Electrophilic amide activation

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

Special concern was also given in the development of milder reaction conditions using mixtures of trifluoroacetic anhydride and 2-chloropyridine or DMAP for electrophilic amide activation. 

Another useful method for introducing formyl and acyl groups onto aromatic nuclei involves the use of N,N-dialkylamides and phosphorus oxychloride this is the Vilsmeier-Haack reaction. The active electrophile shown in the mechanistic outline is a product of phosphorylation of the amide at oxygen ... 

Prolinamides are probably the most large group of (5)-proline (1) derivatives used in the intermolecular aldol reaction, due to their easy preparation, stability of the amide linkage and the enough acidity of the NH-moiety able to activate electrophiles by hydrogen bonding. 

Preformed enolates can be obtained not only from aldehydes and ketones, but also from carboxylic esters, amides, and the acids themselves. The corresponding carbonyl compound aWays acts irreversibly as the CH-acidic component. Thus, the term aldol reaction is no longer restricted to aldehydes and ketones but extended to all additions of preformed enolates to an aldehyde or a ketone. In contrast vith the traditional aldol reaction, this novel approach is based on a three-step procedure (usually, ho vever, performed as a one-pot reaction). First, the metal enolate 25 is generated irreversibly, vith proton sources excluded, and, second, the compound serving as the carbonyl active, electrophilic component is added. The metal aldolate 26 thus formed is finally protonated, usually by addition of vater or dilute acidic solutions, to give the aldol 27 (Scheme 1.4) [45, 46]. 

One of the early auxiliary-based carboxamides to be developed for enolate alkylations was the prolinol-derived amide 103, disclosed independently by Evans [77] and Sonnet [78] (Scheme 3.17). The corresponding enolates are sufficiently nucleophilic to participate in a wide range of alkylation reactions with activated and non-activated electrophiles. It was proposed that the high diastereoselectivity observed in the alkylation reaction arose from the chelated enolate 104. As is generally the case for amide-derived enolates, the Z-enolate is exclusively produced in the course of deprotonation. Some of... 

A-Acido imines (R R"C = N —X=0) like /V-acyl (X = CR) /V-sulfonyl [X = S(R)=0]2-7 or /V-diphenylphosphinoylimines [X = P(C6H5)2]3 are masked inline derivatives of ammonia. Compared to the imines themselves these activated derivatives are better electrophiles showing less tendency to undergo undesired deprotonation rather than addition of organometal-lics1812 The apparent advantages of these compounds have been exploited for asymmetric syntheses of amines, amides, amino acids and /J-lactams1-8 I6. 

The need for electrophilicity at the amide nitrogen was demonstrated by comparison of the mutagenic activity of 28a with that of two analogues with similar structure, A-benzoyloxy-A-benzylbenzamide 117, which possesses a leaving group but without anomeric destabilisation and A-benzyl-A-benzyloxybenzamide 118,... 

Protonated amides and carboxylic acids have also been shown to activate adjacent electrophilic centers. Although protonated carboxylic acids and amides are not typically considered stable cationic groups, in superacidic media they can be readily generated and many have been observed by spectroscopic studies.16 As an example of electrophilic activation by a protonated carboxylic acid, P-phenylcinnamic acid (35) is diprotonated in super- acid to give the dication (36, observable by NMR) which then reacts with benzene and gives the indanone (37) in good yield (eq 12).17 It is known that the 1,1-diphenylethyl... 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

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