Synthesis of Dihydroanthracenes via Palladium-Catalyzed Tandem Mizoroki–Heck/Reductive Heck Reactions Using Cyclic Diaryliodoniums and Alkenes

Abstract

An efficient Pd-catalyzed domino Mizoroki–Heck and reductive Heck reaction of terminal alkenes with six-membered cyclic diaryliodoniums is reported for the facile access to a diverse set of novel dihydroanthracenes. The scope of alkenes is general, leading to concise generation of 30 dihydroanthracenes which are not easily accessed by conventional methods. Furthermore, one of the newly synthesized dihydroanthracene displayed excellent antiproliferative activity against PANC-1 cancer cells (IC₅₀ = 11.74 μM).

Key words

cyclic diaryliodoniums - terminal alkenes - dihydroanthracenes - Heck reaction

Publication History

Received: 31 October 2020

Accepted after revision: 28 December 2020

Accepted Manuscript online:
28 December 2020

Article published online:
27 January 2021

• References and Notes

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• 12 Procedure to Synthesize Dihydroanthracene 4a To a seal tube was added cyclic diaryliodonium salt 2a (0.1 g, 0.226 mmol, 1.0 equiv), methyl acrylate 3a (0.039 g, 0.45 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.026 g, 0.022 mmol, 0.1 equiv), Et₃N (0.069 g, 0.67 mmol, 3.0 equiv), HCOONa (0.031 g, 0.45 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 4a (0.036 g, 78%). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.33–7.29 (m, 2 H), 4.46 (t, J = 7.2 Hz, 1 H), 4.07 (s, 2 H), 3.81 (s, 3 H), 2.80 (d, J = 7.2 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.14, 146.39, 140.91, 127.63, 127.33, 124.47, 120.10, 51.99, 43.72, 41.79, 38.63. HRMS (ESI): m/z calcd for C₁₇H₁₇O₂ [M + H]⁺: 253.1150; found: 253.1146. Procedure to Synthesize Dihydroanthracene 5a To a seal tube was added cyclic diaryliodonium salt 2 (0.1 g, 0.213 mmol, 1.0 equiv), acrylonitrile 3 (0.022 g, 0.426 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.024 g, 0.021 mmol, 0.1 equiv), Et₃N (0.065 g, 0.639 mmol, 3.0 equiv), HCOONa (0.029 g, 0.426 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 5a (0.033 g, 67%). ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 7.6 Hz, 2 H), 7.45 (d, J = 0.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.10 (t, J = 7.2 Hz, 1 H), 4.01 (s, 2 H), 2.79 (d, J = 7.2 Hz, 2 H), 2.44 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 144.22, 138.37, 137.19, 129.22, 125.09, 119.82, 118.73, 42.79, 41.75, 22.24, 21.78. HRMS (ESI): m/z calcd for C₁₈H₁₈N [M + H]⁺: 248.1361; found: 248.1375.