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Synlett 2019; 30(19): 2161-2168
DOI: 10.1055/s-0039-1690707
letter
© Georg Thieme Verlag Stuttgart · New York

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

Fangyu Du
a   Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. of China   Email: chenguoliang@syphu.edu.cn
,
Qifan Zhou
a   Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. of China   Email: chenguoliang@syphu.edu.cn
,
Yang Fu
a   Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. of China   Email: chenguoliang@syphu.edu.cn
,
Yuanguang Chen
a   Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. of China   Email: chenguoliang@syphu.edu.cn
,
Ying Wu∗
b   Yunnan Institute of Tropical Crops, Jinghong 666100, P. R. of China   Email: ynbnwy@163.com
,
Guoliang Chen  ∗
a   Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. of China   Email: chenguoliang@syphu.edu.cn
› Author AffiliationsThis work was financially supported by Natural Science Foundation of Liaoning Province (No. 201602707), Discipline Construction Program of Shenyang Pharmaceutical University (No. 52134606), Yunnan Provincial Science and Technology Department (No. 2017jkys03).
Further Information

Publication History

Received: 12 August 2019

Accepted after revision: 23 September 2019

Publication Date:
16 October 2019 (online)

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§ 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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690707.
  • Supporting Information
 

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  • 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.