ABSTRACT
Magnetically recoverable Pd/Fe3O4-catalyzed Hiyama cross-coupling reactions of 6-Bromo- 5H-benzo[a]phenothiazin-5-one, 6-Bromo-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one and 11-Amino-6-bromo-9-thio-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one (as intermediates) with 2-(Dimethylsilyl)pyridine and Dimethyl(2-thienyl)silanol were investigated. The intermediates were prepared by the reactions of 2-Aminothiophenol, 2- Aminopyridin-3-ol and 4,5-Diamino-6-hydroxylpyrimidin-2-thiol respectively with 2,3- Dibromonaphthalene-1,4-dione in the presence of anhydrous sodium carbonate using benzene/DMF as solvent. Sequel upon the successful syntheses of the intermediates, each was  subjected  to  the  Hiyama  reaction  with  2-(Dimethylsilyl)pyridine  and  Dimethyl(2- thienyl)silanol, refluxed for between 5-8 h (monitored with TLC) at 90-100 oC using NaOH as activator and H2O/THF was used as solvent. The magnetic Fe3O4 supported Pd catalyst used was synthesized by sonicating the nano-ferrites (prepared by co-precipitation of Fe2+ and  Fe3+)  with  dopamine  in  water  for  2  h,  followed  by addition  of  Sodium  Palladium Chloride (Na2PdCl2) and subsequent reduction with NaBH4. Characterization of the catalyst by TEM and XRD confirms a size range of 16-25 nm. The Hiyama reaction gave (i) 6- (Pyridin-2-yl)-5H-benzo[a]phenothiazin-5-one and (ii) 6-(Thiophen-2-yl)-5H– benzo[a]phenothiazin-5-one (iii)  6-(Pyridin-2-yl)-5H-naphtho[2,1-b]pyrido[2,3- e][1,4]oxazin-5-one and (iv) 6-(Thiophen-2-yl)-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin- 5-one (v) 11-Amino-9-thio-6-(pyridin-2-yl)-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5- one and (vi) 11-Amino-9-thio-6-(thiophen-2-yl)-5H-naphtho[2,1-b]pyrimido[5,4- e][1,4]oxazin-5-one as derivatives in 45-63 % yields. The ease of  recovery of the catalyst using an external magnet, efficient recycling and use of water as the solvent are additional eco-friendly attributes of this protocol. All the synthesized compounds were characterized using IR, NMR, UV-Visible spectroscopies and elemental analysis. In the IR spectra of the compounds, the characteristic C=O stretching vibration was observed between 1629-1753 cm-1. The observed decrease in the C=O absorption band for some of the compounds was attributed to ionic resonance effect. The highly deshielded carbonyl signal appeared between 169-184 ppm in the NMR spectra of the compounds. The synthesized compounds were screened for their in vitro antibacterial and antifungal activities on Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae as bacteria and Asperigellus niger and Candida albican as fungi respectively using agar-well-diffusion technique. Ciprofloxacin and Ketoconazole were used as clinical reference drugs. All the synthesized compounds showed significant activity against the tested organisms, with the derivatives 14 and 19 found to be more active antifungal than Ketoconazole. The synthesized compounds could also be used as dye due to their intense colour.
CHAPTER ONE
1.0 INTRODUCTION
1.1 Background of Study
Phenothiazine and phenoxazine belong to the important group of condensed three-ring heterocycles known for their pharmaceutical properties1,2. The core of these compounds are the active component in tranquilizers3, analgesic and anti-inflammatory4, anticonvulsant5, ulcer inhibitors6, CNS depressants7, antitumor2 and antimicrobial agents7 to mention just a few. Besides their pharmaceutical applications, they are used as acid-base and redox indicators2, dyes and pigment in textile, paint and plastic industries and are found useful in petroleum industries where they are used as antioxidants in lubricants and fuels8.
Phenothiazine and phenoxazine are dibenzo analogue of 1,4-thiazine and 1,4-oxazine linked via bridges of nitrogen-sulphur and nitrogen-oxygen respectively. They exist as 10H- tautomers.
The parent ring structures of phenothiazine 1 and phenoxazine 2 were first synthesized by Bernthsen9,10 in 1883 and 1887, by the reaction of diarylamine with sulphur11 and the reaction of o-aminophenol and catechol12 respsectively.
The syntheses of 1 and 2 and their various derivatives have generated intensive scientific interest due to their wide spectrum of applications13,14. As a result, many synthetic methods for their preparation have been developed.
Although phenothiazine 1 and phenoxazine 2 and their various derivatives have many useful medicinal properties (either realised or envisaged), they also have some undesirable effects such as drowsiness, lassitude, aching limbs, dryness of the mouth, flushing of the face15 etc. Therefore, continuous modifications in the molecular structures of 1 and 2 are necessary if it is hoped to eliminate or reduce these undesirable effects and hence open new areas of application.
Such molecular modifications have been reported on the angular derivatives including non- aza and congeneric aza-analogues.
Some angular derivatives of 1 and 2 that have been reported are the benzo[a]phenothiazine16
of the type 3 and the benzo[a]phenoxazine17 of the type 4.
Benzo[h]phenothiazine18 and benzo[h]phenoxazine19 of the type 5 and 6 were also reported.
More structural modifications gave birth to the reports of the following mono and diaza-
analogues of angular phenothiazine compounds of the types 7 20 and 8 21.
Although the syntheses of several angular derivatives of 1 and 2 and their mono-, di- and triaza-complex analogues have been reported, the methods adopted for their syntheses suffer from certain disadvantages such as harsh reaction conditions, long conversion time and unsatisfactory yields. Therefore, the development of facile and environmentally friendly synthetic methods that provide easy access to these versatile compounds is an important goal. Transition metals have a unique ability to activate various organic compounds and through this activation they can catalyze the formation of new bonds22. This property has been utilized in the building up of the backbones of organic molecules, and also in the syntheses of their derivatives.
This material content is developed to serve as a GUIDE for students to conduct academic research
CATALYZED HIYAMA SYNTHESES OF ANGULAR PHENOTHIAZINE AND PHENOXAZINE DERIVATIVES AND THEIR ANTIMICROBIAL ACTIVITIES
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