Copper(II)-Catalyzed C–N Coupling of Aryl Halides and N-Nucleophiles Promoted by Quebrachitol or Diethylene Glycol

^§ Both authors contributed equally to this work.

Abstract

Herein, we report the natural ligand quebrachitol (QCT) as a promoter for a Cu(II) catalyst, which is highly effective for N-arylation of various amines and related aryl halides. A series of diarylamine derivatives were obtained in high yields by using diethylene glycol (DEG) as both ligand and solvent. The C–N coupling reactions proceed under mild conditions and exhibit good functional group tolerance.

Key words

N-arylation - quebrachitol - diethylene glycol - Cu(OAc)₂ - Ullman coupling

• References and Notes

• 1 Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177
• 2a Jarrott B. Pharmacol. Res. 2019; 116: 29
• 2b Motonori T. J. Comput. Aided Mol. Des. 2017; 31: 577
• 2c Yaeko, N.; Kana, M.; Atsuo, S.; Kunihiko, M. J. Infect. Chemother. 2019, in press; DOI: 10.1016/j.jiac.2019.08.002
• 2d Labib MB, Sharkawi SM.Z, El-Daly M. Bioorg. Chem. 2018; 80: 70
• 2e Wang C, Bai X, Wang R, Zheng X, Ma X, Chen H, Ai Y, Bai Y, Liu Y. Org. Process Res. Dev. 2019; 23: 1918
• 3a Kwan EE, Zeng Y, Besser HA, Jacobsen EN. Nat. Chem. 2018; 10: 917
• 3b Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
• 3c Hartwig JF. Acc. Chem. Res. 1998; 31: 852
• 4 Bhunia S, Pawar GG, Kumar SV, Jiang Y, Ma D. Angew. Chem. Int. Ed. 2017; 56: 16136
• 5a Wolfe JP, Wagaw S, Marcoux J.-F, Buchwald SL. Acc. Chem. Res. 1998; 31: 805
• 5b Ma D, Zhang Y, Yao J, Wu S, Tao F. J. Am. Chem. Soc. 1998; 120: 12459
• 5c Klapars A, Antilla JC, Huang X, Buchwald SL. J. Am. Chem. Soc. 2001; 123: 7727
• 6a Xia S, Gan L, Wang K, Li Z, Ma D. J. Am. Chem. Soc. 2016; 138: 13492
• 6b Pawar GG, Wu H, De S, Ma D. Adv. Synth. Catal. 2017; 359: 1631
• 6c Gao J, Bhunia S, Wang K, Gan L, Xia S, Ma D. Org. Lett. 2017; 19: 2809
• 6d Zhai Y, Chen X, Zhou W, Fan M, Lai Y, Ma D. J. Org. Chem. 2017; 82: 4964
• 7 Chida N, Yoshinage M, Tobe T, Ogawa S. Chem. Commun. 1997; 1043
• 8 Wang D, Zhang S, Chang Z, Kong D, Zuo Z. Nat. Prod. Bioprospect. 2017; 7: 113
• 9 Kozikowski AP, Ognyanov VI, Fauq AH, Wilcox RA, Nahorski SR. J. Chem. Soc., Chem. Commun. 1994; 599
• 10 Baars SM, Hoberg JO. Carbohydr. Res. 2006; 341: 1680
• 11 Thakur KG, Sekar G. Chem. Commun. 2011; 47: 6692
• 12a Kwan EE, Zeng Y, Besser HA, Jacobsen EN. Nat. Chem. 2018; 10: 917
• 12b Neumann CN, Hooker JM, Ritter T. Nature 2016; 534: 369
• 13a Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
• 13b Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
• 13c Surry DS, Buchwald SL. Chem. Sci. 2010; 1: 13
• 14a Hartwig JF. Acc. Chem. Res. 1998; 31: 852
• 14b Yang BH, Buchwald SL. J. Organomet. Chem. 1999; 576: 125
• 15 Bhunia S, Kumar SV, Ma D. J. Org. Chem. 2017; 82: 12603
• 16 Zhou Q, Du F, Chen Y, Fu Y, Sun W, Wu Y, Chen G. J. Org. Chem. 2019; 84: 8160
• 17a Wang S, Midgley CA, Scaerou F, Grabarek JB, Griffiths G, Jackson W, Kontopidis G, McClue SJ, McInnes C, Meades C, Mezna M, Plater A, Stuart I, Thomas MP, Wood G, Clarke RG, Blake DG, Zheleva DI, Lane DP, Jackson RC, Glover DM, Fischer PM. J. Med. Chem. 2010; 53: 4367
• 17b Nguyen T, Sakasegawa Y, Doh-ura K, Go M. Eur. J. Med. Chem. 2011; 46: 2917
• 18 Nakatsuka A, Wada J, Makino H. J. Pathol. 2012; 226: 784
• 19 Toyama T, Asano Y, Akamata K, Noda SI, Taniguchi T, Takahashi T, Ichimura Y, Shudo K, Sato S, Kadono T. J. Invest. Dermatol. 2016; 136: 387
• 20 Bao X, Qiao X, Bao C, Liu Y, Zhao X, Lu Y, Chen G. Org. Process Res. Dev. 2017; 21: 748
• 21a Sun Y, Xu L, Xu P, Yuan H, Shen R. Faming Zhuanli Shenqing; CN 103073451, 2013
• 21b Bian H, Xu W. Chin. J. Pharmaceuticals (Zhongguo Yiyao Gongye Zazhi) 2009; 40: 9
• 22a Zelenay B, Besora M, Monasterio Z, Ventura-Espinosa D, White AJ. P, Maseras F, Diez-Gonzalez S. Catal. Sci. Technol. 2018; 8: 5763
• 22b Amanchi SR, Ashok Kumar KV, Lakshminarayana B, Satyanarayana G, Subrahmanyam C. New J. Chem. 2019; 43: 748
• 23 Grasing K, Yang Y, He S. Pharmacol. Res. 2015; 97: 40
• 24 Recanatini M, Cavalli A, Belluti F, Piazzi L, Rampa A, Bisi A, Gobbi S, Valenti P, Andrisano V, Bartolini M, Cavrini V. J. Med. Chem. 2000; 43: 2007
• 25 Tye JW, Weng Z, Johns AM, Incarvito CD, Hartwig JF. J. Am. Chem. Soc. 2008; 130: 9971
• 26 Casitas A, Canta M, Sola M, Costas M, Ribas X. J. Am. Chem. Soc. 2011; 133: 19386
• 27 Paine AJ. J. Am. Chem. Soc. 1987; 109: 1496
• 28 General Information All starting materials, reagents, and solvents were commercially available and used without further purification. Melting points were determined with a X-4 apparatus and are uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded with a Bruker 400 MHz spectrometer in CDCl₃ or DMSO-d ₆ by using tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass spectrometry (ESI-MS) analyses were recorded with an Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reactions were monitored by thin-layer chromatography (TLC: HG/T2354-92, GF254), and compounds were visualized on TLC with UV light. Synthesis of 3a–v; General Procedure A To a solution of aliphatic amine (1.53 mmol), Cu(OAc)₂·H₂O (0.13 mmol), QCT (0.26 mmol), K₂CO₃ (3.85 mmol) in DMSO (3 mL) were added aryl halides (1.28 mmol). The flask was evacuated and backfilled with argon (3×), and the resulting mixture was heated in an oil bath with appropriate temperature under rapid stirring for the indicated time. After the complete consumption of aryl halide as monitored by TLC, the flask was cooled to r.t. The flask was opened to air, and the reaction mixture (if the product was acidic, the mixture was acidified) was extracted with EtOAc (3×10 mL), and the organic layer was washed with water (2×10 mL) and once with brine (10 mL), dried with magnesium sulfate and concentrated in vacuo. The product was purified by column chromatography on silica gel. Synthesis of 4a–p; General Procedure B To a solution of aromatic amine (1.53 mmol), Cu(OAc)₂·H₂O (0.13 mmol), K₂CO₃ (3.84 mmol) in DEG (3 mL) were added aryl halides (1.28 mmol). The flask was evacuated and backfilled with argon (3×), and the resulting mixture was heated in an oil bath with appropriate temperature under rapid stirring for the indicated time. After the complete consumption of aryl halide as monitored by TLC, the flask was cooled to r.t. The flask was opened to air, and the reaction mixture (if the product was acidic, the mixture was acidified) was extracted with EtOAc (3×10 mL), and the organic layer was washed with water (2×10 mL) and once with brine (10 mL), dried with magnesium sulfate and concentrated in vacuo. The product was purified by column chromatography on silica gel. Synthesis of 5a–z, 5aa; General Procedure C A sealed reaction vessel was charged with ammonia (aq, 25%) (1.8 mL, 12.8 mmol), Cu(OAc)₂·H₂O (0.13 mmol), QCT (0.26 mmol) in NMP (1.8 mL) and aryl halides (1.28 mmol). The resulting mixture was heated in an oil bath with appropriate temperature under rapid stirring for the indicated time. After complete consumption of the aryl halide as monitored by TLC, the reaction vessel was cooled to rt. It was opened to air, and the reaction mixture was extracted with EtOAc (3×10 mL), and the organic layer was washed with water (2×10 mL) and once with brine (10 mL), dried with magnesium sulfate and concentrated in vacuo. The product was purified by column chromatography on silica gel.4-Chloro-2-(cyclohexylamino)benzoic acid (3o): According to the general procedure A, 3o was obtained as a white solid (0.28 g, 87%). Mp 173–176 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.04 (br, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 6.77 (d, J = 1.6 Hz, 1 H), 6.54–6.51 (dd, J = 8.5, 1.8 Hz, 1 H), 3.46 (br, 1 H), 1.91–1.88 (m, 2 H), 1.68–1.64 (m, 2 H), 1.58–1.55 (m, 1 H), 1.46–1.35 (m, 2 H), 1.30–1.18 (m, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 170.0, 151.2, 139.8, 134.1, 114.2, 111.2, 109.1, 49.8, 32.6, 31.1, 25.7, 24.4. For IR and MS data see: Martin, A.; Mesa, M.; Docampo, M.; Gomez, V.; Pellon, R. Synthetic Commun. 2006, 36, 271. 1-[2-(Allyloxy)phenyl]piperidine (3v): According to the general procedure A, 3v was obtained as a colorless oil (0.21 g, 75%). ¹H NMR (400 MHz, CDCl₃): 6.95–6.88 (m, 3 H), 6.86–6.82 (m, 1 H), 6.14–6.04 (m, 1 H), 5.49–5.43 (m, 1 H), 5.28–5.24 (m, 1 H), 4.57–4.55 (m, 2 H), 3.03–2.99 (q, J = 9.9, 5.5 Hz, 4 H), 1.78–1.72 (m, 4 H), 1.60–1.53 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 151.4, 143.2, 133.7, 122.3, 121.4, 118.6, 116.6, 113.3, 68.9, 52.3, 26.5, 24.6. For IR and MS data see: Sung, S.; Sale, D.; Braddock, D. C.; Armstrong, A.; Brennan, C.; Davies, R. P. ACS Catalysis 2016, 6, 3965. 5,5,8,8-Tetramethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydronaphthalen-2-amine (4d): According to the general procedure B, 4d was obtained as yellow solid (0.29 g, 71%). ¹H NMR (400 MHz, CDCl₃): δ = 9.48 (br, 1 H), 8.21–8.19 (dd, J = 8.6, 1.5 Hz, 1 H), 7.36–7.32 (m, 2 H), 7.21–7.19 (dd, J = 8.7, 1.1 Hz, 1 H), 7.18 (d, J = 2.3 Hz, 1 H), 7.06–7.03 (dd, J = 8.4, 2.4 Hz, 1 H), 6.75–6.71 (m, 1 H), 1.71 (s, 4 H), 1.30 (s, 6 H), 1.28 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 146.7, 143.7, 142.7, 135.8, 135.6, 132.8, 127.8, 126.7, 122.6, 122.0, 117.0, 116.1, 35.0, 34.9, 34.5, 34.1, 31.9, 31.8. For IR and MS data see: Yan, C.; Yang, L.; Fan, W.; Qian, S.; Wu, Y. Sichuan Daxue Xuebao, Ziran Kexueban. 2010, 47, 847. N-(4-Methoxyphenyl)-2-methyl-3-(trifluoromethyl)aniline (4j): According to the general procedure B, 4j was obtained as white solid (0.21 g, 58%). ¹H NMR (400 MHz, CDCl₃): δ = 7.18–7.09 (m, 3 H), 7.00 (br, 2 H), 6.89–6.87 (m, 2 H), 3.81 (s, 3 H), 2.33 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 155.8, 145.1, 135.5, 130.9, 129.9 (J = 29.1 Hz), 128.9, 126.2, 124.7 (J = 274.9 Hz), 123.2, 118.4, 117.2 (J = 6.0 Hz), 114.9, 55.6, 13.2 (J = 2.3 Hz). HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₃F₃NO: 280.0955; found: 280.0962. See high-resolution mass spectra in SI. 2-(Allyloxy)-N-phenylaniline (4p): According to the general procedure B, 4p was obtained as a brown oil (0.23 g, 80%). ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.25 (m, 3 H), 7.16–7.14 (m, 2 H), 6.96–6.78 (m, 4 H), 6.18 (br, 1 H), 6.14–6.04 (m, 1 H), 5.44–5.38 (dq, J = 17.2, 3.1, 1.6 Hz, 1 H), 5.32–5.28 (dq, J = 10.5, 2.7, 1.3 Hz, 1 H), 4.61–4.59 (dt, J = 8.9, 1.4 Hz, 2 H). For IR and MS see: Ding, X.; Huang, M.; Yi, Z.; Du, D.; Zhu, X.; Wan, Y. J. Org. Chem. 2017, 82, 5416. 2-(Allyloxy)aniline (5aa): According to the general procedure C, 5aa was obtained as brown oil (0.14 g, 72%). ¹H NMR (400 MHz, CDCl₃): δ = 6.81–6.77 (m, 2 H), 6.73–6.67 (m, 2 H), 6.12–6.03 (m, 1 H), 5.42 (dq, J = 17.2, 3.2, 1.6 Hz, 1 H), 5.26 (dq, J = 10.5, 2.8, 1.4 Hz, 1 H), 4.55 (dt, J = 5.3, 1.5 Hz, 2 H), 3.64 (br, 2 H). GC-MS: 149 [M]. For IR and MS see: Carmona, R. C.; Koester, O. D.; Correia, C. R. D. Angew. Chem. Int. Ed. 2018, 5737, 12067. Characterization data for all known compounds are provided in the Supporting Information.