Carbamate from isocyanides

The common impurities found in amines are nitro compounds (if prepared by reduction), the corresponding halides (if prepared from them) and the corresponding carbamate salts. Amines are dissolved in aqueous acid, the pH of the solution being at least three units below the pKg value of the base to ensure almost complete formation of the cation. They are extracted with diethyl ether to remove neutral impurities and to decompose the carbamate salts. The solution is then made strongly alkaline and the amines that separate are extracted into a suitable solvent (ether or toluene) or steam distilled. The latter process removes coloured impurities. Note that chloroform cannot be used as a solvent for primary amines because, in the presence of alkali, poisonous carbylamines (isocyanides) are formed. However, chloroform is a useful solvent for the extraction of heterocyclic bases. In this case it has the added advantage that while the extract is being freed from the chloroform most of the moisture is removed with the solvent. 

Urethanes. Methyl carbamates (1) can be prepared from primary or secondary amines, alkyl halides, and carbon dioxide in a reaction promoted by copper(I) /-butoxide (equation I). The ligand t-butyl isocyanide can be replaced with tri-n-butylphosphine. Copper(I) f-butoxide is more effective than other copper salts. In the case of diethylamine, the intermediates a and b were isolated and b was converted to the methyl carbamate in 86% yield. 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

Another method used to remove phosgene substitutes from the desired products is to destroy them with appropriate nucleophiles such as water or alcohols. This method can, of course, only be applied when the product is insensitive to these nucleophiles, as is the case for carbamates, carbonates, ureas, cyanides, isocyanides, and alkyl chlorides. Chloroformates, carbamoyl chlorides, isocyanates, acyl chlorides, N-carboxylic anhydrides, and carbodiimides, on the other hand, cannot be purified by this method. Consequently, a synthesis of these compounds using phosgene is worthy of consideration. 

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