Protective groups amides

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

Silyl-derived protective groups are also used to mask the thiol function. A complete compilation is not given here since silyl derivatives are described in the section on alcohol protection. The formation and cleavage of silyl thioethers proceed analogously to simple alcohols. The Si—S bond is weaker than the Si—O bond, and therefore sulfur derivatives are more susceptible to hydrolysis. For the most part silyl ethers are rarely used to protect the thiol function because of their instability. Silyl ethers have been used for in situ protection of the — SH group during amide formation. ... 

Many protective groups have been developed for the amino group, including carbamates (>NCO,R), used for the protection of ammo acids in peptide and protein syntheses, and amides (>NCOR). used more widely in syntheses of alkaloids and for the protection of the nitrogen bases adenine, cytosine, and guanine in nucleo-... 

A series of amides has been prepared as protective groups that are cleaved by intramolecular cyclization after activation, by reduction of a nitro group, or by activation by other chemical means. These groups have not found much use since the first edition of this volume and are therefore only listed for completeness. The concept is generalized in the following scheme ... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

Protective group chemistry for these amines has been separated from the simple amines because chemically they behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia ), again, because of the increased acidity of the NH group. 

Protection of the amide — NH is an area of protective group chemistiy that has received little attention, and as a consequence few methods exist for amide — NH protection. Most of the cases found in the literature do not represent protective groups in the true sense, in that the protective group is often incoiporated as a handle to introduce nitrogen into a molecule rather than installed to protect a nitrogen which at some later time is deblocked. For this reason many of the following examples deal primarily with removal rather than with both formation and cleavage. 

Isopropylidene and benzylidene" groups have been used to protect simultaneously amide nitrogens and a neighboring hydroxyl. They can be removed by acid hydrolysis or hydrogenolysis (Pd-C, hydrazine, MeOH, 95% yield), respectively. 

Reactivity Chart 9. Protection for the Amino Group Amides... 

Two new sections on the protection for indoles, imidazoles, and pyrroles, and protection for the amide — NH are included. They are separated from the regular amines because their chemical properties are sufficienth different to affect the chemistry of protection and deprotection. The Reactivity Charts in Chapter 8 are identical to those in the first edition. The chart number appears beside the name of each protective group when it is first discussed. 

The formation of vinylogous amides from primary amines and -dicarbonyl compounds gives rise to hydrolyzable amine derivatives with greatly decreased nucleophilicity of the nitrogen function. Thus these derivatives have found some use as protecting groups in peptide syntheses 617-619). 

The trityl group was introduced on a primary amide, RCONH2, in the presence of a secondary amide with TrOH, AC2O, H2SO4, AcOH, 60°, 75% yield. It is stable to BOC removal with 1 N HCl in 50% isopropyl alcohol, 30 min, 50°, but can be cleaved with TFA. The following table gives the cleavage rates with TFA for a number of protected primary amides. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

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