Phosphorus oxychloride amides

Recently Bredereck and his students have compared the reactivity of a variety of amide complexes in their reaction with 4-amino-l,3-dimethyl-uracil( ) and they came to the conclusion that a mixed carbonyl chloride, phosphorus oxychloride amide complex is the most reactive reagent. 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

An analogous acylation reaction has been described in another 3,4-dihydro-j8-carboline derivative. The amide 315, on Bischler-Napieralski ring closure with phosphorus oxychloride, yields an... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

The initial synthesis of papaverine is due to Pictet, and fittingly enough involved as its key step the name reaction. Acylation of veratrylamine (109) with dimethoxyphenylacetylchlo-ride affords the amide (110). Cyclization by means of phosphorus oxychloride constitutes the same reaction and affords the dihy-droisoquinoline (111). Dehydrogenation by means of a noble metal catalyst affords papaverine (107). ... 

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). ... 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Aluminum chloride-phosphorus oxychloride complex, 31, 88 Amberlite IR-4B resin, 32, 13 Amidation, of isocyanic acid with bromo-aniline and other aromatic amines, 31,8... 

The 2-aminoquinazolines 259 were prepared in two independent ways. The 2-quinazolinone 258 was transformed to 2-aminoquinazoline 259 by treatment with phosphorus oxychloride and subsequently with sodium amide in liquid ammonia, or with phosphorus pentachloride under carefully controlled conditions [75JCS(P1)1471]. Attempts to prepare the N-substituted derivatives failed, but the reaction was successful with the unsubstituted cis cyclopentane-fused homolog [76JCS(P1)1415]. 

Another useful method for introducing formyl and acyl groups is the Vilsmeier-Haack reaction.61 An Ac. V-di alkyl amide reacts with phosphorus oxychloride or oxalyl chloride62 to give a chloroiminium ion, which is the reactive electrophile. 

The acetylated nitriles can also be obtained by dehydration of the corresponding amides. Phosphorus oxychloride is employed as the dehydrating agent. In this way Zempl n and Kiss prepared hexa-acetyl-D-gluco-D-g w/o-heptononitrile, and Ladenburg, Tishler, Wellman and Babson, tetraacetyl-n-ribononitrile, tetraacetyl-n-arabononitrile and pentaacetyl-D-glucononitrile. 

Preparation of acetylated nitriles from amides. Tetraacetyl-j>-ribononitrile. > A mixture of 6 g. of tetraacetyl-n-ribonoamide, 6 g. of phosphorus oxychloride and 20... 

This method is very useful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if necessary can be oxidized to isoquinolines. A P-phenylethylamine (l-amino-2-phenylethane) is the starting material, and this is usually preformed by reacting an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing the adduct to eliminate methanol and give a P-nitrostyrene (l-nitro-2-phenylethene) (Scheme 3.17). This product is then reduced to the p-phenylethylamine, commonly by the action of lithium aluminium hydride. Once prepared, the p-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R = H) and then this is cyclized to a 3,4-dihydro-isoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride (Scheme 3.18). Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal. 

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