Isoquinoline A -oxide

Conflicting evidence for the intermediacy of oxaziridines in these and related photoreactions has been published. Evidence against the formation of oxaziridines in the photorearrangement of isoquinoline A-oxides has been described.63 In contrast, the oxaziridine 71 has been detected on irradiation of 6-cyanophenanthridone 5-oxide (72) in an ethanol or 2-methyltet-rahydrofuran matrix at 77 K leading eventually to 5-ethoxyphenanthridone (73) and 6-cyanophenanthridine (74), respectively.64 6-Cyano-3,l-dibenzo-xazepine (75) was also obtained in both cases, presumably by an oxygen walk process involving oxaziridine 76. 

Catalytic properties of external chiral additives such as (2S,3/ )-4-dimethyl-amino-l,2-diphenyl-3- methyl-2-butoxide (A 16) (574, 575) and 2-magnesium-3-zinc salts of dialkyl (f ,f )-tartrate (A17) were employed in the highly stereoselective addition of organozinc reagents to derivatives of 3,4-dihydro-isoquinoline-A-oxide (Scheme 2.147) (576). 

A series of 2//-imidazole-l-oxides, isoquinoline-A-oxides and pyrrolidine-A-oxides were investigated as to their specificity and efficiency at spin trapping HO and 02 as well as the stability of the corresponding spin-trapped adducts. 2,2-Dimethyl-4-methoxycarbonyl-2A-imidazole (42) has been found to be the most selective of the spin traps investigated for the in vivo, in situ detection of HO at the expense of 02. ... 

Bromination and nitration of some annulated thieno[3,2-6]pyridines were investigated. The reaction of thieno[3,2-c]isoquinoline A-oxide (181) with bromine yields 2,3-disubstituted product 182, whereas treatment of 181 with HN03 affords 2-nitro derivative 183 (1989CS305, 1989CS309). 

The one-pot Stille cross-coupling reaction of compound 256 produced all four isomeric thieno[3,2-c]naphthyridines (1994JHC11). The stepwise formation of the C(7)-C(7a) and C(4)-N(5) bonds of the thieno[3,2-c]pyridine system can be considered as a modification of the above-described approaches. For example, aldehyde 256 reacts with arene 265 to give 266 reduction of its nitro group is accompanied by cyclization to form thieno[3,2-c]isoquinoline A-oxide (267) (1990JHC1127). 

Isoquinoline A-oxide with DMAD and DEAD gave 367 and with EPP, 368.398... 

Other silver salts can efficiently catalyze this reaction at room temperature. These include AgSbFg and AgNTf2 and also some gold salts such as Au(IMes)OTf. Some of the isoquinoline-A-oxide derivatives 56 (Scheme 5.26) can be further converted in 1-cyanoisoquinolines 57 by reacting with TMSCN and DBU as a base. 

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... 

Again, as expected, pyridine A-oxides are very susceptible to nucleophilic attack. Unlike the situation usually prevalent with the quaternary pyridinium salts, the elimination stage of the two-step nucleophilic substitution can occur with relative ease, the oxide grouping serving as a good sink for the leaving hydride ion electron-pair and being itself eliminated in the process. Considerably more work has been carried out on quinoline and isoquinoline A-oxides than on pyridine A-oxide derivatives. 

Thienoisoquinolines can be prepared in high yields by the palladium cross-coupling reaction of o-formylarylboronic acids with aryl halides. By this method, thieno[3,2-c]- (102), thieno[3,4-c]-(103), and thieno[2,3-c]isoquinolines (104) have been prepared in yields of 90%, 52%, and 75%, respectively (Scheme 48) <86CS3il, 89JHC865). This method was unsuccessful for the preparation of thieno[3,2-c]quinoline A-oxide and thieno[3,2-c]isoquinoline A-oxide. The former compounds were readily prepared via a modification of the reaction using a palladium-catalyzed coupling reaction between 2-tributylstannyl-3-thiophenecarboxaldehyde and o-bromonitrobenzene, while the isoquinoline A-oxide was prepared by mcpba oxidation of the parent compound <90JHC1127>. 

Quinoline A -oxide gives a 4-bromo derivative (Br2H20, 100 C). Isoquinoline A -oxide is brominated at the 4-position... 

Related 1,3-oxazepines have been obtained from irradiation of many other heterocyclic A-oxides including pyridine A-oxides, isoquinoline A-oxides, quinoxaline A-oxides, quinazoline A-oxides, phenanthridine A-oxides, benzophenazine A-oxides, and acridine A-oxides.4 However, the reported yields are variable and have generally been higher for phenyl and other aryl-substituted derivatives. 

If, instead of an imine, an oxime is used, the result is an isoquinoline A -oxide. Such closures can be effected with silver catalysis, " or with iodine, 4-iodoisoquinoline A -oxides being the products in the latter cases. "... 

Formylphenyl)ethanal 38 and analogous dicarbonyl compounds undergo cyclization with ammonia to give isoquinolines. Primary amines produce A -substituted isoquinolinium ions, hydroxylamine yields isoquinoline A -oxides, and hydrazines give isoquinolinium A -betaines ... 

Af-Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine 7V-oxide, with the additional possibility of benzene ring electrophilic susbstitution, for example mixed acid nitration of quinoline A -oxide takes place at C-5 and C-8 via the O-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A/ -oxide takes place at C-5. ... 

Diethyl cyanophosphonate converts quinoline and isoquinoline A -oxides into the 1- and 2-cyano heterocycles in high yields in a process which must have O-phosphorylation as a first step, and in which the elimination of diethylphosphate may proceed via a cyclic transition state trimethylsilyl cyanide and diazabicyclounde-cene effect the same transformation. Chloroformates and an alcohol convert the N-oxides into ethers, as illustrated below for isoquinoline A -oxide. ... 

The rate of Jacobsen-Katsuki epoxidation can be enhanced in the presence of additives such as pyridine A-oxide or related aromatic A-oxides. For example, in a synthesis of the potassium channel activator BRL-55834, only 0.1 mol% of the (5,5)-(salen)Mn(III)Cl catalyst 58 was required for efficient epoxidation of the chromene 62 in the presence of 0.1 mol% isoquinoline A-oxide (5.68). In the... 

Quinoline and isoquinoline A-oxides, formed by the action of peracids in quinoline and isoquinoline core, are useful synthetic precursors as they possess both electrophilic and nucleophilic character. The positive charge on nitrogen or the negative charge on oxygen atom can be delocalized to the a-or y-positions, depending on demand fi-om the reagent used. 

In a typical experiment, 18.12 g isoquinoline-A -oxide was added to 150 mL acetic anhydride and refluxed gently for 5 h. The liquid soon turned dark red. The acetic anhydride was removed under an aspirator vacuum, and the residue was distilled. The volatile portion was collected in one fraction, which boiled at 142°C (0.9 mmHg) however, an appreciable non-volatile portion remained. The solid distillate was heated on the steam bath with 4 g NaOH and 75 mL water for 40 min and then allowed to stand at room temperature overnight. A pale yellow solid was filtered off and washed with water to give 9.02 g isocarbostyril, in a yield of 53%, m.p., 208.0-209.5°C. 

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