Synlett
DOI: 10.1055/s-0036-1588538
letter
© Georg Thieme Verlag Stuttgart · New York

N-Arylation of Heterocycles by a Tandem Aza-Michael Addition Reaction and Aromatization Sequence

Santhosh Kumar Chittimalla*, Srinuvasu Nakka, Manikandan Koodalingam, Chennakesavulu Bandi
  • Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park II, Singapore 117525, Singapore   Email: santhosh.chittimalla@amriglobal.com
Further Information

Publication History

Received: 02 June 2017

Accepted after revision: 13 July 2017

Publication Date:
17 August 2017 (eFirst)

Abstract

Cyclohexa-2,4-dien-1-one derivatives, upon reaction with N-heterocycles in the presence of scandium(III) triflate, underwent a tandem Michael addition reaction followed by aromatization of the ­Michael adduct generated in situ to give N-aryl heterocycles in good yields. Because of the ready accessibility of variously substituted cyclohexa-2,4-dien-1-ones, a range of N-aryl heterocycles have become available.

Supporting Information

 
  • References and Notes

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  • 15 Chittimalla SK. Bandi C. Gadi VK. Gunturu SR. Synlett 2017; DOI: DOI: 10.1055/s-0036-1588448.
  • 16 2-Methoxy-3-methyl-5-(1H-pyrazol-1-yl)phenol (1a): Typical Procedure Sc(OTf)3 (30 mg, 0.06 mmol)was added to a solution of dienone 1 (100 mg, 0.60 mmol) and 1H-pyrazole (a; 40 mg, 0.60 mmol) in anhyd CH3CN (2.5 mL), and the mixture was stirred at r.t. for 8 h. The solvent was then evaporated and the residue was purified by column chromatography (silica gel, EtOAc–hexanes) to give an off-white solid; yield: 106 mg (88%). 1H NMR (400 MHz, CDCl3): δ = 7.78 (app d, J = 2.4 Hz, 1 H), 7.68 (app d, J = 1.6 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 7.04 (dd, J = 2.4, 0.4 Hz, 1 H), 6.59 (br s, 1 H), 6.41 (dd, J = 2.4, 2.0 Hz, 1 H), 3.78 (s, 3 H), 2.32 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 149.6 (C), 144.2 (C), 140.7 (CH), 136.4 (C), 131.9 (C), 127.0 (CH), 113.2 (CH), 107.2 (CH), 105.2 (CH), 60.6 (CH3), 16.0 (CH3). ESI-MS: m/z = 205 [C11H12N2O2 + H]+. 5-(1H-1,2,3-Benzotriazol-1-yl)-3-bromo-2-methoxyphenol (5c) Off-white solid; yield: 107 mg (78%). 1H NMR (400 MHz, DMSO-d 6): δ = 10.6 (s, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.36 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 152.2 (C), 145.6 (C), 145.2 (C), 132.9 (C), 131.7 (C), 128.8 (CH), 124.8 (CH), 119.7 (CH), 117.5 (C), 116.7 (CH), 110.9 (CH), 110.8 (CH), 60.0 (CH3). ESI-MS: m/z = 320 [C13H10BrN3O2 + H]+. 5-(2H-1,2,3-Benzotriazol-2-yl)-3-bromo-2-methoxyphenol (5c′) Off-white solid; yield: 7 mg (5%). 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 2.4 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.93–7.89 (m, 2 H), 7.45–7.41 (m, 2 H), 5.92 (s, 1 H), 3.99 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 150.4 (C), 145.118 (C), 145.100 (C), 137.4 (C), 127.5 (CH x 2), 127.3 (C), 118.4 (CH × 2), 116.7 (CH), 116.2 (C), 107.8 (CH), 61.4 (CH3). ESI-MS: m/z = 320 [C13H10BrN3O2 + H]+. 3-Bromo-2-methoxy-5-(1H-1,2,3-triazol-1-yl)phenol (5e) Off-white solid; yield: 65 mg (56%). 1H NMR (400 MHz, DMSO-d 6): δ = 10.6 (br s, 1 H), 8.86 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 1.2 Hz, 1 H), 7.68 (d, 2.4 Hz, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 3.88 (s, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 152.0 (C), 144.9 (C), 134.4 (CH), 133.3 (C), 123.3 (CH), 117.4 (C), 114.0 (CH), 108.3 (CH), 60.0 (CH3). ESI-MS: m/z = 270[C9H8BrN3O2 + H]+. 3-Bromo-2-methoxy-5-(2H-1,2,3-triazol-2-yl)phenol (5e′) Off-white solid; yield: 32 mg (28%). 1H NMR (400 MHz, CD3OD): δ = 7.87 (s, 2 H), 7.71 (d, J = 2.4 Hz, 1 H), 7.57 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H). 13C NMR (100 MHz, CD3OD): δ = 153.2 (C), 146.1 (C), 137.9 (C), 137.0 (CH x 2), 118.5 (C), 114.6 (CH), 107.9 (CH), 61.0 (CH3). ESI-MS: m/z = 270[C9H8BrN3O2 + H]+. 4-Chloro-2-[(4-hydroxy-3-methoxy-2-methylphenyl)(methyl)amino]benzoic acid (22) Yellow solid; yield: 128 mg (63%). 1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.4 Hz, 1 H), 6.94 (dd, J = 8.4, 1.6 Hz, 1 H), 6.87 (d, J = 10.0 Hz, 1 H), 6.79 (d, J = 1.6 Hz, 1 H), 6.22 (d, J = 10.0 Hz, 1 H), 3.83 (s, 3 H), 2.71 (s, 3 H), 2.08 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 179.8 (C), 160.7 (C), 151.5 (C), 148.3 (C), 143.2 (C), 139.2 (CH), 136.2 (C), 132.3 (CH), 129.5 (CH), 120.4 (CH), 113.4 (CH), 110.0 (C), 91.0 (C), 60.3 (CH3), 31.4 (CH3), 11.1 (CH3). ESI-MS: m/z = 322 [C16H16ClNO4 + H]+. 6-Chloro-2-hydroxy-3-methoxy-4,10-dimethylacridin-9(10H)-one (23) POCl3 (0.15 mL, 1.55 mmol) was added to a suspension of acid 22 (100 mg, 0.31 mmol) in CHCl3 (3 mL) under argon, and the tube was sealed. The mixture was heated to 80 °C for 16 h then cooled. C2H5OH (3 mL) was added slowly to the mixture to quench excess POCl3, and the mixture was stirred for 30 min at r.t. The solvents were evaporated, the residue was mixed with sat. aq NaHCO3 (20 mL), and the product was extracted into EtOAc (3 × 25 mL). The extracts were further purified by column chromatography (silica gel, EtOAc–hexanes) to give an off-white solid; yield: 63 mg (67%). 1H NMR (400 MHz, DMSO-d 6): δ = 9.73 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 1.6 Hz, 1 H), 7.57 (s, 1 H), 7.27 (dd, J = 8.8, 1.6 Hz, 1 H), 3.88 (s, 3 H), 3.81 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 175.8 (C), 153.0 (C), 146.8 (C), 146.3 (C), 140.0 (C), 138.0 (C), 127.9 (CH), 121.1 (CH), 120.9 (C), 120.8 (C), 120.0 (C), 117.1 (CH), 108.4 (CH), 59.7 (CH3), 43.2 (CH3), 15.4 (CH3). ESI-MS: m/z = 304 [C16H14ClNO3 + H]+.