Claisen–Schmidt condensation reaction could also be conducted under solvent-free conditions to obtain the products (3a–l) in comparable yields. The two procedures offer easy access to indole-based chalcone derivatives in short reaction times and good yields under mild conditions. Particularly, the advantageous aspect of the solvent-free method could avoid the use of environmentally hazardous and toxic solvents, and also reduced costs. The structures of all the newly synthesized indole-based chalcones 3a–l were confirmed by spectral data and elemental analyses.