Copper(II)-Promoted Mono-Selective ortho C–H Chlorination of Arenes by Using Trimethyl(trichloromethyl)silane

Abstract

The first example of a Cu-promoted ortho-chlorination of aryl C–H bonds by using TMSCCl₃ as chlorinating agent is reported. This reaction features a high selectivity toward monochlorination over dichlorination, compatibility with a variety of functional groups, and gram-scale synthesis.

Key words

C–H activation - copper - chlorination - trimethyltrichloromethylsilane

• References and Notes

• 1 Petrone DA. Ye J. Lautens M. Chem. Rev. 2016; 116: 8003
• 2 De La Mare PB. D. Electrophilic Halogenation: Reaction Pathways Involving Attack by Electrophilic Halogens on Unsaturated Compounds. Cambridge University Press; Cambridge: 1976
• 3 Hodgson HH. Chem. Rev. 1947; 40: 251
• 4 Snieckus V. Chem. Rev. 1990; 90: 879
• 5 For a review, see: Liao G. Shi B.-F. Acta Chim. Sinica 2015; 73: 1283

For selected examples of N-heteroarenes directed, palladium-catalyzed, direct chlorination of C(sp²)–H bonds, see:
• 6a Dick AR. Hull KL. Sanford MS. J. Am. Chem. Soc. 2004; 126: 2300
• 6b Kalyani D. Dick AR. Anani WQ. Sanford M. S. Org. Lett. 2006; 8: 2523
• 6c Song B. Zheng X. Mo J. Xu B. Adv. Synth. Catal. 2010; 352: 329
• 6d Korwar S. Brinkley K. Siamaki AR. Gupton BF. Ellis KC. Org. Lett. 2015; 17: 1782
• 6e Kang K. Lee S. Kim H. Asian J. Org. Chem. 2015; 4: 137
• 6f Zhang Q. Yang F. Wu Y. Org. Chem. Front. 2014; 1: 694
• 6g Zhao X. Dimitrijević E. Dong VM. J. Am. Chem. Soc. 2009; 131: 3466
• 6h Kakiuchi F. Kochi T. Mutsutani H. Kobayashi N. Urano S. Sato M. Nishiyama S. Tanabe T. J. Am. Chem. Soc. 2009; 131: 11310
• 6i Zhang G. Sun S. Yang F. Zhang Q. Kang J. Wu Y. Wu Y. Adv. Synth. Catal. 2015; 357: 443
• 7a Qian G. Hong X. Liu B. Mao H. Xu B. Org. Lett. 2014; 16: 5294
• 7b Zhang P. Hong L. Li G. Wang R. Adv. Synth. Catal. 2015; 357: 345
• 7c Lied F. Lerchen A. Knecht T. Mück-Lichtenfeld C. Glorius F. ACS Catal. 2016; 6: 7839
• 8 Zhan B.-B. Liu Y.-H. Hu F. Shi B.-F. Chem. Commun. 2016; 52: 4934
• 9 For a review on copper-mediated functionalization of nonactivated C–H bonds, see: Rao W.-H. Shi B.-F. Org. Chem. Front. 2016; 3: 1028
• 10 Chen X. Hao X.-S. Goodhue CE. Yu J.-Q. J. Am. Chem. Soc. 2006; 128: 6790
• 11 Wang W. Pan C. Chen F. Cheng J. Chem. Commun. 2011; 47: 3978
• 12 Mo S. Zhu Y. Shen Z. Org. Biomol. Chem. 2013; 11: 2756
• 13 Urones B. Manu Martínez Á. Rodríguez N. Gómez Arrayás R. Carretero JC. Chem. Commun. 2013; 49: 11044
• 14 Li B. Liu B. Shi B.-F. Chem. Commun. 2015; 51: 5093
• 15 Du Z.-J. Gao L.-X. Lin Y.-J. Han F.-S. ChemCatChem 2014; 6: 123
• 16a Fujita M. Hiyama T. J. Am. Chem. Soc. 1985; 107: 4085
• 16b Wu N. Wahl B. Woodward S. Lewis W. Chem. Eur. J. 2014; 20: 7718
• 16c Fustero S. Herrera L. Lázaro R. Rodríguez E. Maestro MA. Mateu N. Barrio P. Chem. Eur. J. 2013; 19: 11776
• 16d Li Y. Cao Y. Gu J. Wang W. Wang H. Zheng T. Sun Z. Eur. J. Org. Chem. 2011; 676
• 16e Wahl B. Lee DS. Woodward S. Eur. J. Org. Chem. 2015; 6033
• 16f Kister J. Mioskowski C. J. Org. Chem. 2007; 72: 3925
• 16g Wahl B. Cabré A. Woodward S. Lewis W. Tetrahedron Lett. 2014; 55: 5829
• 17 Fedoryński M. Chem. Rev. 2003; 103: 1099
• 18 Copper-Promoted Monochlorination of 2-Arylpyridines or 2-Arylpyrimidines 1 with TMSCCl₃; General Procedure A solution of 1 (0.2 mmol), Cu(OAc)₂ (0.2 mmol), TMSCCl₃ (0.4 mmol), and TFA (1.0 mmol) in DCE (2.0 mL) was stirred in a reaction tube under N₂ (1 atm) at 80 °C for 96 h, then cooled to r.t. A 2 M aq solution of NaOH (8.0 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 10.0 mL). The organic layers were combined, dried (MgSO₄), and concentrated under vacuum. The crude product was purified by chromatography [silica gel, PE–EtOAc (20:1)]. 2-(2-Chlorophenyl)pyridine (3a) Yellow oil; yield: 27.2 mg (72%). ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.32 (m, 1 H), 7.32–7.39 (m, 2 H), 7.48 (dd, J = 1.6, 7.2 Hz, 1 H), 7.60 (dd, J = 2.0, 7.6 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.77 (td, J = 1.6, 7.6 Hz, 1 H), 8.73 (d, J = 4.8 Hz, 1 H). 2-(2,6-Dichlorophenyl) pyridine (4a) Yellow oil; yield: 2.2 mg (5%). ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.28 (m, 1 H), 7.34–7.37 (m, 2 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.82 (td, J = 2.0, 8.0 Hz, 1 H), 8.76–8.75 (m, 1 H).