SYNTHESES OF FUNCTIONALISED ANGULAR PHENOTHIAZINES AND PHENOXAZINES OF PHARMACEUTICAL INTEREST VIA TRANSITION METAL-CATALYZED TANDEM REACTIONS

ABSTRACT

The  synthesis  of  new  angular  aza  phenothiazinones,  angular  azaphenoxazines  and  their derivatives are reported. Two key functional intermediates namely 2,6-diamino-4-chloro- pyrimidin-5-thiol and 7-chloro-5,8-quinolinequinone were successfully synthesized from readily available starting materials using such traditional organic methods as nitrosation, nitration, halogenation, reduction, oxidation, direct thiocynation and base-catalyzed hydrolysis. The new angular azaphenothiazinones and angular azaphenoxazinone were prepared by coupling the requisite intermediates. Condensation reaction between 2,6-diamino-4-chloro-pyrimidin-5-thiol or 2-aminothiophenol or 2-aminophenol and 7-chloro-5,8-quinolinequinone in the presence of anhydrous sodium carbonate produced 10-amino-8-chloro-1,9,11-triaza-5H– benzo[a]phenothiazin-5-one,2291-aza-5H-benzo[a]-       phenothiazin-5-one,231                        1-aza-5H–

benzo[a]phenoxazin-5-one233  respectively. Also by coupling 2,6-diamino-4-chloro-pyrimidin-5-

thiol with 2,3-dichloro-1,4-naphthoquinone in the presence of anhydrous sodium carbonate, 10- amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one230 was obtained. These angular azaphenothiazinones and angular azaphenoxazines were converted to their derivatives via palladium, copper and nickel-catalyzed cross-coupling tandem reactions utilizing Mizoroki-Heck, Buchwald-Hartwig  and  Yamamoto  protocols.  Palladium  catalyzed  cross-coupling  reaction between  10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and four phenyl-iodo derivatives utilizing Mizoroki-Heck protocol furnished four new compounds namely 10-amino-8-

chloro-6-(4-nitrophenyl)-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one,  10-amino-8-chloro-6-(2-

Also palladium catalyzed Mizoroki-Heck cross coupling reactions with arylated iodo compounds and  1-aza-5H-benzo[a]phenothiazin-5-one and  1-aza-5H-benzo[a]phenoxazin  -5-one produced

the following new compounds: 6-(4-nitrophenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, 6-(2- hydroxyphenyl)-1-aza-5H-benzo[a]phenothizin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo [a]phenothiazin-5-one, 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, and   6(-(2- hydroxyphenyl)-1-aza-5H-benzo[a] phenoxazin-5-one, 6-(4-nitrophenyl)-1-aza-5H- benzo[a]phenoxazin-5-one,  6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one and 6-(2- carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one  respectively.  The  arylation  of  10-amino-

6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one   with   some   amide   derivatives   via

Buchwald-Hartwig nickel complex cross-coupling reactions gave five new compounds namely:

6-acetamido-10-amino-8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 6-benzamido-10- amino-8-dichloro-9,11-diaza-5H-benzo[a]  phenothiazin-5-one,  6-(4-nitrobenzamido)-10-amino-

6,8-dichloro-9,11-diaza-5H-benzo[a]    phenothiazin-5-one,    6-phthalamido-10-amino-8-chloro-

9,11-diaza-5H-benzo[a]pheno-  thiazin-5-one  and  6-(2-hydrobenzamido)-  10-amino-8-chloro-

9,11-diaza-5H-benzo[a]phenothiazin-5-one.

Arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one using some substituted anilines via Buchwald-Hartwig protocol with palladium acetate (Pd(OAc)2  gave five new derivatives namely: 10-amino-8-chloro-6-((4-nitrophenyl) amino)-9,11-diaza-5H– benzo[a]phenothiazin-5-one, 10-amino-6-((4-bromophenyl)amino) -8-chloro-9,11-diaza-5H– benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-((3-nitrtophenyl)amino)-9,11-diaza-5H– benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-((4-chlorophenyl)amino)-9,11-diaza-5H– benzo[a]phenothiazin-5-one and 10-amino-6-((2-chlorophenyl)amino-9,11-diaza-5H– benzo[a]phenothiazin-5-one. Similarly arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo- [a]phenothiazin-5-one  with  Pd(OAc)2   and  some  heterocyclic  amines  gave  new  derivatives namely: 10-amino-8chloro-6-(pyrimidin-2-ylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one and 10-amino-8-chloro-6-(4-methylpyridylamino)-(9,11-diaza-5H-benzo[a]- phenothiazin-5-one.

Copper-catalyzed N-arylation reaction between 10-amino-8-chloro-1,9,11-triaza-5H– benzo[a]phenothiazin-5-one and potassium aryltriolborates utilizing Yamamoto reaction protocol gave 8-chloro-10-(phenylamido)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one 8-chloro-10-((3- chlorophenyl)amino)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and 10-((4- bromophenyl)amino-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one. Similarly N-arylation of 10- amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, using copper complex and potassium        aryltriolborates        furnished        6,8-dichloro-10-(phenylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one. Structure elucidation of the synthesized compounds were done by UV-visible, IR, ′HNMR 13CNMR spectroscopy and elemental analysis. The infrared (IR) spectra of  these  angular  azaphenothiazinones  and  phenoxazinones  showed  decrease  in  the  C=O absorption band from the expected 1690cm-1 to values ranging from 1682 – 1601cm-1 which were due to ionic resonance effects. Compounds produced from Buchwald-Hartwig cross-coupling reactions using palladium catalysts gave yields of 41 -80%. Nickel complex catalyzed Buchwald- Hartwig reactions gave yields ranging from 71 – 78%. Derivatives obtained by employing Mizoroki-Heck cross-coupling reaction protocol via palladium complex  yields between 69 –86%. Compounds obtained from copper catalysis via potassium phenyltriolborates gave yields 22– 64%. As a a result of extended conjugation in these new angular azaphenothiazinones and phenoxazinones scaffolds, they are intensely coloured and their colours range from yellow to deep red through reddish brown to dark brown. Antimicrobial screening of these new compounds showed   significant   biological   activity   against   Bacillus   subtilis,   Staphylococcus   aureus, Escherichia coli, Enterococus faecalis, pseudomonas aerugionsa, Candida albicaus and Aspergillus niger.

CHAPTER ONE

INTRODUCTION

1.0 Background of study:

In the last few decades, the chemistry of phenothiazine 1, phenoxazine 2 and their derivatives have been of great interest to organic chemists.

Much earlier, Bernthsen in 18831,2  accidentally discovered phenothiazine parent ring 1 and eight years later the same researcher reported2 the first parent ring of phenoxazine2.

All these discoveries were made during his classical studies on the structure of thiazine dyes. Some phenothiazine derivatives, notably Lauth’s Violet 3 and Methylene Blue 41  were commercially available as dyes even before the discovery of the parent

phenothiazine3.

A lot of structural modifications have been carried out since the discovery of parent compounds 1 and 2 in search of compounds with improved properties. Hence

subsequent variations in their parent structure have given rise to a large number of derivatives of pharmaceutical and industrial interests.

Initial attempts were  made on side-chains and  N-alkyl-aminoalkyl derivatives which were used in medicine, agriculture and industry.

Phenothiazine and its derivatives including many other organosulphur compounds find  their  greatest  applications  in  medicine4,  pesiticides5,  dyes  and  pigments,  6,7,8, industrial   antioxidants9,10,    in   gasoline   and   other   petroleum   lubricants;   thermal stabilizers11, acid-base indicators6, sensitizers for photocopying materials, polymerization retardants6 and also very popular in material science as marker for proteins and deoxyribonucleic acid (DNA) 12(a-c)  to mention a few.

In medicine, phenothiazine derivatives possess several biological activities including antibacteria 13-14and antifungal22-24, antipsychotic15-16 and anti-inflammatory17-

18,  antiparkinsonian  activities19,  anti-tubercular20-21,  anticonvulsant25,  anti-worm26   for

livestock and cardiovascular27 activities among others.

Similarly phenoxazine and its numerous derivatives have been shown to possess a broad spectrum of pharmacological activities. Notably among them are tranquilizing agents28, antitumor29-30  antimicrobial31, anti-inflammatory32, antiviral33, insecticidal properities34, antituberculosis35-36, sedative and central nervous system (CNS) depressant37.

Although phenothiazine derivatives have many useful medicinal properties, they also have several undesirable side effects such as dryness of mouth, drowsiness, lassitude38, etc. Many phenoxazine derivatives, in addition to their marked pharmacological effects, also display high levels of toxicity 39-40.

In the effort to control these side effects, some structural modifications were carried out. This led to the synthesis of some important drugs like promethazine 5,

chlorpromazine 6, diethazine 7 and propiomazine 841-42.

These  drugs  are  also  clinically  useful  in  the  chemotherapy  of  mental  and emotional disturbance 42. In addition to the main neuroleptic action of phenothiazine family, other biological activities of importance to their cancer chemopreventive effect were also documented in the literature43-45

More report  by Karreman et  al46   on the  therapeutic action of phenothiazine derivatives showed that promazine 9 and chlorpromazine 6 and their tranquilizing effect is due to the basic nitrogen of phenothiazine ring that releases electrons to the biological receptor by charge transfer mechanism37. Hence the derivatives of phenothazine with annular nitrogen atoms were found to be better drugs than those without annular nitrogen atoms. This inferred that prothipendyl 10 and isothipendyl 11 which are derivatives of 1- azaphenothiazine analogue of promazine are more potent than promethazine 5, chlorpromazine 6 and diethazine 7 in the treatment of mental disorders especially in acute

psychosic complicated with latent epilepsy47.

(CH2)3 – N(CH3)2

N       N

CH3

(CH2) CH – N(CH3)2

10                                                             11

Further search for more potent drugs led to molecular modification of linear phenothiazine leading to aza-phenothiazine ring systems. This resulted in the preparation of derivatives in which a benzo group is fused onto one of the side rings leading to the tetracyclic aza-phenothiazine 1247. Before then,  four monoaza1, ten diaza38  and  four

triaza49-50, phenothiazine ring systems were prepared and characterized.

R1,R2 R3 = any substituent such as -NH2, -NMe2,  X(Cl, Br, I) etc.

As an extension of these works, Okafor et al47  successfully synthesized 1,4,6,8- tetraazabenzo[b] phenothiazine ring system 13 (48,51) as a new ring in these series. The name of the new ring is quinozaline,[2,3-b]1[1,4]pyrimido[5,6-e]thiazine.

Phenoxazine 2 is a useful antioxidant9 although it is inferior to phenothiazine 1. However, its derivative, 2-amino-3H- phenoxazin-3-one 14 exhibits marked inhibiting action on the growth of some selected species of Clostridium botulinum 51-53

Many polycyclic compounds containing a phenoxazine ring system are used as biological stains, fabric dyes and light emitting materials in dye lasers such as cresyl violet and nile blue26a – b

Further works on the synthesis of different structural modification led to the

fusion of the benzene ring in the [a] position of the parent ring of phenothiazine 1 and

phenoxazine    2.    This    resulted    in    the    formation    of    angular    or    non-linear

benzo[a]phenothiazine6 and benzo[a]phenoxazine1 of types 15 and 16.

15                                                  16

Okafor53 – 55,58 reported that compounds 15 and 16 were the earliest and simplest modifications of parent phenothiazine and phenoxazine. Meldola Blue 17 a derivative of the angular phenoxazine 16 was commercially available as a blue dye long before the

parent phenoxazine and phenothiazine were discovered by Bernthsen2.

17                                                         18

The earliest recorded report of an angular phenothiazine was made in 1890 by Kym55a, who synthesized benzo[a]phenothiazine 18 in 40% yield. This was done by heating 1-anilinonaphthalene 19 with sulphur at elevated temperatures. Shirley55b  later improved the yield by adding catalytic amount of iodine to achieve a 71% yield. These compounds were used as drugs, thermal stabilizers and dyes 60. More derivatives of angular phenothiazine 20 and phenoxazine 21 were also synthesized subsequently.

Further structures in which the ring A or D of the non-linear systems 15 and 16 have been replaced by pyridine or pyrimidine fragments giving rise to the aza-analogues of angular phenothiazine and phenoxazine which have been synthesized such as 22, 23 and 241, 48,60.

The first aza analogues of angular phenothiazine 25 and 26 were reported by Okafor60  by heating a mixture of suitably substituted o-amniopyridinethiol and 2,3,- dichloro-1,4-naphthoquinone in chloroform following a similar procedure by Agarwal

and Mital58b using o-aminothiophenol. Other examples are: 1-azabenzo[a]phenothiazine

27 and 8,10-diaza-5H-benzo[a]phenothiazin-5-one 28.

Further variation of these angular azaphenothiazines was achieved by Okafor et al47. by replacing the ring sulphur with oxygen leading to angular azaphenoxazine 29. This was obtained by treating 2-amino-3-pyridinol 30 with a stoichiometric amount of

2,3-dichloro-1,4-naphthoquinone 31 in chloroform in the presence of anhydrous sodium carbonate or sodium acetate to get an orange solid (97%), m.p 232-2330C.

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