Acetanilide synthesis

Acetanilides, benzoyl-colour couplers in colour photography, 1, 372 Acetanilides, pivaloyl-colour couplers in colour photography, 1, 372 Acetazolamide — see l,3,4-Thiadiazole-2-sulfonamide, 5-acetamido-Acetic acid, acetamidocyano-ethyl ester, 1, 307 Acetic acid, 2-acylphenyl-isochroman-3-one synthesis from, 3, 858 Acetic acid, 3-benzo[6]thiophenyl-biological activity, 4, 912 Acetic acid, l,2-benzoxazol-3-yl-electrophilic substitution, 6, 48... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

In the Meth-Cohn quinoline synthesis, the acetanilide becomes a nucleophile and provides the framework of the quinoline (nitrogen and the 2,3-carbons) and the 4-carbon is derived from the Vilsmeier reagent. The reaction mechanism involves the initial conversion of an acylanilide 1 into an a-iminochloride 11 by the action of POCI3. The a-chloroenamine tautomer 12 is subsequently C-formylated by the Vilsmeier reagent 13 derived from POCI3 and DMF. In examples where acetanilides 1 (r = H) are employed, a second C-formylation of 14 occurs to afford 15 subsequent cyclisation and... 

It has been shown that acetamidothiophenes 22 can be converted to either chlorothieno[2,3-h]pyridines 23 or chlorothieno[2,3-h]pyridinecarboxaldehydes 24 using POCI3 and DMF by appropriate choice of reaction conditions. However, unlike the acetanilides, initial ring formylation rather than side-chain formylation is believed to lead to the formation of the pyridine ring. These reactions have been extended to the synthesis of the isomeric thieno[3,2-I>]- and thieno[3,4-I>]pyridines, 25 and 26, from 3-acetamidothiophene and 3-acetamido-2,5-dimethylthiophene, respectively. 

In a useful extension to the Meth-Cohn quinoline synthesis, pyridoquinolin-2-ones 27 are readily prepared in a one-pot procedure by sequential treatment of an acetanilide 3, firstly with the Vilsmeier reagent from DMF and POCI3 to afford the intermediate 16, which is then further reacted in situ with another secondary amide. ... 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in... 

Scheme 11.2 shows some representative halogenation reactions. Entries 1 and 2 involve Lewis acid-catalyzed chlorination. Entry 3 is an acid-catalyzed chlorination using NCS as the reagent. Entry 4 shows a high-yield chlorination of acetanilide by i-butyl hypochlorite. This seems to be an especially facile reaction, since anisole is not chlorinated under these conditions, and may involve the A-chloroamide as an intermediate. Entry 5 describes a large-scale chlorination done with NCS. The product was used for the synthesis of sulamserod, a drug candidate. 

The clinical success of hindered acetanilide derivatives, such as lidocaine, of course, resulted in the synthesis of many analogues. Branching in the acid moiety is consistent with activity as demonstrated by the local anesthetic properties of etidocaine (48)... 

The specific ortho functionalization of arylamines is obviously important in quinoline synthesis (cf. the rc-allyl procedure devised for the preparation of o-allylanilines used as indole and quinoline precursors).76 Recently acetanilides have been subjected to orthopalladation and the ensuing complexes converted into useful precursors of 2-substituted quinoline derivatives (Scheme 143).215... 

Methaqualone is being widely abused by youths in this country. Recently, in the northeast, some abusers were stricken with severe side effects, including bloody urine and gastrointestinal cramps. The tablets were found to be of clandestine manufacture.They contained fairly large amounts of impurities from a poor synthesis. The impurities were o-toluidine, o-aminobenzoic acid, and o-methyl acetanilide—again proving the old proverb Let the buyer beware. ... 

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give (V-acetylindole and N-acetyl-2-methylindole each in 45% yield [409]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 313 and 314 [410]. The regioselectivity was excellent with unsymmetrical alkynes. 

A phase-transfer catalysed nucleophilic displacement reaction on chloro-acetanilides by cyanate ions, followed by ring-closure (Scheme 5.10), provides a simple and viable synthesis of hydantoins [41], The formation of the hydantoins is inhibited by substituents in the orf/to-position of the aryl ring, but the addition of potassium iodide, or tetra-n-butylammonium iodide, generally increases the overall rate of formation of the cyclic compounds, presumably by facilitating the initial nucleophilic substitution step. 

Another base catalyzed side reaction is the formation of Michael adducts between the maleimide and the acetic acid present in the reaction mixture. In general, both the acetanilides and the Michael adducts are favored when high catalyst concentrations and high temperatures are used for the synthesis. 

Of numerous chloral condensations with aromatic hydrocarbons the most interesting for the synthesis of condensation monomers are the reactions with benzene [3], toluene [4], acenaphthene [5], phenol [6], anisol [7], acetanilide [8] and halobenzenes like chlorobenzene [9] and fluorobenzene [10]. In general terms, these reactions proceed according to Scheme 2.2 and give the desired 1,1,1-trichloro-... 

Answer The -NilCOCHj group is an or//io, para directing group. Thus, treating acetanilide with acetyl nitrate via procedure V-7 one can obtain C. Thus, the synthesis of Xll-a... 

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