Imidazole carbamate hydrolysis

The imidazole carbamate group is more stable to hydrolysis in aqueous buffer than the NHS-carbonate group, which is similar in reactivity to an NHS ester. However, this means that the imidazole carbamate also is slower to react and couple with amines. NHS-carbonate reactions usually go to completion within 1-2 hours at room temperature, whereas imidazole carbamates typically require higher pH conditions and overnight incubations to get maximal yield of ligand coupling. 

To remove excess CDI and reaction by-products, Beauchamp et al. (1983) dialyzed against water at 4°C. However, the imidazole carbamate groups on mPEG formed during the activation process are subject to hydrolysis in aqueous environments. A better method may be to precipitate the activated mPEG with diethyl ether as in the protocol described previously for SC activation (Section 1.2, this chapter). 

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. 

Acetylation of the hydroxymethyl imidazole 63 affords the corresponding ester (64), nitration (65) followed by hydrolysis gives intermediate 66, and reaction of this alcohol with potassium cyanate in hydrogen fluoride gives the carbamate ronidazole (67).16... 

Aminoimidazole (25 R = H), which was generated in situ either by reduction of 4(5)-nitroimidazole (27 R = H) (Section III,A,1) or by hydrolysis of f-butyl-imidazole-4-carbamate (Section III,A,2) was diazotized in situ in tetrafluoroboric acid to give 4-fluoroimidazole (73JA4619, 73JOC3647). Diazotization was also successfully performed on the dihydrochloride salt of 4(5)-aminoimidazole (25 R = H) (87JOC5538). 

Three approaches to the synthesis of 4-amino-5-unsubstituted imidazoles (71) have been described and are summarized in Scheme 7. These are (a) reduction of 4-nitroimidazoles (72) (b) hydrolysis of carbamates and amides (73) (c) cyclization of nitrile derivatives (74). 

The other olefin piece for the diene synthesis was prepared via carbamate formation between alcohol 33 and icri-leucine (35) (Scheme 9). The alcohol was first activated with CDl to form acyl imidazole 34, which is labile to hydrolysis. The coupling of the acyl imidazole with icri-leucine (35) has to be carried out in anhydrous DMF at elevated temperature due to poor solubility of icri-leucine in DMF. The reaction afforded icri-leucine carbamate 27 in 84% yield. An impurity... 

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