Phosphorus atom oxychloride

Azinones are readily converted into the corresponding chloroazines on treatment with reagents such as phosphorus oxychloride or thionyl chloride (equation 96), via reaction of the carbonyl oxygen atom at the electrophilic phosphorus atom. This method can be used to introduce several chlorine atoms into polyaza heterocycles in a single operation, and the... 

The second most important nucleophilic substitution in pyridazine A-oxides is the replacement of a nitro group. Nitro groups at the 3-, 4-, 5- and 6-position are easily substituted thermally with a chlorine or bromine atom, using acetyl chloride or hydrobromic acid respectively. Phosphorus oxychloride and benzoyl chloride are used less frequently for this purpose. Nitro groups in nitropyridazine A-oxides are easily replaced by alkoxide. The... 

A variant on this structure, dioxyline, has much the same activity as the natural product but shows a better therapeutic ratio. Reduction of the oxime (113) from 3,4-dimethoxyphenyl-acetone (112) affords the veratrylamine homolog bearing a methyl group on the amine carbon atom (114). Acylation of this with 4-ethoxy-3-methoxyphenyl acetyl chloride gives the corresponding amide (115). Cyclization by means of phosphorus oxychloride followed by dehydrogenation over palladium yields dioxyline (116). ... 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

The incorporation of an indole ring system often leads to an improvement in the light fastness. A suitable example is Cl Acid Blue 123 (6.177), which is derived from 4,4 -dichlorobenzophenone. Condensation with l-methyl-2-phenylindole in the presence of phosphorus oxychloride produces the triarylmethane ring system. Replacement of the chlorine atoms with p-phenetidine, followed by sulphonation, gives the dye. 

Much the same activity is retained when the nitrogen atoms in the heterocyclic nucleus are shifted around. The convergent scheme to this related compound starts with the acylation of alanine (35-1) with butyryl chloride (35-2). The thus-produced amide (35-3) is then again acylated, this time with the half-acid chloride from ethyl oxalate in the presence of DMAP and pyridine to afford the intermediate (35-4). In the second arm of the scheme, the benzonitrile (35-5) is reacted with the aluminate (35-6), itself prepared from trimethyl aluminum and ammonium chloride, to form the imidate (35-7). Treatment of this intermediate with hydrazine leads to the replacement of one of the imidate nitrogen atoms by the reagent by an addition-elimination sequence to form (35-8). Condensation of this product with (35-4) leads to the formation of the triazine (35-9). Phosphorus oxychloride then closes the second ring... 

Ketone Method. In the ketone method, die central carbon atom is derived from phosgene. A diarylketone is prepared from phosgene and a tertiary arylamine and then condenses with another mole of a tertiary arylamine (same or different) in the presence of phosphorus oxychloride or zinc chloride. The dye is produced directly without an oxidation step. Thus, ethyl violet CT Basic Violet 4, is prepared from 4.4 -bis(diethy]amino)benzophenone with diethylaniline in the presence of phosphorus oxychloride. This reaction is very useful for the preparation of unsymmetrical dyes. 

Pyridine can be activated to electrophilic substitution by conversion to pyridine N-oxide 5.17. At first sight it is curious to consider oxidation (i.e. electron loss) as a means of activating a system to electrophilic substitution, but 5.17 can act rather like a sterically-hindered phenolate anion towards electrophiles, producing intermediate 5.18 which then loses a proton to give substituted N-oxide 5.19. For this methodology to be useful it is of course necessary to remove the activating oxygen atom. This can be done with phosphorus trichloride, which becomes oxidised to 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. 

As has already been mentioned, halogenation of the A-oxides with phosphorus pentachloride, phosphorus oxychloride, or sulfuryl chloride involves nucleophilic attack by halide ion upon the substrate complexed at the oxygen atom (with the last reagent, a complex... 

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