Synthesis of Phenazines by Cu-Catalyzed Homocoupling of 2-Halogen Anilines in Water

Journal of Organometallic Chemistry 705 (2012) 75e78

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Journal of Organometallic Chemistry

journal homepage: www.elsevier.com/locate/jorganchem

Note Synthesis of phenazines by Cu-catalyzed homocoupling of 2-halogen anilines in water

Lintao Yu, Xiangge Zhou*, Di Wu, Haifeng Xiang

Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu 610064, China article info abstract

Article history: Phenazines are synthesized by Cu-catalyzed homocoupling of 2-iodoanilines or 2-bromoanilines in water Received 4 November 2011 in moderate to excellent yields up to 85%. Received in revised form Ó 2011 Elsevier B.V. All rights reserved. 14 December 2011 Accepted 26 December 2011

Keywords: Phenazine Copper Homocoupling 2-Halogen aniline Aqueous catalysis

1. Introduction following advantages compared with the reported literatures: water was used as sole solvent instead of organic media; the Substituted phenazine cores are important biologically active reactions could be carried out in the air under mild conditions; the motifs, and are usually found in natural products, dyestuffs, pesti- catalyst was easily available with high catalytic abilities. cides, and antibiotics [1e4]. Majority of the naturally occurring phenazines are produced by bacteria from diverse genera including 2. Results and discussion Pseudomonas, Pelagiobacter, Vibrio and Streptomyces species [5e9]. In the mid-19th century, Sir William Henry Perkin synthe- As shown in Table 1, 2-iodoaniline was initially chosen as model sized mauveine, an impure mixture containing substituted phen- substrate, and 10 mol% complex 1 or 10 mol% CuSO4 in combination azines, which contributed the first example of successful synthetic with ligands L1eL7 (20 mol%) (Fig. 1) were used as catalysts in the dye [10,11]. Thereafter, numerous different synthetic approaches presence of NaOH (2 equiv.) and (nBu)4NBr (20 mol%) at 120 C for to obtain phenazines have been described [12e22]. Two of the 30 h in water. most general and flexible ones were the cyclization of suitably Among the catalysts investigated, complex 1 exhibited prefer- substituted diphenylamines or condensation between diamine and able catalytic activity in 53% yield (Table 1, entries 2e9). Control diphenol (Scheme 1), which utilized palladium catalyst or required experiments confirmed that no product was detected in the harsh reaction conditions as well as organic solvents such as DMSO absence of ligands (Table 1, entry 1). Screening of different bases [12,13,18,20]. indicated K2CO3 to be the best one in 79% yield (Table 1, entries e In recent years, copper-catalyzed C N bond formation has 10e14). Screening of different surfactants indicated (nBu)4NBr to be become one of the most powerful synthetic strategies for the the best one in 79% yield (Table 1, entries 15, 16). Furthermore, the construction of nitrogen-containing intermediates [23e26].In catalyst, base and PTC loading was then investigated, and it was continuation of our studies in aqueous catalysis [27e30], herein is observed that decreasing the amount of the catalyst, base or PTC reported a simple and practical protocol to synthesize phenazines resulted in lower yields (Table 1, entries 17e20). Reaction time was via catalytic homocoupling of 2-iodo or bromoaniline in water by another important factor to affect the results, shorter reaction time sulfonato-Cu(salen), which was successfully applied in CeN cross- than 30 h had a bad effect on the results (Table 1, entry 21). In coupling reaction by us recently [27,29]. This methodology has the addition, lower temperature than 120 C also resulted in lower yields (Table 1, entry 22). Furthermore, several organic solvents * Corresponding author. Tel./fax: þ86 28 85412026. including dichloromethane, DMF, toluene and dioxane were used E-mail address: [email protected] (X. Zhou). instead of water, 10 mol% CuSO4 in combination with ligands L2 or

H NH2 Br N N COOH N [Pd] N + R R R N N N H NO2 X N N N NO2X L1 L2 L3 L4

X=H,NO2,Br N NH2 HO N HOOC N N COOH N N + O2 0 O O O NH2 HO 200 C, 35h N L5 L6 L7 Scheme 1. Reported synthetic methods to obtain phenazines.

N N L6 (20 mol%) were used as catalysts in the presence of K2CO3 Cu

(2 equiv.), and only trace of product could be found, which indi- NaO3S O O SO3Na cated water to be proper reaction media during catalysis. In summary, the optimal conditions for the synthesis of phenazine in Complex 1 water consist of complex 1 (10 mol%), (nBu)4NBr (20 mol%) and Fig. 1. Structure of ligands and sulfonato-Cu(salen) complex 1. K2CO3 (2 equiv.) at 120 C for 30 h. Next, a variety of substrates were then screened by using this catalytic system. As shown in Table 2, most of the substrates provided moderate to excellent yields ranging from 38% to 85%. Electron-donating groups seemed to be a little beneﬁcial for the Table 2 catalysis, while steric effects showed few effects on the results. Synthesis of phenazines by complex 1 catalyzed homocoupling of 2-iodoanilines in a And the highest yields 85% was obtained by using 2-iodo-4,6- water. N dimethylbenzenamine (Table 2, entry 2). NH2 Complex 1 In an endeavor to expand the scope of the methodology, this R R R K CO ,PTC catalytic system was applied to a variety of 2-bromoanilines. As I 2 3 N H2O

Table 1 Screening reaction conditions of catalytic homocoupling of 2-iodoaniline in water.a Entry 2-Iodoaniline Product Yield [%]b NH N 2 Catalyst NH2 N base, PTC 1 83 I N I N H2O N NH2 2 85 Entry Catalyst (mol%) Base Yield [%]b I N 1 CuSO4(10) NaOH 0 2 L1 + CuSO4 (10) NaOH trace NH 3 L2 + CuSO4 (10) NaOH 30 2 N 4 L3 + CuSO (10) NaOH trace O 4 3 O 69 5 L4 + CuSO (10) NaOH 21 I O 4 N 6 L5 + CuSO4 (10) NaOH 13 7 L6 + CuSO4 (10) NaOH 32 8 L7 + CuSO (10) NaOH trace 4 NH N NO 9 1 (10) NaOH 53 2 2 10 1 (10) KOH 59 4 69 O2N I O2N N 11 1 (10) K2CO3 79 12 1 (10) Cs2CO3 76 13 1 (10) Py trace NH2 N Cl

14 1 (10) NH3.H2O19 5 73 c Cl I Cl N 15 1 (10) K2CO3 56 d 16 1 (10) K2CO3 60 Cl NH N Cl 17 1 (5) K2CO3 62 2 e 18 1 (10) K2CO3 26 6 71 f 19 1 (10) K2CO3 34 I Cl N g 20 1 (10) K2CO3 76 h F NH N F 21 1 (10) K2CO3 56 2 i 22 1 (10) K2CO3 17 7 75 j 23 1 (10) K2CO3 78 I F N a Unless otherwise noted, the reactions were carried out with 2- iodoaniline NH N F (0.5 mmol), catalyst (10 mol %), PTC (20 mol %), base (1 mmol) in water (10 mL) at 2 8 72 120 C. F I F N b Isolated yields. c Sodium dodecylsulfonate (20 mol%) was added as PTC. d Sorbitan monostearate (20 mol%) was added as PTC. NH2 N e K2CO3 (0.5 mmol) was added. 9 58 f (nBu)4NBr (5 mol %) was added as PTC. I N g (nBu)4NBr (10 mol %) was added as PTC. h a Reaction time was 24 h. Reaction conditions: 2-iodoaniline (0.5 mmol), complex 1 (10 mol%), (nBu)4NBr i Reaction temperature was 100 C. (20 mol%), K2CO3 (1 mmol), H2O (10 mL), 120 C, 30 h. j Reaction temperature was 140 C. b Isolated yield. L. Yu et al. / Journal of Organometallic Chemistry 705 (2012) 75e78 77

Table 3 Table 4 Synthesis of phenazines by complex 1 catalyzed homocoupling of 2-bromoanilines Synthesis of phenazines by complex 1 catalyzed cross-coupling between two in water.a different 2-iodoanilines.

N N NH2 Complex 1 R R R K2CO3,PTC N N Br NH2 I H2O Complex 1 N 4 + I H N N 2 K2CO3,PTC N H2O N Entry 2-Bromoaniline Product Yield [%]b 12 3 5

NH2 N 1 72 Br N Entry 123Yield [%]a 4 Yield [%]a 5 Yield [%]b 1 1.0 1.0 38 42 44 NH2 N 2 77 2 1.0 3.0 48 26 70 Br N 3 1.0 5.0 61 15 62 a Isolated yield based on 1. N b NH2 Isolated yield based on 2. 3 80 Br N 3. Conclusions

In summary, we have developed a simple, efﬁcient, economical NH2 N O and environmentally friendly protocol for the synthesis of phena- 4 O 56 Br O N zines via Cu-catalyzed homocoupling of 2-halogen anilines in water. This methodology could be also successfully applied to coupling reactions between two different 2-iodoanilines in moderate yields.

NH2 N NO2 5 44 4. Experimental section O2N Br O2N N Typical Procedure for the Catalysis: Catalyst (0.05 mmol), 2- NH2 N Cl 6 44 halogen aniline (0.5 mmol), K2CO3 (1.0 mmol), (nBu)4NBr Cl Br Cl N (0.1 mmol), and water (10 mL) were added to a sealed tube. The reaction mixture was stirred at 120 C for 30 h and then cooled to

NH2 N F room temperature and extracted with ethyl acetate. The organic 7 58 layer was then dried with anhydrous Na2SO4, and the solvent was F Br F N removed under reduced pressure. The product was ﬁnally obtained by column chromatography on silica gel. All the products were a Reaction conditions: 2-bromoaniline (0.5 mmol), complex 1 (10 mol%), ﬁ 1 13 (nBu)4NBr (20 mol%), K2CO3 (1 mmol), H2O (10 mL), 120 C, 30 h. con rmed by H and C NMR spectroscopic analysis. b Isolated yield. Acknowledgments

This project was sponsored by the Natural Science Foundation of China (Nos. 20901052, 21072132), Sichuan Provincial Foundation (08ZQ026-041) and Ministry of Education (NCET-10-0581).

Appendix. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jorganchem.2011.12.030.

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