Curtius rearrangements

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. 

During the more than 110 years since its discovery, chemists have explored the details of the Curtius rearrangement and applied it in synthesis. They have addressed mechanistic questions common to many other rearrangements Is the process concerted or stepwise How is 

During the 1890s, Thomas Curtius studied the preparation and reactions of acyl azides. For example, treatment of benzoylhydrazine (1) with nitrous acid provided benzoyl azide, which Curtius represented as 2, consistent 

Heating benzoyl azide with ethanol or benzoylhydrazine gave the corresponding urethane (5) or benzoylphenyl semicarbazide (6), respectively. The explosive diacyl azide 8, prepared from fumaric acid-derived 7, underwent double rearrangement in ethanol to the dicarbamate 9.  

Although early proposals by Stieglitz and Jones and Hurd invoked a univalent nitrogen derivative as an intermediate in the Curtius rearrangement, mechanistic studies support C N migration occurring in concert with extrusion of molecular nitrogen (10 12) as opposed to initial 

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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). 

In these cases the acyl azides formed have been used to prepare amines via Curtius rearrangement. The acyl chloride or azide intermediates can. however, also be reacted with amines or alcohols to form amides or esters. 

The Curtius rearrangement in acetic anhydride of the azide (8) prepared from 4-carboxythiazole yields 4-acetamidothiazole (Scheme 8) (47). The same reaction starting with ethyl-2-methyl-4-thiazolyl carboxy-late, failed to give the 4-aminothiazole (48). Heterocyclizations are more convenient synthetic methods (Chapter II. Table 40). 

A related reaction sequence, which proceeds through a Curtius rearrangement, allows the transformation of a-cyano acids into hydantoins (66) ... 

The preparation and properties of these tertiary aminimides, as weU as suggested uses as adhesives (qv), antistatic agents (qv), photographic products, surface coatings, and pharmaceuticals, have been reviewed (76). Thermolysis of aminimides causes N—N bond mpture foUowed by a Curtius rearrangement of the transient nitrene (17) intermediate to the corresponding isocyanate ... 

If primary or secondary amines are used, A/-substituted amides are formed. This reaction is called aminolysis. Hydra2ines yield the corresponding hydra2ides, which can then be treated with nitrous acid to form the a2ides used in the Curtius rearrangement. Hydroxylamines give hydroxamic acids. 

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). 

Indolo[2,3-d][l,3]thiazine-2,4-dithione formation, 4, 299 Indolothiazines synthesis, 4, 519 Indoloyl azides Curtius rearrangement, 4, 288 Indolyl anions acylation, 4, 232 alkylation, 4, 235 Michael-type additions, 4, 236 Indomethacin... 

An alternative to the synthesis of arylsulfonylmethylcarbamates by the Mannich condensation as described here, is the Curtius rearrangement of the hydrazides of arylsulfonylacetic acids. 

The Hofmann and Curtius rearrangements have been applied to 2-thienylacryl amides for the preparation of 2-thiophene acetaldehydes. The Hofmann rearrangement proceeds also with 3-thenamides but fails with 2-thenamide. ... 

In contrast to diamino/urazan, diamino/uraxan is probably unstable. All attempts to generate it from rearrangements shown in Scheme 107 failed. However, Curtius rearrangement of 3,3 -bis(azidocarbonyl)-4,4 -azofuroxan 182 with subsequent isomerization afforded 4,4 -diamino-3,3 -azofuroxan 183 in 69% yield (Scheme 108) (98DOK499, 98MI2, 98MI6). 

The thermal decomposition of an acyl azide 1 to yield an isocyanate 2 by loss of N., is called the Curtius reaction - or Curtius rearrangement. It is closely... 

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. 

An isocyanate 2 formed by a Curtius rearrangement can undergo various subsequent reactions, depending on the reaction conditions. In aqueous solution the isocyanate reacts with water to give a carbaminic acid 6, which immediately decarboxylates to yield an amine 3. When alcohol is used as solvent, the isocyanate reacts to a carbamate 7 ... 

Acyl azides can undergo photolytic cleavage and rearrangement upon irradiation at room temperature or below. In that case acyl nitrenes 8 have been identified by trapping reactions and might be reactive intermediates in the photo Curtius rearrangement. However there is also evidence that the formation of isocyanates upon irradiation proceeds by a concerted reaction as in the case of the thermal procedure, and that the acyl nitrenes are formed by an alternative and competing pathway " ... 

The Curtius rearrangement is a useful method for the preparation of isocyanates as well as of products derived thereof. The substituent R can be alkyl, cycloalkyl, aryl, a heterocyclic or unsaturated group most functional groups do not interfere. 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

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... 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

Like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. For example, the antidepressant drug tranylcypromine is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride. 

How would you prepare o-methvlbenzylamine from a carboxylic acid, using both Hofmann and Curtius rearrangements ... 

Curtius rearrangement, 933 diazotization reaction, 941 Gabriel amine synthesis, 929 heterocycle, 945... 

Curtius rearrangement (Section 24.6) The conversion of an acid chloride into an amine by reaction with azide ion, followed by heating with water. 

Claisen rearrangement, 660 conjugate carbonyl addition reaction, 725-726 Curtius rearrangement, 935 cyanohydrin formation, 707 dichlorocarbene formation, 227 Dieckmann cyclization reaction, 892-893... 

The methyl ester 2 can be converted into the trithiatriazepinamine 12 via the hydrazide 9. Nitrosation gives the azide 10. which undergoes a Curtius rearrangement to the isocyanate 11, which is not isolated but hydrolyzed in situ to the amine 12.418... 

The actual product of the reaction is thus the ketene, which then reacts with water (15-3), an alcohol (15-5), or ammonia or an amine (15-8). Particularly stable ketenes (e.g., Ph2C=C=0) have been isolated and others have been trapped in other ways (e.g., as P-lactams, 16-64). The purpose of the catalyst is not well understood, though many suggestions have been made. This mechanism is strictly analogous to that of the Curtius rearrangement (18-14). Although the mechanism as shown above involves a free carbene and there is much evidence to support this, it is also possible that at least in some cases the two steps are concerted and a free carbene is absent. 

The Curtius rearrangement involves the pyrolysis of acyl azides to yield isocy-anates. " The reaction gives good yields of isocyanates, since no water is present to... 

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