Curtius

Curtius transformation An alternative to the Hofmann transformation for obtaining an amine from an ester via the hydrazide, azide and isocyanate. Thus ethyl ethanoate is converted into melhylamine by the following series of reactions ... 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

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). 

These compounds are easily prepared from the appropriate 2-aminothiazole and acyl chloride (see Section III.2.D) or by general heterocydization methods. Acyl chlorides may be replaced by the corresponding anhydrides (471). Acids themselves may be used as acylating agents provided that the imidazole-triphenyl phosphine mixture is used as a catalyst (472). The Curtius degradation of 247 yields 2-acetamido-4-phenylthiazole (248) (Scheme 149) (473). 

Diamides and triamides have been obtained from the action of an aqueous saturated solution of ammonia on the corresponding ester (Scheme 18) (88). Amides can also be obtained by the Curtius (16) or Hofmann reactions (80). Thus the Curtius reaction with 2-substituted 4-thiazolecarboxylic acids gives the 4-acetamido compounds (16). 

Current Patents Curry and curry powder Curry powder Curtain spin process Curtius degradation Curved laminates Curvilinear regression Curvularia falcata Curvularia lunata var. aeri Curvularia trifolii Curzate... 

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

Hydrazine [302-01-2] (diamide), N2H4, a colorless liquid having an ammoniacal odor, is the simplest diamine and unique in its class because of the N—N bond. It was first prepared in 1887 by Curtius as the sulfate salt from diazoacetic ester. Thiele (1893) suggested that the oxidation of ammonia (qv) with hypochlorite should yield hydrazine and in 1906 Raschig demonstrated this process, variations of which constitute the chief commercial methods of manufacture in the 1990s. 

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 ... 

The first synthetic route for isocyanates was reported in 1848 (10,11)- Subsequent efforts by Hofmann, Curtius, and Hentschel pioneered alternative synthetic approaches (12). These efforts highlighted the phosgene—amine approach. Staudinger presented the stmctural similarities between isocyanates and ketenes and stimulated interest in this class of compounds (13). However, it was not until 1945, when the world was pressed for an alternative to natural mbber, that synthetic routes to isocyanates became an area of great importance. Several excellent review articles covering the synthesis and chemistry of isocyanates have been presented (1 9). 

Preparation from Nitrene Intermediates. A convenient, small-scale method for the conversion of carboxyhc acid derivatives into isocyanates involves electron sextet rearrangements, such as the ones described by Hofmann and Curtius (12). For example, treatment of ben2amide [55-21-0] with halogens leads to an A/-haloamide (2) which, in the presence of base, forms a nitrene intermediate (3). The nitrene intermediate undergoes rapid rearrangement to yield an isocyanate. Ureas can also be formed in the process if water is present (18,19). 

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. 

Special reactions of hydrazides and azides are illustrated by the conversion of the hydrazide (205) into the azide (206) by nitrous acid (60JOC1950) and thence into the urethane (207) by ethanol (64FES(19)105Q) the conversion of the same azide (206) into the N-alkylamide (208) by ethylamine the formation of the hydrazone (209) from acetaldehyde and the hydrazide (205) and the IV-acylation of the hydrazide (205) to give, for example, the formylhydrazide (210) (65FES(20)259). It is evident that there is an isocyanate intermediate between (206) and (207) such compounds have been isolated sometimes, e.g. (211). Several of the above reactions are involved in some Curtius degradations. 

Of the classical Hofmann, Curtius, Lossen and Schmidt degradations, only a rare example of the first is known, hypobromite converting 4,7-diamino-2-phenyl-6-pteridinecar-boxamide (208) into 8-amino-2,3-dihydro-6-phenyl-l//-imidazo[4,5-g]pteridin-2-one (209 equation 64) (63JOC1203). 

The fundamental subject of this section is the transformation of A -pyrazolines into cyclopropanes (Buchner-Curtius and Kishner cyclopropane syntheses). The cyclopropane is often accompanied by alkenes (67HC(22)l). When applied to A -pyrazolines the reaction occurs via the A isomers (Scheme 37). 

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). 

Application of the Curtius reaction to the 3-carboxyl of a penicillin has provided intermediates which have been used for the construction of cephem derivatives. As can be seen in Scheme 23, this route allows the selective cleavage of the C(3)—N(4) bond of the thiazolidine ring, thereby allowing a reconstruction of that ring in a different form (72HCA388 and the following three papers). The preparation of a related intermediate is shown in Scheme 24 (76HCA2298). 

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... 

Pyrimidine-5-carboxamide, 4-amino-purine synthesis from, 5, 582 Pyrimidine-5-carboxamide, 4-amino- N- pheny synthesis, 3, 122 Pyrimidinecarboxamides Curtius degradation, 3, 82 dehydration, 3, 82 Hofmann degradation, 3, 82 hydrolysis, 3, 81 reactions, 3, 81 synthesis, 3, 127 Pyrimidinecarboxamides, thio-synthesis, 3, 128... 

Pyrrole-2-carboxamide, N,N-dimethyl-conformation, 4, 194 Pyrrole-3-carboxamide, N,N-dimethyl-conformation, 4, 194 Pyrrolecarboxamides synthesis, 4, 242 Pyrrole-2-carboxamides synthesis, 4, 148, 360 Pyrrolecarboxylhydrazides Curtius degradation, 4, 362 Pyrrole-2-carboxylic acid, l-benzyl-3-hydroxy-ethyl ester... 

D A R A P S K I Amino Acid Synthesis (see Curtius) Amino acid synthesis from ethyl cyanoacetates... 

Phenylsemicarbazide has been obtained by the action of hydrazine hydrate on diphenylurea, phenylurethane,i phenyl isocyanate, or the potassium salt of dibenzohydroxamic acid. For its preparation, Curtius method of treating phenylurea with hydrazine liydratc is better Ilian either the older method of... 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

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