Amide reactivity

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

A common explanation of the DMAP acceleration suggests that DMAP, as a stronger nucleophile than the alcohol, reacts with the O-acylisourea leading to a reactive amide ( active ester ). This intermediate cannot form intramolecular side products but reacts rapidly with alcohols. DMAP acts as an acyl transfer reagent in this way, and subsequent reaction with the alcohol gives the ester. 

A novel asymmetric synthesis of a-amino acids via electrophilic amination has been demonstrated by Zheng and Armstrong and co-workers.94 No +NHBoc was observed when lithium tert-butyl-A-tosyloxycarbamate (LiBTOC) was reacted with zinc and lithium enolates of 48. Transmetallation of the lithium enolate with copper cyanide was necessary to generate a reactive amide cuprate, which then added efficiently to the electrophile. The electrophilic amination of chiral cuprates with LiBTOC provided an expedient approach to a-amino acids with predictable absolute configuration in high enantiomeric purity and good yield (Scheme 24.23). 

Biological Reactivity of /8-Lactams /3-Lactams are unusually reactive amides and are capable of acylating a variety of nucleophiles. The considerable strain in the four-membered ring appears to be the driving force behind the unusual reactivity of /3-lactams. When a /3-lactam acylates a nucleophile, the ring opens and the ring strain is relieved. 

Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives (for details see Chapter 12) from direct addition to the carbonyl group, while with the ester it undergoes conjugate addition to give an amine. 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

Penicillin and related P-lactams kill bacteria by a nucleophilic acyl substitution reaction. All penicillins have an unreactive amide side chain and a very reactive amide that is part of a p-lactam. The P-lactam is more reactive than other amides because it is part of a strained, four-membered ring that is readily opened with nucleophiles. 

Shortly after the successful synthesis and characterization of various lanthanide(III) tris(amidinate) derivatives the first disubstituted lanthanide(III) amidinate species were reported. Such compounds appeared to be interesting synthetic targets due to their metallocene-like coordination environment which was expected to allow the isolation and characterization of stable though reactive amide, alkyl, and hydride species. In this respect, the bulky amidinate and guanidinate ligands resemble... 

The imide 189 is easily made from protected tartaric acid 190 and the vinyl silane 188 coupled in a Mitsunobu reaction. Reduction of one of the carbonyl groups of the imide 191 may seem tricky but the molecule is C2 symmetric so the two carbonyl groups are the same and once one is reduced the molecule is a much less reactive amide. The stereochemistry of the acetate in 192 does not matter as it disappears in the cyclisation to 186. Notice that the alkene geometry is retained. 

Preparation (4, 94). Details for the preparation have been submitted to Organic Synthesis. The phosgenation of amides is general caution the reaction can be exothermic. With less reactive amides DMF can be used as catalyst. AU a-haloenamines are highly hygroscopic. 

So far we have shown you conjugate additions mainly of a,P-unsaturated aldehydes and unsaturated a,P-ketones. You won t be at all surprised to learn, however, that unsaturated acids, esters, amides, and nitriles—in fact all carboxylic acid derivatives—can also take part in conjugate addition reactions. Two examples, an amide and an ester, are shown on the right below. But notice how the selectivity of these reactions depends on the structure of the unsaturated compound compare the way butyllithium adds to this a,P-unsaturated aldehyde and a,P-unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives from direct... 

Figure 19.1 shows the structures of various derivatives of acetic acid (acetyl chloride, acetic anhydride, ethyl acetate and acetamide) arranged in order of decreasing reactivity toward nucleophilic acyl substitution. Acyl chlorides are the most reactive, amides the least reactive. The reactivity order ... 

Protection of an alcohol function by esterification sometimes offers advantages over acetal protecting groups such as the tetrahydropyranyl ethers. Generally, acetals are stable in base and labile in acid, while esters are more stable in acid than acetals and are readily hydrolyzed in base. Esters are notably useful in reactions such as oxidations, but are not satisfactory in organometallic reactions. Acetates and benzoates are the most common ester protecting groups they can be conveniently prepared by reaction of unhindered alcohols with acetic anhydride or benzoyl chloride, respectively, in the presence of pyridine or other tertiary amine. The use of reactive amides such as N-acylimidazoles (imidazolides) allows the reaction to be carried out in the absence of added bases ... 

Although isatins having adjacent carbonyls of very different reactivity— amide vs. ketone—undergo a variety of chenucal reactions [86,87], the focus here is on synthetic transformations to indoles. Accordingly, isatins can be reduced directly to indoles (Scheme 11, equations 1-7) [16,89-93]. Given the availability of isatins from aromatic amines (e.g., Sandmeyer synthesis [86], Gassman synthesis [88]), the reduction of isatins to indoles can be an important alternative to other methods. 

It is worth noting that monocyclic p-lactams of weakly basic amines can be as chemically reactive as penicillins and cephalosporins. It is not necessary to make the P-lactam part of a bicyclic system to have a reactive amide. 

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