Project Abstract

<p> </p><p>Tandem amidation catalyzed synthesis of linear diazaphenoxazine carboxamide derivatives is reported. This was<br>achieved by the reaction of 2-amino-3-hydroxypyridine and 2,3,5-trichloropyridine in aqueous basic medium which<br>gave 3-chloro-1,9-diazaphenoxazine as white solid crystals. 3-Chloro-1,9-diazaphenoxazine was then subjected to<br>Buchwald-Hartwig amidation coupling reaction with various amides namely formamide, phthalamide, 4-<br>nitrobenzamide, benzamide and acetamide via water promoted catalyst preactivation protocol to afford the<br>following, 3-amido derivatives of 1,9-diazaphenoxazine namely 3-formamido-1,9-diazaphenoxazine, 3-<br>phthalamido-1,9-diazaphenoxazine, 3-(4-nitrobenamido)-1,9-diazaphenoxazine, 3-benzamido-1,9-<br>diazaphenoxazine and 3-acetamido-1,9-diazaphenoxazine. The compounds were characterized using UV-visible,<br>FTIR, 1HNMR and 13CNMR spectroscopy.</p><p><strong>&nbsp;</strong></p> <br><p></p>

Project Overview

<p> 1.0 INTRODUCTION<br>1.1TANDEM CATALYSIS<br>The term tandem catalysis represents processes in which “sequential transformation of the<br>substrate occurs via two (or more) mechanistically distinct processes”1 and there is no need to<br>isolate the individual intermediates as the entire reaction takes place in one pot.<br>Types of tandem catalysis<br>There are three types of tandem catalysis<br>Orthogonal tandem catalysis: In this type of catalysis, there are two or more mechanistically<br>distinct transformations, two or more functionally and ideally non-interfering catalysts with all<br>catalysts present from the outset of the reaction, as shown in Scheme 1.<br>Scheme 1<br>Substrate Mechanism B A Mechanism A Product A Mechanism B Product B<br>Catalyst B Catalyst A Catalyst B<br>Auto-tandem catalysis: In this type of catalysis, there are two or more mechanistically distinct<br>transformations which occur via a single catalyst precursor; both catalytic cycles occur<br>11<br>spontaneously and there is cooperative interaction of all species present at the outset of the reaction<br>as shown on Scheme 2<br>Scheme 2<br>Mechanism A Product A Mechanism B Product B<br>Catalyst A<br>Substrate A<br>Catalyst A<br>(A)<br>Assisted tandem catalysis: In this type, two or more mechanistically distinct transformations are<br>promoted by a single catalytic species while the addition of a reagent is needed to trigger a change<br>in catalyst function,2 as shown in Scheme 3.<br>Scheme 3<br>Catalyst B<br>Mechanism A Product A Mechanism B Product B<br>Catalyst A<br>Substrate A<br>trigger<br>1.2 TANDEM REACTIONS<br>In so far as one of the fundamental objectives of organic synthesis is the construction of complex<br>molecules from simpler ones, the importance of synthetic efficiency becomes immediately<br>apparent and has been well recognized. The increase in molecular complexity that necessarily<br>accompanies the course of a synthesis provides a guide (and a measure) of synthetic efficiency. As<br>12<br>a goal, one would like to optimally match the change in molecular complexity at each step with<br>reaction of comparable synthetic complexity.<br>Thus, the creation of many bond, rings and stereocenters in a single transformation is a necessary<br>(although not sufficient) condition for high synthetic efficiency. The ultimate, perfect match would<br>constitute a single-step synthesis. More realistically, especially In view of the desire for general<br>synthetic methods, the combination of multiple reactions in single operations increase molecular<br>complexity is a powerful means to enhance synthetic efficiency.<br>The concept for reactions in tandem as a strategy for the rapid construction of complex structures is<br>well-known and has been reviewed1. In addition, a recent international attention, and books<br>dedicated to tandem reaction3 and multi component cyclizations have now appeared. Within the<br>universe of tandem reactions, the constellation of consecutive pericyclic reactions is still vast.<br>Consecutive pericyclic reactions involving at least one cycloaddition have enjoyed extensive<br>application in synthesis as exemplified by tandem benzocyclobutene opening, Diels-Alder<br>reactions4, Danheiser’s aromatic annulation5, electrocyclic opening of 1,3-dipolar cycloaddition and<br>endiandric acid cascade6.<br>1.3 DEFINITION OF TANDEM REACTIONS<br>The dictionary definition of tandem as “one behind the other” is in itself, insufficient since every<br>reaction sequence would then be a tandem reaction. However, a rigorous and all encompassing<br>definition of tandem or sequential reactions is very difficult to formulate because of the continuum<br>of chemical reactivity. In other words we must decide what constitutes a reactive intermediate or a<br>13<br>stable, isolable entity which given the circumstances of reactant structure or reaction conditions,<br>undergoes a secondary transformation .What is unique about the type of tandem process<br>exemplified by tandem pericyclic reaction is the structural change that accompanies the initial<br>reaction and the creation of an intermediate with the necessary functionality to perform the second<br>reaction .Furthermore, if the process involves sequential addition of reagents the second reagent<br>has to be included into the product. In addition, new bonds and stereocenters have to be created in<br>the second reaction.<br>There is an all-encompassing definition of tandem as reactions that occur one after the other, and<br>use the modifiers cascade (domino), consecutive, and sequential to specify how the two (or more)<br>reactions follow. Thus, the family tandem cycloaddition reaction can be divided into three<br>categories with the following definitions.<br>Tandem cascade cycloadditions: In this, the reactions are intrinsically coupled, that is, each<br>subsequent stage can occur by virtue of the structural change brought about by the previous step<br>under the same reaction conditions7.<br>In tandem cascade cycloadditions, both processes take place without the agency of additional<br>components or reagents. Everything necessary for both reactions is incorporated in the starting<br>materials .The product of the initial stage may be stable under the reaction conditions; however, the<br>intermediate cannot be an isolable species but rather is converted to the tandem product upon<br>workup. The classic examples of tandem cascade cycloadditions are “pincer”(path a) and<br>“domino” (path b) modes of Diels-Alder reactions which have served as the corner stone in the<br>14<br>synthesis of the formidable pagodane and dodecahedrane8 structures respectively, as shown in<br>Scheme 4<br>Scheme 4<br>(4 + 2)<br>(4 + 2)<br>(4 + 2)<br>(4 + 2)<br>H<br>CO2Me<br>CO2Me<br>CO2Me<br>CO2Me<br>H<br>MeO2C<br>“pincer mode”<br>MeO2C<br>path a<br>MeO2C CO2Me<br>path a<br>CO2Me<br>CO2Me<br>“domino mode”<br>Tandem consecutive cycloaddtion, are reactions where the first cycloaddition is necessary but not<br>sufficient for the tandem process, i.e external reagents or changes in reaction conditions are also<br>required to facilitate propagation9.<br>15<br>Tandem consecutive reactions differ from cascade reactions in that the intermediate is an isolable<br>entity. The intermediate contains the required functionally to perform the second reaction, but<br>additional promotion10 in the form of energy (heat or light) is necessary to overcome the activation<br>barriers. Many examples of such consecutive cycloadditions have been documented10. A<br>particularly illustrative example is shown in Scheme 5.<br>Scheme 5<br>OMe<br>OMe<br>+<br>(2 + 2)<br>OMe<br>(4 + 2)<br>OMe<br>O<br>O<br>MeO<br>Cl<br>Cl<br>Cl O<br>O<br>hv<br>Cl<br>O<br>O<br>Cl<br>Cl<br>Cl<br>Cl<br>Cl<br>Cl<br>Cl<br>MeO<br>Cl<br>The [4+2] cycloaddition produces a new olefin which is poised for an intramolecular [2+2]<br>cycloaddition. Although, the first reaction is necessary, it is not sufficient for the tandem process,<br>and a change in conditions (photochemical activation) is required.<br>Another example shown in Scheme 6 illustrates the problem of rigorous definition11 while the first<br>[4+2] cycloaddition is not strictly necessary in that the second [4+2] process are already present in<br>the precursor, the important structural consequences of intra molecularity is probably equally<br>significant for the success of the tandem process as shown in scheme 6.<br>16<br>Scheme 6<br>H3C CH2<br>OR H3C<br>OR<br>Ph O<br>H2C<br>Ph O<br>[4+2]<br>OR<br>Ph O<br>H3C<br>heat<br>[4+2]<br>Tandem sequential cycloadditions are reactions wherein the second stage requires the addition of<br>the cycloaddition partners or another reagent.<br>Tandem sequential cycloadditions require the addition of the second component for the tandem<br>process to occur in a separate step. To qualify as a tandem reaction, the first stage must create<br>the functionality in the product to enable it to engage the second reaction. The intermediate may be<br>isolable, though this is not a necessity. This class of reaction is not as well recognized as the<br>previous ones, but it is nonetheless clearly illustrated in the synthesis of vernolepin and<br>vernomenin by Danishefsky12 (Scheme7)<br>Scheme 7<br>[4 + 2] [4 + 2]<br>H<br>CO2Me<br>TMSO<br>MeO<br>O<br>O<br>H<br>CO2Me<br>17<br>Components of tandem [4+2]/[3+2] cycloaddition<br>The design of a tandem [4+2]/[3+2] cycloaddition process for nitroalkenes can be understood by<br>recognizing the central role played by nitrates (Scheme 8). Early studies on the use of nitroalkenes<br>as heterodienes (vide infra) led to the development of a general, high yielding, and stereoselective<br>method for the synthesis of cyclic nitronates. These dipoles are well-known to undergo 1,3-dipolar<br>cycloadditions (vide infra); however, synthetic applications of this process are rare. This is<br>undoubtedly due to the lack of general methods for the preparation of nitronates and their<br>instability. Thus, as illustrated in Scheme 8, the potential for a powerful tandem process is<br>formulated in the combination of an inverse electron demand [4+2] cycloaddition of a donor<br>dienophile (D denotes electron withdrawing group). The resulting tandem process can construct<br>four new bonds, up to four new rings, and up to six new stereogenic centers (three of which bear<br>hetero atoms).<br>18<br>Scheme 8<br>R2<br>R1<br>N+ O- O CH3<br>CH3<br>nitro alkene<br>O<br>N<br>CH3<br>CH3<br>R2<br>R1<br>O-<br>*<br>* *<br>*<br>*<br>[4+2]<br>Lewis acid<br>nitronate<br>R<br>O<br>Y+<br>NHO +<br>X<br>nitronate<br>[4+2]<br>Z Z<br>R<br>Y+<br>O N<br>Z<br>Z X<br>nitroso acetal<br>D<br>A N+ O- O A NO + O D –<br>N<br>O O D<br>A *<br>* * *<br>*<br>*<br>1.4 BUCHWALD-HARTWIG AMINATION<br>The Buchwald-Hartwig amination is an organic process describing a coupling reaction between an<br>aryl halide and an amine in the presence of base and a palladium catalyst which results in the<br>formation of a new carbon-nitrogen bond 13.<br>The first example of a Buchwald-Hartwig amination reaction was realized in Kiev, Ukraine, in<br>1985, by Yagupolskii et al14. Polysubstituted activated chloroarenes and anilines underwent C-N<br>coupling reaction catalyzed by one mole percent of [PdPh2(PPh3)2] in moderate yield.<br>19<br>Buchwald-Hartwig amination usually requires a catalytic process containing four components to<br>generate the C-N bond15.<br>Solvents: The solvent used in Buchwald-Hartwig coupling play two important roles which are to<br>dissolve the coupling partners as well as being part of the base and allowing for a respective<br>temperature window for the reaction and also plays a crucial role in stabilizing intermediates in the<br>catalytic cycle16.<br>Ligands: ligand stabilizes the palladium precursor in solution and also raises the electron density at<br>the metal to facilitate oxidative addition as well as provide sufficient bulkiness17 to accelerate<br>reductive elimination in the catalytic system.<br>Palladium precursor: palladium facilitates the reaction by acting as a catalyst in the reaction.<br>Bases: A base deprotonate the amine substrate prior to or after coordination to the palladium<br>centre.<br>1.5 LINEAR PHENOXAZINE<br>Phenoxazine 1 is the parent compound of a large number of useful organic dyes which have been<br>extensively studied due to the wide range of application of these compounds as acid-base and<br>redox indicators18. The parent ring phenoxazine 1 was first synthesized by Bernthsen19 in 1887<br>soon after his pioneer work on phenothiaziine in 1879.<br>20<br>N<br>O<br>H<br>1<br>N<br>O<br>R2<br>NH2<br>O<br>R1<br>N<br>O<br>COpeptide<br>NH2<br>O<br>CO peptide<br>2 CH3 CH3<br>3<br>There are numerous naturally occurring phenoxazine derivatives. These have beer classified as<br>Ommochromes, Fungalmetalolites, Questiomycins, and Actiomycins. Phenoxazine derivatives of<br>type 2 are responsible for the coloration in microorganisms such as wood-rotting fungi and<br>moulds20. The actinomycins, which are groups of very toxic antibiotics obtained from certain<br>species of the genus Streptomyces19 are complex chromopeptide derivatives21 of phenoxazine 3.<br>Many of them have been isolated and they differ mainly in the peptide chain. In small dies,<br>actinomycin antibiotic show anti-tumor activities in the treatment of Hodgkin’s disease, a cancerlike<br>disease of the lympthatic system20.<br>Following repeated reports on the pharmacological properties of phenoxazine, attention was<br>diverted from their dyeing properties to a study of biological activities. From tests carried out with<br>laboratory animals and man, it was found that many phenoxazine derivatives showed pronounced<br>pharmacololgical properties as central nervous system depressants, sedatives, antiepileptics,<br>herbicides, tranquilizers, anti-tumor, antibacterial spasmolytic, anthelminthic and parasticidal<br>agents19,20,21.<br>Furthermore, early improvement on the structure of phenoxazine involves change in the side chain<br>and the 10-alkylamino group. However, nowadays interest is being showed on the modifications on<br>21<br>the pheoxazinwe ring itself through replacement of one benzo groups with furan, pyrrole, pyridine<br>and pyrazine ring as the case may be. The modification could also involve expansion of the<br>oxazine ring leading to oxazepines and oxazocines<br>N<br>O<br>H<br>4<br>N<br>O<br>H<br>N N<br>O<br>H NO2<br>NO2<br>N<br>N<br>O<br>H NO2<br>NO2<br>N<br>O<br>N<br>H NO2<br>N<br>N<br>O<br>H NO2<br>NO2<br>Cl N<br>O<br>N<br>N<br>H<br>Cl<br>Cl N<br>N<br>O<br>N<br>H<br>5 6 7<br>8 9<br>10 11<br>N<br>O N<br>N<br>CH3<br>Cl<br>12<br>Compounds 4 and 5 are described as “linear phenoxazines” because of the linear arrangement of<br>the ring system22. Consequently, polynuclear phenoxazines with a straight arrangement of the ring<br>systems are generally referred to as linear phenoxazines. There are also structures which<br>incorporates additional annular nitrogen atom(s). These are known as the aza analogues. Aza<br>analogues which bear one nitrogen atom is called mono aza analogues as shown in structures 6, 7,<br>8 and 9 above. Compounds 6, 7, 8 and 9 are known as 1-azaphenoxazine, 2-azaphenoxazine, 3-<br>azaphenoxazine and 4-azaphenoxazine, respectively, because of the position of the additional<br>annular nitrogen atom22.<br>Further, there are also sometimes where two nitrogen atoms are added in the ring. These are called<br>diazaphenoxazines as shown in compounds 10, 11 and 12 above. Compounds 10, 11 and 12 are<br>called 1,4-diazaphexazine, 1,9-diazaphenoxazine and 3,4-diazaphenoxazine, respectively, because<br>of the position of the added annular nitrogen.<br>22<br>1.6 STATEMENT OF THE PROBLEM<br>The unending pharmaceutical applications of phenoxazine derivatives and unavailability of the<br>chemistry of 1,9-diazaphenoxazine-3-carboxamide derivatives in literature informed this research.<br>1.7 OBJECTIVES OF THE STUDY<br>I. To synthesize 3-chloro-1,9-diazaphenoxazine by a condensation reaction.<br>II. To use this systhesized diazaphenoxazine to couple the following amides: formamide,<br>phthalamide, 4-nitrobenzamide, benzamide and acetamide via the Buchwald-Hartwig<br>tandem amination protocol.<br>III. To use combined information from Uv-visible, IR and NMR (13C and 1H) in the assignment<br>of structures of the synthesized 1,9- diazaphenoxzine-3-carboxamides.<br>1.8 JUSTIFICATION OF THE STUDY<br>Interest in naturally occurring and synthetic phenoxazine derivatives as pharmaceuticals prompted<br>the synthesis of new rings derived from phenoxazine with consistent reports on improved<br>pharmacological applications. Thus it is necessary to synthesize more compounds of phenoxazine<br>derivatives to increase the available raw materials for pharmaceutical industries. <br></p>