Pyridine 1-oxide reaction with phosphorus oxychloride

Both pyridones can react with electrophiles at positions ortho and para to the activating oxygen atom. For instance, 4-pyridone reacts with electrophiles at the C3 position (the mechanism can be formulated from either mesomeric representation) to give intermediate 5.24. As with pyridine N-oxides, reaction with phosphorus oxychloride gives useful chloropyridines 5.25. We shall see the utility of 2- and 4-chloropyridines in the next section. 

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. 

Reaction of l-(tri-0-acetyl-/3-D-ribofuranosyl)imidazo[4,5-fc]pyridine 4-oxide (99) with phosphorus oxychloride or the Vilsmeier reagent gave 7-chloro-l-(tri-0-acetyl-/3-D-ribofuranosyl)imidazo[4,5-fc]pyridine (100) (82Mi4i00l). 

Thus, Mathis et al. [1, 2] investigated oxidation reactions with 4-nitroperbenzoic acid, sodium hypobromite, osmium tetroxide and ruthenium tetroxide. Hamann et al. [3] employed phosphorus oxychloride in pyridine for dehydration. However, this method is accompanied by the disadvantages that the volume applied is increased because reagent has been added and that water is sometimes produced in the reaction and has to be removed before the chromatographic separation. 

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... 

Halogenation of the imidazo[4,5-6]pyridine 4-oxides has provided some interesting results. Treatment of compound (123 R = H) with phosphorus oxychloride gave, with loss of the /v-oxide group, a mixture of the 5-chloro (124) and 7-chloro (125) isomers in comparable amounts in an overall 74% yield (Equation 3) <82JHC513>. The reaction of 3-methylimidazo[4,5-6]pyridine 4-oxide (123 R = CH3) with phosphorus oxychloride also gave a mixture of products but the yields were different, i.e. 5-chloro (124) (20%) and 7-chloro (125) (41%). However, with l-methylimidazo[4,5-6]pyridine 4-oxide (126), the chlorine atom was introduced exclusively into the more sterically hindered 7 position to give the 7-isomer (127). None of the 5-isomer was detected in this reaction (Equation (4)). 

Meutermans and Alewood [48] reported the solid-phase synthesis of tetrahydroisoquinolines 13 and dihydroisoquinolines 13a using the Bischler-Napieralski reaction (Fig. 5). The polystyrene resin-bound deprotected L-3,4-dimethoxyphenylalanine was acylated with acetic acid derivatives using N- [(IH-benzotriazol-1 -yl)(dimethylamino)methylene] -iV-methylmethana-minium hexafluorophosphate A-oxide (HBTU) as a coupling reagent. The product obtained was then treated with phosphorus oxychloride under optimized conditions to afford a Bischler-Napieralski cyclization. Hutchins and Chapman [49] reported the synthesis of tetrahydroisoquinolines 13b and 4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridines 14 via cyclocondensation of the appropriate dipeptidomimetic with various aldehydes (Fig. 6). 

Although the mechanism of chlorination of pyridine A-oxides by the action of phosphorus oxychloride, phosphorus pentachloride, or sulfuryl chloride has not been established, it seems most likely that some of these reactions involve intra- or inter-molecular attack by chloride ion or potential chloride ion following complexing at oxygen (see Sections II and IV). With a few exceptions, they are therefore more appropriately discussed under the heading of nucleophilic substitutions (Section IV, A, 3). One such exception may be the reaction of A-hydroxy-4-pyridone with sulfuryl chloride, which ultimately gives l,2,2,3,3,5,6-heptachloro-2,3-dihydro-4-pyridone (65). It has been proposed that the first step in this reaction is the formation of 3,5-dichIoro-AT-hydroxy-4-pyridone.157 If this is so, then it must involve electrophilic attack at the two /3-positions, followed by the more usual nucleophilic substitutions. 

PHOSPHORUS OXYCHLORIDE (10025-87-3) Fumes in moist air. Contact with water, steam, or alcohols produces hydrochloric acid, phosphoric acid, and phosphine gas, which is pyrophoric, with possible ignition or explosion (may be a delayed reaction). Contact with air produces corrosive fumes. Violent reaction with carbon disulfide, 2,6-dimethylpyridine-V-oxide, dimethyl sulfoxide, ferrocene-l,l -dicarboxylic acid, pyridine, zinc powder. Reacts, possibly violently, with acids, alkali metals, alkalis, combustible materials, dimethyl formamide, organic matter, zinc powder. Incompatible with acetic anhydride, A,AI-dimethyl formamide, 2,5-dimethylpyrrole, sodium. Rapid corrosion of steel and most metals, except lead, occurs in the presence of moisture. 

Thionyl chloride, as well as other inorganic acid chlorides, reacts with polyols to form mixed esters (see under Sulfate esters. Chapter III). In the presence of pyridine, partial chlorohydrin formation may occur (95), Selenium oxychloride forms a selenite ester upon reaction with mannitol (96), Phosphorus pentachloride yields unsaturated chlorohydrins of mannitol and galactitol which have the composition CeHeCU (97), Extremely interesting are the so-called complexes of alditols with various inorganic polybasic acids, their salts, or anhydrides in aqueous solutions. Complexes with boric, molybdic, tungstic, and other acids, as well as the oxides of antimony and arsenic, have been reported. It is believed that these complexes are true esters with one or more moles of alditol, a chelate type of structure being involved at some point. For the hexitols a compound with boric acid such as the following is postulated (98),... 

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