Synthesis of Tetraaza Derivatives of Benzoxazinophenothiazine BENJAMIN

Tetraaza benzoxazinophenothiazine heterocyclic rings were synthesized and characterized. The key intermediate, 11-amino-6-chlorobenzo[a]-8,10-diazaphenoxazin-5-one was prepared by reaction of 4,5-diamino-6-hydroxypyimidine with 2,3-dichloro-1,4-naphthoquinone in anhydrous sodium carbonate. Whereas the parent tetraaza derivatives: 15-amino-8-bromo6,9,12,14-tetraazabenzo[a][1,4]benzoxazino[3,2-c] phenothiazine, 9,15-diamino-6,8,12,14tetraazabenzo[a][1,4]benzoxazino[3,2-c]phenothiazine and 15-amino-6,8,12,14tetraazabenzo[a][1,4]benzoxazino[3,2-c]phenothiazine were synthesized by base catalyzed condensation reactions of 11-amino-6-chlorobenzo[a]-8,10-diazaphenoxazin-5-one with 2-amino5-bromopyrazin-3-thiol, 4,6-diaminopyrimidine-5-thiol and 4-diaminopyrimidine-5-thiol respectively. The compounds are intensely coloured and are readily reduced with sodium dithionite to their leuco bases which can make them applicable as vat dyes. Their wash fastness, sublimation fastness and staining undyed fabric were evaluated.


INTRODUCTION
The application of phenoxazine and phenothiazine compounds and their derivatives in drug, textile, agriculture and other related industries has long been recognized.Phenoxazine and its derivatives were found to show tremendous pharmacological activities as antiepileptic, However, phenothiazines and their derivatives are useful in medicine as antitussive and antitumor agents, anticonvulsants, tranquilizers, antipsychotics, antimalarial agents 8 and in the treatment of prion diseases 9 , to mention but a few.In textile, paint and plastic industries, they are used as vat dyes and pigments 10 ; and in agricultural industries, as insecticides and nematodicides. 11In petroleum industries, they have been found useful as antioxidants in lubricants and fuels. 12e three-branched fused phenothiazine ring of the type 1 13 has been known for more than a century.The monoaza-, diaza-and triaza-analogues of benzoxazinophenothiazine rings of the types 2, 3, 4 14 have been known.The authors wish to report here the successful synthesis of tetraaza-analogue.

EXPERIMENTAL
The solvents were of analytical grade from Sigma-Aldrich.
2-aminopyrazine, 4,6diaminopyrimidine, 4,5-Diamino-6hydroxypyrimidine and 2,3-dichloro-1,4naphthoquinone were also products of Aldrich chemicals.Melting points were determined using electrothermal melting point apparatus in open capillaries and were uncorrected.The reactions were monitored with TLC and also the purity was ascertained with TLC.Infrared spectra were recorded on FT-IR 8400S spectrophotometer using KBr discs.Nuclear magnetic resonance spectra ( 1 H-NMR and 13 C-NMR) were determined using Brucker 300 MHz instrument; chemical shifts were reported on (ppm) scale.

Elemental analysis was obtained on Heraous rapid analyzer 2-Amino-5-bromopyrazin-3-thiol (8)
Procedure as reported in literature. 15 mixture of 2-amino-3,5-dibromopyrazine 6 (10 g, 42 mmole) and sodium hydrosulphide (4.86 g, 84 mmole) was poured in a 250 mL reaction flask attached to reflux condenser.Methanol (100 mL) was added and the mixture was refluxed for 13 h in water bath.A little amount of activated carbon was added and the mixture boiled for additional 15 min.It was then filtered and the filtrate was allowed to cool.It was neutralized with dilute hydrochloric acid to give dirty brown precipitates which was filtered and dried in a desiccator.Pure sample for analysis were further recrystallized from aqueous DMF.M.p. > 300 o C; FT-IR (KBr):  max 3488, 3420 (NH 2 ), 1589 (C=C, C=N), 770 and 728 cm -1 .

4,6-Diamino-5-thiocyanatopyrimidine (10)
4,6-Diaminopyrimidine 9 (15.00 g, 14 mmol) was poured into a litre of three-necked flask equipped with a reflux condenser, mechanical glass stirrer and dropping funnel.Glacial acetic acid cooled to 18 o C was added and the mixture was further cooled in an ice-salt bath.Sodium thiocyanate (22.00 g) was added with stirring while maintaining the temperature at -5 o C and 0 o C. Bromine (8.00 mL) was added in droplets from the dropping funnel to the ice cooled mixture for over 1 h and stirring was continued for a period of 5 h while maintaining the temperature near 0 o C. The slurry was left overnight, water was added and mixture warmed to 80 o C and filtered hot.The filtrate was preserved and the orange residue extracted with acetic acid.The acetic acid extract was combined with the preserved filtrate and neutralized with concentrated ammonia while cooling and maintaining the temperature below 30 o C. It was then filtered and the residue recrystallized from methanol to give 4,6-diamino-5-thiocyanatopyrimidine as bright yellow solid, m.p.181-182 o C (lit.183-184 o C) [15]; FT-IR (KBr):  max 3475, 3415 (NH 2 ), 1579 (C=C, C=N), 1160, 790 and 730 cm -1 .

-A m i n o -6 -c h l o r o b e n z o [ a ] -8 , 0diazaphenoxazin-5-one (14)
4,5-Diamino-6-hydroxypyrimidine 12 (2.0 g, 15 mmol) and anhydrous sodium carbonate (2.5 g, 23 mmol) were poured in a three-necked reaction flask (250 mL).A solution of benzene (120 mL) and DMF (15 mL) was added and the mixture was boiled for 45 min until complete dissolution.2,3-Dichloro-1,4-naphthoquinone 13 (3.60 g, 15 mmol) was later added and the mixture refluxed for 5 h in water bath at 75-80 o C. At the end of the reflux period, benzene was distilled off and the slurry poured into water (100 mL) and stirred to dissolve the inorganic material.It was cooled overnight, filtered and the residue was recrystallized from acetone after treatment with activated carbon to give

General Procedure for the Preparations of the Complex Compounds
2-Amino-5-bromopyrazin-3-thiol 8 (2.0 g, 97 mmol) and anhydrous sodium carbonate (1.0 g, 97 mmol) were poured in 3-necked reaction flask (250 mL) containing a solution of benzene (100 mL) and DMF (20 mL).The mixture was warmed in a water bath for 45 min until complete dissolution. 1 1 -A m i n o -6 -c h l o r o b e n z o [ a ] -8 , 1 0diazaphenoxazin-5-one 14 (2.89 g, 97 mmol) was later added and the entire mixture was refluxed in a water bath with continuous stirring for 11 h.Benzene was distilled off and the slurry was poured into water (600 mL) and warmed to dissolve the inorganic material.It was filtered, washed with water, recrystallized from aqueous acetone and later treated with activated charcoal to yield 18 as intense red powder.M. p. > 320 o (dec.);IR (KBr):  max cm -1 3466, 3396 (NH 2 ), 1598, 1472 (C=N, C=C).

General Method of Dyeing with the Compounds 14, 18 and 22
The dye compounds (0.20 g) each were weighed into separate reaction flasks attached to reflux condensers and thermometers.Acetone (60 mL) was added to the separate reaction mixtures each and warmed in water bath to achieve dissolution.Little volume of DMF (5.0 mL) was also added to aid complete dissolution.Sodium dithionite (5.0 g) was later added and the mixtures refluxed for 2 h and allowed to cool to 40 o C. Pieces of rayon fabrics were inserted into the separate solutions followed by addition of glacial acetic (5.0 mL).The mixtures were refluxed with gradual increase in temperature and occasional agitation for further 1 h.They were quickly cooled to room temperature and the fabrics were removed and air-dried.Their wash fastness, stain on undyed fabric and sublimation fastness based on the international geometric gray standard (1 for poor and 5 for excellent respectively) were ascertained.

Scheme 7 :
Scheme 5: Product 18 was likely formed by the proposed mechanism