Oxidation with phosphorus oxychloride

Treatment of pyridazine 1-oxides with phosphorus oxychloride results in a-chlorination with respect to the N-oxide group, with simultaneous deoxygenation. When the a-position is blocked, substitution occurs at the y-position. 3-Methoxypyridazine 1-oxide, for example, is converted into 6-chloro-3-methoxypyridazine and 3,6-dimethylpyridazine 1-oxide into 4-chloro-3,6-dimethylpyridazine. 

Treatment of 6-phenylphenanthridine N-oxide with phosphorus oxychloride results in reductive chlorination, the chlorine entering at position 2 (Scheme 12). 

Pyridine and quinoline /V-oxides react with phosphorus oxychloride or sulfuryl chloride to form mixtures of the corresponding a- and y-chloropyridines. The reaction sequence involves first formation of a nucleophilic complex (e.g. 270), then attack of chloride ions on this, followed by rearomatization (see also Section 3.2.3.12.5) involving the loss of the /V-oxide oxygen. Treatment of pyridazine 1-oxides with phosphorus oxychloride also results in an a-chlorination with respect to the /V-oxide groups with simultaneous deoxygenation. If the a-position is blocked substitution occurs at the y-position. Thionyl chloride chlorinates the nucleus of certain pyridine carboxylic acids, e.g. picolinic acid — (271), probably by a similar mechanism. 

Pyridine iV-oxides also provide access to 2-chloropyridines. Treatment of 4-cyanopyridine iV-oxide with phosphorus oxychloride under reflux for 24 h results in the formation of 2-chloro 4-cyanopyridine in 69% yield <2001TL6815> (Equation 80). 

Benzimidazole 3-oxides, e.g. (189), react with phosphorus oxychloride or sulfuryl chloride to form the corresponding 2-chlorobenzimidazoles. The reaction sequence involves first formation of a nucleophilic complex (190), then attack of chloride ions on the complex, followed by rearomatization involving loss of the fV-oxide oxygen (191 -> 192). 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

A piridazine ring forms the nucleus for a rather unusual nontricyclic antidepre.ssant. Condensation of the keto ester 136 with hydrazine leads to the cyclic hydrazide 137. Oxidation, for example with bromine, gives the corresponding pyridazone 138. The oxygen is then replaced by chlorine by reaction with phosphorus oxychloride. Displacement of the halogen in 139 with N-ethylami-nomorpholine affords minaprine 140 [30]. 

Acetanilide and maleic acid are condensed to give /3-(p-acetaminoben2oyl)acrvlic acid which is hydrogenated to give methyl- y-(p-aminophenyl)butyrate. That is reacted with ethylene oxide and then with phosphorus oxychloride to give the methyl ester which is finally hy-droly2ed to give chlorambucil. 

The iV-oxide derivative 272 when treated with phosphorus oxychloride yielded a 7-chloro compound 273 with simultaneous reduction of the iV-oxide function which could be hydrolyzed by sodium hydroxide to the 7-oxo derivative 274. This compound 274 also formed directly from 272 upon treatment with acetic anhydride-acetic acid. 

The conversion of 166 to 167 (Scheme 45) most likely involves initial acylation of an N-oxide function. Interestingly, 63 (but perhaps the authors meant 65) did not show typical A-oxide reactions either with phosphorus oxychloride or with acetic anhydride. ... 

The chloride ion is a very weak nucleophile, and no reaction is observed with uncharged pyridines, or with pyridine 1-oxides unless they are coordinated at oxygen. Chlorination of A-oxides may be carried out fairly easily by treatment with phosphorus oxychloride (at 40 °C to reflux for 0.5 to 5 h) or sulfuryl chloride (at 110 °C for 2 h) (Table 11). In the first... 

---