Trifluoroacetamides, amine protecting

A complex of copper ions was used for the chemoselective preparation of the 6, 3-di-NHBoc derivative of kanamycin A (29) from the parent AG (6) in 72% yield (Scheme 6.3b) [43]. Another example for selective amine-protecting group manipulations on the scaffold of the pseudo-trisaccharide scaffold of the AG sisomicin (13) is demonstrated in Scheme 6.3c. Three amine groups of sisomicin (13) were selectively protected using the NH-trifluoroacetamide and NH-Boc groups. The 6 -aminomethylene of the free base form of 13 was selectively... 

Protected primary allylic amines were generated from allylic carbonates and ammonia equivalents. Iridium-catalyzed allylic substitution has now been reported with sulfonamides [90, 91], imides [89, 91-93], and trifluoroacetamide [89] to form branched, protected, primary allylic amines (Table 5). When tested, yields and selectivities were highest from reactions catalyzed by complexes derived from L2. Reactions of potassium trifluoroacetamide and lithium di-tert-butyhminodi-carboxylate were conducted with catalysts derived from the simplified ligand L7. Reactions of nosylamide and trifluoroacetamide form singly-protected amine products. The other ammonia equivalents lead to the formation of doubly protected allylic amine products, but one protecting group can be removed selectively, except when the product is derived from phthalimide. 

Monoalkylation of support-bound amines can also be realized by a three-step protocol involving initial protection/activation of the amine (e.g. as 2-nitrobenzenesulfon-amide [132,133], trifluoroacetamide [102], or 4,4 -dimethoxybenzhydrylamine [66]) followed by N-alkylation and deprotection. In particular, if monomethylations (see, e.g., Entry 7, Table 10.7) or allylations are to be performed, this three-step strategy will generally give the best results. 

A simple modification of this technique has dramatic effects on the stability of the protecting group. If trifluoroacetyl is used rather than acetyl, the trifluoroacetamide (N-COCF3, N-TFA) is generated. Trifluoro-acetyl is usually attached by reaction of the amine with trifluoroacetic anhydride [(CF3C0)20] in the presence of triethylamine or pyridine, This group retains its stability to acid but is more sensitive to base (pH 1-... 

In contrast to esters, amide hydrolysis usually requires rather forcing conditions hence, amide protection of amines is not as common as gentler alternatives. Notable exceptions include trifluoroacetamides and phthalimides. Trifluoroacet-amides are so labile that they can be removed with potassium carbonate in methanol under conditions that preserve some methyl esters. 

Starting material for the synthesis of varenicline is o-bromofluorobenzene, which reacts (via benzyne) with cyclopentadiene in a Diels-Alder reaction. Oxidative ring-opening and reductive amination provides a N-benzylbenz-azepine derivative. After N-protection with trifluoroacetic anhydride, nitration with a mixture of nitric andtrifluoromethanesulfonic acids, reduction, and condensation with glyoxal, hydrolysis of the trifluoroacetamide as a final step provides the active compound in good overall yield. [568, 569]... 

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