Substituent-directed oxidation

Similarly, Schlecht and Kim have reported a substituent-directed oxidation method for the synthesis of 8-lactones by oxidative cyclization of hydroxyalkenes [80] (Scheme 36). Addition of alkenyl Grignard reagent to ketones 184 afforded hydroxyalkene 185, which upon treatment with chromium trioxide in acetic acid and acetic anhydride provided spiro-8-lactone 186. 

Direct oxidation of ethylpyrazines to the corresponding acetylpyrazines may also be carried out in favourable circumstances using hot chromic acid (75JOC1178). Treatment of 2-ethyl-3-alkylpyrazines with chromic acid yields the corresponding 2-acetyl-3-alkyl-pyrazines in yields of 50-70%. In the absence of the 3-alkyl substituent the yields fall dramatically to less than 10%. Acetylpyrazines are more generally prepared by the inverse addition of a Grignard reagent to a cyanopyrazine. 

AT-Oxidation is very sensitive to steric effects, since 1-substituted lumazines and pterins give only 5-oxides and the presence of bulky substituents at position 7 also directs oxidation to N-5. The pteridine 5-oxide (52) and 8-oxide (53) and the 5,8-dioxide (55) contain the AT-oxide groups as such, even when the possibility of AT-hydroxy tautomers exists, as in (53) i(54). 

One of the best methods of synthesis of isothiazoles is by direct oxidation of y- iminothiols (169) or their tautomers. The reaction is capable of many ramifications and is represented by the general equation shown in Scheme 27. The substituents represent a wide range of groups. Thus, iminothioamides (169 R = NH2) are oxidized to give 3-alkyl-5-aminoisothiazoles (170 = NH2), amidines (169 R = NH2) produce 3-amino compounds,... 

Hydroxypyridine and pyridin-2-one are sufficiently reactive to undergo Elbs oxidation, and in both cases the substituent directs hydroxylation mainly para (Scheme 40) (58JA3717). Quinoline may be converted into 3-hydroxyquinoline (6% yield) by Udenfriend oxidation (ascorbic acid and oxygen in the presence of iron(II)) which is believed to involve attack by OH+ rather than radicals (54JBC(208)74i). 

The methyl substituent of 2-methyl-4,8-dihydrobenzo[l,2- 5,4-. ]dithiophene-4,8-dione 118 undergoes a number of synthetic transformations (Scheme 8), and is therefore a key intermediate for the preparation of a range of anthraquinone derivatives <1999BMC1025>. Thus, oxidation of 118 with chromium trioxide in acetic anhydride at low temperatures affords the diacetate intermediate 119 which is hydrolyzed with dilute sulfuric acid to yield the aldehyde 120. Direct oxidation of 118 to the carboxylic acid 121 proceeded in very low yield however, it can be produced efficiently by oxidation of aldehyde 120 using silver nitrate in dioxane. Reduction of aldehyde 120 with sodium borohydride in methanol gives a 90% yield of 2-hydroxymethyl derivative 122 which reacts with acetyl chloride or thionyl chloride to produce the 2-acetoxymethyl- and 2-chloromethyl-4,8-dihydrobenzo[l,2-A5,4-3 ]-dithiophene-4,8-diones 123 and 124, respectively. 

Tertiary amine oxides can be converted into TV-hydroxy secondary amines provided that one of the TV-substituents can be selectively eliminated. This procedure has been applied to the synthesis of secondary A-hydroxy-a-amino acids 34 from the corresponding secondary a-amino acids using the /V-cyanoethyl group for transient protection of the secondary amine (Scheme 10) J40l More recently, direct oxidation with 2,2-dimethyldioxirane of a primary amine has been described for H-L-Val-OMe (82% yield) and H-L-Phe-OMe (54% yield))13 The reaction proceeds smoothly without epimerization, but no experimental details have been reported. 

Electron-donating substituents direct the incoming nucleophile predominantly to the meta-position and electron-withdrawing substituents to the ortho-position. Oxidative demetallation (DDQ, iodine) is applied to reoxidize the cyclohexadienyl ligand, releasing a substituted arene. Addition of nucleophiles to halobenzene-FeCp complexes leads to nucleophilic substitution of the halo substituent (Scheme 1.34). Demetallation of the product complexes is achieved by irradiation with sunlight or UV light in acetone or acetonitrile. 

The major studies in this field are the work of one group102 using mainly in vitro techniques. The action of xanthine oxidase (XO), a milk enzyme, converts purine through hypoxanthine and xanthine to uric acid, in which the order of oxidation is seen to be the same as for base substitution of 2,6,8-trichloropurine. It was first held that the nucleophilic reagent responsible was water, which added across the double bonds and resulted in dihydropurines which then lost hydrogen, so restoring the aromaticity of the system.103 This view has now been modified and hydroxyl-ions are assumed to be the nucleophiles.104 As purine contains no substituents, directive influences are supplied by the dipolar forms extant at the time of reaction, of which 59 represents... 

The o-, m-, and p-dichlorobenzenetricarbonylchromium complexes 18a-c react with stabilized carbanions LiCHRRi (R = Ph, C02Et Ri = CN, C02Et) both under phase-transfer conditions and in DMSO solution. Only one chloro substituent is replaced by the carbanion. In all cases, the intermediates are not isolated but are directly oxidized with iodine. Shorter reaction times and/or lower reaction temperatures are required in DMSO. It is possible to replace the second chloro substituent of the o- and p-dichloro regioisomers with a different nucleophile such as nBuS or CH(CN)C02Et [23]. 

Direct oxidation of furazans to furoxans has not been achieved. The resistance of the oxadiazole ring to oxidizing agents is illustrated by the preferential attack of potassium permanganate at alkyl substituents dimethylfurazan is converted into furazandicarboxylic acid via the methylfurazanmonocarboxylic acid (see Section 4.22.3.4.1). Furazans appear to be less susceptible to ozonolysis than furoxans. 

Alkyl groups, whether attached directly to the heterocycle or to aryl substituents, are oxidized by potassium permanganate to carboxylic acids. Both methylfurazancarboxylic acid and furazandicarboxylic acid can be formed from dimethylfurazan similarly di( p-tolyl)-furazan yields the di(p-carboxyphenyl) derivative (73MI42200). 

---