Urea derivatives reaction with, phosgene

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 12), which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype, in the synthesis of 146, reaction of the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141). Cyclization of the ortho nitrourea function by means of sodium hydroxide leads to the N-oxide (142) this last reaction represents... 

The reaction proceeds via the formation of an isolable tetrasubstituted urea derivative, the carbonyl group of which reacts with phosgene to give an intermediate chloroformyl group, which then undergoes decarboxylation. Other derivatives (R = R = Et, Pr, Me CH, or Me(CH2)3 R = Me, R = Ph) were found to behave in a similar way [433]. 

The urea derivatives (H0NR)jC=O were prepared from the reaction of phosgene with RNHOH (R = CMCj, cych, 1-adamantyl, Ph, PhCHj or PhjCH) [2255]. In contrast, with RNHOH (R = CMBj, cych or Ph), RNHC(0)NROH is said to be formed as the major product and (HONR)jC=0 as the minor product [1802]. 

The reaction of Me jCPCSiMe 3) j with phosgene occurs with the elimination of Me3SlCl and CO, and the formation via several detectable intermediates) of a cyclic phospha-urea derivative, (10.31), as illustrated in the following scheme [71] ... 

Reactions with nucleophiles other than alcohols can produce other carbonic acid derivatives. For example, reaction with anhydrous ammonia yields urea, 0 = C(NH2)2. Aromatic primary amines can, depending on reaction conditions, react with phosgene to form carbamoyl chlorides (Csuros et al., 1969). 

Double amidation of phosgene, to give symmetrical ureas, is considerably easier to perform. Considerable interest is attached to the recent reaction of imidazole with phosgene, which led to l,T-carbonyldiimidazole, an extremely reactive compound on account of the lability of its amide bonds 597 The ease with which the imidazole group can be replaced by other groups offers the widest possibilities for synthesis of other carbonic acid derivatives, carboxylic esters, amides, and hydrazides, peptides, phosphoric esters, etc., all under the mildest conditions.598 Since l,T-carbonyldiimidazole is hydrolysed even by atmospheric moisture, it must be prepared under the most strictly anhydrous conditions. 

Whereas the reaction of phosgene with an excess of a free amine leads to symmetrical urea derivatives, isocyanates can be prepared by the action of phosgene in excess on the hydrochlorides of primary amines. High temperatures are necessary for the latter reaction, which can be interpreted as preliminary loss of hydrogen chloride to give a carbamoyl chloride which decomposes, when heated, to isocyanate and hydrogen chloride ... 

It is, however, also possible to start with the free amine, provided that reaction is first converted with an excess of phosgene in the cold. The amine, sometimes in solution, is usually added to a cooled solution of an excess of phosgene the symmetrical urea derivative is not formed under these conditions, but instead a mixture of the amine hydrochloride and the carbamoyl chloride which then reacts further with phosgene as described above. For instance, the 4,4 -diisocyanate from diphenylmethane was prepared in this way.629... 

The following section highlights some selected recent applications of the use of phosgene equivalents in the preparation of Vilsmeier-type chlorinated derivatives of amides and ureas. Thionyl chloride, carbonyl bromides, phosphorus oxychloride, phosgene, triphosgene, oxalyl chloride, and p-toluenesulfonyl chloride are all efficient oxophilic promoters capable of generating Vilsmeier-type chloro imi-nium ion intermediate 1770 by reaction with formamides, particularly dimethyl-formaraide, and ureas. 

While the use of phosgene allows direct conversion of the alkylamine into the isocyanate, the phosgene-free route requires for the same transformation three sequential reaction steps. First, the alkylamine is reacted with urea. The resulting urea derivative is then reacted with an alcohol to give the corresponding urethane. The urethane can then be cleaved in a third step to the desired isocyanate while liberating the applied alcohol again. 

At higher temperatures, in an inert solvent such as chlorobenzene,, lV -disubstituted ureas react with COCl to give guanidine derivatives, RNHC(=NR)NHR (R = various alkyl or aryl substituents) [724a], formed from the further reaction of the Vilsmeier salt with an excess of urea. With an excess of phosgene present, -chloroformyl derivatives may be obtained [724a] ... 

The developed solid-phase approach started with the preparation of immobilised ureas 114 obtained via acylation of amino acids linked to acid-labile Sasrin resin 104 with ortho-methoxycarbonyl aryl isocyanates or activated para-nitrophenyl carbamates 113. Alternatively, ureas of type 114 could also be generated by reaction of anthranilic esters 115 with immobilised amino acid-derived isocyanates (easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of a base such as 2,6-lutidine) or activated carbamates 116 (Scheme 4.1.23). 

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