Synthesis and Characterization of Non-linear 6, 8 and 9, 12-Dichloroazaphenothiazine Derivatives

The synthesis of non-linear diaza and tetraaza dichlorophenothiazine derivatives is reported in this article. This was achieved through the thiocyanation of 2,6-diamino-4-chloropyrimidine using potassium thiocyanate, bromine and glacial acetic acid at –5°C to give 2,6-diamino-3-thiocynatopyrimidine, which was hydrolyzed using 20% sodium hydroxide to furnish 2, 6-diamino-4-chloropyrimidin-3-thiol. Base catalyzed condensation reaction of 2, 6-diamino-4-chloropyrimidin-3thiol and 2, 3-dichloro-1, 4-naphthoquinone gave the first derivative, 10-amino-6, 8-dichloro-9, 11-diazabenzo [a] phenthiazin5-one, a reddish crystalline product. Similarly, another condensation reaction of 2, 6-diamino-4-chloropyrimidin-3-thiol with the first derivative, 10-amino-6, 8-dichloro-9, 11-diazabenzo[a]phenthiazin-5-one using the same reaction conditions, furnished the second derivative known as 7, 14-diamino-9,12-dichloro-6, 8, 13, 15-tetraazabenzo [a] [1,4] benzothiazino-[3,2c] phenothiazine, a deep reddish crystalline compound. The synthesized compounds were characterized on the basis of UVVisible, IR, 1 HNMR and 13 CNMR spectra data.


Introduction
The chemistry of phenothiazine 1 and its derivatives has remained unabated. These groups of heterocyclic compounds play important roles in medicinal chemistry [1]. For the past two centuries, attention has been focused on the synthesis of phenothiazine and its derivatives as well as their screening for biological activities [2]. Phenothiazine derivatives are very important because they exhibit a wide range of applications. Their usage as drugs, antioxidants in petroleum, thermal stabilizers, pesticides, light sensitive (photographic) materials, dyes and high temperature lubricants make their chemistry very interesting [3]- [9].
Any variation in the substitution pattern of the phenothiazine nucleus often causes a marked difference in activity, for this reason many phenothiazine derivatives with different substituents have being synthesized, characterized and screened for biological activities in order to produce better drugs [10], [11]. For instance the non-linear azaphenothiazine derivatives of the types 2 and 3 with monohalide atoms have been synthesized and reported by Ezema and co-workers [12] as well as by Ayuk and coworkers [13]. Although the synthesis of the type 4 derivative was described in our recent work [13], but that of the type 5 with dihalide atoms has not been reported.

Materials and Methods
The reagents used were sourced locally from commercial chemical shops and were obtained in sealed containers and used without further purification. The melting points of the synthesized compounds were determined in open capillary tubes and are uncorrected. The UV-Vis spectra were recorded in DMF on a UV-2500PC series V2.30 spectrum version at NARICT, Zaria, Nigeria, using matched 1 cm quartz cells. Absorption maxima are given in nanometer (nm) while the numbers in parenthesis are ԑ-values. Infrared Spectral data were obtained on FTIR-8400S (Fourier Transform Infrared Spectrophotometer), NARICT in Zaria, Nigeria using KBr disc and absorptions are given per centimeter (cm -1 ). Nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) were determined using Varian mercury 200 BB spectrometer at Obafemi Awolowo University Ile-Ife, Nigeria. (Chemical Shifts are reported on δ scale relative to tetramethylsilane (TMS) as an internal standard). The analytical samples were obtained by recrystallization from acetone.
Compounds 7 and 8 were synthesized as described in the literature [14].
The color of the reaction mixture changed from light red to deep red as the reaction progressed. At the end of 9hr, the solvent was distilled off and the slurry was poured into crushed ice, stirred to dissolve inorganic matter. The solution was filtered, dried and recrystallized from acetone to give 7, 14-diamino-9, 12-dichloro-6, 8, 13, 15-tetraazabenzo[a] [1,4]

benzothiazin-[3, 2, c] phenothiazine 5.
The IR and 13 CNMR spectra of compound 4 showed absorption bands at 1670cm -1 and δ 181.7, which indicate the presence the carbonyl group, but on these were not observed in the spectra of compound 5. These revelations are consistent with the assigned structures of the above compounds. The mechanism for the formation of compound 4 is described thus; the first step is the abstraction of a proton from the mercapto group of the thiol 8 by the base to form a mercapto ion 10. The mercapto ion formed, mounts a nucleophilic attack on the chlorine atom of the naphthoquinone 9 to form the sulphide 11, which cyclizes by the nucleophilic attack of the amino group of the thiol on the carbon of the carbonyl group of compound 9 followed by the loss of water to give compound of interest [12], [13] as shown in figure 5 below. The infrared spectrum, of compound 4 showed a lowering of the carbonyl [C=O] absorption from the expected 1700cm -1 to 1670cm -1 . This is due to the ionic resonance contribution which increases the [C=O] bond length with its attendant decrease in the vibration frequency of absorption [12], [13], [14], as shown in figure 6 below; In proton magnetic resonance spectrum δ 3.22 -3.39 is due to the amine proton NH2, while δ 7.72-7.96 is due to 4-H attached to benzene (C-1, C-2, C-3, C-4), these are consistent with the assigned structure. In 13 C-NMR the peak at δ 181.7 is due to the carbonyl carbon.
The mechanism of this reaction is similar to that of compound 4, thus: Compound 5 is probably formed by initial nucleophilic attack by the thio-pyrimidine ion on compound 4 by displacing the reactive halogen group to form a diaryl sulphide intermediate 16 [15], [16]. Condensation of the amino and the carbonyl groups of 16 followed by the loss of a water molecule gave 7, 14-diamino-9, 12-dichloro-6, 8, 13, 15-tetraazabenzo [a] [1,4]

Conclusions
The synthesis of the phenothiazine derivatives discussed above was carried out using simple commercially available starting materials. The methods employed are straight forward and stereo-selective products were obtained. These newly synthesized compounds will be useful in pharmaceutical, textile, petroleum, agricultural industries etc.
The high melting points exhibited by these compounds suggest that they can be used as thermal stabilizers. Also, due to their highly coloured nature, they are suitable to be used as vat dyes. However, studies in their dying and antimicrobial activity are ongoing in our laboratory.
From the spectroscopic data assigned to the structures of the above synthesized compounds, their molecular formulae are C 14 H 9 Cl 2 N 4 OS and C 18 H 8 Cl 2 N 8 S 2 respectively.