Practical and Metal-Free Electrophilic Aromatic Halogenation by Inter­halogen Compounds Generated In Situ from N-Halosuccinimide and Catalytic TMSCl

Abstract

Halomonochloride compounds (ClCl, BrCl, ICl) generated in situ from N-halosuccinimide and catalytic chlorotrimethylsilane (TMSCl, 0.1 equiv) can efficiently halogenate aromatic compounds to give halogenated products in good to excellent yields and selectivities. The reaction can be carried out at room temperature or at lower temperatures, requires only one hour, is practical to apply to a wide range of substrates, and provides a simple access to a variety of haloarene compounds.

Key words

interhalogens - electrophilic aromatic halogenation - isocryptolepine - chlorotrimethylsilane - N-halosuccinimide

• References and Notes

• 1a Davis SG In Organotransition Metal Chemistry: Applications to Organic Synthesis. Pergamon Press; Oxford, UK: 1982
• 1b Cannon KC, Krow GR In Handbook of Grignard Reagents . Dekker; New York: 1996
• 2a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 2b Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
• 2c Meijere A, Meyer FE. Angew. Chem., Int. Ed. 1994; 33: 2379
• 3 Hernandes MZ, Cavalcanti SM. T, Moreira DR. M, de Azevedo JrW. F, Leite AC. L. Curr. Drug Targets 2010; 11: 303
• 4 Kamigata N, Satoh T, Yoshida M, Matsuyama H, Kameyama M. Bull. Chem. Soc. Jpn. 1988; 61: 2226
• 5a Zhang Y, Shibatomi K, Yamamoto H. Synlett 2005; 2837
• 5b Zhang Y, Yamamoto H. Eur. Patent 1928599B1, 2006
• 6a Mo F, Yan JM, Qiu D, Li F, Zhang Y, Wang J. Angew. Chem. Int. Ed. 2010; 49: 2028
• 6b Qiu D, Mo F, Zheng Z, Zhang Y, Wang J. Org. Lett. 2010; 12: 5474
• 7 Tanemura K, Suzuki T, Nishida Y, Satsumabayashi K, Horaguchi T. Chem. Lett. 2003; 32: 932
• 8 Castanet A.-S, Colobert F, Broutin P.-E. Tetrahedron Lett. 2002; 43: 5047
• 9 Yu G, Mason HJ, Wu X, Endo M, Douglas J, Macora JE. Tetrahedron Lett. 2001; 42: 3247
• 10 Bovonsombat P, Ali R, Khan C, Leykajarakul J, Pla-on K, Aphimanchindakul S, Pungcharoenpong N, Timsuea N, Arunrat A, Punpongjareorn N. Tetrahedron 2010; 66: 6928
• 11 Goldberg Y, Alper H. J. Org. Chem. 1993; 58: 3072
• 12 Schmid H. Helv. Chim. Acta 1946; 29: 1144
• 13 Shao L.-X, Shi M. Synlett 2006; 1269
• 14 Mahajan T, Kumar L, Dwivedi K, Agarwal DD. Ind. Eng. Chem. Res. 2012; 51: 3881
• 15 Bunrit A, Ruchirawat S, Thongsornkleeb C. Tetrahedron Lett. 2011; 52: 3124
• 16 Tummatorn J, Thongsornkleeb C, Ruchirawat S. Tetrahedron 2012; 68: 4732
• 17a Sharaf MH. M, Schiff JrP. L, Tackie AN, Phoebe JrC. H, Martin GE. J. Heterocycl. Chem. 1996; 33: 239
• 17b Cimanga K, De Bruyne T, Pieters L, Claeys M, Vlietinck A. Tetrahedron Lett. 1996; 37: 1703
• 17c Grellier P, Ramiaramanana L, Millerioux V, Deharo E, Schrével J, Frapper F, Trigalo F, Bodo B, Pousset J.-L. Phytother. Res. 1996; 10: 317
• 17d Baelen GV, Hostyn S, Dhooghe L, Tapolcsányi P, Mátyus P, Lemière G, Dommisse R, Kaiser M, Brun R, Cos P, Maes L, Hajós G, Riedl Z, Nagy I, Maes BU. W, Pieters L. Bioorg. Med. Chem. 2009; 17: 7209
• 17e Whittell LR, Batty KT, Wong RP. M, Bolitho EM, Fox SA, Davis TM. E, Murray PE. Bioorg. Med. Chem. 2011; 19: 7519
• 18 Thongsornkleeb C, Rabten W, Bunrit A, Tummatorn J, Ruchirawat S. Tetrahedron Lett. 2012; 53: 6615
• 19 General Procedure for the Electrophilic Aromatic Halogenation; 4-Bromo-2-chloro-1-methoxybenzene (2a-Cl) and 2,4-Dichloro-1-methoxybenzene (2a-diCl; Ref 20): To a solution of 4-bromoanisole (1a; 200.8 mg, 1.09 mmol, 1.0 equiv) in MeCN (2 mL) was added N-chlorosuccinimide (NCS; 158.3 mg, 1.19 mmol, 1.1 equiv) at r.t. to give a slightly cloudy mixture. Chlorotrimethyl-silane (TMSCl; 14 μL, 0.11 mmol, 0.1 equiv) was then added dropwise to the reaction mixture. Within a few minutes, the reaction mixture became clear pale yellow solution. The mixture was stirred continuously at r.t. for 1 h and H₂O was added to it. The separated aqueous layer was extracted with EtOAc. The combined organic phases were washed with sat. aq NaCl, dried over Na₂SO₄ and concentrated. The crude material was purified by flash SiO₂ column eluted with 5–10% EtOAc–hexane to give a mixture of 4-bromo-2-chloro-1-methoxybenzene (2a-Cl) and 2,4-dichloro-1-methoxybenzene (2a-diCl): 237.0 mg yield (88% of 2a-Cl and 11% of 2a-diCl, based on NMR ratio 2a-Cl/2a-diCl = 7.1:1.0; as a pale yellow solid). IR (neat): 2854, 1288, 1222, 1028 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.49 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 0.15 H, minor), 7.32 (dd, J = 8.7, 2.4 Hz, 1 H), 7.19 (dd, J = 9.0, 2.7 Hz, 0.14 H, minor), 6.84 (d, J = 8.7 Hz, 0.15 H, minor), 6.79 (d, J = 8.7 Hz, 1 H), 3.87 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 154.4, 132.6, 130.5, 129.9 (minor), 127.6 (minor), 123.6, 113.3, 112.8 (minor), 112.5, 56.34, 56.28 (minor).
• 20 Garcia P, Lau YY, Perry MR, Schafer LL. Angew. Chem. Int. Ed. 2013; 52: 9144