Acyl azides Curtius degradation

Amines have been prepared on insoluble supports by Hofmann degradation of amides [222] followed by hydrolysis of the intermediate isocyanates (Figure 10.5). One reagent suitable for this purpose is [bis(trifluoroacetoxy)iodo]benzene, which can be used both on cross-linked polystyrene [223] and on more hydrophilic supports such as polyacrylamides (Figure 10.6). Support-bound carboxylic acids can also be degraded via the acyl azides (Curtius degradation [224,225]) to yield isocyanates. 

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. 

Curtius reaction org chem A laboratory method for degrading a carboxylic acid to a primary amine by converting the acid to an acyl azide to give products which can be hydrolyzed to amines. kard e as re,ak-shan cyanaicohoi See cyanohydrin.. sT an al ka.hol ... 

Anhydride 150 and trimethylsilyl azide in dioxane yielded an acyl azide, which by thermolysis, and Curtius degradation spontaneously furnished the isocyanate 151 (72CB3958 74CB3533). Anhydride 152 was formed by silyl ester cleavage on hydrolysis [73MI2 90JCS(P1)375]. 

Curtius degradation of the acyl azide and subsequent transesterification with tert-butanol and hydrolysis resulted in the A/-BOC amino acid 156. Compound 156 was readily cyclized with thionyl chloride, resulting in anhydride 157 diendo, R = H, Me diexo, R = H) in one step. In the cyclization step, acid chlorides were formed first and thereafter an intramolecular cyclization took place with loss of hydrogen chloride (93BSB227,93T1985). 

Support-bound aliphatic alcohols react smoothly with isocyanates in the presence of catalytic amounts of a base to yield carbamates (Table 14.7). In an interesting variant of this reaction, isocyanates were generated in situ by Curtius degradation of acyl azides (Entry 2, Table 14.7). 

Support-bound isocyanates can be conveniently prepared from carboxylic acids by Curtius degradation. Because the reaction of the intermediate acyl azides with alcohols to yield esters is slow, Curtius degradation can be conducted in the presence of alcohols to yield carbamates directly (Entries 4 and 5, Table 14.8). 

Curtius degradation of acyl azides a. acyl azide from hydrazide... 

Curtius degradation of acyl azides (obtained from acid chlorides)... 

The mono-esters thus prepared have been used by Bolm et al. for selective synthesis of two-stranded peptidic structures with parallel arrangement of the peptide strands [12]. They also enable easy access to unnatural /i-amino acids in enan-tiomerically pure form. The latter reaction sequence involves conversion of the carboxyl group to an acyl azide and subsequent Curtius degradation [11, 13, 14]. 

The Curtius degradation of acyl azides (Figure 14.43) expels molecular nitrogen and at the same time leads to the [1,2]-rearrangement of the substituent that is attached to the carboxyl carbon. It is the simultaneous occurrence of these two events that prevents the formation of an energetically unacceptably disfavored acylnitrene intermediate. The rearranged product is an isocyanate. 

The isocyanate can he isolated if the Curtius degradation is carried out in an inert solvent. The isocyanate also can be reacted with a heteroatom-nucleophile either subsequently or in situ. The heteroatom nucleophile adds to the C=N double bond of the isocyanate via the mechanism of Figure 8.12. In this way, the addition of water initially results in a carbamic acid. However, all carbamic acids are unstable and immediately decarboxylate to give amines (see Figure 8.5). Because of this consecutive reaction, the Curtius rearrangement represents a valuable amine synthesis. The amines formed contain one C atom less than the acyl azide substrates. It is due to this feature that one almost often refers to this reaction as Curtius degradation, not as Curtius rearrangement. 

Fig. 14.44. A one-pot diastereoselective degradation of a carboxylic acid to a Boc-protected amine via a Curtius rearrangement Boc refers to tert-butoxylcarbonyl. The mixed anhydride B is formed by a condensation of the phosphorus ) reagent with the carboxyl group. The anhydride B acylates the concomitantly generated azide ion forming the acyl azide A. A Curtius degradation converts A to C, and the latter reacts subse-guently with tert-butanol to the Boc-protected amine.

Figure 14.44 also shows how the Curtius degradation of an acyl azide can be combined with the addition of ferf-butanol to the initially obtained isocyanate. This addition gives a carbamate. In the present case a fert-butoxycarbonyl-protected amine ( Boc-protected amine ) is formed. 

The Curtius degradation of acyl azides (Figure 11.39) consists of the thermolysis of the inner N=N double bond. This thermolysis expels molecular nitrogen and at the same... 

Numerous aminocyclopropanes have been prepared by the Curtius degradation (Scheme 1). The acyl azides (15) were obtained in many cases from the acid chloride (16) and sodium azide either in an organic solvent ( Dry Sodium Azide Procedure ) or in water ( Wet Sodium Azide Procedure ). A modified preparation was reported by... 

Acyl halides react with TMSA to give trimethylsilyl halides and the corresponding isocyanates in a range of 83-98% yields, which are rearranged from the acyl azides via the Curtius degradation (eq 2). However, a reaction of aroyl chlorides with TMSA in the presence of zinc iodide at 0 °C gives the corresponding azides in 85-96% yields (eq 3). ... 

Acylated Amino Acids. The complications arising in the Curtius degradation of amino acids are eliminated to a large extent when the amino group is acylated. Many azides of acylated aliphatic ot-amino acids have been synthesized, not for the purpose of remranging them to diamines which can be hydrolyzed to aldehydes, but for use as acylating agents in place of the less tractable acid chlorides. Curtius and his students have explored this field extensively. ... 

Asymmetric synthesis of unnatural j8-amino acids derivatives based on azide chemistry is known. Enantioselective desymmetrization of mera-anhydride 293 mediated by cinchona alkaloids gives optically active monomethylester 294. This compound was converted into the acyl azide, which underwent Curtius degradation followed by alcoholysis of the intermediate isocyanate affording 8-amino acid derivative 295 in high enantiomeric excess. The authors observed that Grubbs catalyst was able to polymerize norbomene-type monomer 295 affording the corresponding polymer 296 in quantitative yield (Scheme 3.45). 

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. 

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. 

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