Isoquinoline, activation

Fluorination. Attention has been focused on the direct fluorination of isoquinolines activated by conversion into 2-methylisocarbostyril (80). With gaseous fluorine (diluted to 10% with argon) in acetic acid a 54% yield of the 4-fluoro derivative was obtained. (Scheme 40). With methylene chloride as the solvent, only the 4-chloro analogue was formed [82H( 17)429]. Fluoroisoquinolines have also been made by displacement of nitro groups, and from diazonium fluoroborates (87JHC181). Hepta-chloroisoquinoline was converted into a perfluoro derivative by heating it in an autoclave with anhydrous potassium fluoride [66JCS(C)2328]. 

Allyl and benzyl bromides react with a,/ -unsaturated nitriles in the presence of indium(i) iodide under sonication to produce the corresponding allylated and benzylated imines, involving exclusive addition of the allyl/benzyl group to the nitrile moiety (Equation (63)).273 The reaction of allylindium reagents with methyl cyanoacetates affords the corresponding allylation-enamination products (Equation (64)).27 l-Acyl-l,2-dihydropyridines are prepared by indium-mediated allylation of 1-acylpyridinium salts (Equation (65)).275 Quinoline and isoquinoline activated by... 

Asymmetric hydrogenation of isoquinolines activated by chloroformates also... 

In addition to the very important palladium-catalysed reactions, boronic acids undergo a number of useful reactions that do not require transition-metal catalysis, particularly those involving electrophilic ipso-substitutions by carbon electrophiles. The Petasis reaction involves ip,y(9-replacement of boron under Mannich-like conditions and is successful with electron-rich heterocyclic boronic acids. A variety of quinolines and isoquinolines, activated by ethyl pyrocarbonate, have been used as the Mannich reagent . A Petasis reaction on indole 3-boronic acids under standard conditions was an efficient route to very high de a-indolylglycines. " ... 

Iminothioamides, isothiazoles from, 108 Indole, 2,3-dehydro-JV-methyl-, 143 Ionization constants, anomalous, 6-7 covalent hydration, effect on, 5-7 Isoquinoline, activation of, 313, 314, 318, 344... 

A three-component synthesis of l,4-benzoxazepin-2-one derivatives 155 (Scheme 32) by the reaction of isoquinoline, activated acetylenes, and a phenolic furan derivative in water without using any catalyst was recently reported [103]. The one-pot protocol proceeded in high yield under very mild conditions. When quinoline was used instead of isoquinoline, the isomeric product 156 was formed. Mechanistically, initial formation of the adduct 157 followed by its nucleophilic captiu e by the phenolate ion derived from 154 leading to 159, and a subsequent intramolecular esterification may explain the formation of the products (Scheme 33). 

Noscapine [128-62-1] (45) is the second most abundant alkaloid found in opium. Unlike most opium alkaloids, however, it has an isoquinoline rather than a phenanthrene ting system. Noscapine was first isolated in 1817 but its antitussive activity was not demonstrated pharmacologically until 1952 (63). Clinical studies have confirmed its effectiveness. It is not a narcotic and has a wide margin of safety when given orally. Death could be produced in rats only with doses > 800 mg/kg (64). Noscapine is isolated from the water-insoluble residue remaining after processing opium for the manufacture of morphine. 

The preparation of benzo fused pyrido[3,2- i]pyrimidines has furnished the only examples of the classic reaction of this type, the Bischler-Napieralski, involving the cyclization of 5-aryl-4-acylaminopyrimidines to 6-alkylpyrimido[4,5-c]isoquinolines, e.g. (157)->(158) (73YZ330). As often found in this reaction, the presence of activating substituents appears necessary (78CPB245). 

Pyrazolo[3,4-d][l,2]diazepines synthesis, 7, 597 Pyrazolop, 4- 6][ 1,4]diazepines synthesis, 5, 272 Pyrazolo[l, 4]diazepinones as anticonvulsant, 1, 170 Pyrazolo[2,3-e]diazepinones synthesis, 5, 272 1 H-Pyrazolo[l,5-6]imidazoles synthesis, 6, 992 Pyrazolo[2,3-a]imidazoles biological activity, 6, 1024 Pyrazolo[2,3-c]imidazoles reactions, 6, 1041 synthesis, 6, 1047 Pyrazolo[2,3-imidazoles synthesis, 6, 991 Pyrazolo[3,2- njisoquinolines synthesis, 5, 339 Pyrazolop, 4-c]isoquinolines synthesis, 5, 273 Pyrazolonaphthyri dines synthesis, 5, 339 Pyrazolone, diazophotolysis, 5, 252 Pyrazolone, 4,4-dihalo-rearrangements, 5, 250 Pyrazolone, ethoxy-hydrazinolysis, 5, 253 Pyrazolone, 4-halo-... 

Many hydantoins are endowed with significant pharmacological activities as highlighted by 5,5-diphenylhydantoin (Dilantin ), an anticonvulsant and antiepileptic discovered by Parke-Davis in 1940 s. Despite the lapse of more than half a century, Dilantin still plays an important rote in modem medicine. Meanwhile, another anticonvulsant 15 was synthesized from 9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-pyrido[2,l-a]isoquinolin-2-one (14) under the standard Bucherer-Lieb variation in a 2 1 water-ethanol solution (15a 15b = 8 l). ... 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

Resonance activation in the 8-substituted-isoquinolines (344) or -2-nitronaphthalenes is predicted to be greater than that in 5-substituted-quinolines (345) or -1 -nitronaphthalenes due to the lower energy charge-... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

The halo-2-nitronaphthalenes (Table XIII) enable one to draw tentative conclusions about intranitclear and internitclear activation in the isoquinolines for which data are not available. These compounds are numbered so as to show their relation to their isoquinoline analogs. The relative rates are summarized in the following tabulation along with the ratio of the rates of piperidino-debromination to that of the appropriate bromonaphthalene (res. = resonance activation, ind. = inductive activation). 

Line No. Isoquinoline substituents Nucleophile (solvent) Rate constant (temp. °C) 106 A liter mole i sec i Activation energ3 kcal mole-1 Entropy of activation cal mole-1, j0g- Frequency factor 1 logioA Ref. 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

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... 

An asymmetric synthesis of 1-aryltetrahydroisoquinolines 79 from chiral amide 78 was reported <96TL(37)4369>. Optically active cis- or rranj-1,3-disubstituted tetrahydro-isoquinolines can he prepared hy a modification of this procedure. 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

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