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Authors: Prakash, Om
Issue Date: 1976
Abstract: Heterocyclic compounds are present in various natural products such as alkaloids, vitamins, .antibiotics, cell constituents etc., and play a vital role in biological processes. Their economic importance is also considerable because some of these are valuable pharmaceuticals. Ihspite of the fact that chemistry of the heterocyclic compounds is comparatively recent, about half of all the organic compounds known belong to this class. The study of heterocyclic compounds is rather an observation of organic chemistry in its broadest aspect and as such its scope is very wide. The present study has been confined to the synthesis of few pharmacologically important nitrogen and oxygen heterocyclic compounds such as pyrimidine, pyrazole and benzofuran derivatives and physicochemical studies of some of these pyrimidines. Pyrimidine and its derivatives play a key role in biological systems . Their presence in nucleic acids, vitamins, coenzymes, uric acid and other purines is well recognized. Quite a few pyrimidine derivatives are used as drugs, for example, barbituric acid and its .1,2 derivatives, sulfadiazine etc. The recent use of 5-FU (5- fluorouracil) in the treatm'ent of cancer has further stimulated research fa this field. Oxygen heterocyclic compounds have also attracted special attention since some of the metabolites such as griseofulvin, citrfain. - 2 - fuscin, novobiocin, geodin, erdin and nidulin etc., are all oxygen heterocyclic compounds and are endowed with a wide variety of biological activity. In view of the great physiological and medicinal importance of the compounds as stated above, it was considered worthwhile to undertake some basic investigations on pyrimidine and benzofuran derivatives. The present work of thesis has been divided into two parts (A and B): PART (A) » Physico-chemical studies of some substituted pyrimidines: (i) Kinetic study of piperidino and morpholino-dechlorination of differently 5- substituted-2- chloro-4, 6-dimethylpyrimidines (dealt in Chapter I). (ii) Electrochemical reduction of some 5- substituted 4- hydroxy-2-methylthiopyrimidines at d.m. e. (dealt in Chapter II). These studies have been found to be especially suitable in evaluating the effect of substituents on the reactivity of 2-chloropyrimidine in the former and on half wave potential (Ei ) in the latter. 2 PART (B) : In this part, some synthetic studies of oxygen and nitrogen heterocyclic compounds have been carried out: (i) Some typical studies in benzofurans have been carried out. These have been described in Chapter HI, which has been subdivided into 3 sections: - 3 - (a) Synthesis of some 2-aroylbenzofurans in view of their antifertility activity. (b) A novel method for the synthesis of 3-alkylbenzofurans. (c) Synthesis of spiran derivatives related to griseofulvin having an azaheterocyclic ring C. (ii) Syntheses of a few typical 5-phenylazopyrimidines have been dealt in Chapter IV. and (iii) T. L.C. separation of a large number of differently substituted pyrimidines has been described in Chapter V. Physical methods are perhaps the most important tools in the hands of chemists for undertaking effective chemical research in the field of organic cheinistry. Although initiaUy applied to simple molechles, they are now being frequently used to tackle molecules of complex nature. The systematic application of these methods to heterocyclic compounds has been rather slow, this is perhaps due to the complexity of the reactions involved therein. A halogen atom at position -2, -4 or -6 in the pyrimidine is nucleophilic active, and therefore a kinetic method can be applied to study their reactivity. Chemical kinetics deals with aU the factors that affect the rate of reaction and therefore it provides one of the most powerful method for ascertaining the mechanism of a chemical change involving all elementary processes of atoms, molecules, radicals, ions or other species that originate and take part in the overall reaction. - 4 - It is, however, not always possible to get absolute information through kinetic studies. Therefore, theories based on certain postulates are put forward to explain the facts obtained by experiments. It generally happens that in order to accommodate the new facts, mechanisms are changed many times or a new concept is developed. Still the data on kinetic studies coupled with other techniques provide one of the most satisfactory ways for obtaining information about the mechanism and pathways involved. Furthermore, the courses of a large number of organic reactions are controlled by the reaction rate of several competing steps and only kinetic studies can predict the conditions required for favouring a desired product. Thus, kinetic studies are fruitful in two ways - firstly to investigate the intricacies involved and secondly to work out the conditions for optimum yields so that the wastage may be minimised and efforts utilized. Of the various classes of organic reactions, nucleophilic substi- 3-11 . tution reactions on carbon have been most extensively studied . fa the field of nucleophilic aromatic substitution, two classes of compounds are of special interest - nitrobenzene derivatives and N- hetero-aromatic substances. The reactions of both the classes are known for a long time and it has been recognised that they are fundamentally analogous. Although heterocyclic chemistry has expanded tremendously, the kinetic and mechanistic aspects of the subject have long been neglected. Such studies offer a potential advantage fa unravelling the reactions of heterocycles fa general and in the development of synthetic methods fa this field fa particular. 5 - Aza-activation is responsible for the nucleophilic displacement reactions in the pyrimidfaes. For quantitative evaluation of such an influence, it is necessary to study the kinetics of alarge number of reactions. Chapman and coworkers7 initiated these studies and acquired valuable data on the reactivity of chlorine atom at positions -2 and -4 in the pyrimidine ring. It has been found that chlorine at position -4 is more reactive than when it is at position -2. Further, the influence of methyl group on the reactivity of chlorine at position -2 has also been evaluated, fa extension of this work, the reactivities of other groups such as alkoxy12' 13, alkylthio14, alkylsulphonyl and alkyl sulphinyl15 both fa pyrimidfaes and purines have been determined kfaetically. fa all these cases, however, the effect of 5- substituent on the reactivity of chlorine at position -2 has not been undertaken so far. It was thought that 5- substituted derivatives of 2- chloro-4, 6- dimethylpyrimidine shouH be very suitable for such studies. During the course of these studies, the effect of different substituents at position-5 (H, CL Br, J, CH3, C2H,., n-C3H?, Ph,COOH), on the reactivity of chlorine atom (at position -2), has been evaluated. Further, the validity of Hammetfs relationship16 has been tested for the above reactions. Pyrimidines have also the property of acquirfag electrons under suitable conditions. Therefore, among the many physical methods, polarography, which can quantitatively measure the electron density in the - 6 - molecule, has been used fa their analysis. During the present investiga tions, some of 5- substituted-4- hydroxy-2- methylthiopyrimidfaes have 17 been synthesized by a modified procedure and subjected to polaro graphic reduction. Such studies are of considerable importance since the reactions at d.m.e. and in biological processes have been shown to 18 follow a similar pathway . Conclusions, which can be made as a result 19-24 of the studies carried out earlier ' and now durfag this work, are given below: (i) The most natural reduction site fa the pyrimidine system is 43 - carbon - nitrogen double bond ( ^C = N - ). (ii) The carbon nitrogen double bond fa position2:1 resists the reduction, being a part of the stable cyclic amidine system. (iii) Substituents fa the ring greatly alter the reducibility of pyrimidfaes. It has been observed that an amino or hydroxy pyrimidine gets reduced at relatively more negative potential. Further, if two or more such substi tuents are present, the reduction is almost inhibited. A hydroxy substituent at position -4 has been shown to exist 2 R mainly in keto-form . The tautomeric change results in the disappearance of the natural reduction site, a carbon- -nitrogen double bond at position4-3 (Ng • C4). (iv) Reduction of pyrimidine at d.m.e. can take two courses - one involving 2 electron transfer in which 3, 4 double bond is saturated and other where the dimerisation of the compound takes place. - 7 - AU the pyrimidfaes, studied polarographicaUy, viz 5-unsubstituted; 5-methyl-; 5-ethyl; 5-phenyl-; 5-p-methyl phenyl-; 5-p-methoxyphenyl and 5-chloro-4-hydroxy-2-S-methyl pyrimidfaes were prepared fa the laboratory by a modified method, fa which sodium hydride was used fa place of sodium to obtain a pure product and better yields. The technique employed in present studies for the separation of pyrimidfaes is 'thin layer chromatography' (t.l.c). Out of the various techniques of chromatography, "t.l.c.' is the most widely used technique today. It is now used by organic chemists, quality control technicians hospital personnel and others in affecting the separation of closely related products. The technique is easy to learn and its application is comparatively inexpensive. fa view of such great importance of the t.l.c. technique, it was considered worthwhile to apply this technique for the separation of various interesting pyrimidine derivatives. Thus, 15 pyrimidfaes were separated by 't.l.c.' method on silica gel *G' and their Rf values were determined fa different developers. Rf values can be utilized for the identification of individual pyrimidine derivative. The present synthetic study includes the synthesis of a few well known physiologically active compounds, rather than general examination of pyrimidfaes. Since 2-aroylbenzofurans possess antifertility and esterogenic actrity, a number of 2-aroylbenzofurans have bean prepared by various methods. Their preparation is described fa Chapter III(A). - 8 - The synthesis of 3- alkylbenzofurano, a synthetic intermediate fa the preparation of usnolic acid analogous, has been affected by an entirely new approach. Readily available coumaran-3-one when reacted with alkylidine phosphine (Wittig reagent) are found to give the corresponding alkylbenzofuran in good yield. The methods described 26 in literature are lengthy and tedious. The spirocoumaran ring skeleton in fungal metabolity griseofulvin' , has focussed interest on the spirans of benzofuran class, as possible antibacterials and fungicides. During this work, the carbocyclic spiran ring- ring C of the griseofulvin has been successfully replaced by pyrimidine and pyrazolone rings. It has been thought that insertion of these rings would alter the properties of the parent compound and one can except that the new derivatives might be better drugs. The substitution of these rings provides sufficient experience for chemical synthesis. 5-Phenylazopyrimidines have been shown to possess antitumor activity2^"2^. Various manipulations have been carried out in the pyrimidine ring to enhance the activity of these compounds. During this study, 6- methyl uracil, 2- amino-4- hydroxy-6- methyl- and 2-hydroxy-4 , 6- dimethylpyrimidines have been condensed with phenyl-diazonium chlorides from various anilines. The structures of these compounds have been confirmed by their reduction to 5-amino derivatives.
Other Identifiers: Ph.D
Appears in Collections:DOCTORAL THESES (chemistry)

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