The Acid Chloride Method

The chlorine atom is an obvious choice for the role of the electron-withdrawing moiety (X). The powerful activation present in acid chlorides was well known by the turn of the century when the first attempts at peptide bond formation were made. Yet, both preparation and application of amino acid chlorides are far from unequivocal and the success achieved with the add chloride method (Emil Fischer 1903) remained fairly limited. Conversion of the carboxyl group of the amino acid (partially blocked by the amine-protecting group Y) to the chloride was carried out with phosphorus pentachloride in the cold  

While the HCl generated in the reaction readily escapes, the acid chlorides remain contaminated with the less volatile phosphorus oxychloride. The use of 

Under the conditions of the reaction, however, the commonly applied alkyloxy-carbonyl blocking groups become involved in the process and give rise to the formation of N-carboxyanhydrides (Leuchs anhydrides Leuchs 1906) 

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Method (1) is most frequently used for aliphatic acid amides, while Methods (2a), (2b) and (zc) are used most frequently for aromatic acid amides. Of the last three methods, the Acid Chloride Method (zb) is the most rapid and certain. The Ester Method (za) is practicable only when the amide is insoluble in water, and even then is often very slow unless the ester itself is appreciabb soluble in the aqueous ammonia solution. 

The acid chloride method was successfully employed to produce a number of 1,1 -disubstituted ferrocenoyl peptide and amino acid systems.42-44 Active esters, initially employed by Degani and Heller for introducing the Fc-label into larger proteins at the... 

If in the second stage another zinc alkyl be used, tertiary alcohols con-taming two or three different alkyl groups can be prepared (A., 175, 374 188,110,122 0., 1910, II., 1201). Only zinc methyl and zinc ethyl thus furnish tertiary alcohols zinc propyl produces only those of the secondary type (B., 16, 2284 24, R., 667). The historical importance of the acid chloride method lies in the fact that in 1864 it led to the discovery of tertiary alcohols. 

The reaction of 42 with 43 was attempted with dicyciohexylcarbodiimide (DCC) or water-soluble carbodiimide in solvent systems. All these reactions seemed to be unsuccessful because of the low solubility and low reactivity of 43. Among the methods of activation of a carboxy group, only the activated ester method of p-nitrophenyl ester was successful. In the acid chloride method a side reaction with the amino group of adenine was reported56. ... 

The acid chloride method has been successfully used for the synthesis of depsipeptides by O-acylation of hydroxy acids. Although Fmoc amino acid chlorides were recommended for such reactions, and can be used for the introduction of the first amino acid onto hydroxy resins for SPPS, oxazol-5(4//)-one formation promoted by the presence of the required tertiary amine leads to relatively low yields compared to other activation methods such as those involving UNCA groups. ... 

Bechtolsheimer, H.-H. Kunz, H., Coupling of Sterically Hindered Peptide Bonds - A Renaissance of the Acid Chloride Method. Angew. Chem. Int. Ed. Engl. 1982, 21, 630. 

Several major synthetic approaches are available for the preparation of Fc-peptide conjugates. The acid chloride, active ester, and the oxazolone methods are all viable approaches that will result in the formation of the desired conjugate.28 The acid chloride method makes use of... 

Friedel-Crafts reaction of the difunctional acid chloride of 361 gave exclusively monocyclization to 362 (70%). Compound 363 (obtained as a 1.8 1 mixture of cis-trans isomers, 67%) gave a mixture of 364 (54%) and 25 (20%) from reduction plus dehydration. Dehydrogenation of this mixture produced 25 only (50%). Lamberton and Paine129 used the acid chloride method to convert acid 364a to phenol 364b (42%, m.p. 250°C methyl ether, m.p. 163°C). 

The acid chloride method comprises the condensation of aromatic tricarboxylic acid chloride with aromatic diamine. This method is subdivided... 

The diene insertion reaction will take place intramolecularly if the diene system is part of the acyl group in the acylcobalt tetracarbonyl (13). Thus, /ra j-2,4-pentadienoyl(triphenylphosphine)cobalt tricarbonyl, prepared by the acid chloride method, cyclizes on heating in ether solution in a closed vessel at 75° C for an hour, to 7r-cyclopentenonyl(triphenylphosphine)cobalt dicarbonyl in 30% yield. 

Comments l,l -Carbonyldiiinidazole is an effective reagent and in most cases avoids the problems of racemi-zation, enantioselectivity and other side reactions which can occur when using the acid chloride methods [69]. 

Scheme 1 Synthesis of ferrocenoyl amino acid esters (3) and peptides (4) via the acid chloride method.

The coupling of sterically hindered amino-acid fragments has been achieved, using the acid chloride method and the acid-stable (Peoc) protecting group (Scheme 147). ... 

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