Amides protonated, activating electrophilic

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

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]. 

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. 

Nitriles (RCN) get hydrolysed to carboxylic acids (RC02H) in acidic or basic aqueous solutions. The mechanism of the acid-catalysed hydrolysis (Following fig.) involves initial protonation of the nitrile s nitrogen atom. This activates the nitrile group towards nucleophilic attack by water at the electrophilic carbon. One of the nitrile n bonds breaks simultaneously and both the n electrons move onto the nitrogen yielding a hydroxyl imine. This rapidly isomerises to a primary amide which is hydrolysed under the reaction conditions to form the carboxylic acid and ammonia. 

Perhaps the most interesting developments in the area of selective lithiations to appear this year have been concerned with the control of absolute stereochemistry. The application of chiral amide bases to the enantioselective deprotonation of epoxides was first described some years ago by Whitesell and co-workers, but this year several groups have reported on other aspects of these useful reaqents. Symmetrically substituted ketones (5 R=Me, CH2Ph) have been shown by Simpkins to undergo an enantioselective deprotonation under kinetically controlled conditions to give, after reaction with an electrophile (iodomethane, allyl bromide or acetic anhydride), optically active ketones (6) or enol acetates (7) (Scheme 2). The ability of a number of bases to discriminate between the two prochiral protons present in (5) were evaluated and the most effective of those studied was the camphor derivative (8) deprotonation of (5 R=Me) proceeded in 74% enantiomeric excess... 

Arylethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydroisoquinolines result from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. After protonation of the imine, a Mannich-type electrophile is generated since these are intrinsically less electrophilic than the intermediates in Bischler-Napieralski closure, a strong activating substituent must be present, and appropriately sited on the aromatic ring, for efficient ring closure. 

In an aldol reaction, an enolizable carbonyl compound reacts with another carbonyl compound that is either an aldehyde or a ketone. The enolizable carbonyl compound, which must have at least one acidic proton in its a-position, acts as a nucleophile, whereas the carbonyl active component has electrophilic reactivity. In its classical meaning the aldol reaction is restricted to aldehydes and ketones and can occur between identical or nonidentical carbonyl compounds. The term aldol reaction , in a more advanced sense, is applied to any enolizable carbonyl compounds, for example carboxylic esters, amides, and carboxylates, that add to aldehydes or ketones. The primary products are always j5-hydroxycarbonyl compounds, which can undergo an elimination of water to form a,j5-unsaturated carbonyl compounds. The reaction that ends with the j5-hydroxycarbonyl compound is usually termed aldol addition whereas the reaction that includes the elimination process is denoted aldol condensation . The traditional aldol reaction [1] proceeds under thermodynamic control, as a reversible reaction, mediated either by acids or bases. 

Proton removal adjacent to a heteroatom is further facilitated if the lithium can be internally coordinated to proximate electron donors, such as the carbonyl oxygen, permitting the formation of dipole-stabilized carbanions. Thus lithiations of various amides, thioamides, imides, esters, Boc derivatives of cyclic amines (pyrrolidines, piperidines, and hexahydroaze-pines), thioesters, )V,iV-dialkylthiocarbamates, and various formamidine derivatives are achieved conveniently using s-BuLi (eqs i3 i7) 32,43b.44.47a,48a Subsequent addition of electrophiles followed by hydrolytic removal of the activating carbonyl, carbamoyl, or formamidine moiety provides a valuable synthetic route to a variety of a-substituted amines, alcohols, and thiols. Successful alkylation of the dipole-stabilized car-banions may require the conversion of the initial lithio carban-ions into their organocuprate derivatives, e.g. by the addition of n-PrC=CCu. ... 

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