Activation of carboxyl groups in organic synthesis

Abstract

Activation of different carboxylic acids and amino acids using some selected heterocyclic compounds which contain light sensitive chromophore were investigated under different conditions with a view to identifying the specific conditions under which the activation of these carboxylic acids could be effected. These selective heterocyclic compounds are 2-mercaptobenzothiazole (1) and 2 - mercaptobenzothiazole (2) which are capable of undergoing facile conversion to the S-acyl derivatives. These S-acyl derivatives are easily transformed to the thermodynamically stable N-acyl derivatives under the experimental conditions used. A number of 3-acyl benzothiazoline-2-thiones, 3-acyl b e n z o x a z o l i n e - 2 - t h i o n e s , 3-(N-protected amino acid) benzoxazoline-2-thiones and 3-(N-protected amino acid) benzothiazoline-2-thiones were synthesised and characterised by analytical and spectral methods and subjected to nucleophilic attack using amines, amino acids and alcohols under direct and photochemical conditions. The resulting products were analysed and characterised. The main intention of these reactions is not the preparation of Simple amides and esters through a complicated route but to illustrate the usefulness of activation strategy. The results of these investigations can be summarised as follows: i) Direct nucleophilic attack of amines on 3-acyl benzothiazoline-2-thione was very quick and give products (amides) in very good yield. Regeneration of 3-mercaptobenzothiazole in quantitative yield is an attractive feature of this reaction. ii) Direct reaction of 3-acyl benzothiazoline-2-thione with alcohols was a failure, however, irradiation of 3-acyl b e n z o t h i a z o l i n e - 2 - t h i o n e in presence of equimolar amount of alcohol results in the formation of esters in very good yield. Though most of the 3-acyl derivatives react with alcohols under photochemical conditions, 3- benzoyl and o-chlorobenzoyl benzothiazoline-2-thione do not give rise to any ester. This observation points to the role of A-hydrogen at the acyl group, the formation of ketene intermediate - the ke step in the 51 photochemical activation of carboxyl group - is prevented. The mechanism of photochemical activation is essentially the same as that of 3-acyl thiazolidine- 2-thione. iii) The difference in behaviour of amines and alcohols towards 3-acyl benzothiazoline-2-thiones makes possible for the selective aminolysis of amino alcohols/phenols. Hydroxy amides are formed in very good yield and that too in a very short time. iv) Analogous to 3-acyl benzothiazoline-2-thiones, 3-acyl benzoxazoline-2-thiones form amides with amines, esters during irradiation and hydroxyamides on selective aminolysis. Good yield, ready conversion and isolation of 2-mercaptobenzoxazole in quantitative yield are the important characteristics of the reaction. vl The spectrophotometric monitoring of the aminolysis of 3-acyl benzo(thiazoline/oxazoline)-2-thione shows that the nature of the attacking amine has a profound influence on the rate of the reaction. With the increase in nucleophilicity at the nitrogen atom, the rate of aminolysis increases. vi) Investigation of aminolysis reactions of 3-acyl benzo(thiazoline/oxazoline)-2-thione using different solvent systems show that the formation of amides is favoured in chloroform solvent. Moreover a close scrutiny of the aminolysis using the above two acyl derivatives reveals that the aminolysis reaction is faster in 3-acyl benzoxazoline-2-thione. vii) The nucleophilic attack of 3-acyl benzo(thiazoline/ oxazo1ine)-2-thiones with amines is extended to the synthesis of dipeptides. A number of dipeptides like Z-Gly-Gly-OMe are prepared using the solution phase method of aminolysis of 3-acyl benzo(thiazoline/ oxazo1ine)-2-thiones with protected amino acids. These dipeptides are analysed and characterised. viii)One of the important shortocming usually encountered in solution phase method of peptide synthesis - the separation problem - to a large extend is overcome by carrying out the synthesis following solid phase peptide strategy. Peptide sequences of (di-, tri- and tetra-) are synthesised and characterised in very good yield and also in very high purity. From the investigations carried out it is found that 2- mercaptobenzothiazole and 2-mercaptobenzoxazole are effective candidates for the mild activation of carboxyl groups. The activated carboxyl derivatives are easy to handle unlike conventional acid chlorides and azides. The least reactivity towards water and very good shelf life are the added attractions of these activated carboxyl derivatives. Regeneration of the heterocyclic thiol in quantitative yield permits the recyclisation of the spent reagent and also helps in monitoring the reaction spectrophotometrically. The investigations carried out on the activation of carboxyl group in this work can be extended in different perspectives. Since peptide synthesis using solid phase method made the process easier and gave peptides in very high purity, peptides of any sequence can be designed by the activation strategy. The synthesis of biologically active small chain peptides like Gly-His-Arg-Pro, which is a 1-4 fragment of human fibrin chain, Gly-Gly-Tyr-Arg, an inhibitor of papain chain etc. can be investigated for this purpose. 1687169 Thus, the activation of carboxyl group both conventional and photochemical using 2-mercaptobenzothiazole and 2-mercaptobenzoxazole could animate interest not only in areas like the synthesis of peptides (solution phase and solid phase) and synthesis of macrolides, but also helps in studying the fundamental aspects of the reaction mechanism viz. the nature of the substrate molecule, the effect of solvent and the role of electronic structure of the attacking reagent.