Selective Horner–Wittig/Nazarov vs. Knoevenagel/Nazarov Reactions in the Synthesis of Biologically Active 3-Aryl-Substituted 1-Indanones

Abstract

3-Aryl-1-indanones and a previously unknown group of 3-aryl-2-phosphoryl-1-indanones have been synthesized from β-ketophosphonates and aromatic aldehydes via corresponding chalcones, in a selective Horner–Wittig or Knoevenagel olefination, followed by a Nazarov cyclization. In preliminary tests, the final compounds and the intermediate chalcones revealed anticancer activity against HeLa and K562 at the μM level.

Key words

Knoevenagel reaction - Horner–Wittig reaction - Nazarov reaction - β-ketophosphonates - 1-indanones

• References and Notes

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• 10 General Procedure for the Synthesis of 3 To a stirred solution of β-ketophosphonate 1 (1.757 mmol) and the corresponding aldehyde 2 (1.933 mmol) in dry toluene, piperidine (2.531 mmol) was added, and the resulting solution was refluxed for 30 h using a Dean–Stark apparatus. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (hexane–EtOAc = 2:1, v/v) to afford desired compounds 3a (f): yellow crystals, mp 116–117 °C. R_f = 0.30 (hexane–EtOAc = 2:1 v/v), 0.64 (hexane–EtOAc = 1:2, v/v); yield 53%. ¹H NMR (200 MHz, CDCl₃): δ = 3.73 (s, 3 H, C(O)OCH₃), 3.77 (d, J ³ _PH =10.1 Hz, 6 H, P(O)(OCH₃)₂), 5.93 (s, 2 H, OCH₂O), 6.64 (d, J ³ _HH =8.1 Hz, 1 H, ArH), 7.27–7.34 (m, 3 H, ArH), 7.40 (d, J ³ _PH =9.6 Hz, 1 H, HC=CP(O)), 7.77–7.80 (m, 3 H, ArH), 7.82 (s, 1 H, ArH). ³¹P NMR (81 MHz, CDCl₃): δ = 16.28. ¹³C NMR (50 MHz, CDCl₃): δ = 51.99 (s, C(O)CH₃)), 52.04 (d, J ² _PC = 6.0, P(O)OCH₃)₂), 100.80 (s, OCH₂O), 106.82 (s, ArH), 107.05 (s, ArH), 125.88 (s, ArH), 128.25 (s, 2 × o-PhH), 128.47 (d, J ¹ _PC = 145.7 Hz, =C-P(O)), 128.55 (s, 2 × m-PhH), 136.60 (s), 136.13 (s), 136.56 (s), 143.77 (s, COCH₂O), 143.89 (s, COCH₂O), 151.6 (s, HC=CP), 164.9 (s, C(O)OCH₃), 186.4 (s, C=O). MS (CI, isobutane): m/z = 419.1 (42) [M⁺ + 1], 361 (100) [M⁺ + 1 – C(O)OCH₃], 344.1 (40) [M⁺ + 1 – C(O)OCH₃; –OH]. HRMS-EI (70 eV): m/z calcd for C₂₀H₁₉PO₈: 418.08110; found: 418.08089; Δ: 0.55 (<5).
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• 14 Nazarov Cyclization for the Synthesis of 5b with FeCl₃ To chalcone 3a(e) (0.100 g, 0.278 mmol) in dry CH₂Cl₂ (100 mL), FeCl₃ (0.090 g, 0.555 mmol) was added, and the solution was refluxed by 5 h. The reaction mixture was washed with water (3 × 30 mL), dried (MgSO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by column chromatography (acetone–PE = 1:1, v/v) to afford 5b (0.080 g, 80%). Compound 5b: beige solid; mp 131–133 °C; R_f = 0.35 (acetone–PE = 1:1, v/v). ¹H NMR (200 MHz, CDCl₃): δ = 3.22 (dd, J ³ _HH = 3.4 Hz, J ² _PH = 26.1 Hz, 1 H, HCP(O)), 3.75 (d, J ³ _PH = 10.6 Hz, 3 H, P(O)OCH₃), 3.80 (d, J ³ _PH = 10.3 Hz, 3 H, P(O)OCH₃), 4.78 (dd, J ³ _HH = 3.4 Hz, J ³ _PH = 12.40 Hz, 1 H, HCHCP(O)), 6.06 (s, 2 H, OCH₂O), 6.59 (s, 1 H, ArH) 7.04–7.33 (m, 6 H, ArH). ³¹P NMR (81 MHz, CDCl₃): δ = 24.45. ¹³C NMR (50 MHz, CDCl₃): δ = 46.71 (s, CHPh), 53.91 (d, ¹ J _PC = 146.5 Hz, CHP(O)), 53.43 (d, ² J _PC = 4.9 Hz, P(O)(OCH₃)₂), 102.43 (s, OCH₂O), 105.4 (s, ArH), 105.8 (s, ArH), 127.5 (s), 127.65 (s), 130.9 (s), 142.2 (s), 149.1 (s), 154.2 (s, OCH₂OC), 155.0 (s, OCH₂OC), 196.5 (s, C=O). MS (CI, 70 eV): m/z = 361.0 (100) [M⁺ + 1]. HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₇PO₆: 360.07679; found: 360.07689; Δ 1.42 (<5). IR (KBr): 3400, 3064, 3027, 2956, 2915, 1696, 1604, 1474, 1452, 1305, 1255, 1041, 867, 833 cm^–1.
• 15 The Nazarov Cyclization for the Synthesis of 6a with AlCl₃ To chalcone 4a(a) (0.110 g, 0.377 mmol) in dry toluene (100 mL), AlCl₃ (0.101 g, 0.754 mmol) was added, and the solution was stirred for 18 h. The reaction mixture was washed with water (3 × 30 mL), dried (MgSO₄), and evaporated The crude product was purified by column chromatography (hexane–EtOAc = 1:3, v/v) to afford 6a (0.099 g, 50%). Compound 6a: beige solid; mp 103–105 °C; R_f = 0.09 (hexane–acetone = 1:9, v/v); yield 90%. ¹H NMR (200 MHz, CDCl₃): δ = 3.63 (dd, J ³ _HH = 5.6 Hz, J ² _HH = 9.1 Hz, 1 H, CH₂C(O)), 4.63 (dd, J ² _HH = 9.1 Hz, J ³ _HH = 5.1 Hz, 1 H, CH₂C(O)), 4.73 (dd, J ³ _HH = 5.6 Hz, J ³ _HH = 5.0 Hz, 1 H, CHCH₂C(O)), 6.99–7.14 (m, 4 H, ArH), 7.55 (d, J ³ _HH = 5.1 Hz, 1 H, CH=CH-C(S)), 7.72 (d, J ³ _HH = 5.1 Hz, 1 H, CH=CHS). ¹³C NMR (50 MHz, CDCl₃): δ = 37.72 (s, CH₂), 48.12 (s, CH₂), 123.35 (s, =CBr), 125.91 (s, 2 × o-Ar), 126.32 (s, ArH), 126.74 (s, 2 × m-ArH), 127.13 (s, ArH), 127.95 (s), 130.46 (s), 132.31 (s), 195.84 (s, C=O). MS (CI, isobutane): m/z = 294 (100) [M⁺ + H (⁸⁰Br)], 292 (100) [M⁺ + H (⁷⁹Br)], 214 (52) [M⁺ – Br]. HRMS (EI, 70 eV): m/z calcd for C₁₃H₉SBrO: 291.95614; found: 291.95647; Δ 1.3 (<5).