Phosphorus oxychloride, reaction with amides

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). ... 

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),... 

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. 

Dihydralazine (67-3) is the less important of the two phthalazine antihypetensive agents its preparation is however recorded first because of its simplicity. Thus, reaction of phthaUiydrazide (67-1) with phosphorus oxychloride leads to the by now very famihar conversion of the amide functions to enol chlorides (67-2). The displacement of halogen by hydrazine leads directly to the antihypertensive agent dihydralazine (67-3) [76]. 

In 1958, Ikekawa10 synthesized 2,7-naphthyridine and various substituted derivatives. His approach involved the reaction of 4-methylnicotinic acid with formaldehyde to afford the lactone 99 (R = H). The reaction of 99 with ammonia in methanol yields the amide (100) which, on oxidation with chromium trioxide, afforded 2,7-naphthyridin-l-one (101). This substance was converted into 2,7-naphthyridine (102, R = H) by consecutive treatment with phosphorus oxychloride, hydrazine, and copper sulfate. The 3-methyl derivative was similarly prepared starting with acetaldehyde. 

Dihydrothieno[2,3-6][l,5]benzothiazepines (42) were synthesized from 2-(2-thienylthio)aniline (40). Compound 40 was acylated by treatment with acetic anhydride or benzoyl chloride to give N-acyl derivatives (41), which afforded compounds 42 by cyclization with phosphorus oxychloride and subsequent reduction with sodium borohydride or Zn/HCl. N-Dimethylaminopropyl derivatives 43 were prepared by reaction with di-methylaminopropyl chloride in the presence of sodium amide (Scheme 13) (67CZP124935 68CCC1846). 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Protopine has been isolated from Bocconia frutescens,110 Fumaria judaica,111 F. schleicheri,112 and Papaver bracteatum,146 cryptopine from F. schleicheri,112 and allocryptopine from B. frutescens110 and Zanthoxylum nitidum.141 The protopine ring-system has been prepared from tetrahydrobenzindenoazepines (75) by photo-oxidation to the amides (76) followed by reduction with lithium aluminium hydride and re-oxidation with manganese dioxide.148-150 The tetrahydrobenzindenoazepines have been prepared from A-chloroacetyl-/ -phenylethylamines (73) by cyclization to the lactam (74) followed by reaction with a benzyl bromide and phosphorus oxychloride. -Protopine (77 R R2 — CH2)148 and fagarine II (77 R1 = R2 = Me)149 have been synthesized in this way. 

Substituted 4- or 5-halopyrimidines with sodium amide in liquid ammonia give 4-methyl-1,3,5-triazines (Scheme 317) the reaction is general and yields are good cf., the related conversion of 6-substituted 2-bromopyridines into pyrimidines (Section 4.3.3.3.4). 4-Amino-5-nitrosopyrimidines are converted into 1,3,5-triazines by acetic anhydride or phosphorus oxychloride (Scheme 318). 1,3,5-Triazines can be obtained from 1,3,5-oxadiazinium cations (Section 3.2.1.6.1.3). 

A synthesis, which leads to enamines in the form of their iminium salts, involves the cyclization of N-fi-arylethyl tertiary amides with phosphorus pentoxide or phosphorus oxychloride (Bischler-Napieralski reaction)441-445. 

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