Synthesis of Amrinone,A Cardiotonic Agent

A new synthesis of amrinone, 1, from 5-(4-pyridinyl) ?2(1H)-pyridone, 5 , is reported. Nitration at C-3 of the pyridone ring of 5 followed by reduction afforded amrinone. Another synthetic route was also carried out by bromination at C-3 of the pyridone ring of 5 followed by substitution with sodium azide to give the corresponding azide compounds 8 which was reduced to amrinone.     

Alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1h)-pyridone by active halomethylene compounds. The molecular structure of 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine

The alkylation of 3-cyano-4-methoxymethyl-6-methyl-2(1H)-pyridone by active halomethylene compounds has been studied. It was shown that the reaction of the pyridone with methyl- and ethylchloroacetates and phenacyl and p-bromophenacyl bromides occurs to give N- and O-structural isomers. Only the N-derivatives are separated from the reaction mixture when the pyridone is alkylated with iodoacetamide. It was found that 2-aroylmethyl-3-cyano-4-methoxymethyl-6-methylpyridines cyclize in the presence of KOH to 3-amino-2-aroyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridines. The molecular structure of 3-amino-2-benzoyl-4-methoxymethyl-6-methylfuro[2,3-b]pyridine has been studied using an X-ray analytical method.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1670–1682, November, 2004.     

Synthesis of methylpyridine derivatives. XXXV. Reaction of acetylpyridine with phosphoryl chloride to give alkynylpyridine

Reaction of 3-acetyl-4,6-dimethyl-2-(1H)pyridone ( 9a ) with phosphoryl chloride gives 2-chloro-3-ethynyl-4,6-dimethylpyridine ( 10a ). 3-Acetyl-4-hydroxy-6-methyl-2(1H)pyridone (14a) and 3-acetyl-2,6-dimethyl-4-(1H)-pyridone (21) undergoes similar reaction to give the corresponding ethynyl (16 and 23) and chlorovinyl (15 and 22) pyridines, respectively. The chlorination of 3-acetylpyridine and pyrimidine derivatives is further described.     

Structural effects on the solid-state photodimerization of 5-chloro and 5-nitro-2(1<Emphasis Type="Italic">H</Emphasis>)-pyridone in molecular compounds

Abstract  

The preparation and crystal structure of six molecular compounds consist of light-stable host molecules [(1-cyclohexyl-4-hydroxybenzene, 1,1,6,6-tetraphenyl-2,4-hexadiyne-1,6-diol, 4-((10-[4-(ethoxycarbonyl)phenoxy]decyl)oxy)benzene, 1,2,4,5-benzenetetracarboxylic acid, resorcinol] and light-sensitive guest molecules [(5-chloro-2(1H)-pyridone or 5-nitro-2(1H)-pyridone] are described in light of their failure to undergo [4 + 4] photodimerization in the solid-state upon irradiation with UV light. Unlike in many cases were pyridone and its derivatives undergo such dimerization in the solid-state due to the packing arrangement in the crystalline form in which the geometric requirement for photodimerization meet, the compounds described here failed to pack in ways to enable such photodimerization. The distances between the potentially reactive atoms ranged from 4.620 to 8.408 ? which are too long to react.     

Synthesis and Reactions of Some Novel Nicotinonitrile,Thiazolotriazole, and Imidazolotriazole Derivatives for Antioxidant Evaluation

The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation of compound 2 with thiosemicarbazide and/or hydrazine hydrate afforded the mercaptotriazole and the corresponding acetic acid hydrazide derivatives 3 and 4, respectively. The latter compound reacted with ethyl acetoacetate, ethyl cyanoacetate, and maleic anhydride to give compounds 5, 6, and 7, respectively. Alkylation of compound 3 with methyl iodide or chloroacetic acid afforded methylsulfanyltriazole and thiazolotriazole derivatives 8 and 9, respectively. Compound 8 reacted with glycine to afford the imidazotriazole derivative 10. Both compounds 9 and 10 reacted with glucose and benzaldehyde to give compounds 11, 12, 13, and 14, respectively. Some of the prepared products were selected and subjected to screening for their antioxidant activity.     

Structure and chemistry of 4-hydroxy-6-methyl-2-pyridone

The structure of 4-hydroxy-6-methyl-2-pyridone formed by the reaction of 6-methyl-2H-pyran-2,4(3H)-dione and ammonia is characterized. A method is discussed for the structure determination of pyridone type compounds. Reaction of 4-hydroxy-6-methyl-2-pyridone with an equivalent amount of benzenesulfonyl chloride gives 4-benzenesulfonyloxy-6-methyl-2-pyridone. With two equivalent amounts of benzenesulfonyl chloride, 2,4-dibenzenesulfonyloxy-6-picoline is formed. 4-Hydroxy-6-methyl-2-pyridone is preferentially attacked by electrophiles at the 3 position.     

Reaction-phase-selective inter- and intramolecular photochemical reaction of 2-pyridone derivatives

Phase-selective photochemical reaction of 2-pyridone derivatives was examined. Irradiation of 1 in benzene mainly gave rearrangement products 2. However, intermolecular [4 + 4] photocycloaddition proceeded quantitatively in the solid state, affording photodimers 3. An effective pi-pi stacking and dipole-dipole interaction between two pyridone moieties might play important roles in an effective arrangement of 1 for photodimerization in their crystal structures. [reaction: see text]     

C-acylation of heterocyclic keto-enols Communication 10. Cyclization of 3-acyl-4-hydroxy-6-methyl-2(1H)-pyridone phenylhydrazones and their 1-methyl and 1-phenyl derivatives

Conclusions The cyclization of 3-acyl-4-hydroxy-6-methyl-2 (1H)-pyridone phenyl hydrazones and their 1-methyl and 1-phenyl derivatives goes by reaction at the 4-position of the pyridone ring with formation of the corresponding 1H-pyrazolo[4,3-c]pyridin-4(5H)-one derivatives.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya No. 10, pp. 1785–1788, October, 1966.     

Reactions of 4-pyrones with primary amines. A new class of ionic associates

Primary aliphatic amines react with 2,6-dimethyl-4-pyrone to give 2,6-dialkylamino-2,5-heptadien-4-one derivatives. When the alkyl group was methyl, the diamino derivative cyclized on warming to give 1,2,6-trimethyl-4-pyridone. The corresponding butylamino derivative did not thermally cyclize, but did give a pyridone on treatment with acid. The isopropylaminoketone did not cyclize. Several examples of 1,2,6-trisubstituted-4-pyridones formed “ionic associates” consisting of two parts of the pyridone and one part of perchloric acid. These associates are useful primary standards for nonaqueous titrations.     

Ambident reactivities of pyridone anions

The kinetics of the reactions of the ambident 2- and 4-pyridone anions with benzhydrylium ions (diarylcarbenium ions) and structurally related Michael acceptors have been studied in DMSO, CH(3)CN, and water. No significant changes of the rate constants were found when the counterion was varied (Li(+), K(+), NBu(4)(+)) or the solvent was changed from DMSO to CH(3)CN, whereas a large decrease of nucleophilicity was observed in aqueous solution. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of the electrophiles according to the correlation log k(2) = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and s for the pyridone anions. The reactions of the 2- and 4-pyridone anions with stabilized amino-substituted benzhydrylium ions and Michael acceptors are reversible and yield the thermodynamically more stable N-substituted pyridones exclusively. In contrast, highly reactive benzhydrylium ions (4,4'-dimethylbenzhydrylium ion), which react with diffusion control, give mixtures arising from N- and O-attack with the 2-pyridone anion and only O-substituted products with the 4-pyridone anion. For some reactions, rate and equilibrium constants were determined in DMSO, which showed that the 2-pyridone anion is a 2-4 times stronger nucleophile, but a 100 times stronger Lewis base than the 4-pyridone anion. Quantum chemical calculations at MP2/6-311+G(2d,p) level of theory showed that N-attack is thermodynamically favored over O-attack, but the attack at oxygen is intrinsically favored. Marcus theory was employed to develop a consistent scheme which rationalizes the manifold of regioselectivities previously reported for the reactions of these anions with electrophiles. In particular, Kornblum's rationalization of the silver ion effect, one of the main pillars of the hard and soft acid/base concept of ambident reactivity, has been revised. Ag(+) does not reverse the regioselectivity of the attack at the 2-pyridone anion by increasing the positive charge of the electrophile but by blocking the nitrogen atom of the 2-pyridone anion.     

Saccharide recognition-induced transformation of pyridine-pyridone alternate oligomers from self-dimer to helical complex

Co-oligomers involving (1H)-4-pyridone and 4-alkoxypyridine rings were studied, and it was found that their supramolecular transformation was caused by saccharide recognition. In the co-oligomers, pyridone and pyridine rings are alternately linked at their 2,6-position with an acetylene bond. The pyridine rings behave as a hydrogen bonding acceptor, and the pyridone rings and tautomerized 4-pyridinol work as a donor. Pyridine-pyridone-pyridine 3-mer was found to self-dimerize on the basis of vapor pressure osmometry in CHCl(3), and the association constant was obtained as 2.3 x 10(3) M(-1) by (1)H NMR titration. Longer 5-, 7-, 9-, and 11-mer oligomers showed considerable broadening and anisotropy in the (1)H NMR spectra due to self-association. These longer oligomers recognized octyl beta-D-glucopyranoside and changed their form into a chiral helical complex, showing characteristic circular dichroism.     

Acidities of anthraquinone and its hydroxy derivatives

The acidities of anthraquinone and its 1- and 6-hydroxy derivatives were studied. It is shown that the anthrone ring in the anthrapyridone molecule displays a strong electron-acceptor effect that stabilizes the anion during the development in the pyridone ring of a negative charge as a result of ionization; as a consequence of this, anthrapyridone and 1-hydroxyanthrapyridone are considerably stronger acids than 2-pyridone and 3-hydroxy-2-pyridone, respectively.Communication VII from the series Structure and Properties of Dyes. See [1] for communication VI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1373–1376, October, 1978.     

Synthesis of the angiotensin converting enzyme inhibitor (-)-A58365A via an isomünchnone cycloaddition reaction

[formula: see text] The angiotensin converting enzyme inhibitor (-)-A58365A (1) was synthesized by a process based on the [3 + 2]-cycloaddition reaction of a phenylsulfonyl-substituted isomünchnone intermediate. The starting material for this process was prepared from L-pyroglutamic acid and involved using a diazo-phenylsulfonyl-substituted pyrrolidine imide. Treatment of the diazoimide with Rh2(OAc)4 in the presence of methyl vinyl ketone afforded a 3-hydroxy-2-pyridone derivative which was subsequently converted to the ACE inhibitor in six additional steps.     

Oxidative DNA Damage in the Photolysis of Af-Hydroxy-2-Pyridone, a Specific Hydroxyl-Radical Source

Abstract The photooxidative DNA damage by iV-hydroxy-2-pyri-done (1) is caused by hydroxyl radicals, as confirmed by electron paramagnetic resonance studies with the spin trap 5,5-dimethylpyrroline JV-oxide. Irradiation of the pyridone 1 at 300 nm induced strand breaks in super-coiled pBR322 DNA, while in calf-thymus DNA and 2'-deoxyguanosine (dG), respectively, 8-oxoguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine were formed. Time-dependent control experiments disclosed that photoprod-ucts of pyridone 1, e.g. 2-pyridone (3), are not responsible for the modification of DNA. Also the photosensitization by the pyridine-2-one chromophore was excluded, because JV-methylpyridine-2-one (2), which cannot generate hydroxyl radicals, was ineffective in the photooxidation of DNA and dG. Thus, the photolysis of pyridone 1 serves as a specific source of hydroxyl radicals for DNA damage, both strand breaks and base modifications.     

Catalytic enantioselective total synthesis of (+)-torrubiellone C

Silyl-protected (R)-methyl 2-(hydroxymethyl)butanoate was obtained by an enantioselective Ir-catalyzed hydrogenation in high yield and selectivity. Elaboration of this building block via Takai and Stille reactions gave a protected hydroxy polyene chain, which was coupled to a 5-hydroxyphenyl-4-hydroxy-2-pyridone derivative by a modified Horner-Wadsworth-Emmons reaction. Deprotection gave synthetic (+)-torrubiellone C, which led to the assignment of the configuration of the natural product as (R).     

The synthesis of 3-deazaorotidine and related nucleoside derivatives of 4-hydroxy-2-pyridone

Condensation of 6-earbethoxy-4-hydroxy-2-pyridone or a silyl derivative of 5-earbomethoxy-4-hydroxy-2-pyridone with 2′,3′,5′-tri-O-benzoyl-D-ribofuranosyl halide has provided the 3-deaza analogs of orotidine and uridine-5-carboxylic acid. The corresponding amides have also been prepared in view of their possible structural relationship to l-β-D-ribohiranosyl nicotinamide. Tri-O-benzoyl-3-deazauridine was treated with N-bromosuccinimide to give, after deblocking, 3-bromo-4-hydroxy-1-(β-D-ribofuranosyl)-2-pyridone. The anomeric configuration of these nuclcosides was confirmed by pmr spectroscopy.     

The addition of methylhypobromite to 4-acetamido-3-bromo-2-pyridone

Bromination of 4-acetamido-3-bromo-2-pyridone in methanol results in the addition of methylhypobromite to the 5,6 double bond of the pyridone.     

A novel redox reaction between 8-Aza-5,7-dimethyl-2-trifluoromethylchromone and alkyl mercaptoacetates. Facile synthesis of CF3-containing 2-pyridone derivatives

8-Aza-5,7-dimethyl-2-trifluoromethylchromone reacts with alkyl mercaptoacetates in the presence of triethylamine to give pyrido derivatives of 2-oxa-7-thiabicyclo[3.2.1]octane, which undergo the reductive ring opening to alkyl 2-[[3-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-oxo-1-(trifluoromethyl)propyl]sulfanyl]acetates.The latter can be also obtained directly from 8-aza-5,7-dimethyl-2-trifluoromethylchromone and behave as the masked alpha,beta-unsaturated ketone, 4,6-dimethyl-3-(4,4,4-trifluorobut-2-enoyl)pyridin-2(1H)-one. This compound was independently synthesized from 3-acetyl-4,6-dimethyl-2-pyridone, and its synthetic potential was studied. A wide variety of 2-pyridone derivatives containing the CF(3) group have been prepared in good to moderate yields.     

Influence of the counterion and the solvent molecules in the spin crossover system [Co(4-terpyridone)2]Xp.nH2O

A series of new complexes belonging to the [Co(4-terpyridone)2]X(p) x nS family (4-terpyridone = 2,6-bis(2-pyridyl)-4(1H)-pyridone) have been synthesized and characterized, using X-ray single crystal determination and magnetic susceptibility studies, to be X = [BF4]- (p = 2) and S = H2O for polymorphs 1 and 2, X = [BF4]- (p = 1) and [SiF6]2- (p = 0.5) and S = CH(3)OH for 3, X = [SiF6]2- (p = 1) and S = 3CH3OH and H2O for 4, X = [Co(NCS)4]2- (p = 1) and S = 0.5CH3OH for 5, X = I- (p = 2) and S = 5H2O for 6, X = [PF6]- (p = 1) for 7, and X = [NO3]- (p = 2) for 8. Compounds 1-7 can be grouped in three sets according to the space group in which they crystallize: (i) P1 triclinic (1, 3), (ii) P2(1) monoclinic (2), and (iii) P2(1)/c monoclinic (4-7). The tridentate 4-terpyridone ligands coordinate the Co(II) ions in a mer fashion defining essentially tetragonally compressed [CoN6] octahedrons. The Co-N axial bonds involving the pyridone rings are markedly shorter than the Co-N equatorial bonds collectively denoted as Co-N(central) and Co-N(distal), respectively. The differences in the average Co-N(central) or Co-N(distal) distances observed for 1-7 reflect the different spin states of Co(II). Complexes 7 and 4' are fully high spin (HS), while 5 and 6 are low spin (LS). However, the counterion [Co(NCS)4]2- in complex 5 is high spin. Complexes 1, 2, 3, and 8 exhibit spin-crossover behavior in the 400-100 K temperature region. Compounds 1 and 2 are polymorphs, and interestingly, 1 irreversibly transforms into 2 above 340 K because of a crystallographic phase transition which involves a drastic modification of the crystal packing. The relevant thermodynamic parameters associated with the spin transition of polymorph 2 have been estimated using the regular solution theory leading to DeltaH = 3.04 kJ mol(-1), DeltaS = 20 J K(-1) mol(-1), and Gamma = 0.95 kJ mol(-1).     

Acetals of lactams and acid amides. 47. Investigation of the behavior of substituted 6-(Β-dimethylamino) vinyl-4-pyrimidinones in acidic media. Synthesis of 3-cyano-4-anilino-5-formyl-2-pyridone and 3-chloro-4-cyanobenzo[b] [1,6]-naphthyridine

The hydrolysis of 1-substituted 5-cyano-6-(-dimethylamino)vinyl-4-pyrimidinones in acidic media was studied. It was shown that the 1-benzyl derivative is converted to a mixture of -cyano--benzylamino-crotonamide and 3-cyano- and 3-carbamido-4-benzyl-amino-2-pyridones. The principal product in the hydrolysis of the 1-phenyl derivative is 3-cyano-4-anilino-5-formyl-2-pyridone. Cyclization of the latter by heating in phosphorus oxychloride leads to 3-chloro-4-cyanobenzo[b] [1, 6]naphthyr idine.See [1] for Communication 46.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1118–1123, August, 1986.