Urea acyl azide

Conventional chemistry converted carbinol 277 into acyl azide 278, which was treated under Curtius rearrangement conditions to obtain either amine 279 or urea derivative 280, the respective precursors of guanine derivative 281 and thymidine analogue 282. 

The acyl azide undergoes a rearrangement similar to the Hofmann rearrangement (method 446) and to the Lossen rearrangement (method 448). This step is carried out in inert solvents like benzene and chloroform to give the isocyanate directly or in solvents like alcohol and water which will react with the isocyanate to form urethanes and ureas. 

The preparation of acyl azides has received considerable attention due to the value of these compounds as synthetic intermediates. In the Gurtius rearrangement for example, acyl azides arc converted into isocyanates, urethans, ureas and amines and this aspect of the chemistry of acyl azides is considered in detail in a later chapter. The use of acyl azides in peptide synthesis has increased the scope of general... 

Acyl azides (61) and (62) ° and isocyanate (63), the reaction intermediates of the modified Curtius reaction using DPPA, have been isolated in a pure state, since they are relatively thermally stable, and further converted to urethanes or ureas by the addition of alcohols or amines respectively. 

Synthesis of 1,3,5-oxadiazines from acyl azides consists of treatment of the acyl azides 187 with urea or thiourea at 170 °C to afford the l,3,5-oxadiazin-4-ones 188a and 188b by diazido displacement with subsequent cyclization (Scheme 31) <1998MI91>. 

Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to-nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, often in situ, provides carbamates, ureas, and other A-acyl derivatives. Alternatively, hydrolysis of the isocyanates leads to primary amines. 

Aldehydes can also be precursors for the Curtius acyl azide rearrangement tScheme 4.24) Aliphatic and aromatic aldehydes can be converted to the corresponding acyl azides by treatment with iodine azide. Subsequent heating gave various carbamoyl azides in high yields. A radical pathway, proceeding by homolysis of the iodine-azide bond, was proposed. The resulting carbamoyl azides 65 are relevant precursors for the synthesis of amines or ureas, for example. 

Curtius rearrangement of these azides leads to ketones via loss of an isocyanic acid (HN=C=0) equivalent, which can be trapped in situ as shown for 49 where benzophenone resulted and addition of aniline to the isocyanic acid gave urea 50. or-Alkoxy- and or-amino acyl azides, meanwhile, are precursors to hemiaminals and hisaminals, respectively. Examples in complex natural product synthesis are shown for 81 and 66 in the Variations and Improvements Section. 

Curtius degradation of [l- " C]acyl azides and [ " C]carbonylation of aliphatic and aromatic primary amines have become established methods for the synthesis of [ " C]isocyanates, key precursors for the preparation of labeled ureas, carbamates and thiocarbamates (see also Chapter 7, Section 7.4). Phosgene, classically the most common reagent for preparing such compounds in normal organic synthesis, is less attractive for use in carbon- 14-labeled form because it is difficult to prepare in the laboratory (see Section 5.2), it is costly to purchase. 

Isocyanate Formation. The coupling reaction described above occurs via an acyl azide intermediate, which at 50 °C suffers a Curtius rearrangement to give an isocyanate (eq 2), which can further react with amines to give the corresponding ureas. 

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