Alkylation of Amines and Amides

The alkylation of neutral amines by halides is one of the oldest known organic reactions. The process is complicated from a synthetic point of view in that it can 

Kobayashi, K. Soai, S. Ikeda, and T. Mukaiyama, Chem. Lett., 635 (1977). 

Schweng and E. Zbiral, Justus Liebig s Ann. der Chem., 1089 (1978) H. Loibner and E. Zbiral, Helv. Chim. Acta. 59, 2100 (1976). 

SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON 

The enhanced acidity of the NH group in phthalimide permits formation of an anion which is readily alkylated by alkyl halides or tosylates. The alkylated amine can be liberated by reaction of the substituted phthalimide with hydrazine. 

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are sufficiently fast that a mixture of products may be obtained. For this reason, when monoalkylation of an amine is desired, the reaction is usually best carried out by reductive alkylation, a reaction which will be discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid will normally result in complete reaction. 

Amides are only weakly nucleophilic and react very slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.  

Secondary amides can be alkylated by the use of sodium hydride for proton abstraction, followed by reaction with an alkyl halide  

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Alkylation of amines and amides with benzylic halides is an early and useful method for the protection of amines and amides. Primary amines can alkylate twice to give the W,N-dibenzyl derivative, but severe steric congestion prevents quatemisation [Scheme 8.199].410... 

Alkylation of amines and amides. Major and Peterson " replaced the two amino... 

KY zeolite induces mono-Y-alkylation of amines and amides by alkyl halides at 80°C with good yields and selectivity [49]. Sabu et al. investigated the acid properties and catalytic activities of natural kaolinitic clays containing transition metals for Friedel-Crafts alkylation [50]. High catalytic activity and selectivity for the reaction of benzyl chloride and benzene to diphenylmethane was reported. 

Simple palladium(II) salts such as chloride and acetate efficiently catalyse aerobic oxidative A-alkylation of amines and amides with alcohols. This method is suitable for a variety of sulfonamides, amides, aromatic and heteroaromatic amines as well as benzylic and heterobenzylic alcohols with a low loadings of the catalyst (0.5-1 mol%) and the alcohols. A selective carbon-carbon double bond assisted o-C-H olefination is catalysed by palladium(II) acetate. The terminal oxidant is oxygen. Addition of TFA is essential for any meaningful yield. (PdOCOCF3)+ has been proposed as the active catalyst. The observed large difference in the inter- and intra-molecular KIE values implied that the coordination of the C=C bond occurs before C-H palladation in the catalytic cycle consequently, a mechanism involving the initial coordination of allylic C=C bond to (PdOCOCF3)+ followed by selective o-C-H bond metalation has... 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of 5 2 displacement with C followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

TABLE 6.23 Room Temperature Rate Constants and Estimated Atmospheric Lifetimes for the Gas-Phase Reactions of Some Alkyl Amines and Amides with OH and 03b... 

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