N-Alkylation of primary amides

Reductive N-Alkylation of Primary Amides with Carbonyl Compounds... 

Scheme 10.11 Cobalt carbonyl catalyzed reductive N-alkylation of primary amides (partially reproduced from Ref [62]).

A. Zwierzak, ACS Symp. Ser. 171,169-172 (1981) N-Alkylation of Organophosphorus Amides. A New, Convenient Route to Primary and Secondary Amines". 

Another useful strategy for the activation of an amide towards hydrolysis involves intramolecular 0-alkylation of the amide carbonyl. An early rendition of this strategy entailed the use of 4-chlorobutanamides in which cleavage was initiated by treatment with silver(I) perchlorate in aqueous acetone. More re-cently the Fraser-Reid group showed that N-pent-4-enoyl derivatives are rapidly and efficiently cleaved under mild conditions by brief treatment with 3 equivalents of iodine in aqueous THF [Scheme 8.29]. These deprotection conditions do not affect oxidisable functionalities including p-methoxybenzyl ethers and alkyl sulfides though allyloxycarbonyl groups appear to be incompatible. Primary and secondary amines are readily protected as N-pent-4-enoyl derivatives by reaction with pent-4-enoic anhydride. 

Potassium fluoride in combination with alumina has been shown to be a good catalyst for the iV-alkylation of carboxamides, lactams and other N-heterocycles using alkyl halides or dialkyl sulfates under mild conditions [47]. The system was also used to AT-alkylate secondary amides and N,N-dialkylate primary amides. Potassium hydroxide and alumina make a useful combination for the catalysis of the selective mono-AT-alkylation of primary amines (e.g. equation 4.6) [48]. 

Several important hormones such as oxytocin, secretin, and LHRH are known to be peptidyl amides (1-3). In addition to these, other peptidyl amides such as indolicidin and the protegrins have been shown to exhibit potent antimicrobial activity (4, 5). The in vivo production of such compounds is via endogenous enzymatic cleavage of propeptides (6), making their synthesis by genetic engineering notoriously difficult. Furthermore, to facilitate the survival of synthetic peptidyl amides in vivo, an obvious defence against the action of carboxypeptidases is the N-alkylation of the carboxylic amide terminus. Such secondary amides would be expected to exhibit vastly different solubility and transport properties to primary amides, thus their chemical synthesis is of immense importance. 

Amides can be N-alkylated in good yield with alkyl iodides in the presence of potassium hydroxide in DMSO. A study has been made of the factors affecting the preparation of triamides by diacylation of primary amides with acid chlorides in the presence of pyridine. 

Lithium amides of primary / fZ-alkylamines yield N-(/ f2 -alkyl)-0-(/ f2 -butyl)hydroxylamines, whereas lithium amides of primary alkylamines yield A/-alkylbenzamides and LiOO—due to nucleophilic attack on the carbonyl group (245). 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

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... 

The course of the reaction of phosphinous amides with carboxylic acid chlorides is dependent on the characteristics of the iV-residue. Thus with N-aryl compounds this reaction gives chlorophosphanes and carboxamides. With AT-alkyl analogs the primary reaction products have not been identified but they hydrolyzed to carboxaldehydes [120]. 

Phthalimide and N-alkyl-toluenesulfonamide salts are similarly alkylated, and can furthermore be cleaved to polymer-bound secondary and primary amines respectively (57). Potassium pyrrolidonide gives polymer-bound tertiary amide, of interest as a solid cosolvent catalyst ... 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

O-Protonated cations of eimides in concentrated and anhydrous acids are now well characterized by nmr spectroscopy. O-Protonated cations of N,N-dimethyl amides are most easily observed, even in 72% perchloric acid which has a water activity of about 10 , because for tertiary amides the N-protonated forms is relatively less stabilized by hydration (Liler, 1972a). O-Protonated cations of N-alkyl amides show considerable exchange of NH-protons with the solvent in 72% perchloric acid owing to the intervention of the N-protonated form. For primary amides (acetamide), however, O-protonated cations are not observable in that solvent (Liler, 1972b),... 

Catalytic hydrogenation of (23-12) over palladium on charcoal results in the scission of the weak N—O bond and the formation of amino alcohol (24-1). This is converted to a pyrrolidine by an internal alkylation reaction. Thus, reaction of the intermediate with carbon tetrabromide and triphenyl phosphine presumably converts the alcohol to a bromide internal displacement by the primary amine forms the five-membered ring (24-2). Alkylation of that amine with the complex bromo amide (24-3) then affords the endothehn antagonist atrasentan (24-4) [25]. 

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