Curtius rearrangement isocyanates from

Acyl azides may loose N2 on heating and rearrange to isocyanates (Curtius rearrangement), which may be solvolyzed. Some of the possibilities of classical carboxyl conversions are exemplified in the schemes below, which are taken from a triquinacene synthesis (R. Russo, 1971 C. Merder, 1973) and the ergotamine synthesis of A. Hofmann (1963). 

A third approach to 3-amino-/3-lactams is by Curtius rearrangement of the corresponding acyl azides. These are readily prepared from r-butyl carbazides, available via photochemical ring contraction of 3-diazopyrrolidine-2,4-diones in the presence of f-butyl carbazate (c/. Section 5.09.3.3.2). Thus treatment of (201) with trifluoroacetic acid followed by diazotiz-ation gives the acyl azide (202) which, in thermolysis in benzene and subsequent interception of the resulting isocyanate with r-butanol, yields the protected 3-amino-/3-lactam (203) (73JCS(P1)2907). 

The Curtius rearrangement can be catalyzed by Lewis acids or protic acids, but good yields are often obtained also without a catalyst. From reaction in an inert solvent (e.g. benzene, chloroform) in the absence of water, the isocyanate can be isolated, while in aqueous solution the amine is formed. Highly reactive acyl azides may suffer loss of nitrogen and rearrange already during preparation in aqueous solution. The isocyanate then cannot be isolated because it immediately reacts with water to yield the corresponding amine. 

Fusion of an all cyclic ring onto the piperidine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56 onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid ( ) followed by Curtius rearrangement leads to isocyanate Acid... 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

Section A of Scheme 10.15 contains a number of examples of Curtius rearrangements. Entry 1 is an example carried out in a nonnucleophilic solvent, permitting isolation of the isocyanate. Entries 2 and 3 involve isolation of the amine after hydrolysis of the isocyanate. In Entry 2, the dihydrazide intermediate is isolated as a solid and diazotized in aqueous solution, from which the amine is isolated as the dihydrochloride. Entry 3 is an example of the mixed anhydride procedure (see p. 948). The first stage of the reaction is carried out in acetone and the thermolysis of the acyl azide is done in refluxing toluene. The crude isocyanate is then hydrolyzed in acidic water. Entry 4 is a reaction that demonstrates the retention of configuration during rearrangement. 

The pyrido[l,2-tf][l,3,5]triazine-2,4(3//)-dione derivative 89 was obtained in a cycloaddition reaction of diphenyl-methyl isocyanate 90 with 2-pyridyl isocyanate 91 derived from the corresponding acyl azide via Curtius rearrangement <2002ARK438>. Compound 89 was also synthesized by the reaction of diphenylacetyl chloride 118 and picolinyl azide 116a in the presence of triethylamine (Scheme 11) <2002ARK438>. ... 

Curtius rearrangement is a well-known reaction of azides to form isocyanates [37]. It is taken into account in this overview, since in the example the azides are produced and reacted with a nucleophile in situ (in one flow), and thus the final product is composed from three starting components. 

The pyrido[3,2-rflpyrimidines 370 were prepared from 2,3-pyridinedicarboxylic acid anhydride 366 by the action of boiling MeOH to give the stable isomer of half-ester 367. Subsequent treatment with ethyl chloroformate in presence of EtsN and NaNs formed the azide 368 that was transformed by Curtius rearrangement into the isocyanate 369. Reaction of 369 with a series of amino acids under mild conditions gave adducts 370 (Scheme 12) <2003TL2745>. 

Eloy and Deryckere have applied their synthesis of isocarbostyrils (69HCA1755) to the preparation of thieno[2,3-c]- and thieno[3.2-c]-pyridines (Scheme 65) (70BSB301). Thermal-cyclization of 3-thienylvinyl isocyanate prepared from the corresponding azide (269) by Curtius rearrangement yields thieno[2,3-c]pyridin-7-one (270), which is transformed to (259) following usual methods. 

In both reactions, the alkyl group (R) gets transferred from the carbonyl group to the nitrogen to form an intermediate isocyanate (0=C=N-R). This is then hydrolysed by water to form carbon dioxide and the primary amine. The Curtius rearrangement has the advantage that nitrogen is lost as a gas that helps to take the reaction to completion. 

Forosamine is an amino sugar component of the antibiotic Lepicidin. Since Le-picidin is sensitive to acid and catalytic hydrogenation, an Fmoc group was selected to protect the amino function. A rather unconventional method was used to introduce it [Scheme 8.94].230 A Curtius rearrangement on the acyl azide derived from carboxylic acid 94.1 proceeded with retention of configuration to give the isocyanate intermediate 94.2 that was trapped with 9-fluorenylmethanol to afford the N-Fmoc derivative 94J in 72% yield. 

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