N-substituted amides

Reactions of acid halides (acyl halides). Acyl halides are very reactive and easily converted to esters, anhydrides, amides, N-substituted amides, and carboxylic acids. In the following reactions, X represents any halide. 

Reaction of anhydrides. Anhydrides react rapidly to form esters, amides, N-substituted amides, and carboxylic acids. 

The formation of diastereomeric amides from chiral acylating reagents is one of the most widely used reactions, which can be attributed to both the commercial availability of the chiral acids and the separability of the amide. N-Substituted L-prolyl chlorides are versatile... 

If the amide is an N-(mono- or di)-substituted amide, or the imide an N-substituted imide, the above alkaline hydrolysis will give a solution... 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

Primary amines (RNH2) yield N substituted amides (R CNHR)... 

With sodium azide, salts of secondary nitroparaffins rearrange to N-substituted amides (29). With SO2, primary or secondary nitroparaffins give imidodisulfonic acid salts (30). Potassium nitroform reacts quantitatively with nitryl chloride in ether to form tetranitromethane (31). 

Ammonolysis or aminolysis of an ester can be used to make the respective amide or N-substituted amide. 

A general method for malting Camps precursors has been developed/ Treatment of an anthranilic acid 15 with an acid anhydride or chloride in the usual way results in the corresponding benzoxazinone (16). Subsequent treatment with the dianion of an N-substituted acetamide furnishes P-keto amide 17. The reactions were run with crude 16, yields typically 50-80% overall. The effect of substituents on the reaction has not been extensively investigated. 

The cationic species 4 thus formed reacts with water to give the iminol 5, which tautomerizes to a more stable amide tautomer, the N-substituted carboxylic amide 2. Those steps correspond to the formation of amides by the Schmidt reaction. A side reaction can give rise to the formation of nitriles. 

A compound in which the —OH group of an acid is replaced by —NH2 is called an amide. When the —OH is replaced by —NHR, the product is called a nitrogen-substituted amide or, abbreviated, an N-substituted amide. One way to make amides is to react ammonia (or an amine) with an ester ... 

Aqueous, removable, pressure-sensitive adhesive compositions, useful for high-performance applications, comprise a mixture of a copolymer of alkyl (meth)acrylate and N-substituted (poly)amide of (meth)acrylic acid and a copolymer of alkyl (meth)acrylate and ethylenically unsaturated carboxylic acid, where at least one of the copolymers is an emulsion copolymer. Polyoxyalkyl-enes and phosphate esters may be used as surfactants [234]. 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

The reaction of amides with half equiv. of BTMA Bf3 and one equiv. of DBU in dichloromethane-methanol at room temperature gave N-substituted acylureas in fairly good yields (Fig. 34). Furthermore, in the presence of a large excess of methanol, the reaction of amides with one equiv. of BTMA Bt3 and two equiv. of DBU in dichloromethane gave methyl carbamates as main products (Fig. 35). In these reactions, we assumed that in the presence of DBU, intermediary isocyanates react with excess of amides to afford acylureas, and react with excess of methanol to afford methyl carbamates (ref. 42). 

The four mechanisms involving alkyl—N cleavage (the AL mechanisms) do not apply to this reaction. They are not possible for unsubstimted amides, since the only N—C bond is the acyl bond. They are possible for N-substituted and N,N-disub-stituted amides, but in these cases they give entirely different products and are not anude hydrolyses at all. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

N-Substituted amides can be converted to N-nitrosoamides, which are more easily hydrolyzable than the orginal amide. For example, see Rull, M. Serratosa, F. Vilarrasa, J. Tetrahedron Lett., 1977,A5A9. For another method of hydrolyzing N-substituted amides, see Flynn, D.L. Zelle, R.E. Grieco, PA. J. Org. Chem., 1983, 48, 2424. Ladenheim, H. Bender, M.L. J. Am. Chem. Soc., 1960, 82, 1895. 

N-Substituted amides can be prepared by direct attack of isocyanates on aromatic rings.The R group may be alkyl or aryl, but if the latter, dimers and trimers are also obtained. Isothiocyanates similarly give thioamides. The reaction has been carried out intramolecularly both with aralkyl isothiocyanates and acyl isothiocyanates.In the latter case, the product is easily hydrolyzable to a dicarboxylic acid this is a way of putting a carboxyl group on a ring ortho to one already there (34 is... 

When secondary amines are treated with nitrous acid, N-nitroso compounds (also called nitrosamines) are formed. The reaction can be accomplished with dialkyl-, diaryl-, or alkylarylamines, and even with mono-N-substituted amides RCONHR -I-HONO RCON(NO)R. Tertiary amines have also been N-nitrosated, but in these cases one group cleaves, so that the product is the nitroso derivative of a secondary amine.The group that cleaves appears as an aldehyde or... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

Primary and secondary amines add to ketenes to give, respectively, N-substituted and N,N-disubstituted amides " ... 

The addition of Grignard reagents to isocyanates gives, after hydrolysis, N-substituted amides. This is a very good reaction and can be used to prepare derivatives of alkyl and aryl halides. The reaction has also been performed with... 

Reaction of N-substituted amides with certain catalysts... 

Under appropriate conditions, they are readily N-nitrosated. The authors tentatively concluded that the major contribution of N-substituted amides, if they were present in foods, could be as precursors of N-nitroso compounds formed by vivo N-nitrosation reactions ... 

Five-membered ring imides in cyclopolymers of N-substituted dimethacrylamides such as PSPDM can be hydrolyzed to amic acids under moderately basic conditions. The resulting N-substituted amide is extremely resistant to basic hydrolysis. Consequently, this basic hydrolysis approach can still not be employed for the preparation of head-to-head poly(methacrylic acid). 

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