Synthesis of 6-Aryl Substituted Derivatives of 6-Bromo-8-Methyl-1, 11-Diazabenzo[A]Phenothiazin-5-One Via Palladium Catalyzed Suzuki Coupling Reaction

Introduction

Phenothiazine compounds have for long been of interest to chemists as a result of wide range applicability of these compounds. Their uses include as drugs, pesticides, dyes and pigments and antioxidants in petroleum products [1-5]. The parent phenothiazine ring which is dibenzo analogue of 4H 1,4-thiazine has undergone a lot of structural modification in order remove some of the undesirable side effects observed from their various uses and also to expand applicability [6]. Suzuki-Miyaura reaction which is the reaction between an organo halide or pseudohalide and arylboronic acid or its ester in the presence of a base and catalyzed by a transition -metal complex is a powerful method for C-C bond formation [7]. A large number of compounds of great importance in medicine and industries have been prepared using this Suzuki coupling [8,9]. Haloazaphenothiazines noted for their usefulness have not received much attention as aryl halide of choice in this cross- coupling [10]. It is the interest in their use as substrate in Suzuki-coupling that promoted the present synthesis of these compounds.

Materials and Methods

Melting points of the synthesized compounds were determined by the use of Fischer John’s electro-thermal melting point apparatus in open capillaries and were uncorrected. Ultraviolet visible spectra were done on scan Buffer 16 CEUL CE 9050 spectrophotometer using matched 1 cm quartz cells in Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka. The absorption maxima were given in nanometer (nm). Infrared spectra were recorded with FTIR-8400s Fourier Transform Infrared Spectrophotometer in NARICT, Zaria, Nigeria using KBr discs, and the absorption values were given in per centimeter (cm^-1). Nuclear Magnetic Resonance (NMR) was determined with Varian NMR-Mercury 200BB spectrometer in Central Science Laboratory Obafemi Awolowo University, Ile-Ife Nigeria. Chemical shift δ is reported in ppm. MS spectra were obtained from GCMS-QP2010 PLUS SHIMADZU, in NARICT, Zaria, Nigeria. Elemental analyses were done on a CE 440 Elemental Analyser at the Central Science Laboratory University of Cairo, Cairo, Egypt. Most of the chemicals were purchased from Aldrich chemical company and were used without further purification. Column chromatography was done using silica gel (mesh 60-80).

Synthesis of 2-Amino-4-methyl-3-thiocyanatopyridine 3

2-amino-4-methypryidine 1 (3.8 g, 0.03 mol) was placed in a 500 cm³ two-necked flask containing 50% of methanol (50 cm³). Sodium hydrogen carbonate (8.4 g, 0.1 mol) was added and bromine (10 cm³) was added from a dropping funnel and stirred for 40 minutes at room temperature. An additional 5.0 g of NaHCO₃ was added and the reaction mixture stirred for a period of 2 h and left overnight. The crude product was filtered, washed with water and transferred to a round bottom flask containing 200 cm³ of hot water stirred until it dissolved, potassium thiocyanate (6.0 g, 0.06 mol) in 30 cm³ of water was add and refluxed for 3 h. The reaction mixture was cooled, filtered and the crude product re-crystallized from acetone after treatment with activated charcoal. 2-Amino-4-methyl-3-thiocyanatopyridine (2.7 g, 55%) was obtained as white crystals which melted at 178°C.

Synthesis of 2-Amino-4-methylpyridine-3-thiol 4

2-Amino-4-methyl-3-thiocyanatopyridine (5.0 g, 0.03 mmol) was placed in a 250 cm³ reaction flask equipped with a reflux condenser. Sodium hydroxide solution (20%, 50 cm³) was added and refluxed for 3 h. The reaction mixture was then filtered hot and the filtrate was cooled, neutralized with cold acetic acid. The crude product was re-crystallized from acetone and dried in a desiccator to obtain 2-amino-4-methylpyridine-3-thiol (2.9 g, 70%); M.p. 207°C (IR (KBr) ν_max 3304, 3139, 2921, 2611, 1643, 1561, 1451, and 1173 cm .

Synthesis of 6, 7-Dibromo-5, 8-quinolinequinole 8

5-Amino-8-hydroxyquinoline sulphate (12.0 g, 0.05 mol) was dissolved in 40 cm³ of concentrated hydrobromic acid in a 250 cm³ round bottom flask and stirred with a magnetic stirring bar while aqueous solution of sodium bromate (9.0 g, 0.06 mol) in 50 cm³ of water was added in portions. It was heated at 50°C for 2 h and stirred at room temperature for another 3 h. The reaction mixture was diluted with cold water and the precipitate filtered out. The crude product was washed with cold water and recrystallized from ethanol to obtain a dark yellow compound which melted at 245°C (Lit 248°C) [11]. UV λ_max 300 nm, IR (KBr) ν_max (cm^-1) 1580 cm^-1, 1505 cm^-1, 1458 cm^-1, and 826 cm^-1.

Synthesis of 6-Bromo-8-methyl-1,-11-diazabenzol[a]phenothiazin-5-one 9

2-Amino-4-methylpyridine-3-thiol (0.7 g, 5.0 mmol) and anhydrous sodium carbonate (1.1 g, 10.0 mmol) were placed in a 250 cm³ two necked flask containing a magnetic stirring bar and 45 cm³ of chloroform mixed with 3 cm³ of DMF. The mixture was stirred and refluxed for 1 h before the addition of 6, 7-dibromo-5.8-quinolinequinone (1.6 g, 5.0 mmol). The resulting mixture was refluxed for 6 h with vigorous stirring after which the reaction mixture was filtered hot and the filtrate was allowed to evaporate leaving a dark red solid product which was subjected to column chromatography using benzene-methanol in the ratio of 2: 1 as eluent. The first reddish fraction obtained was identified as 6-brono-8-methyl-1, 11-diazabenzo[a]phenothiazine-5-one (0.9 g, 52.5%), M.p.=289°C; UV-visible (EtOH) λ_max; 299 nm, 444 nm; IR (KBr) ν_max (cm^-1) 3059, 2965, 167; ¹H-NMR (DMSO) δ (ppm)=9.2, 8.9, 8.4, 7.7 and 2.5 ppm; ¹³C-NMR (DMSO) δ (ppm)=179, C=O, 154, C=N, 148, 138, 128, C=C, MS: (m/z, % intensity); 357 (M⁺, 30%), 359 (M⁺+2, 25%), 278(-Br, 20%), 250(-CO. 50%). Calculated: C, 50.42; H, 2.24; N, 11.76; S0z, 8.9; Br, 22.12. Found: C, 50.30; H, 2.19; N, 11.69; S, 9.00; Br, 22.40.

6-bromo-8-methyl-4,11-diazabenzo[a]phenothiazin-5-one 9e

The last fraction eluted which was reddish brown is 6-bromo-8-methyl-4, 11-diazabenzo[a]phenothiazin-5-one (0.32 g, 18%) M.p. 292°C, UV (EtOH) λ_max (nm); 269, 291, and 496, IR (KBr) ν_max (cm^-1); 3082, 2930, 1635, 1528, 1456, and 1387; ¹H-NMR (DMSO) δ (ppm)=9.2, 8.9, 8.4, 7.7 and 2.5 ppm; ¹³C-NMR (DMSO) δ (ppm)=185(C=O), 164(C=N), 142, 135.125(C=C). MS: (m/z, % intensity) 357 (M⁺, 70%), 359(M⁺+2, 60%), 342(-Me, 20%), 263(-Br, 50%).

General procedure for the synthesis of 6-aryl-8-methyl-1,11-diazabenzo[a]phenothiazin-5-one 9 a-d

In a two-necked round bottom flask was placed 15 cm³ of methanol and a magnetic stirring bar, 1,4-bis(2-hydroxy-3,5-di-tert-butybenzyl) piperazine (0.02 g, 4 mol%), PdCl₂ (0.007 g, 4 mol%) were added and stirred with heating for 30 min. Na₂CO₃ (1.1 g, 11 mmol), arylboronic acid (7.5 mmol) and 6-bromo-8-methyl-1,11-diazabenzo[a]phenothiazin-5-one (1.8 g, 5 mmol) were added and refluxed for 3 h and filtered hot. The filtrate was allowed to evaporate leaving gumming solid which was re-crystallized twice from acetone.

8-Methyl-6-phenyl-1, 11-diazabenzo[a]phenothiazin-5-one 9a

Following the general procedure, a mixture of the piperazine ligand, PdCl₂, Na₂CO₃, phenylboronic acid (0.92 g, 7.5 mmol) and 6-bromo-8-methyl-1,11-diazabenzo[a]phenothiazin-5-one (1.8 g, 5 mmol) was refluxed in methanol for 3 h, the crude product was purified by recrystallization from acetone to provide the titled compound as intense red powder (1.42 g, 80% yield) M.p. 120°C-121°C UV (EtOH) λ_max (nm); 260, 329, 456; IR (KBr) ν_max (cm^-1); 2924 (C-H, methyl), 1676 (C=O), 1575, 1489, 1399 (C=C, C=N; ¹H-NMR δ (ppm)=7.9 (d, 2H), 7.8 (m, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.5 (S, 5H), 2.5 (S, 3H); ¹³C-NMR (DMSO) δ (ppm)=188(C=O), 167(C=N), 135, 125(C=C). MS: m/z 355 (M⁺), 320(-Cl). Anal calculated for C₂₁H₁₃N₃OS; C, 70.9; H, 3.66; N, 11.83; 0, 4.51; S, 9.01. Found; C, 70.94; H, 3.49; N, 11.75; O, 4.53; S, 9.71.

8-Methyl-6-(3-chlorophenyl)-1,11-diaabenzo[a]phenothiazin-5-one 9b

A mixture of 3-chlorophenylboronic acid (1.2 g, 75 mmol) and 6-bromo-8-methyl-1,11-diazabenzo[a]phenothiazin-5-one (1.8 g, 5 mmol) refluxed in methanol for 3 h gave dark reddish powder (1, 38 g, 71% yield), M.p.130°C-132°C. UV (EtOH) λ_max (nm); 269, 292, 496; IR KBr ν_max (cm^-1); 3063 (C-H, aromatic), 2957 (C-H, methyl), 1637 (C=O), 1563, 1439 (C=C, C=N); ¹H-NMR δ (ppm)=7.51 (2H, aromatic), 7.63 (2H, aromatic), 7.80 (2H, aromatic) 7.70 (1H, aromatic), 7.75 (2H aromatic), 4.0 (3H, methyl). MS (m/z, % int) (M⁺), 389 (M⁺, 25), 391 (M⁺+2, 10), 354 (-Cl, 20). Calculated for C₂₂H₁₂N₃OSCl. C, 64.70; H, 3.08; N, 10.78. Found; C, 64.75; H, 3.10; N, 10.75; S, 8.31; Cl, 9.15.

8-Methyl-6-(3-bromophenyl)1,11-diazabenzo[a]phenothiazin-5-one 9c

Using the general procedure reported above, from 3-bromophenylboronic acid (1.5 g, 7.5 mmol) and 6-bromo-8-methyl-1-11-diazaphenothiazin-5-one (1.8 g, 5 mmol) was obtained (1.34 g, 62 % yield) of title compound as reddish brown powder upon repeated recrystalization from acetone. UV-visible (EtOH) λ_max (nm); 291, 497, 657. IR (KBr) ν_max (cm^-1); 1639 (C=O). 1559, 1412 (C=C. C=N), 806 (C-Br). MS (m/z, % int), 433 (M⁺), ¹H-NMR δ (ppm)=7.52 (2H. aromatic), 8.20 (2H, aromatic), 8.3 (2H, aromatic) 8.6 (1H, aromatic), 9.4 (2H, aromatic), 3.5 (3H, methyl); 13C-NMR (DMSO) δ (ppm)=183, C=O, 167, C=N, 148, 135, 112 C=C. Calculated for C₂₁H₁₂N₃OSBr: C, 58.20; H, 2.7; N, 9.70; S, 7.39; Br, 18.24. Found: C, 58.09; H, 2.75; N, 9.70; S, 7.40; Br, 18.51.

8-Methyl-6-(3-nitrophenyl)-1,11-diazabenzo[a]phenothiazin-5-one 9d

A mixture of 3-nitrophenylboronic acid (1.3 g, 75 mmol) and 6-bromo-8-methyl-1,11-diazabenzo[a]phenothiazin-5-one (1.8 g, 5 mmol) yielded the title compound, brown powder (1.62 g, 75% yield) M.p. 150°C-150°C. UV-visible λ_max (nm); 291, 498, 658; IR (KBr)ν_max (cm^-1); 1614 (C=O), 1563, 1411, 1385 (C=C,C=N); 1H-NMR δ (ppm)=8.9 (m, 2H), 8.7 (d, 2H), 7.7 (m, 2H), 7.3 (m, 1H), 174, C=O, 161, C=N, 135, 125, C=C MS (m/z, % int); 400 (M⁺, 70), 354 (-NO₂, 50), 339 (-Me, 30), 263 (-Ph, 100). Calculated for C₂₁H₁₂N₄O₃S: C, 63.00; H, 3.00; N, 14.00; O, 12.00; S, 8.00. Found: C, 62.96; H, 3.08; N, 14.12; S, 8.05.

Conclusion

In the present study, novel 1,11-diazabenzo[a]phenothiazin-5-one derivatives were designed and synthesized in good yields. All the synthesized compounds were characterized by using UV, elemental analysis, 1H & 13C NMR and Mass spectral data. In addition, we have also established and reported the reaction mechanism for the formation of the isomeric products of parent compound i.e. 1,11-diazabenzo[a]phenothiazin-5-one (9). Furthermore, 1,11-diazabenzo[a]phenothiazin-5-one derivatives (9a-e) possesses to have an aptitude as vat dyes. From the above results it can be concluded that the synthesized compounds could be a best initiation to find new lead to class of vat dyes in the future.

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