Isoquinoline iV-oxides

Treating dimethylsulfonium acetylcarbamoylmethylide (297) with isoquinoline IV-oxide in the presence of acetyl chloride in dimethylformamide gave a complex reaction mixture from which 4-methyl-3-methylthio-2//-pyrimido[2,l-a]isoquinolin-2-one (156) and sulfur ylide (236) were isolated in 5.9% and 19.2% yields, respectively (80YZ1261). 

Shin s group80 also used AgOTf (5 mol%) to catalyze the formation of isoquinoline-IV-oxide structures 56 (Scheme 5.26) from cycloisomerization of 2-alkynylbenzaldox-imes 55. This synthesis is of interest since these structures are usually made by oxidation of the parent nitrogen heterocycles. 

Diethyl cyanophosphonate converts quinoline and isoqninoline iV-oxides into the 1- and 2-cyano-heterocycles in high yields in a process which must have 0-phosphorylation as a first step, and in which the elimination of diethylphosphate may proceed via a cyclic transition state trimethylsilyl cyanide and diazabicyclonndecene effect the same transformation. A chloroformate and an alcohol convert the iV-oxides into ethers, as illustrated below for isoquinoline iV-oxide, a chloroformate and a Grignard reagent prodnce 2-snbstitnted quinolines, and a chloroformate then an isonitrile produce 2-carbamoyl-... 

A two-step synthesis of 4-hydroxyindole derivatives (87) has also been reported and involves photorearrangement of isoquinoline iV-oxides (88) via oxaziridines (89) to the benzoxazepines (90), followed by treatment with acid, as shown in Scheme 9. In a separate study, 3,1-benzoxazepines have been shown to undergo... 

Aromatic isoquinolones can be obtained by the thermal rearrangement of isoquinoline iV-oxides thus it was possible to derive the isoquinoline 3 from the iV-oxide 2. Compound 3 could be further functionalized through bromina-tion and subsequent treatment with a mixture of cuprous cyanide and sodium cyanide. ... 

Among the bicyclic AT-oxides which have been irradiated are the indole JV-oxides (670)" and the isoquinoline A -oxides (671)." The proportion of each of the products isolated from photoisomerization of (670) was dependent on the nature, position, and number of substituents." The photoisomerization of isoquinoline iV-oxides has been investigated using a range of solvents... 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Ochiai and Ohta have used lead tetraacetate in benzene to convert aromatic iV-oxides (67) to the corresponding acetylated hydroxamic acids (68). Similar oxidation of quinoline and isoquinoline JV-oxides... 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

Photochemical hydroxyalkylation has been carried out with pyri-dines, quinolines, isoquinolines,acridine, pyridazines, pyrimidines, ethoxyquinolinium salts,and imidazoles. It also occurs with iV-oxides the mechanism of Scheme 13 has been suggested for pyridazine iV -oxide. ... 

Quinoline 1-oxide undergoes nucleophilic attack by ozone to yield a hydroxamic acid (128), and 40% of the starting iV-oxide is recovered (Scheme 74). When an excess of ozone is employed the aldehydes (129) and (130) are obtained. Formation of these products has been attributed to electrophilic attack by ozone rather than further oxidation of (128), because in a separate experiment (128) yielded carbostyril on treatment with ozone. Isoquinoline 2-oxide yields 2-hydroxyisoquinolin-l-one, and acridine 10-oxide gives 10-hydroxyacridone and acridone in a similar manner to the above. Likewise, phenanthridine 5-oxide affords mainly 5-hydroxyphenanthridone. Quinoline 1-oxide undergoes oxidation by lead tetraacetate as shown (Scheme 75). 

With methyl-3-nitropyridine iV-oxides, use of selenium dioxide results in complete oxidative demethylation (80TL2433). In isoquinoline methyl groups at positions 1 and 3 are efficiently oxidized to the corresponding aldehyde with selenium dioxide. 

The 1,3-oxazepine (848) is thermally labile the main products are formylpyrroles but some 3-hydroxy-2-phenylpyridine is obtained (75TL1067). The benzoxazepines of type (849) are intermediates in the photochemical breakdown of quinoline iV-oxides and can sometimes be isolated. They normally break down to give 3-hydroxyquinolines (66TL2145, 67CPB663), but compound (849) can be converted by methylamine into the diaminoquinoline (850) (67TL5237). The benzoxazepinone (851) with sodamide forms a mixture of three isoquinoline... 

Pyridazino[4,5 -cjisoquinoline, 6-aryl-synthesis, 3, 244 Pyridazino[3,4-c]isoquinolines alkylation, 3, 238 iV-oxide, 3, 327 synthesis, 3, 247-248 Pyridazino[4,3-c]isoquinolines synthesis, 3, 247 Pyridazino[4,5-c]isoquinolines alkylation, 3, 238 Pyridazin-3(2//)-one, 6-acryloxy-polymers, 1, 288... 

Among the iV-oxides of this series of compounds isoquinoline 2-oxide shows the simplest behaviour on nitration. The acidity dependence of the rate of nitration (table 8.1), and comparison with the 2-methoxyiso-quinolinium cation (v, R = Me) (table 10.3) show the oxide to be nitrated as its conjugate acid (v, R = H) in 76-83 % sulphuric acid. The... 

An efficient procedure for the reduction of pyridine iV-oxides to piperidines using ammonium formate and palladium on carbon has been developed (Equation 98) <2001JOC5264>. The reaction conditions are mild and can also be applied to the iV-oxides of quinoline and isoquinoline. 

The isoquinoline ring undergoes attack by the nucleophilic aluminum hydride anion in much the same manner as the pyridine ring to produce 1,2-dihydroisoquinolines,91,92 although tetrahydroisoquino-lines have been reported as products even though no proton source was apparently present.92 (For a probable mechanism see Section IV,B.) The reduction of isoquinoline A-oxide by lithium aluminum hydride was also reported to yield the 1,2-dihydroisoquinoline.93... 

Radical attack on isoquinoline, as either free base or isoquinolinium cation, always occurs at position 1 and the method is not suitable for the preparation of benzo ring-substituted products. The same can be said of radical attack on the IV-oxides of quinoline and isoquinoline. 

Benzo c,d indol 4-Amino-2-oxo-l, 2-dihydro- XI/1, 151 3,4-Benzo-2-oxa-7-aza-bicyclo 3.2.0 hepta-3,6-dien 1-Cyan-8-methyl- IV/5b, 1307 1,3-Benzoxazepin 2-Cyan-4-meihyl-lV/5b, 1307/E9d, 307 (1 -CN — 3-R — isoquinolin-2-oxid hv)... 

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