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Authors: Raisinghani, Meera Rani
Issue Date: 1972
Abstract: Heterocyclic compounds occupy a unique position in the field of organic chemistry. Conventionally they can neither be categorised under aromatic nor aliphatic compounds. In fact they belong to an entirely new category (remaining unnamed so far) which takes In its fold a large variety of compounds of physiological and medicinal importance, both naturally occuring and synthetically prepared. Truly speaking, the major developnents in the field of pharmaceu ticals have come through the synthesis of nitrogen hetero cyclic compounds - an approach based on the fact that most of the naturally occuring biologically active substances have in their skeleton at least one nitrogen. Synthesis of nitrogen heterocycles, thus became an important preoccupation of organic chemists and innumerable outstanding achievements have been made by them. One aspect that deserves special mention is concerned with suitable modifications in their molecular architecture, in order to obtain products of greater therapeutic value. New methods of synthesis and a better appreciation of their chemical nature, in recent years, have sufficiently strengthened the fabric of hetero cyclic compounds and many astounding developments are expected in the near future. In view of the great physiological and medicinal importance of heterocyclic compounds as stated above it was considered worthwhile to undertake some basic investigations on pyrimidlne derivatives. Two important aspects were chosen for critical and comprehensive studies. (1) Physico chemical studies of some substituted pyrimidines - Chapter I deals with electrochemical reduction studies of 5-substituted pyrimidlnes at d.m.e. The reaction of 2-chloro -5- differently substituted pyrimidlnes with piperidine has been kinetlcally followed and the results are included in Chapter II. Both the approaches have been found especially suitable in evaluating the effect of substituenteon half wave potential (Ei) in the former and reactivity and rate constant in the latter. (2) Sjmthesfcs of a few typical pyrimidlnes and pyrazole3 have been described in Chapter III and IV. While Chapter III deals with the synthesis of griseofulvin analogs having a heterocyclic splran ring C, Chapter IV Includes assorted studies of the syntheses of some benzofurano-pyrazoles and pyrimidlnes, 5-aryl azo pyrimidine, V-aryloxy pyrazole and 5-aryloxy pyrimidlnes• Physical methods are perhaps the most important tools in the hands of chemists for undertaking effective chemical research in the field of organic chemistry. Although, Initially applied to simple molecules they are now being frequently used to tackle molecules of complex nature. The systematic application of these methods to heterocyclic chemistry has been rather slow, perhaps due to their comple xity. Heterocyclic compounds have the property of acquiring electrons under suitable conditions, therefore, among the many physical methods, polarography, vMch can quantitatively measure the electron density in the Jiolecule, has been quite extensively used in their analysis. During the present investigations some substituted pyrimidlne derivatives have been subjected to polarographic analysis. Such a study assumes considerable importance since the pyrimidlne nucleus is present in many biologically important systems such as purines, which are the building blocks of RNA, DNA and vitamins. It has also been recognised that the behaviour of these compounds at d.m.e. is similar to that in biological systems. A literature survey reveals that the polarographic reduction pyrimidlnes has been i—5 studied quite extensively the mein workers in the field being Lowy and Elving et^al. As a result of their study certain facte become clear. (1) The most natural reduction site in the pyrimidlne system is the nitrogen carbon double bond either at positions 1,6 or Iffaa (2) The carbon nitrogen double bond in positions 2,3 or 1,2 resists reduction, being part of the stable cyclic amidine system. (3) Substituents greatly alter their reduclbility. It has been observed that an amino or hydroxy substituent causes 4 the reduction to occur at a relatively more negative poten tial. Further if two or more such substituents are present, the reduction is almost inhibited. A hydroxy substituent at position-** has been shown to exist mainly in the keto form*7. This tautomeric change results in the disappearance of the natural reduction site, a bond at position N-| =05. (10 Reduction of pyrimidlne at d.m.e. can take two courses - one Involving 2-electron transfer in which the 1,6 or 3,1* double bond is saturated and the other involving transfer of only one electron, where dimerization of the compound takes place. All the pyrftaldine derivatives studied polarographically viz ethyl 2-methyl if-hydroxy pyrimidlne 5-carboxylate, ethyl 2-S-methyl U-hydroxy pyrimidlne -5-carboxylate, 2- methyl if-hydroxy pyrimidlne -5-carbohydrazlde, ethyl 2, Udimethyl pyrimidlne 5-carboxylate and 2, *f dimethyl pyrimidlne 5-carboxamide reduced at d.m.e. giving well defined polarographic waves. The study of kinetics of a chemical reaction deals with the rates of the processes, whereby one system changes from one state to another. Since chemical kinetics also deals with the factors that affect this rate, it provides the most powerful method of investigating the mechanism of a process. The mechanism engulfs all elementary processes involving atoms, molecules Radicals, ions and other species that take part in producing the overall reaction. 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 way for obtaining information about the mechanisms 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 vays - firstly to investigate the intricacies involved and secondly to work out the conditions for optimum yields so that the wastage may be stopped and efforts utilized. Of the various classes of organic reactions, nucleophilic substitution reactions on carbon have been most extensively studied8""11. In the field of nocleophilic aromatic substitution two classes of compounds are of special interest - nitrooenzene derivatives and N-heteroaromatic substances. The reactions of both 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 in unraveling the reactions of heterocycles in general and in the development of synthetic methods in this field in particular. Aza activation is responsible for the nucleophilic displacement reactions in pyrimidlnes. For quantitatively evaluating such an influence, it is necessary to study the kinetics of large number of reactions. Chapman and Coworkers®"11 initiated these studies and acquired valuable data on the reactivity of chlorine atom substituted at position 2 and h in tne pyrimidlne ring. It has been found that chlorine at position -** is more reactive than when it is at position 2. Further the influence of the presence of a methyl group on the reactivity of chlorine at position -2 has also been evaluated. In an extension of this work, the reactivity of other negatively substituted groups such as clkoxy12'13, aikylthio1^, alkyl sulphonyl and alkyl sulphinyl1? both in pyrimidlne and purine has been determined klnetically. In all these studies, however, the effect of a 5- substltuent on the reactivity of chlorine in position -2 has not been undertaken. It was thought that readily available 2-chloro if, 6-dimethyl pyrimidlne derivatives should be very suitable for such studies. During the course of these studies Chapman's* experiments on the piperidinolysis of 2-chloro V, 6-dimethyl pyrimidlne were repeated and the rate constants were found to be of the same order. Further, the effect of another halogen atom on the reactivity of chlorine in position -2 has been evaluated. Fluoro derivative could not be included in this study because of the inherent difficulties of synthe sis. The present synthetic study includes the synthesis of a few well known physiologically active compounds, rather than a general examination of pyrimidlnes and pyrazoles. The splro coumaran ring skfileton in some important 16 17 fungal metabolities such as griseofulvin' , geodin and erdin etc. has focussed inter3^ i on the spiralis of benzofuran class, as possible antibacterials and fungicides. During this work, the carbocyclic spiran ring - ring C of the griseofulvin has beeu successfully replaced by hydropyrimidine and pyrazolone rings. It has been thought that the insertion of these rings would alter the properties of the parent compound and one can expect that the new derivatives might be bettar drugs. The substitution of these rings provides sufficient experience for chemical synthesis. A literature survey reveals that benzofurano pyrazoles and pyrimidlnes have not been synthesised. It is expected that these new heterocyclic systems having mixed features should be interesting. Therefore, the use of ethyl, 2, 3-dihydro jcnacfuxan -3-one-2-carboxylates, which have been employed earlier as0-keto esters in the 8 \ 19 20 I synthesis of coumarino coumarones 7 and Griseofulvin , has j been exploited in the course of tne present studies. It •I, has been observed that they condense readily with hydrazines to give faemzpforauo-pyrazol-2 in -5 ones. Their structure depends on the mode of their cyclisation and has been confir med by IR spectra of the compound. Condensation of ethyl 2, 3-dihydro benzofuran -3-one-2 carboxylate with ureas and amiaines gave the corresponding benzofurano pyrimidlnes. 5-.£henyr azc jyrlmidincs have been shown to possess antitumor activity21,22. Various manipulations have been carried out in the pyviW&jMm ring to enhance the activity of these compounds. During this study, 2--mino~k~hydroxy -6- ?nethyl isocytorin and 2-hydroxy 1+, 6 dimethyl pyrimidine have been condensed with phenyl diazonium chlorides derived from various anilines. The structures of these compounds have been confirmed by their reduction to 5-amino derivatives. Phonory Atrlvatlvef of ethyl acetoacotate obtained by condensation of ethyl <x-chloro acetoacetats with sodium phenoxide was first prepared and used by Harrtasch 3 in the synthesis of Counarones. During the present investigations the phenoxy derivatives of ethyl acetoace tate have been used in the synthesis of otherwise difficultly available V-aryloxy pyrazoles and 5-phsnoxy pyrimidlnes.
Other Identifiers: Ph.D
Appears in Collections:DOCTORAL THESES (chemistry)

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