Project Abstract

<p> </p><p>The synthesis of new angular aza phenothiazinones, angular azaphenoxazines and their<br>derivatives are reported. Two key functional intermediates namely 2,6-diamino-4-chloropyrimidin-<br>5-thiol and 7-chloro-5,8-quinolinequinone were successfully synthesized from readily<br>available starting materials using such traditional organic methods as nitrosation, nitration,<br>halogenation, reduction, oxidation, direct thiocynation and base-catalyzed hydrolysis. The new<br>angular azaphenothiazinones and angular azaphenoxazinone were prepared by coupling the<br>requisite intermediates. Condensation reaction between 2,6-diamino-4-chloro-pyrimidin-5-thiol<br>or 2-aminothiophenol or 2-aminophenol and 7-chloro-5,8-quinolinequinone in the presence of<br>anhydrous sodium carbonate produced 10-amino-8-chloro-1,9,11-triaza-5Hbenzo[<br>a]phenothiazin-5-one,2291-aza-5H-benzo[a]- phenothiazin-5-one,231 1-aza-5Hbenzo[<br>a]phenoxazin-5-one233 respectively. Also by coupling 2,6-diamino-4-chloro-pyrimidin-5-<br>thiol with 2,3-dichloro-1,4-naphthoquinone in the presence of anhydrous sodium carbonate, 10-<br>amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one230 was obtained. These angular<br>azaphenothiazinones and angular azaphenoxazines were converted to their derivatives via<br>palladium, copper and nickel-catalyzed cross-coupling tandem reactions utilizing Mizoroki-Heck,<br>Buchwald-Hartwig and Yamamoto protocols. Palladium catalyzed cross-coupling reaction<br>between 10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and four phenyl-iodo<br>derivatives utilizing Mizoroki-Heck protocol furnished four new compounds namely 10-amino-8-<br>chloro-6-(4-nitrophenyl)-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(2-<br>hydroxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(4-<br>carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one and 10-amino-8-chloro-6-(2-<br>carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one.<br>Also palladium catalyzed Mizoroki-Heck cross coupling reactions with arylated iodo compounds<br>and 1-aza-5H-benzo[a]phenothiazin-5-one and 1-aza-5H-benzo[a]phenoxazin -5-one produced<br>vi<br>the following new compounds 6-(4-nitrophenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, 6-(2-<br>hydroxyphenyl)-1-aza-5H-benzo[a]phenothizin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo<br>[a]phenothiazin-5-one, 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, and 6(-(2-<br>hydroxyphenyl)-1-aza-5H-benzo[a] phenoxazin-5-one, 6-(4-nitrophenyl)-1-aza-5Hbenzo[<br>a]phenoxazin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one and 6-(2-<br>carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one respectively. The arylation of 10-amino-<br>6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one with some amide derivatives via<br>Buchwald-Hartwig nickel complex cross-coupling reactions gave five new compounds namely<br>6-acetamido-10-amino-8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 6-benzamido-10-<br>amino-8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-(4-nitrobenzamido)-10-amino-<br>6,8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-phthalamido-10-amino-8-chloro-<br>9,11-diaza-5H-benzo[a]pheno- thiazin-5-one and 6-(2-hydrobenzamido)- 10-amino-8-chloro-<br>9,11-diaza-5H-benzo[a]phenothiazin-5-one.<br>Arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one using some<br>substituted anilines via Buchwald-Hartwig protocol with palladium acetate (Pd(OAc)2 gave five<br>new derivatives namely 10-amino-8-chloro-6-((4-nitrophenyl) amino)-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one, 10-amino-6-((4-bromophenyl)amino) -8-chloro-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one, 10-amino-8-chloro-6-((3-nitrtophenyl)amino)-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one, 10-amino-8-chloro-6-((4-chlorophenyl)amino)-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one and 10-amino-6-((2-chlorophenyl)amino-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one. Similarly arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo-<br>[a]phenothiazin-5-one with Pd(OAc)2 and some heterocyclic amines gave new derivatives<br>namely 10-amino-8chloro-6-(pyrimidin-2-ylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one<br>and 10-amino-8-chloro-6-(4-methylpyridylamino)-(9,11-diaza-5H-benzo[a]- phenothiazin-5-one.<br>Copper-catalyzed N-arylation reaction between 10-amino-8-chloro-1,9,11-triaza-5Hbenzo[<br>a]phenothiazin-5-one and potassium aryltriolborates utilizing Yamamoto reaction protocol<br>gave 8-chloro-10-(phenylamido)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one 8-chloro-10-((3-<br>chlorophenyl)amino)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and 10-((4-<br>bromophenyl)amino-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one. Similarly N-arylation of 10-<br>amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, using copper complex and<br>potassium aryltriolborates furnished 6,8-dichloro-10-(phenylamino)-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one, 6,8-dichloro-10-((3-chlorophenyl)amino)-9,11-diaza-5Hbenzo[<br>a]phenothiazin-5-one and 10-((4-bromophenyl)amino)-6,8-dichloro-9,11-diaza-5Hvii<br>benzo[a]phenothiazin-5-one. Structure elucidation of the synthesized compounds were done by<br>UV-visible, IR, ′HNMR 13CNMR spectroscopy and elemental analysis. The infrared (IR) spectra<br>of these angular azaphenothiazinones and phenoxazinones showed decrease in the C=O<br>absorption band from the expected 1690cm-1 to values ranging from 1682 – 1601cm-1 which were<br>due to ionic resonance effects. Compounds produced from Buchwald-Hartwig cross-coupling<br>reactions using palladium catalysts gave yields of 41 -80%. Nickel complex catalyzed Buchwald-<br>Hartwig reactions gave yields ranging from 71 – 78%. Derivatives obtained by employing<br>Mizoroki-Heck cross-coupling reaction protocol via palladium complex yields between 69 –<br>86%. Compounds obtained from copper catalysis via potassium phenyltriolborates gave yields 22<br>– 64%. As a a result of extended conjugation in these new angular azaphenothiazinones and<br>phenoxazinones scaffolds, they are intensely coloured and their colours range from yellow to<br>deep red through reddish brown to dark brown. Antimicrobial screening of these new compounds<br>showed significant biological activity against Bacillus subtilis, Staphylococcus aureus,<br>Escherichia coli, Enterococus faecalis, pseudomonas aerugionsa, Candida albicaus and<br>Aspergillus niger.</p><p>&nbsp;</p><p><strong>&nbsp;</strong></p> <br><p></p>

Project Overview

<p> </p><p>INTRODUCTION<br>1.0 Background of study:<br>In the last few decades, the chemistry of phenothiazine 1, phenoxazine 2 and their<br>derivatives have been of great interest to organic chemists.<br>S<br>N<br>H<br>1<br>O<br>N<br>H<br>2<br>Much earlier, Bernthsen in 18831,2 accidentally discovered phenothiazine parent<br>ring 1 and eight years later the same researcher reported2 the first parent ring of<br>phenoxazine2.<br>All these discoveries were made during his classical studies on the structure of<br>thiazine dyes. Some phenothiazine derivatives, notably Lauth’s Violet 3 and Methylene<br>Blue 41 were commercially available as dyes even before the discovery of the parent<br>phenothiazine3.<br>S<br>N<br>H2N NH2<br>Cl<br>3<br>+<br>S<br>N<br>NMe2<br>Cl<br>4<br>+<br>Me2N<br>A lot of structural modifications have been carried out since the discovery of<br>parent compounds 1 and 2 in search of compounds with improved properties. Hence<br>2<br>subsequent variations in their parent structure have given rise to a large number of<br>derivatives of pharmaceutical and industrial interests.<br>Initial attempts were made on side-chains and N-alkyl-aminoalkyl derivatives<br>which were used in medicine, agriculture and industry.<br>Phenothiazine and its derivatives including many other organosulphur compounds<br>find their greatest applications in medicine4, pesiticides5, dyes and pigments, 6,7,8,<br>industrial antioxidants9,10, in gasoline and other petroleum lubricants; thermal<br>stabilizers11, acid-base indicators6, sensitizers for photocopying materials, polymerization<br>retardants6 and also very popular in material science as marker for proteins and<br>deoxyribonucleic acid (DNA) 12(a-c) to mention a few.<br>In medicine, phenothiazine derivatives possess several biological activities<br>including antibacteria 13-14and antifungal22-24, antipsychotic15-16 and anti-inflammatory17-<br>18, antiparkinsonian activities19, anti-tubercular20-21, anticonvulsant25, anti-worm26 for<br>livestock and cardiovascular27 activities among others.<br>Similarly phenoxazine and its numerous derivatives have been shown to possess a<br>broad spectrum of pharmacological activities. Notably among them are tranquilizing<br>agents28, antitumor29-30 antimicrobial31, anti-inflammatory32, antiviral33, insecticidal<br>properities34, antituberculosis35-36, sedative and central nervous system (CNS)<br>depressant37.<br>Although phenothiazine derivatives have many useful medicinal properties, they<br>also have several undesirable side effects such as dryness of mouth, drowsiness,<br>lassitude38, etc. Many phenoxazine derivatives, in addition to their marked<br>pharmacological effects, also display high levels of toxicity 39-40.<br>3<br>In the effort to control these side effects, some structural modifications were<br>carried out. This led to the synthesis of some important drugs like promethazine 5,<br>chlorpromazine 6, diethazine 7 and propiomazine 841-42.<br>N<br>S<br>CH2-CH-N(CH3)2<br>CH3<br>5<br>N<br>S<br>Cl<br>(CH2)3N(CH3)2<br>6<br>N<br>S<br>(CH2)2N(C2H5)2<br>7<br>N<br>S<br>CH2CH-N(CH3)2<br>CH3<br>COCH2CH3<br>8<br>N<br>S<br>(CH3)2 N- (CH2)3<br>9<br>These drugs are also clinically useful in the chemotherapy of mental and<br>emotional disturbance 42. In addition to the main neuroleptic action of phenothiazine<br>family, other biological activities of importance to their cancer chemopreventive effect<br>were also documented in the literature43-45<br>4<br>More report by Karreman et al46 on the therapeutic action of phenothiazine<br>derivatives showed that promazine 9 and chlorpromazine 6 and their tranquilizing effect<br>is due to the basic nitrogen of phenothiazine ring that releases electrons to the biological<br>receptor by charge transfer mechanism37. Hence the derivatives of phenothazine with<br>annular nitrogen atoms were found to be better drugs than those without annular nitrogen<br>atoms. This inferred that prothipendyl 10 and isothipendyl 11 which are derivatives of 1-<br>azaphenothiazine analogue of promazine are more potent than promethazine 5,<br>chlorpromazine 6 and diethazine 7 in the treatment of mental disorders especially in acute<br>psychosic complicated with latent epilepsy47.<br>S<br>N N<br>(CH2)3 – N(CH3)2<br>10<br>S<br>N N<br>(CH2) CH – N(CH3)2<br>CH3<br>11<br>Further search for more potent drugs led to molecular modification of linear<br>phenothiazine leading to aza-phenothiazine ring systems. This resulted in the preparation<br>of derivatives in which a benzo group is fused onto one of the side rings leading to the<br>tetracyclic aza-phenothiazine 1247. Before then, four monoaza1, ten diaza38 and four<br>triaza49-50, phenothiazine ring systems were prepared and characterized.<br>5<br>S<br>N<br>N<br>H<br>12<br>R1 R3<br>R2<br>R1,R2 R3 = any substituent such as -NH2, -NMe2, X(Cl, Br, I) etc.<br>As an extension of these works, Okafor et al47 successfully synthesized 1,4,6,8-<br>tetraazabenzo[b] phenothiazine ring system 13 (48,51) as a new ring in these series. The<br>name of the new ring is quinozaline,[2,3-b]1[1,4]pyrimido[5,6-e]thiazine.<br>N<br>N<br>S<br>N<br>N<br>N<br>H 1<br>R1<br>2 R3<br>3<br>11<br>12<br>13<br>14<br>6 5 1<br>7<br>8<br>9 10<br>4<br>13<br>Phenoxazine 2 is a useful antioxidant9 although it is inferior to phenothiazine 1.<br>However, its derivative, 2-amino-3H- phenoxazin-3-one 14 exhibits marked inhibiting<br>action on the growth of some selected species of Clostridium botulinum 51-53<br>O<br>N NH2<br>O<br>14<br>Many polycyclic compounds containing a phenoxazine ring system are used as<br>biological stains, fabric dyes and light emitting materials in dye lasers such as cresyl<br>violet and nile blue26a – b<br>Further works on the synthesis of different structural modification led to the<br>fusion of the benzene ring in the [a] position of the parent ring of phenothiazine 1 and<br>6<br>phenoxazine 2. This resulted in the formation of angular or non-linear<br>benzo[a]phenothiazine6 and benzo[a]phenoxazine1 of types 15 and 16.<br>S<br>N<br>H<br>A B C<br>D<br>15<br>O<br>N<br>H<br>A B C<br>D<br>16<br>Okafor53 – 55,58 reported that compounds 15 and 16 were the earliest and simplest<br>modifications of parent phenothiazine and phenoxazine. Meldola Blue 17 a derivative of<br>the angular phenoxazine 16 was commercially available as a blue dye long before the<br>parent phenoxazine and phenothiazine were discovered by Bernthsen2.<br>O<br>N<br>Me2N<br>+ Cl<br>17<br>S<br>N<br>H<br>18<br>The earliest recorded report of an angular phenothiazine was made in 1890 by<br>Kym55a, who synthesized benzo[a]phenothiazine 18 in 40% yield. This was done by<br>heating 1-anilinonaphthalene 19 with sulphur at elevated temperatures. Shirley55b later<br>improved the yield by adding catalytic amount of iodine to achieve a 71% yield. These<br>compounds were used as drugs, thermal stabilizers and dyes 60. More derivatives of<br>angular phenothiazine 20 and phenoxazine 21 were also synthesized subsequently.<br>7<br>N<br>H<br>19<br>S<br>N<br>O<br>R<br>O<br>N<br>O<br>20 21<br>R2<br>R1<br>R = R1 = Et2N, R2 = H, and R1 = Et2N, R2 = PhNHCO]<br>Further structures in which the ring A or D of the non-linear systems 15 and 16<br>have been replaced by pyridine or pyrimidine fragments giving rise to the aza-analogues<br>of angular phenothiazine and phenoxazine which have been synthesized such as 22, 23<br>and 241, 48,60.<br>X<br>N<br>H N<br>22<br>X<br>N<br>H<br>N<br>23<br>X<br>N<br>H<br>2N<br>24<br>X = O or S<br>The first aza analogues of angular phenothiazine 25 and 26 were reported by<br>Okafor60 by heating a mixture of suitably substituted o-amniopyridinethiol and 2,3,-<br>dichloro-1,4-naphthoquinone in chloroform following a similar procedure by Agarwal<br>8<br>and Mital58b using o-aminothiophenol. Other examples are: 1-azabenzo[a]phenothiazine<br>27 and 8,10-diaza-5H-benzo[a]phenothiazin-5-one 28.<br>N S<br>N H<br>R<br>Cl<br>O<br>25<br>N<br>N<br>S<br>N<br>NH2<br>Cl<br>O<br>26<br>R = H,Cl, OMe<br>S<br>N<br>H N<br>27<br>N<br>N<br>S<br>N<br>O<br>28<br>Further variation of these angular azaphenothiazines was achieved by Okafor et<br>al47. by replacing the ring sulphur with oxygen leading to angular azaphenoxazine 29.<br>This was obtained by treating 2-amino-3-pyridinol 30 with a stoichiometric amount of<br>2,3-dichloro-1,4-naphthoquinone 31 in chloroform in the presence of anhydrous sodium<br>carbonate or sodium acetate to get an orange solid (97%), m.p 232-2330C.<br>9<br>N<br>O<br>N<br>Cl<br>O<br>29<br>N NH2<br>OH<br>30<br>Cl<br>Cl<br>O<br>O<br>31<br>Prior to Okafor’s report58a, Noelting59 in 1922 reported the synthesis of 4-azaanalogue<br>32. He obtained the blue dye by the reaction of 8-hydroxyquinoline 33 with ohydroxy-<br>N,N-dimethylaniline hydrochloride 34 in the presence of a trace of zinc. This<br>product is a good blue mordant dye for cotton mordanted with tannin and fixed by iron,<br>aluminum or chromium mordant.<br>O<br>N N<br>O<br>32<br>N<br>OH<br>33<br>NMe2<br>OH<br>34<br>HCl<br>Interest in the aza-analogues of phenoxazine derivatives has grown tremendously<br>since the dawn of the 20th century. Some angular aza-phenoxazines especially the<br>10<br>pyridol[3,2-a]phenoxazines occur in nature. Among them are rhodommatin 3561-63 and<br>xanthommatin 36 which are responsible for the coloration in the wings of insects of the<br>Lepidoptera family and in the eyes of the butterfly-papilio xuthus as examined by some<br>Japanese workers.63<br>O<br>N NH<br>O<br>C<br>O O 2C-CH-CH2<br>NH3<br>H<br>CO2H<br>O<br>O<br>OH<br>OH<br>HOH2C<br>OH<br>+<br>35<br>Further variations in the structure of non-linear aza phenothiazines and<br>phenoxazines were observed and in an effort to synthesize new dyes, pigments and drugs,<br>Okafor63 and Okoro64-65et al synthesized new non-linear and three(Y)-branched azaphenothiazine<br>and aza-phenoxazine systems represented as 37,38,39.<br>O<br>N N<br>HO<br>O2C-CH-CH2-C=O<br>NH3<br>CO2H<br>O<br>+<br>36<br>11<br>N<br>S<br>N<br>S<br>N<br>N<br>37<br>N<br>S<br>N<br>S<br>N<br>N<br>H2N<br>35<br>38<br>N<br>O<br>N<br>S<br>N<br>R<br>39<br>R = H, Cl, OMe<br>1.1 Transition metal catalyzed tandem reactions<br>Tandem reactions constitute a fascinating branch of organic chemistry. It is an<br>organic reaction in which several bonds are formed in sequence without isolating the<br>intermediates or changing reaction conditions or adding reagent66. It allows the synthesis<br>of complete multinuclear molecule from single precursor and that may be the reason why<br>some researchers called it a one-pot synthesis. This is because everything that is<br>necessary for the reaction must be incorporated into the starting materials.<br>There are undeniable benefits of tandem reactions which have been established<br>and have been recounted on numerous occasions. These include: atom economy,<br>economy of time, labour, resource management, minimal waste generation and functional<br>12<br>group tolerant of the starting partner67. Tandem reactions have wide applications mostly<br>in transition metal-catalyzed organic synthesis. They have been used extensively in both<br>the ring synthesis and the functionalisation of heterocycles68-74.<br>For more than two decades palladium-catalyzed cross-coupling reactions have<br>blossomed into extraordinarily powerful tools for carbon-carbon and carbon-heteroatom<br>bond formation and research in this field continues apace72,75-76. Palladium catalyst<br>occupies a special place followed by the nickel and most recently the soluble copper<br>complexes which serve as a convinenent replacement of Ullman harsh reaction<br>conditions77-78. Despite that, palladium has the advantage of being compatible with many<br>functional groups including its synthetic versatility. It is an ideal catalyst for tandem<br>reactions79.<br>Among the palladium – catalyzed C-C bond formation reactions, the Mizoroki-<br>Heck has undoubtedly found the most applications in tandem processes especially in<br>intramolecular reactions80-82.<br>Other transition metal catalyzed cross-coupling reactions that have revolutionized<br>synthetic strategies include:<br>i. Buchwald-Hartwig coupling reaction<br>ii. Suzuki-Miyaura cross-coupling reactions.<br>iii. Sonogashira reactions of arylalide using terminal alkynes<br>iv. Stille cross-coupling reactions of arylhalides using stannanes<br>v. Migita-kosugi cross-coupling reactions using organotin substances and<br>vi. Negishi palladium-catalyzed cross-coupling reactions using allyl-alkenyl<br>substrates among others. These interesting studies opened the new way for reactions<br>13<br>which brought about the recognition of Richard Heck, Akira Suzuki and El-ich<br>Negishi who were the receipients of 2010 Nobel Prize83 in chemistry.<br>Mizoroki-Heck cross-coupling reations have been applied to diverse array of<br>fields ranging from natural products and to material science, including biologically<br>important molecules82. Several reviews of Mizoroki-Heck cross-coupling reaction have<br>been published in literature84-86.<br>Similarly, transition metal catalyzed amination and amidation are reactions which<br>utilize Buchwald-Hartwig protocols for the formation of carbon-nitrogen bonds. The<br>success of these reactions is tremendous and has found its use in the synthesis of natural<br>products, material science products and nitrogen containing ligands81.<br>A plethora of reports has appeared during the last few years regarding the<br>application of the C-N coupling methodology for the synthesis of natural products or<br>active ingredients for pharmaceutical or agricultural use. These reactions were<br>traditionally performed with aryliodides under Goldberg who modified Ullmann harsh<br>cross-coupling reaction conditions of stiochiometric copper and high reaction<br>temperature3, 5,86-88. More advances in this area have allowed for the reactions of amides<br>and aryliodides or arylbromides using catalytic amount of copper under mild reaction<br>conditions 89-91.<br>Owing to the frequent occurrence of N-arylamines, N-arylanilines and N-aryl<br>imidazoles in pharmaceutically and agriculturally interesting compounds Yammamoto et<br>al96-98, carried out copper-catalyzed N-arylation with potassium aryltriolborate in the<br>presence of a reoxidant, trimethylamine N-oxide, a catalytic amount of Cu(OAC)2;<br>molecular sieves, toluene solvent and at room temperature. Hence they discovered and<br>14<br>reported that aryltriolborates are better aryl donors than traditional boronic acids and<br>trifluoroborates for copper(II)-catalyzed.<br>1.2 Statement of the problem<br>Phenothiazines and phenoxazines are compounds of great importance in<br>pharmaceutical, 7 agricultural8 and textile industries9,10,11. The most reported methods of<br>their synthesis have been based on classical procedures in which several intermediates<br>were prepared in order to get the finished products. There is however, loss of time,<br>material and resources in these processes due to difficulties in isolation and purification<br>of the required intermediates. Furthermore, most of these methods do not tolerate some<br>functional groups in the starting materials thereby limiting the functionalisation of the<br>final products. Hence, there is need to explore other methods of synthesizing the<br>functionalised angular phenothiazines and phenoxazines which will circumvent or<br>ameliorate these problems. Synthesis of these compounds employing Mizoroki-Heck,<br>Buchwald-Hartwig and Yamamoto transition metal-catalyzed tandem cross-coupling<br>reactions are viable options.<br>1.3 Objectives of the study<br>The main objective of this study is to synthesize new derivatives of phenothiazine and<br>phenoxazine using transition metal-catalyzed tandem reactions, and evaluate them for<br>antimicrobial activities.<br>The specific objectives of this work therefore were to:<br>i. synthesize functionalised organic intermediates leading to the synthesis of new<br>angular phenothiazine and phenoxazine compounds.<br>15<br>ii. convert the angular phenothiazine and phenoxazine compounds to their<br>derivatives via Mizoroki-Heck, Buchwald-Hartwig cross-coupling reactions and<br>copper-mediated N-arylation with aryltriolborates (Yamamoto et al)<br>iii. characterize the synthesized compounds and<br>iv. carry out antimicrobial screening on the new phenothiazine and phenoxazine<br>moieties.<br>1.4 Justification for the study<br>Phenothiazines and phenoxazines have been known for their usefulness and<br>applicability in different fields of human endeavour but their methods of preparation have<br>remained poorly developed54. There is also scarcity of works on their syntheses and<br>applications in most chemical literature. Our use of transition metal- catalyzed tandem<br>reactions in synthesizing alkenyl, amino and aryl derivatives of phenothiazines and<br>phenoxazines will help provide such information.</p><p>&nbsp;</p> <br><p></p>