Isoquinoline-5,8-dione

Strong effects of the catalyst on the regioselectivity have been observed in the cycloadditions of a variety of heterocyclic dienophiles. Some results of the BF3-catalyzed reactions of quinoline-5,8-dione (21) and isoquinoline-5,8-dione (22) with isoprene (2) and (E)-piperylene (3) [25], and of the cycloadditions of 4-quinolones (23a, 23b) as well as 4-benzothiopyranone (23c) with 2-piperidino-butadienes, are reported [26] in Scheme 3.8 and Equation 3.2. The most marked... 

Isoquinoline-5,8-diones undergo Diels-Alder cycloaddition to give derivatives of the linear system similar to 283 (69JHC697). Cycloaddition between 1,4-naphthoquinone and l-dimethylamino-3-methyl-2-azabutadiene gives cycloadducts in moderate yield (75JA4409 82TL3261). 

C-NMR spectra of several isoquinoline-5,8- and -7,8-diones were recorded (85CPB823). A comparative study of electrochemical reduction of isoquinoline-5,8-dione and other heterocyclic quinones revealed that all compounds show two well-defined reduction peaks and that these reductions are reversible (72MI2). 

Diels-Alder Reactions. Bp3-OEt2 is used to catalyze and reverse the regiospecificity of some Diels-Alder reactions, e.g. with pen-hydroxylated naphthoquinones, sulfur-containing conpounds, the reaction of 1-substituted trans-1,3-dienes with 2,6-dimethylbenzoquinones, and the reaction of 6-inethoxy-l-vinyl-3,4-dihydronaphthalene with p-quinones. BFs-OEta has a drastic effect on the regioselectivity of the Diels-Alder reaction of quinoline- and isoquinoline-5,8-dione with piperylene, which produces substituted azaanthraquinones. This Lewis acid is the most effective catalyst for the Diels-Alder reaction of furan with methyl acrylate, giving high endo selectivity in the 7-oxabicyclo[2.2.1]heptene product (eq 35). ... 

Scheme 17 Regioselective oxidative alkylamination of isoquinoline-5,8-dione 16...

Kobayashi, K., Takanohashi, A., Watanabe, S., Morikawa, O., and Konishi, H., One-pot synthesis of isoquinoline-5,8-dione derivatives from acylquinones and enamines. Tetrahedron Lett., 41, 7657-7660, 2000. 

In the past year, reviews on 1,8-naphthyridines, perimidines, polyazaphen-anthrenes, 3-azabicyclo[3.3.1]nonanes, and 1,2- and 2,1-benzothiazines have appeared. Reviews on specialist aspects of pyridine chemistry are devoted to the reactions of newly available pyridines, a,a -disubstituted pyridines, the reactions of pyridines with nucleophiles, the electrochemistry of IjT-disubstituted 4,4 -bipyridinium ions (the viologens such as paraquat), dihydropyridines, and 4-aryl-dihydropyridines (a new class of calcium antagonists). Reviews have been published on the cyclization of oximes and amides to quinolines and isoquinolines, quinoline- and isoquinoline-diones, benzo[fl ]- and benzo[c]-quinolizinium ions, azachrysene preparation, quinazolines with plant-growth-regulating and biocidal activities, quinazolines in pharmaceutical research, isotopic hydrogen exchange in... 

Isoquinoline-l,3-dione, 5,6,7,8-tetrahydro-synthesis, 2, 408 Isoquinoline hydrobromide bromination, 2, 49 Isoquinolines adducts... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

The mass spectral fragmentations of 9,10-dimethoxy-2,3,4,6,7,ll/)-hexa-hydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140 and -2,4-diones 141, under electron ionization (at 70 eV) were examined by metastable ion analysis, a collosion-induced dissociation technique and exact mass measurement (97RCM1879). Methyl substituent on N(3) in 140 (R = Me) had a larger effect on both the fragmentation and on the peak intensities, than a methyl substituent on C(6) (R = Me). The ionized molecules of 140 (R = H) were rather stable, whereas 4-phenyl substitution on C(4) of 140 (R = Ph) promoted the fragmentations of the molecular ions. The hexahydro-1//-pyrimido[6,l-n]isoquinoline-2,4-diones 141 were more stable, than the hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140, and the molecular ions formed base peaks. 

Treatment of pyrimidine-2-thione 193 with AICI3 in PhN02 yielded 2-(4-benzylphenyl)-6-oxo-6,7-dihydro-4//-pyrido[6,l-a]isoquinolin-4-thione (194) (98MI47). Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquina-zoline-2,4-dione (195) in PPA afforded l,2,3,5,6,7-hexahydropyrimido[3,2, l-//]quinazoline-l,3,7-trione (196) (97CHE96). 

Cyclocondensation of a-aryl-2-pyridylacetamides and 2-(3,4-dihydroiso-quinolin-l-yl)acetamide with Et2C03 in the presence of NaOEt in boiling EtOH afforded 4-aryl-2,3-dihydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones (99JHC389) and 6,7-dihydro-4//-pyrimido[6,1 -a]isoquinoline-2,4-dione (98MIP15), respectively. 

Structure of 4//-pyrido[l,2-a]pyrazines 348-350 was confirmed by X-ray investigations (99JPR332). The stereostructure of 1,3,4,6,1 l,lla-hexahydro-2/f-pyrazino[l,2-A]isoquinoline-l,4-dione 351 was determined by X-ray investigation (01TL543). 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

The side chain C=C double bond of 2,3,4,6,ll,lln-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 354 was saturated by catalytic hydrogenation over Pd/C catalysts in EtOH to give 355 (98MIP7). 7-(2-Pyridylmethyl)amino derivative was obtained by reduction of 7-[(2-pyridylmethylene)amino]-2,3,11,11 n-tetrahydro-6//-pyrazino[l, 2-i]isoqui-noline-l,4-dione (356) with NaBH4 in EtOH at ambient temperature for 24 h. 

Nitration of 2-cyclohexyl-8-hydroxy-2,3,4,6,11,11 u-hexahydro-1 //-pyra-zino[l,2-6]isoquinoline-l,4-dione with 70% HNO3 at room temperature for 30 min afforded an 1 1 mixture of 7- and 9-nitro derivatives (98MIP7). 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Aminothiocarbonylphenyl)methoxy] derivative 384 was obtained from 8-[(4-cyanophenyl)methoxy]-2-cyclohexy 1-2,3,4,6,11,11 a-hexahydro-l/7-pyrazino[l,2-i]isoquinoline-l,4-dione by treatment with (EtO)2P(S)SH and one drop of H2O at room temperature for 17 h, then followed by addition of more H2O (98MIP7). Reaction of 8-[(4-aminothiocarbonylphe-nyl)methoxy] derivative 384 and MeCOCH2Cl yielded 8- [4-(4-methylthia-zol-2-yl)phenyl]methoxy derivative 385. 7-Bromomethyl derivative was prepared from the 8-hydroxymethyl-8-[(4-cyanophenyl)methoxy]-2-cyclo-pentyl-2,3,4,6,11,1 la-hexahydro-177-pyrazino[l, 2-i]isoquinoline-1,4-dione with PBr3 in CH2CI2 at room temperature. 7-[(l-Pyrazolyl)methyl] derivative was obtained from 7-bromomethyl derivative by treatment with pyrazole in the presence of NaH in DMF at 50 °C. 

Treatment of 8-[(4-cyanophenyl)methoxy]-7-formyl-2-cyclopentyl-2,3,4,6,11,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione with (Et0)2P(0)CH2C00Et and NaH in THF at 40 °C overnight, or with (2-pyridylmethyl)-, 4-[(ethoxycarbonyl)benzyl]-, (4-nitrobenzyl)-, and (meth-oxymethyl)triphenylphosphonium halogenide in the presence of KH in THF at room temperature gave 7-ethylene derivatives 386 (98MIP7). 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

Cyclocondensation of 2-(2-chloroacetyl)-l, 2,3,4-tetrahydroisoquinoline-3-carboxylate 418 (R =N02, R = Me) with liquid NH3 in MeOH in a stainless steel pressure vessel at room temperature overnight gave 8-nitro-2,3,4,6,1 1,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione (419, R=H, R =N02) (97MIP4). (1 la/i)-2-Cycloalkyl-8-hydroxy-2,3,4,6,ll, 1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 419 (R = cycloalkyl, R = OH) were prepared in the reactions of (3/i)-2-chloroace-tyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (418, R = OH, R = Et) with cycloalkylamines (98MIP7). 

Inhibition of human multidrug resistance P-glycoprotein 1 was investigated by analogs of a potent. 5-opioid antagonist, including (35, 1 lu5)-3-[(4-hydroxy-2,6-dimethylphenyl)methyl]-11,11 u-dihydro-2//-pyrazino[l, 1-b] isoquinoline-l,4(3//,6//)-dione (OIMIIO). Opioid antagonist activity of... 

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