New Diimine-Copper Complexes: An Efficient and Simple Catalyst System for Buchwald N-Arylation of Indole Mariappan Periasamy,* Pothiappan Vairaprakash, and Manasi Dalai School of Chemistry, UniVersity of Hyderabad, Central UniVersity P.O., Hyderabad 500 046, India ReceiVed December 20, 2007 Summary: A new method of N-arylation of indole with (()-trans- 2,3-diarylpiperazines/copper(I) halide and aryl halides is described. Whereas electron-donating substituents in the phenyl group enhance the reactiVity, the yields are lower with electron- withdrawing substituents. OxidatiVe cleaVage of piperazines in the presence of oxygen to diimines has been obserVed under these reaction conditions. On the basis of this obserVation, a new catalyst system using diimines and CuI was also deVeloped for the N-arylation of indole. Introduction The N-aryl nitrogen heterocycle motif is present in a multitude of bioactive natural products and pharmaceutically interesting compounds. 1 Various strategies have been developed for the N-arylation of heterocycles. The century old copper-catalyzed Ullmann reaction 2a,2b has limitations because of the harsh reaction conditions such as high temperatures, requirement of stoichiometric amounts of copper reagents, long reaction times, and low yields. 2c The palladium-catalyzed N-arylation is an alternative method under mild reaction conditions. 3 The copper- catalyzed Ullmann reactions have seen a gradual expansion in the past few years and by the correct choice of copper sources, bases, ligands, and other additives, several mild and efficient methods have been reported for the N-arylation of indoles. 4,5 Ligands based on diamines, 6 oxime-phosphine oxide, 7 ami- noacids, 8 phosphoramidite, 9 and proline (pyrrolidinylmethylimi- dazole) 10 have been introduced to promote copper-catalyzed N-arylation of indoles and other heterocycles. In this paper, we report a simple reagent system consisting of the easily accessible (()-trans-2,3-diarylpiperazines and copper(I) halides, which catalyzes the N-arylation of indoles in the presence of base. Also, N-arylation catalyzed by a diimine copper complex prepared in situ is also described. Results and Discussion The (()-2,3-diarylpiperazines 2 (Chart 1) have been readily synthesized in good yields by the intramolecular reductive coupling of the corresponding diimines 3 in the presence of Zn and Ti(O i Pr) 2 Cl 2 reagent system developed in this laboratory. 11 These piperazines 2 as well as simple piperazine 1 have been examined for use in the N-phenylation studies. The product was obtained by using the catalyst in 10 mol % (Table 1). Simple piperazine 1 gave the product N-phenylindole in 75% yield (Table 1, entry 1). When the N-phenylation of indole was carried out with (()-2,3-diphenylpiperazine and CuI in the presence * Corresponding author. E-mail: mpsc@uohyd.ernet.in. Phone: +91 40 2313 4814. Fax: +91 40 2301 2460. (1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Elsevier: Oxford, 1996. (b) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton, C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384. (b) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853–854. (c) Lindley, J. Tetrahedron 1984, 40, 1433–1456. (3) (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Ferna ´ndez-Rivas, C. J. Am. Chem. Soc. 1998, 120, 827–828. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575–5580. (c) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403–1406. (d) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 2000, 41, 481–483. (e) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729–7737. (4) For recent reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337–2364. (c) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651–2710. (5) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400– 5449. (6) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684–11688. (7) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005, 61, 6553–6560. (8) Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496–499. (9) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435–4443. (10) Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737–2743. (11) Vairaprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71, 3636– 3638. Chart 1 Table 1. (()-2,3-Diarylpiperazines/CuI-Catalyzed N-Phenylation of Indole with Iodobenzene and Base a yield (%) b entry piperazine condition K 2 CO 3 c K 3 PO 4 d 1 1 reflux, 24 h 70 75 2 2a reflux, 24 h 44 52 3 2b reflux, 24 h 39 45 4 2c reflux, 24 h 63 74 5 2d reflux, 24 h 90 94 6 2e reflux, 24 h 93 96 7 2e rt, 48 h <5 a Unless noted otherwise, all the reactions were carried out with 0.1 mmol of piperazine, 0.1 mmol of CuI, 1.0 mmol of indole, and 1.5 mmol of PhI in toluene (2 mL). b Yields are of the isolated product and the product was identified by using spectroscopic data (IR, 1 H, 13 C NMR) and comparison with reported data. 12 c With 5.0 mmol of K 2 CO 3 . d With 2.0 mmol of K 3 PO 4 . Organometallics 2008, 27, 1963–1966 1963 10.1021/om7012748 CCC: $40.75  2008 American Chemical Society Publication on Web 03/18/2008