Etherspaltung an Pyridinen mit ungewöhnlichem Halogenierungsverlauf zu isomeren Diamino-pyridon-carbonitrilen und ihre Verwendung als Kupplungskomponenten

Ether cleavage of the two isomeric diamino-methoxy-pyridine-carbonitriles1 and2 leads to the isomeric 4,6-diamino-2(1H)-pyridone-3-carbonitrile (3 a) and 2,4-diamino-6(1H)-pyridone-3-carbonitrile (4 a), resp. Dependent on the reaction conditions in glacial acetic acid containing hydrogen bromide or potassium iodide the halogenated pyridones (3 b, 4 b–c) can be obtained.pK _s -values and UV-spectra of the pyridones are discussed.3 a and4 a can be used as azo-coupling components, yielding the azo-dyes5 and6. Similarly 4-amino-6-hydroxy-2(1H)-pyridones (7 a–b) are coupled with several aryl- and heteroaryl-diazoniumsalts to form the azo-dyes8 a–g.

Herrn emer. o. Univ.-Prof. Dr.Otto Hromatka zum 80. Geburtstag gewidemet.     

Synthesis and reactions of 4-Hydroxy-2(1H)-pyridones with thienyl and pyridyl substituents in position 6 starting with azomethines and malonates

The reaction of 4 with substituted diethyl malonates 5a , or “magic malonates” (bis-2,4,6-trichlorophenylmalonates 5b ) leads to 4-hydroxy-2(1H)-pyridones 6. The azomethines 4 are prepared via the Strecker compounds 3 starting with methyl ketones 1 , anilines, and potassium cyanide. Chlorination of pyridones 6 with sulfuryl chloride leads to compounds 7 while nitration gives 9.     

A novel approach to the synthesis of 5-trifluoromethyl-3-substituted pyrazoles

The 3-cyano-4-trifluoromethyl-6-phenyl or substituted phenyl 2(1H) pyridones (1) on reaction with hydrazine hydrate, gave exclusively in 5-trifluoromethyl-3-substituted pyrazoles (3) through a novel method. A possible mechanistic pathway for change in the site of nucleophilic attack due to the CF₃ group in 2(1H) pyridones is described.     

Synthesis of 2H‐chromeno[4,3‐b]pyridine‐2,5(1H)‐diones and related heterocycles via the erlenmeyer‐ploechl reaction

1,2‐Dihydro‐5H‐[1]benzopyrano[4,3‐b]pyridine‐2,5‐diones 4a‐j were synthesized from 4‐alkylamino‐coumarin‐3‐carbaldehydes 1 and 5(4H)‐oxazolinones (azalactones) derived from N‐acetylglycine ( 2a ) and hippuric acid ( 2b ). The intermediates 3 ( 3j isolated only) underwent spontaneous recyclization via opening of the azalactone and successive formation of the fused 2‐pyridones 4 . Attempts to synthesize the selected 2H‐chromeno[3,4‐f]‐1,7‐naphthyridine 6 by Vilsmeier reaction of 4e failed. Instead, N‐deacetylation took place, followed by formylation of the amino group to the formamidine 7a . In addition, pyranopyridine 9a was obtained by condensation of the 3‐formyl‐2‐pyridone 8 with the azalactone derived from 2a and acetic anhydride.     

Reaction of malonates with camphoranile synthesis of 4‐hydroxy‐2‐pyridones attached to the bornane ring system

The reaction of camphoraniles 3a,b with “magic malonates” (bis‐2,4,6‐trichlorophenylmalonates) 4a,b leads to 4‐hydroxy‐2(1H)‐pyridones attached to bornane ring system 6a‐c in good yields. Less satisfactory yields were obtained with the diethyl malonate 5b . The reaction of an excess of diethyl malonate 5 itself with 3b yields the pyrono derivative 7 , which can readily be degraded via the acetyl derivative 8 to the basic structure 9 .     

Reactions of α,β-unsaturated ketones with cyanoacetamide

3-Aryl-1-phenyl-2-propen-1-ones Ia-f and aroylphenylacetylenes Va-d reacted under reflux for 3 hours with cyanoacetamide in the presence of sodium ethoxide to give the corresponding 4-aryl-3-cyano-6-phenyl-2-(1H)pyridones VI. However, when ketones Ia-e were refluxed with cyanoacetamide for one hour in the presence of sodium ethoxide or piperidine, they gave the corresponding 4-aryl-3-cyano-3,4-dihydro-6-phenyl-2-(1H)pyridones IIIa-e, which upon heating with selenium gave the corresponding 2-pyridones VI. The structures of the products are based on chemical and spectroscopic evidence.     

A comparative study of conventional conditions versus microwave irradiation for the preparation of novel 1,2‐dihydro‐2‐imino‐7‐methyl‐1,6(6H)‐naphthyridin‐5‐ones

The synthesis of novel 1,6‐naphthyridines 6 with potential activity against tuberculosis is described using the reaction sequence 2←4←6. Depending on the ring N‐substitution of the 4‐alkylamino‐6‐methyl‐2(1H)‐pyridones 1 and 2 the electrophilic attack of the Vilsmeier reagent gives rise to the formation of the exocyclic N‐formyl derivatives 3 from 1 and the corresponding 3‐carbaldehydes 4 from 2. 1,2‐Dihydro‐2‐imino‐7‐methyl‐1,6(6H)‐naphthyridin‐5‐ones 6a‐j are prepared by the Knoevenagel reaction of 4 with CH‐acidic nitriles 5. These reactions are carried out using a comparative study of conventional conditions (room temperature or reflux) versus microwave irradiation.     

Condensation Products of 1-Aryl-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones with Hydrazine, Phenylhydrazine, and Hydroxylamine

We have studied condensation of 1-(4-bromophenyl- and 2,5-dimethylphenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones with hydrazine, phenylhydrazine, and hydroxylamine, as a result of which we obtained nucleophilic substitution and intramolecular cyclization products: 5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazole[4,3-c]pyridin-3-ones, 5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-6,7-dihydroisoxazole[4,3-c]pyridin-3(5H)-ones. We used computer modeling of the molecules of the studied compounds to obtain additional information on the structural features of the reaction products.     

Long range 13C?1H coupling constants IV—methoxy-, amino- and hydroxypyridines

One bond and long range ¹³C? ¹H coupling constants for some methoxy-, amino- and hydroxypyridines are described. An unambiguous assignment of carbon-13 resonances is carried out based on the analysis of the fine splitting caused by long range couplings. J values for compounds other than 2- and 4-hydroxy-pyridines are explainable in terms of the values previouly obtained for cyano- and methylpyridines. The hydroxypyridine-pyridone tautomerism affects ²J(H_α), i.e. ²J associated with the α proton. This effect can be used to differentiate pyridones from hydroxypyridines.     

Synthesis of N-substituted 3-hydroxy-2-methyl-4-pyridones and -pyridonimines

Carbohydrates with 1,4 glycosidic bonds like maltose, lactose, dextrin or starch react with primary amines as well as amino acids or proteins to give i.e. 3-hydroxy-2-methyl-4-pyridones 5 and 3-hydroxy-2-methyl-4-pyridonimines 7. A generally applicable synthesis of compounds of this type is described. The pyridones 5 and pyridonimines 7 are strongly complexing agents. Molybdenum-derivatives, for instance, are suitable as fairly stable oxidation catalysts.     

Facile synthesis of 6-organyl-4-(trifluoromethyl)pyridin-2(1H)-ones and their polyfluoroalkyl-containing analogs

The three-component cyclization of 3-polyfluoroalkyl-3-oxopropanoates and methyl ketones with ammonium acetate affords 6-organyl-4-(polyfluoroalkyl)pyridin-2(1H)-ones (organyl is alkyl, aryl, or hetaryl). The synthesized pyridones were evaluated for antifungal, antibacterial, and analgesic activity.

     

Photocyclisierungen von 1, 1'-Polymethylen-di-2-pyridonen. 46. Mitteilung über Photoreaktionen

Photocyclization of 1, 1′-Polymethylene-di-2-pyridones . Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material. The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10 . This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1–4 .     

Pyridinethiones. XI. Diastereoselective aldol condensations with 2(1H)-pyridones, 2(1H)-pyridinethiones,and the crystal structure of 3-(1-hydroxy-2-methyl-3-oxo-3-(4-chlorophenyl)propyl-1-isoprpyl-2(1H)-pyridinethione

Aldol condensation of 3-formyl-2(1H)-pyridinethiones and the corresponding pyridones with ketones such as acetophenones in aqueous base yields 3-hydroxy-1-propanones in high yields. Reaction with propiophenone showed this reaction to be highly diastereoselective as only the erythro-isomer is formed at room temperature. This assignment was based on an X-ray crystallographic investigation of the compound given in the title. Aldol condensations of a number of related 3-acetyl-2(1H)-pyridinethiones with benzaldehyde yielded the corresponding trans-vinyl ketones.     

Action of amines and carbonyl reagents on 3,5-diphenyl-4-pyrone and its thio analogue

Several N-substituted, 3,5-diphenyl-4-pyridones and 4-thiopyridones were obtained by the action of amines on 3,5,-diphenyl-4-pyrone and its thio analogue. With hydrazine hydrate, the products were 1-amino-3,5-diphenyl-4-pyridone and the corresponding thione. The spectral characteristics ol these pyridones were studied.     

Efficient Synthesis of N‐Alkylated 4‐Pyridones by Copper‐Catalyzed Intermolecular Asymmetric Propargylic Amination

Copper‐catalyzed intermolecular asymmetric propargylic amination with 4‐hydroxypyridines has been realized for the first time. In the presence of Cu complex derived from Pybox ligand, the N‐propargylated 4‐pyridones were obtained under mild reaction conditions with up to 99 % yield and 95 % ee. The Pybox ligand bearing a 4‐F‐phenyl substituent plays a key role for the high enantioselectivity. The products can be easily transformed to the core structure of quinolizidine alkaloids.     

Studies with enaminones: The reaction of enaminones with aminoheterocycles. A route to azolopyrimidines,azolopyridines and quinolines

The enaminones 1b,d,f react with 4‐phenyl‐3‐methyl‐5‐pyrazoleamine 3a to yield the pyrazole derivatives 4a‐c that cyclised readily on reflux in pyridine solution in presence of hydrochloric acid to yield the pyrazolo[1,5‐a]pyrimidines 5a‐c. Similarly 3(5)‐amino‐1H‐triazole (3b) reacted with 1b,d,f to yield the triazolo[1,5‐a]pyrimidines 5d‐f. In contrast attempted condensation of the 5‐tetrazoloamine (3c) with 1a,d,e resulted in its trimerisation and only triaroylbenzene 8a,d,e was isolated. The reaction of 1a,b,d with anthranilonitrile 9a and the reaction of 1a‐c with the 2‐aminocyclohexene thiophene‐3‐nitrile 10a afforded the cis enaminones 11a‐c and 12a‐c. Similarly, reaction of 1a‐c with the methylanthranilate 9b and reaction of 1b,e with ethyl 2‐aminocyclohexene thiophene‐3‐carboxylate 10b afforded the cis enaminones 11d‐f and 12d,e respectively. Attempted cyclization of 11a‐c into quinoline failed. Successful cyclization of 11d into the quinolinone 13 could be affected, on heating for five minutes in a domestic microwave oven at full power. The reaction of 1a‐c,f with piperidine afforded the trans enaminones 14a‐d. Similarly, trans 14e was formed from the reaction of 1b with morpholine. The coupling reaction of 1b with excess of benzene diazonium chloride afforded the formazane 16. The enaminone 2 reacted with heterocyclic amines to yield the pyridones 17,18.     

Synthesis of Novel Fluorinated 11H‐Azaindolo[3,2‐c]isoquinolines

A series of novel fluorinated 11H‐azaindolo[3,2‐c]isoquinolines ( 7 ) have been synthesized starting from 2(1H)pyridones ( 1 ) via azaindoles ( 5 ). Initially, compound 1 was treated with POCl₃/DMF, and the resulting compound 2 was reacted with benzylamine to obtain compounds 3 that were subjected to cyclization after protecting the secondary amine to get azaindoles ( 5 ). Further, compounds 5 were subjected to cyclization as per Pictet–Spengler reaction condition. However, it was not successful. Subsequently, the azaindoles ( 5 ) were acetylated and then cyclized to give title compounds 7 . These compounds are new and well characterized by spectral data.     

Heterocondensed thiophenes and thiazoles by THORPE‐ZIEGLER cyclization

The syntheses of novel thieno‐pyridones, thiazolo‐pyridones, thiazolo‐pyridines and amino‐ and diamino‐dieno‐pyridines were described. Simultaneously, it was demonstrated that in these compounds and in the related 3‐aminothiophenes the replacement of the methylthio by the morpholino group is possible. The structures were characterized using ¹H‐, ¹³C‐NMR, IR and elemental analysis.     

A simple compound with an ­unexpectedly complex structure: 4‐pyridone 6/5‐hydrate

The crystal structure of the title compound, C₅H₅NO·H₂O, contains five independent mol­ecules of pyridone and six independent water mol­ecules. The space group is P2₁, but four of the pyridones and four waters correspond closely to P2₁/n. The packing involves two layers; one consists of head‐to‐tail chains of pyridone mol­ecules 1–4 linked by N—H?O hydrogen bonds, and a second layer involves all the waters and the fifth pyridone. The layers are linked by hydrogen bonds from water to pyridone oxy­gen. The four water O atoms that accept only one classical hydrogen bond have their environment completed by C—H?O interactions.     

2-Alkyliden-1, 3-dithia-Heterocyclen aus 5-Sulfonyl-1, 2-dithiol-3-onen und Alkoholaten

Asymmetrically substituted 5-sulfonyl-1, 3-dithiafulvenes (9a–g), all of which have the same configuration (called α), are obtained by reaction of 4-chloro-5-sulfonyl-1, 2-dithiol-3-ones (3a–e) with sodium alkoxides. Side-products formed are 4-chloro-5-alkoxy-1, 2-dithiol-3-ones (5a and 5b), 3, 5-bis-alkylidene-1, 2, 4-trithiacyclopentanes (21 and 22), and (in some instances) minor amounts of compounds 33, 34, or 35. Reaction of 4-phenyl-5-methylsulfonyl-1, 2-dithiol-3-one with sodium methoxide results in the formation of 4-phenyl-5-methoxy-1, 2-dithiol-3-one (5c), the two cis-trans-isomers of 2, 4-bis-alkylidene-1, 3-dithiacyclobutane 24 and 25, and the 2, 5-bis-alkylidene-1, 2, 4, 5-tetrathiacyclohexane 26. Some conceivable reaction mechanisms are discussed, and proof is given for the structure of the major compounds. By treating 4-chloro-5-(2′-chloro-ethylthio)-1, 2-dithiol-3-one with sodium methoxide, the 2-alkylidene-1, 3-dithiolane 13 is obtained. The sulfonyl groups of the 1, 3-dithiafulvenes 9a–g described may be easily replaced by hydrogen or secondary amines, yielding compounds 14, 16 and 19, respectively. When dissolved in strong acids and reprecipitated, asymmetrically substituted 2-alkylidene-1, 3-dithia compounds may be converted into mixtures of all possible cis-trans-isomers thereof. Those isomers may be separated by fractional crystallization. Isomers 31 (called β) of 9 a--g, and 32 of 16a, b, are obtained accordingly.