Acid anhydrides Curtius reaction

Phenylcyclopentylamine has also been prepared from 1-phenylcyclopentanecarboxylic acid by means of the Hofmann degradation of the intermediate amide4 6 and from the intermediate carboxylic acid chloride by the Curtius reaction.6 In the method described, using the mixed carboxylic-carbonic anhydride,7 improved yields of the amine are obtained. 

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>. 

Curtius reaction. The overall process of converting an acid through the azide and isocyanate into an amine is known as the Curtius reaction. For application of the Curtius reaction to Cii-2-phenylcyclopropanecarboxylic acid, J. Weinstock found the route to the azide through the acid chloride unsatisfactory because of ready isomerization to the trans acid chloride. An efficient alternative method utilizes a mixed anhydride intermediate of a type found serviceable in the synthesis of peptides. A solution of the acid in aqueous acetone was treated with triethylamine to... 

Curtius Reaction. The Curtius reaction involves conversion of an acid chloride (or anhydride) to an isocyanate (eq 14). Trapping of the isocyanate is possible in the presence of a nucleophile. Some cyclic anhydrides react to give isocyanates which can cyclize subsequently. 

The Curtius reaction of l-phenyl-3-azidocarbonyl-2-pyrazolin-5-one (320) in glacial acetic acid does not lead to the expected product (321), giving instead 2-acetyl-3-amino-l-phenyl-3-pyrazolin-5-one (322). A six-membered transition state involving the intermediate mixed anhydride (323) is proposed. 

Scheme 9.134. A representation of the formation of phenyiisocyanate from the reaction between the acid anhydride of benzenecarboxylic acid [benzoic anhydride, (QH5C0)20] and sodium azide (NaNs) foiiowed by rearrangement of the benzoylazide (a Curtius-type reaction, vide supra).

Diphenylphosphoryl azide (15), a stable, non-explosive liquid, functions as a convenient reagent for a modified Curtius reaction and as a coupling agent (Scheme 52) the yields in either reaction are high. Similarly, tri-methylsilyl azide is recommended for the Curtius rearrangement of acid anhydrides to isocyanates. 

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. 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

The reaction has been thoroughly investigated, especially with regard to reaction conditions, as it has been observed that different by-products can be formed. There is a marked effect of the reaction medium on the condensation between maleic anhydride and hydrazine. For instance, if hydrazine hydrate is added to 2 moles of the anhydride in acetic acid, the linear hydrazide (23) is formed. In ether or alcohol as solvent a mixture of products is formed and besides 23 the formation of the monohydrazide (24) has been assumed, as this upon heating is transformed into maleic hydrazide (21, R = Bi = R2 = H). Likewise, 23 is converted into maleic hydrazide and maleic acid at elevated temperature, and moreover this reaction occurs in aqueous solution. Another possible reaction product, A-aminomaleimide (25, R = Rx = R2 = H) or analogs, was reported first by Curtius although later workers reported failure to obtain these compounds, ... 

The Curtius rearrangement has been extensively utilized for the synthesis of numerous cyclo-propylamines 4 from cyclopropanecarboxylic acids 1. The necessary acyl azides 2 are most conveniently obtained by reaction of sodium azide with the mixed anhydride of the cyclopropanecarboxylic acid and ethyl chloroformate. ... 

N-oxide 220, which with acetic anhydride afforded the acetate 22L Treatment of 221 first with KaCOs/MeOH and then with SOCI2 led to the formation of chloride 222. Reaction of 222 with A -cyanomethylpyrrolidine gave the quaternary salt 223, which was, without isolation, converted into aldehyde 224 by treating first with f-BuOK and then with oxalic acid. Oxidation of 224 with pertrifiuoroacetic acid and then further oxidation of the N-oxide product with KMn04 gave the carboxylic acid 225. This compound was subjected to the Yamada modification of the Curtius rearrangement, then hydrolysis, to provide the amine 226. Treatment of 226 with... 

In 1899, Erdmann obtained the same compound in good yield from anthranilic acid and phosgene and suggested the name isatoic anhydride. An alternative synthesis of isatoic anhydride [2//-3,l-benzoxazine-2,4(lH)-dione, subsequently abbreviated as lA] was found by Curtius and Semper from phthalic acid monoazide (5) via o-carboxyphenyl isocyanate. Similar rearrangements were discovered by Bredt and Hor [from potassium phthal-imide (6)] and by Mohr [from phthalimide (7)] leading to IA via a Hoffmann reaction. 

The mechanism proposed for the Curtius degradation starts with the activation of carboxylic acid 119 by the (Boc)20, catalyzed by Zn(OTf )2, to generate carbonic anhydride 120, which is attacked by the azide ion to provide the unstable acyl azide 121 and sodium t-butoxide as a byproduct (Scheme 26). Next, isocyanate 122 is obtained by the decomposition of intermediate 121 with extrusion of N2. Reaction with sodium t-butoxide provides the desired carbamate 112. 

The thermal decomposition of acyl azides into isocyanate intermediates is known as Curtius rearrangement reaction (Scheme 5.2) [27, 28]. Conventionally used general methods to synthesize aroyl azides are limited to diazotization of hydrazides and reactions of NaNs with acid chlorides, mixed anhydrides, and Al-acyl benzotriazoles [35-38]. However, these procedures involve highly reactive chemicals which put significant limitations on functionalities of the substrate. The development of methodologically new, highly functional-group tolerant, catalytic routes to aroyl azides is particularly desirable. 

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