Amides nucleophilic aromatic substitution

Among the different chemical reactions usable to synthesize polymeric materials by step polymerisation are esterification, amidation, nucleophilic aromatic substitution and urethane (carbamate) formation. Polymerisation... 

Bromo 1 3 dimethylbenzene is inert to nucleophilic aromatic substitution on treatment with sodium amide in liquid ammonia It is recovered unchanged even after extended contact with the reagent Suggest an explanation for this lack of reactivity... 

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

Several chemical methods have been devised for identifying the N terminal ammo acid They all take advantage of the fact that the N terminal ammo group is free and can act as a nucleophile The a ammo groups of all the other ammo acids are part of amide linkages are not free and are much less nucleophilic Sanger s method for N terminal residue analysis involves treating a peptide with 1 fluoro 2 4 dimtrobenzene which is very reactive toward nucleophilic aromatic substitution (Chapter 23)... 

Nucleophilic aromatic substitution of the anthranilic acid derivatives, 72, on ortho-bromonitrobenzene affords the diphenyl-amine, 73. The ester is then saponified and the nitro group reduced to the amine (74). Cyclization of the resulting amino acid by heat affords the lactam (75). Alkylation on the amide nitrogen with 2-dimethylaminoethyl chloride by means of sodium amide affords dibenzepine (76). ... 

A mild and efficient a-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described <06OL1447>. Treatment of 2-chloro-benzo[//Jthiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[c(jthiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed a-arylation reactions. First, heteroaryl chlorides... 

A practical a-heteroarylation of simple esters or amides has been developed via nucleophilic aromatic substitution. Exposure of chlorothiadiazoles 317 and 319 to NaHMDS and tert-butyl acetate or iV-dimethylacetamide leads to the formation of functionalized... 

A note of warning both MOM acetals and methyl ethers ortho to electron-withdrawing groups—particularly oxazolines, aldehydes, imines and amides—are susceptible to nucleophilic aromatic substitution reactions involving loss of the alkoxy substituent ... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

In the original process using tin amides, transmetallation formed the amido intermediate. However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed. In the tin-free processes, reaction of palladium aryl halide complexes with amine and base generates palladium amide intermediates. One pathway for generation of the amido complex from amine and base would be reaction of the metal complex with the small concentration of amide that is present in the reaction mixtures. This pathway seems unlikely considering the two directly observed alternative pathways discussed below and the absence of benzyne and radical nucleophilic aromatic substitution products that would be generated from the reaction of alkali amide with aryl halides. 

A final mechanism for nucleophilic aromatic substitution occurs when aromatic halides are reacted with very strong bases, such as amide anion, or with weaker bases, such as hydroxide ion, at high temperatures. For example, an older industrial method for the... 

The amide can be formed by the reaction of acetyl chloride with the appropriate amine, which is produced by reduction of the nitro group of the starting material. A nucleophilic aromatic substitution of -F by -0(033)3 can take place because the ring has an electron-withdrawing nitro group para to the site of substitution. Acetic anhydride can also be used to acetylate the amine. 

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