Synthesis of Acridones by Palladium-Catalyzed Buchwald–Hartwig Amination

Abstract

The Buchwald–Hartwig amination allows an efficient and convenient synthesis of biologically and pharmaceutically important acridones by formation of a six-membered ring. With the described method, a number of derivatives have been synthesized in up to 95% yield by using a variety of anilines as well as benzylic and aliphatic amines.

Key words

palladium catalysis - Suzuki–Miyaura reaction - Buchwald–Hartwig amination - acridones - cyclization

• References and Notes

• 1 Del Buttero P, Gironda R, Moret M, Papagni A, Parravicini M, Rizzato S, Miozzo L. Eur. J. Org. Chem. 2011; 2265
• 2 Huang P.-C, Parthasarathy K, Cheng C.-H. Chem. Eur. J. 2013; 19: 460
• 3 Kobayashi K, Nakagawa K, Yuba S, Komatsu T. Helv. Chim. Acta 2013; 96: 389
• 4 Pal C, Kundu MK, Bandyopadhyay U, Adhikari S. Bioorg. Med. Chem. Lett. 2011; 21: 3563
• 5 Zhao J, Larock RC. J. Org. Chem. 2007; 72: 583
• 6 Nishio R, Wessely S, Sugiura M, Kobayashi S. J. Comb. Chem. 2006; 8: 459
• 7a Mayur YC, Peters GJ, Lemos C, Kathmann I, Prasad VV. S. R. Arch. Pharm. 2009; 342: 640
• 7b Sathish NK, GopKumar P, Prasad VV. S. R, Kumar SM. S, Mayur YC. Med. Chem. Res. 2010; 19: 674
• 8 Singh P, Kaur J, Yadav B, Komath SS. Bioorg. Med. Chem. 2009; 17: 3973
• 9a Hegde R, Thimmaiah P, Yerigeri MC, Krishnegowda G, Thimmaiah GN, Houghton PJ. Eur. J. Med. Chem. 2004; 39: 161
• 9b Allen CF. H. McKee G. H. W. 1939; 19: 6
• 10a Suzuki N, Kazui Y, Kato M, Izawa Y. Heterocycles 1981; 16: 2121
• 10b Suzuki N, Kazui Y, Tsukamoto T, Kato M, Izawa Y. Bull. Chem. Soc. Jpn. 1983; 1519
• 11 Zhao J, Larock RC. J. Org. Chem. 2007; 72: 583
• 12a Dubrovskiy AV, Larock RC. J. Org. Chem. 2012; 77: 11232
• 12b Pintori DG, Greaney MF. Org. Lett. 2010; 12: 168
• 13a Hoang HD, Janke J, Amirjanyan A, Ghochikyan T, Flader A, Villinger A, Ehlers P, Lochbrunner S, Surkus A.-E, Langer P. Org. Biomol. Chem. 2018; 16: 6543
• 13b Pham NN, Janke S, Salman GA, Dang TT, Le TS, Spannenberg A, Ehlers P, Langer P. Eur. J. Org. Chem. 2017; 5554
• 13c Ohlendorf L, Diaz Velandia JE, Konya K, Ehlers P, Villinger A, Langer P. Adv. Synth. Catal. 2017; 359: 1758
• 13d Kitawaki T, Hayashi Y, Chida N. Heterocycles 2005; 65: 1561
• 13e Nozaki K, Takahashi K, Nakano K, Hiyama T, Tang H.-Z, Fujiki M, Yamaguchi S, Tamao K. Angew. Chem. Int. Ed. 2003; 42: 2051
• 14a Christensen H, Schjoth-Eskesen C, Jensen M, Sinning S, Jensen HH. Chem. Eur. J. 2011; 17: 10618
• 14b Sato K, Inoue Y, Mori T, Sakaue A, Tarui A, Omote M, Kumadaki I, Ando A. Org. Lett. 2014; 16: 3756
• 15a Zhang L, Huang X, Zhen S, Zhao J, Li H, Yuan B, Yang G. Org. Biomol. Chem. 2017; 15: 6306
• 15b Zhang X, Yang Y, Liang Y. Tetrahedron Lett. 2012; 53: 6406
• 16 Typical Procedure – Synthesis of 10-(4-Methylphenyl)-acridin-9(10H)-one (4a) A dried glass pressure tube under argon was charged with 2,2'-dibromobenzophenone 3a (100 mg, 0.3 mmol), Pd₂dba₃ (14 mg, 0.015 mmol), dppf (16 mg, 0.03 mmol), KOtBu (200 mg, 1.8 mmol), and amine (0.1 ml, 0.9 mmol). The solids were dissolved in dry toluene (3 mL), sealed with a Teflon^® cap before being heated to 100 °C. After 24 h, the mixture was allowed to cool to room temperature. The residue was dissolved in CH₂Cl₂ (20 mL), washed with hydrochloric acid (1 M, 20 mL) and dried with Na₂SO₄. After filtration and removal of the solvents under reduced pressure, the crude solid was purified by column chromatography (heptane/ethyl acetate 10:1) to give 10-(4-methylphenyl)acridin-9(10H)-one (4a) as a yellow solid (80 mg, 95%), mp 290–292 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.58 (dd, ³ J = 8.0 Hz, ⁴ J = 2.1 Hz, 2 H, CH_Ar), 7.53–7.45 (m, 4 H, CH_Ar), 7.30–7.21 (m, 4 H, CH_Ar), 6.80 (d, ³ J = 9.0 Hz, 2 H, CH_Ar), 2.54 (s, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 178.2 (CO), 143.3 (2 C_Ar), 139.8 (C_Ar), 136.3 (C_Ar), 133.3 (2 CH_Ar), 131.8 (2 CH_Ar), 129.7 (2 CH_Ar), 127.3 (2 CH_Ar), 121.9 (2 C_Ar), 121.5 (2 CH_Ar), 117.0 (2 CH_Ar), 21.4 (CH₃). IR (ATR, cm^–1): 3033 (w), 2921 (w), 2853 (w), 1630 (m), 1596 (m), 1485 (m), 1456 (m), 1299 (m), 1271 (m), 1156 (m), 1038 (m), 1025 (m), 935 (m), 824 (m), 753 (s), 673 (m), 520 (m). MS (EI, 70 eV): m/z (%) = 286 (20), 285 ([M]⁺, 100), 284 (12), 241 (15), 166 (11), 140 (17), 139 (10), 91 (12), 89 (13), 77 (12), 76 (13), 65 (22), 63 (15), 50 (11), 39 (15). HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₅O₁N₁: 285.11482; found: 285.11482.
• 17 Gao Q, Xu S. Org. Biomol. Chem. 2018; 16: 208