Acyl azides acid chloride method

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. 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

The acyl azide of Curtius [9, 10] and the acid chloride of Fisher [11] were the predominant methods of peptide bond formation until 1955 when Sheehan [12], Khorana [13], and their co-workers introduced the highly efficient A, N -dicyclohexylcarbodiimide (DCC) coupling reagent. In contrast to the older reagents, DCC did not require carboxyl group pre-activation, and could be used in situ. The convenience and efficiency of DCC were quickly recognized and incorporated into many peptide synthesis protocols. 

In 1956, Hattori and co-workers estabUshed that aluminum azide adds to alkyl isocyanates or acid chlorides in tetrahydrofuran to afford l-aUcyl-A -tetrazoline-5-ones in excellent yields [ 101 ]. Three years later, Horwitz and coworkers reported on the synthesis of l-aryl-A -tetrazoline-5-ones by reaction of aryl isocyanates with a mixture of sodium azide and aluminum chloride in tetrahydrofiuan at reflux temperature [102]. The in situ produced aluminum azide adds to the N=C-bond of the corresponding isocyanate 122 and yields the 1-substituted A -tetrazoHne-5-one 124. According to this method, different 1-substituted A -tetrazoUne-5-ones 124 were synthesized by reaction of phenyl isocyanate and further 1-p-substituted phenyl isocyanates with aluminum azide. In addition, acyl halides 123, like acetyl chloride and benzoyl chloride, were converted to 1-methyl and 1-phenyl-A -tetrazoline-5-one with aluminum azide under the same conditions (Scheme 28A). It is assumed that in the initial step of the reaction, aluminum azide is able to coordinate to the aryl isocyanate by foiu pathways, forming an aluminum salt 129. The first two possibilities (Scheme 28B 125 and 126) require the separation of an azide ion from the complex, recombination at the electrophihc carbon atom followed... 

Azide ions have been added to a variety of acyl chlorides under phase transfer conditions and react as anticipated. By this method, acid chlorides have been transformed into acyl azides in good yield as formulated in equation 9.4 [22]. The acyl azides thus produced can be further transformed into the corresponding isocyanates by a Curtius rearrangement [23]. 

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. 

The racemic acid 399 was treated with oxalyl chloride to afford an acyl chloride 401, which on reaction with anhydrous hydrazine yielded the hydra-zide 402. The latter was converted to the azide 403 by treatment with nitrous acid. Photolysis of 403 which a high-pressure mercury lamp afforded the lactam 404. This lactam was synthesized earlier by Japanese chemists by an entirely different method (187). 

The sodium azide pathway (Pathway A), Figure 4, begins with a thionylchloride treatment of the free acid to form the acyl chloride. Subsequent treatment with sodium azide may involve a non-aqueous environment (1,2-dimethoxy ethane, "dry method"), or an aqueous medium ("wet method"). The organic azide is recovered from the reaction mixture and converted into the isocyanate by the Curtius rearrangement. This may be accomplished in solid form ("dry method"), or in a non-aqueous solvent like dioxane or DMF ("solution method"). 

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