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Activation of carboxyl groups in organic synthesis

Shodhganga@INFLIBNET

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Title Activation of carboxyl groups in organic synthesis
 
Contributor Purashothaman, E
 
Subject organic synthesis
Carboxyl groups
 
Description 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.
Referencwes p.191-205, List of abrreviation included
 
Date 2010-07-23T06:52:25Z
2010-07-23T06:52:25Z
2010-07-23
April 1989
July 20, 1996
 
Type Ph.D.
 
Identifier http://hdl.handle.net/10603/241
 
Language English
 
Rights university
 
Format 205p.
CD
 
Publisher Kottayam
Mahatma Gandhi University
School Of Chemical Sciences
 
Source INFLIBNET