Heterocyclische Spirocyclohexadienone, 2. Mitteilung

Heterocyclic Spirocyclohexadienones, II. Hofmann-Martius rearrangement of differently subsituted aniline derivatives is investigated and the synthesis of spirocyclohexadienones 5 and 25 is performed. In comparison with 9 , a N-aliphatic spiro compound, 5 and 25 give partially different reactions, the cause of which is discussed.     

Über Mannichbasen, 18. Mitt. Mannichreaktionen mit 1-Naphthol und sekundären Aminen

Mannich Bases, XVIII: Mannich Reactions with 1-Naphthol and Secondary Amines The aminomethylation of 1-naphthol with equimolar amounts of secondary amines yields 2-monosubstituted Mannich bases plus multicyclic aromatic compounds. With two moles each of formaldehyde and secondary amine the reaction predominantly yields 2,4-disubstituted aminoalkyl compounds. With iminium salt mainly p-substituted derivatives result in addition to some o-compound. Reaction mechanisms are discussed.     

Über Mannichbasen, 17. Mitt. Amino- und Amidoalkylierung von 2-Methylnaphthol bzw. 1-Naphthol

Mannich Bases, XVII: Amino- and Amidoalkylation of 2-Methylnaphthol and 1-Naphthol Under the usual conditions of aminoalkylation 2-methylnaphthol yields the Mannich bases or the methylene biscompound 4 depending on the basicity of the amine. With iminium salts, however, the hydrochlorides of the aminoalkyl derivatives are obtained. The amidoalkylation of 1-naphthol yields mono- or disubstituted products depending on the starting components.     

Antimycotic agents. 16. Halogenated cyanaminomethylenepiperidines and -piperazines

Antimycotic Agents, XVI: Halogenated (Cyanaminomethylene)piperidines and -piperazines The aminomethinylation of cyanamide ( 1 ) by means of s-triazine ( 2 ), carried out as three-component reaction in the presence of the secondary amines 5a – e , yields the cyanaminomethylene heterocycles 6a – e , which are to be classed as dehydro-N-Mannich bases. Compounds 6a and 6e in particular show antimycotic activity.     

Taxol and Related Taxanes. I. Taxanes of Taxus brevifolia Bark

The published procedures for the isolation of taxol from the Pacific yew (Taxus brevifolia) and other species of Taxus are cumbersome, and the yields of taxol are in the range of 0.0075–0.01%. This paper describes a simple and efficient procedure for the isolation of taxol and its major natural analogues from the bark of T. brevifolia consisting of a single chromatographic column (using silica gel, Florisil, or a reverse-phase C18-silica), followed by crystallization. Isolated yields of taxol from five pooled bark samples (blended from many different batches by the supplier) were in the range of 0.02–0.04%, and from bark collected from a more restricted locale, yields reached 0.06%. The procedure also yielded taxol analogues, such as 10-deacetylbaccatin III (0.02–0.04%), 10-deacetyltaxol-7-xyloside (0.06-0.1%), taxol-7-xyloside (0.005–0.01%), 10-deacetyltaxol (0.01–0.02%), 10-deacetylcephalomannine-7-xyloside (0.006–0.01%), and cephalomannine (0.005–0.007%). Of these, 10-deacetyltaxol-7-xyloside is the most abundant taxane in the Pacific yew bark.     

Über Mannichbasen, 19. Mitt. Mannich-Reaktionen mit 1-Naphthol und primären Aminen

Mannich Bases, XIX: Mannich Reactions with 1-Naphthol and Primary Amines Under conventional Mannich conditions primary amines rarely react with 1-naphthol to yield uniform products. The hydrochlorides partly give methylene linked derivatives. However, mono- and disubstituted Mannich bases are formed from azomethines of tert.-alkylamines. Hexahydrotriazines of simple primary amines yield mono-Mannich bases in good yields.     

Addition von β-Dicarbonylverbindungen an 2-Acetyl-p-benzochinon, 3. Mitt.1): Untersuchung der Umsetzung mit α-Hydroxymethylencycloalkanonen

Addition of β-Dicarbonyl Compounds to 2-Acetyl-p-benzoquinone, III¹⁾: The reaction of α-hydroxymethylenecyclopentanone 2 with acetylquinone 1 yields the spiro-compound 3 . α-Hydroxymethylenecyclohexanone 7 gives the dibenzopyran 8 and the spiro-compound 9 as by-product. Compounds 3, 8 , and 9 are labile, rearrangement to 6 and 11 is examined by NMR spectroscopy. Acetylation of 6 and 11 yields 5 and 12 . With hydrochloric acid the spiro-compounds 6, 11 are rearranged to 16 and 17 , respectively.     

Intramolekulare Aromatenalkylierungen, 16. Mitt. Synthese von 4-Methyl- und 2,4-Dimethyl-5-benzyl-5,6,7,8-tetrahydrochinolinen

Intramolecular Alkylations of Aromatic Compounds, XVI¹⁾: Syntheses of 4-Methyl- and 2,4-Dimethyl-5-benzyl-5,6,7,8-tetrahydroquinolines The carbinols 9, 10 are prepared conveniently from the methylquinolinones 6, 7 and the Grignard reagents 8 . Position 2 of the quinolinone 6 is substituted only in the reaction with 8c which yields small amounts of 13 as a by-product. The title compounds 11, 12 are obtained easily from 9, 10 by dehydration and hydrogenation in a one-pot reaction. They are not available from 6, 7 by Wittig or Wadsworth-Emmons-Horner carbonyl olefination.     

Mannich-Basen von Hydroxy-indolen, 2. Mitt

Mannich Bases of Hydroxyindoles, II¹ The 2-hydroxy-cyclohept[b]indolones 2a-c react with bis(dimethylamino)methane to yield the phenol Mannich bases 3a-c . The 1,3-benzoxazine derivatives 5a-c are synthesized from 2a,b,d and hexahydrotriethyl-1,3,5-triazine 4 . Reaction of 6-hydroxyindole 6 with triazine 4 yields benzoxazine 7 .     

Potentielle Antineoplastica, 2. Mitt. Synthese diarylsubstituierter 2- und 3-Hexene

Synthesis of Diaryl-2- and ?3-Hexenes Dehydration of 5 yields the 2-hexene derivative 7 as the main product and the isomeric trans-stilbene 6 in small amounts. 6 and 7 are converted to the mustard derivatives 9 and 11 via 8 and 10 , respectively. Compounds 5 – 11 , the by-product 12 and some intermediates, which occur in the synthesis of 5 , were investigated by UV, IR, ¹H-NMR and (partially) mass spectroscopy.     

Lactone, 3. Mitt.1) Zur Synthese von α-Aminoalkyl-γ-lactonen

Lactones, III: Synthesis of α-Aminoalkyl-β-lactones Alkylation of α-acetyl-β-lactones with α-aminoethyl and -propyl chlorides, followed by in situ cleavage of the acetyl group with an excess of ethanolate is a general synthetic route to α-aminoethyl- and α-aminopropyl-β-lactones. The yields are limited by side reactions.     

Beiträge zur Chemie des Pyridazinsystems, 29. Mitt. Synthese von 4-Arylpyrimido[4,5-d]pyridazinen aus (5-Amino-4-pyridazinyl)arylketonen

Pyridazine Chemistry XXIX: Synthesis of Pyrimido[4,5-d]pyridazines from (5-Amino-4-pyridazinyl)arylketones The pyrimido[4,5-d]pyridazin-2(1H)ones 4 and 6 are prepared in high yields from the amino ketones 1 or 5 . Procedures for the synthesis of the 4-arylpyrimido[4,5-d]pyridazines 8a, b, c via the imido esters 7a, b, c are described.     

Reaktionen von N-Alkoxycycliminiumsalzen, 9. Mitt. Nucleophile Substitutionsreaktionen an halogensubstituierten N-Methoxypyridiniumsalzen

Reactions of N-Alkoxycycliminium Salts, IX: Nucleophilic Substitutions of Halogeno-N-methoxypyridinium Salts The chloro-N-methoxypyridinium compounds 2a and 2c react with nucleophiles by substitution of the halogen atom. With pyridine derivatives, 2a yields the N-(2-pyridyl)pyridinium compounds 7 . With aromatic amines, the 1:1 products 16 or the 1:2 products 13 are formed, depending on the basicity of the amine. The 2-pyridoniminium or 6-amino-2-pyridoniminium structure of 16 or 13 follows from electronic and NMR spectra. In contrast, 2b undergoes base induced ring cleavage yielding the derivatives 21 and 22 of glutaconic dialdehyde with all-trans configuration.     

Protoberberine aus Reissert-Verbindungen, 2. Mitt.: Eine neue Synthese von 8-Methyldibenzo[a,g]chinolizidinen

Protoberberines from Reissert Compounds, II: A New Synthesis of 8-Methyldibenzo[a,g]quinolizidines The Reissert compounds 16 are benzylated by 2-bromomethylacetophenone dioxolane 14 to give the dihydroisoquinolines 5 . Treatment of 5 with KOH yields the 1-benzylisoquinolines 6 which spontaneously form the deoxygenated coralynes 4 in acidic solution. 4a and 18 are reduced by NaBH₄ to give the 8-methyl-trans-dibenzoquinolizidines 19 . The sequence 5 → 6 → 4 → 19 is a new efficient access to coralyne analogues and 8-substituted tetrahydroprotoberberines.- Bromination of 2-methylacetophenone does not lead to 2-bromomethylacetophenone but to the benzalbromide 9 or to the phenacylbromide 11 .     

Michael-Additionen mit Acylaminosäureestern, 7. Mitt. Trans-3-Aryl-2-hydroxymethyl-pyrrolidone-5 als Synthone für azaanaloge Pharmaka

Michael Additions with Acylamino Acid Esters, VII: Trans-3-Aryl-2-(hydroxymethyl)-5-pyrrolidones as Synthons for Aza-Analogous Drugs Cyclizing Michael addition of aryl acrylates to N-acetylamino acid esters yields stereoselectively new trans-3-aryl-5-oxopyrrolidine-2-carboxylic acids 4 . Esters of 4 are reduced with NaBH₄ to yield the trans-3-aryl-2-(hydroxymethyl)-5-pyrrolidones 6.     

Reaktionen mit Aziridinen (Aziranen), 25. Mitt. Amidoethylierung monosubstituierter Cyanessigester

Reactions with Aziridines (Aziranes), XXV:¹⁾ Amidoethylation of Monosubstituted Ethyl Cyanoacetates The amidoethyl derivatives of ethyl cyano(phenyl)acetate (1) , which are generated from N-(arylcarbamoyl)aziridines 2 in ethanolic ethanolate solution, cyclize to give high yields of 1-acyl-3-cyano-3-phenyl-2-pyrrolidones 4 . In the amidoethylation of ethyl 2-cyano-3-methyl-valerianate, however, the analogous N-acylpyrrolidone 7 is deacylated. Besides, a small amount of the primarily formed amidoethyl derivative 6 can be isolated by chromatography.     

Über Hexahydrotriazine, 4. Mitt. Addition N-monosubstituierter Amide an Azomethine

Hexahydrotriazines, IV: The Addition of Monosubstituted Amides to Azomethines The reaction of tert. alkylamines with formaldehyde yields Schiff bases. As an exception, tert. butylamine additionally gives hexahydro-s-triazine. The Schiff bases (or the tert. alkylamines and formaldehyde) can be used to aminomethylate N-monosubstituted formamides.     

Asymmetrische reduktive Aminierung von Cycloalkanonen, 11. Mitt.1,2): Synthese optisch aktiver 2-substituierter Cycloheptanamine

Asymmetric Reductive Amination of Cycloalkanones, XI^1,2): Synthesis of Optically Active 2-Substituted Cycloheptanamines Asymmetric synthesis of 2-substituted cycloheptanamines from racemic cycloheptanones by means of reductive amination in a three-step procedure is described. Condensation of the ketones 1 with the optically active auxiliary R-(+)- or S-(-)-1-phenylethylamine leads to the imine mixtures 2 which are hydrogenated over Raney nickel to give the optically active, diastereomerically pure secondary amines 3 . Hydrogenolysis with Pd/C yields the optically active cis-2-substituted cycloheptanamines 4 .     

Thion- und Dithioester, 39. Mitt. Zur Kondensation von 2-Morpholino-dithiooxalsäure-O-ester mit Malondinitril oder Cyanessigester

Thiono- and Dithioesters XXXIX: Condensation of 2-Morpholinodithiooxalic O-esters with Malonodinitrile or Cyanoacetate Condensation of 2-morpholino- or 2-piperidino-dithiooxalic O-esters 1 with malonodinitrile or cyanoacetate in the presence of potassium ethanolate leads to the formation of the potassium salts 3 , which are alkylated by alkyl iodides to give the thioenol ethers 4. With CH-acidic alkylating agents the thiophenes 6 are obtained directly. Compound 3a cyclises with hydroxylamine-O-sulfonic acid to form the isothiazole 8 ; compound 4 with hydrazine yields the pyrazoles 10. S-Alkylation of the thiophenes 6 at the thioamide sulfur followed by hydrazinolysis gives the thiopheno[2.3-d]pyridazines 13 and 14.     

Pyridazin-Analoga biologisch aktiver Verbindungen, 2. Mitt. 4-Aryl-pyridazino[4,5-d]pyridazine mit cyclischem Amin-Substituenten an C-1

Pyridazine Analogues of Biologically Active Compounds, II: 4-Arylpyridazino[4,5-d]pyridazines with Cyclic Amine Substituents at C-1 Preparation of the title compounds 6a-f by treatment of the 1-chloro-4-arylpyridazino[4,5-d]pyridazines 4a,b with various cyclic amines is described. The compounds 4a,b are obtained in satisfying yields by reaction of 4-arylpyridazino[4,5-d]pyridazin-1(2H)-ones with POCl₃ in the presence of pyridine. Some of the new compounds show diuretic activity.