Synthesis of 3-Hydroxy-9H-fluorene-2-carboxylates via Michael Reaction, Robinson Annulation, and Aromatization

Abstract

A series of 3-hydroxy-fluorene-2-carboxylate compounds were prepared from Michael addition of acetoacetate to 2-benzylideneindan-l-one followed by Robinson annulation and aromatization. In this reaction, we were able to isolate two Robinson annulation products and characterize them. This sequential reaction could proceed without the isolation of intermediates to give the desired products directly in reasonable yields.

1. Introduction

Fluorenes are important structural frameworks in natural products [1,2,3], pharmacophores [4,5,6,7], and carcinogens [8,9]. Figure 1 illustrates a few typical examples in this regard. Aelaginpulvilin B isolated from the Chinese medicine Selaginella pulvinata shows a potent activity against PDE4 [3]. Both I and II are fluorene derivatives for pharmaceutical uses, whereas N-(1-Methoxy-9H-fluoren-2-yl)acetamide III and 2-nitrofluorene V are known to be carcinogens [8,9]. Modification of fluorene cores with electron-donating or accepting groups makes the corresponding molecules useful materials for organic light-emitting devices such as compounds V and VI [10,11,12].

Substituted fluorenes are quite often obtained by reduction of the corresponding fluorenones, which could be prepared via the intramolecular Friedel–Crafts acylation or the related reaction followed by reduction (Scheme 1) [13,14]. Nevertheless, numerous approaches have been disclosed including metal-catalyzed reactions (Scheme 2A) [15,16]. Liang and coworkers reported a unique preparation of 9-substituted fluorene via a sequential cyclization of 2-en-4-yn-1-yl acetate (VII) and a terminal alkyne in the presence of BiBr₃ as the Lewis acid catalyst [17] (Scheme 2B). On the other hand, the construction of aromatic ring fused to inden-1-one is another manner to yield the fluorene cores. A [3+3] cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes (VIII) with trimethylsilylated 2-trifluoroacetyl-3-indenol (IX) to provide a highly substituted fluorene derivatives was investigated by Langer’s research group [18] (Scheme 2C).

Back in the 1960s, Anderson and Leaver investigated that Michael reaction of acetoacetate with 2-benzylideneindan-l-one (1a) provided the annulation product 2a as the sole product (Scheme 3) [19]. However, in this early work, no detailed NMR structural data or side products were reported. We envisioned that further oxidation of 2a should give the corresponding fluorene. In addition, as well as 2a, it will be also interesting to know any side product formed in this annulation. Thus, we decided to examine in more detail this reaction and to study the oxidation of 2a leading to fluorenes with the substrate scope.

2. Materials and Methods

2.1. Materials and Instrumentation

All chemicals were purchased and used without any further purifications. Flash chromatography was performed using silica gel 230–400 mesh. Nuclear magnetic resonance spectra were recorded in CDCl₃ or acetone-d₆ on either a Bruker AM-300 or AVANCE 400 spectrometer. Chemical shifts are given in parts per million relative to Me₄Si for ¹H and ¹³C{¹H} NMR. Infrared spectra were measured on a Nicolet Magna-IR 550 spectrometer (Series-II) as KBr pallets. HRMS spectra were determined on a Bruker micrOTOF-QII spectrometer with electrospray ionization. Compound 1a was prepared according to the reported procedure [20].

2.2. Reaction of 1a with Ethyl Acetoacetate

A solution of 2-benzylidene-1-indanone 1a (110.1 mg, 0.5 mmol) with ethyl acetoacetate (220.3 mg, 2.5 mmol) and t-BuOK (0.5 mmol) in 5 ml of dioxane was heated with stirring at 50 °C under nitrogen atmosphere for 24 h. After the reaction, mixture was quenched with 5 ml of saturated NH₄Cl aqueous solution then extract with 5 ml of ethyl acetate for three times. The crude product was then concentrated under reduced pressure. The residue was chromatographed on silica gel to afford the products 2a and 3a. Their spectral data are shown below.

Ethyl 3-hydroxy-1-phenyl-4,9-dihydro-1H-fluorene-2-carboxylate (2a) [19]. Light yellow solid. R_f = 0.40 (hexane/EA = 19:1); mp: 137–138 °C; ¹H NMR (400 MHz, CDCl₃): δ12.7 (s, 1H), 7.32–7.24 (m, 3H), 7.23–7.09 (m, 6H), 4.67 (t, J = 5.3 Hz, 1H), 4.13–4.00 (m, 2H), 3.59 (ddt, J = 22 Hz, J = 5.3 Hz, J = 2.8 Hz 1H), 3.48 (ddt, J = 22 Hz, J = 5.3 Hz, J = 2.5 Hz 1H), 3.21 (dt, J = 22 Hz, J = 2.5 Hz, 1H), 2.97 (dt, J = 22 Hz, J = 2.5 Hz, 1H), 1.06 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 172.0, 170.2, 144.9, 143.9, 143.2, 141.9, 130.0, 128.0, 127.8, 126.2, 126.1, 124.6, 123.5, 118.2, 100.9, 60.4, 43.3, 38.5, 28.2, 13.7. IR (KBr) υ_C=O 1663 cm⁻¹. ESI-HRMS (TOF) m/z [M+Na]⁺ Calcd. for C₂₂H₂₀O₃Na: 355.1305. Found: 355.1298. The structure of this compound was confirmed by X-ray crystallography (see Supplementary Materials) and ORTEP plot of 2a is illustrated in Figure 2.

Ethyl 3-oxo-1-phenyl-2,3,9,9a-tetrahydro-1H-fluorene-2-carboxylate (3a). Yellow orange oil. R_f = 0.26 (hexane/EA = 9:1); ¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J = 7.6 Hz, 1H), 7.38 (td, J = 11.2 Hz, 1.2 Hz, 1H), 7.36–7.24 (m, 7H), 6.43 (d, J = 2.6 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.74 (d, J = 12.3 Hz, 1H), 3.56 (t, J = 11.9 Hz, 1H), 3.51–3.42 (m, 1H), 2.91 (dd, J = 16.5 Hz, 7.7 Hz, 1H), 2.70 (dd, J = 16.5 Hz, 6.7 Hz, 1H), 0.99 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 195.0, 169.3, 164.6, 145.0, 136.8, 135.7, 132.6, 129.1, 128.5, 127.9, 126.1, 124.0, 117.1, 78.1, 60.9, 60.3, 55.7, 52.5, 45.2, 13.8; IR (KBr) υ_C=O 1738, 1655 cm⁻¹; ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₂H₂₁O₃: 333.1485. Found: 333.1467.

2.3. Direct Preparation of Fluorenes without Isolation

A mixture of 2-benzylidene-1-indanone (0.5 mmol), ethyl acetoacetate, and t-BuOK (0.5 mmol) in toluene (5 mL) was heated at 80 °C for 24 h. After cooling, the reaction mixture was quenched with saturated NH₄Cl aqueous solution and extracted with ethyl acetate (5 mL × 3). Upon concentration, the residue was re-dissolved in dioxane (5 mL). DDQ (0.55 mmol) was added and the resulting mixture was heated at 100 °C under oxygen atmosphere for another 24 h. The reaction mixture was filtered to remove insoluble solid and the filtrate was concentrated. The residue was chromatographed on silica gel with elution of hexane/ethyl acetate (19:1) to provide the desired product 4a as a white yellow solid. ( mg, %): R_f = 0.34 (hexane/EA = 19:1); mp 162–163 °C; ¹H NMR (400 MHz, CDCl₃ ): δ 11.3 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.42–7.28 (m, 7H), 7.22–7.18 (m, 2H), 3.94 (q, J = 7.2 Hz, 2H), 3.50 (s, 2H), 0.70 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 172.0, 170.2, 144.9, 143.9, 143.2, 141.9, 130.0, 128.0, 127.8, 126.2, 126.1, 124.6, 123.5, 118.2, 100.9, 60.4, 43.3, 38.5, 28.2, 13.7. IR (KBr) υ_O–H 3500–3200 (br), υ_C=O 1655 cm⁻¹. ESI-HRMS (TOF) m/z [M+Na]⁺ Calcd. for C₂₂H₁₈O₃Na: 353.1148. Found: 353.1160.

Other fluorenes were prepared by a similar procedure and spectral data are listed below.

Ethyl 1-(4-fluorophenyl)-3-hydroxy-9H-fluorene-2-carboxylate (4b). White solid. R_f = 0.32 (hexane/EA = 19:1); mp 107–108 °C; (85 mg, 46%). ¹H-NMR (400 MHz, CDCl₃): δ11.3 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.42–7.28 (m, 4H), 7.20–7.06 (m, 4H), 3.99 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 0.80 (t, J = 7.2 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ171.1, 163.1, 162.3, 160.6, 147.0, 145.1, 140.1, 139.6, 137.6, 134.0, 129.4, 129.3, 128.3, 126.9, 124.9, 121.2, 114.8, 114.6, 110.1, 107.9, 60.8, 36.4, 13.0. IR (KBr) υ_O–H 3400–3200 (br), υ_C=O 1655 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₂H₁₈FO₃: 349.1234. Found: 349.1224.

Ethyl 3-hydroxy-1-(4-(trifluoromethyl)phenyl)-9H-fluorene-2-carboxylate (4c). Pale yellow solid. R_f = 0.35 (hexane/EA = 19:1); mp 160–161 °C. (120.7 mg, 58%). ¹H-NMR (400 MHz, CDCl₃): δ 11.4 (s, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.42–7.29 (m, 6H), 3.97 (q, J = 7.2 Hz, 2H), 3.43 (s, 2H), 0.70 (t, J = 7.2 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 170.8, 162.5, 147.3, 145.7, 145.0, 140.0, 139.1, 133.4, 129.5, 129.2, 128.8, 128.5, 128.3, 127.0, 125.7, 124.9, 124.8, 124.8, 122.9, 121.2, 109.5, 108.3, 60.9, 36.3, 12.6. IR (KBr) υ_O–H 3410–3200 (br), υ_C=O 1660 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₃H₁₈F₃O₃: 399.1203. Found: 399.1193.

Ethyl 3-hydroxy-1-(4-nitrophenyl)-9H-fluorene-2-carboxylate (4d). Light yellow solid. R_f = 0.20 (hexane/EA = 19:1); mp 209–210 °C. (111.5 mg, 59%). ¹H-NMR (400 MHz, CDCl₃): δ 11.4 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 7.2 Hz, 1H), 7.45–7.27 (m, 6H), 3.98 (q, J = 7.2 Hz, 2H), 3.42 (s, 2H), 0.72 (t, J = 7.2 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 170.5, 162.6, 148.9, 147.6, 146.8, 144.8, 139.8, 138.2, 133.1, 128.9, 128.7, 127.1, 125.0, 123.2, 121.3, 109.1, 108.7, 61.1, 36.2, 13.0. IR (KBr) υ_O–H 3500–3200 (br), υ_C=O 1669 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₂H₁₈NO₅: 376.1179. Found: 376.1170.

Ethyl 3-hydroxy-1-(p-tolyl)-9H-fluorene-2-carboxylate (4e). Pale yellow solid. R_f = 0.32 (hexane/EA = 19:1); mp 104–105 °C. (89.7 mg, 51 %). ¹H-NMR (400 MHz, CDCl₃): δ 11.3 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.43–7.28 (m, 4H), 7.22 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.51 (s, 2H), 2.44 (s, 3H), 0.75 (t, J = 7.1 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 171.4, 162.1, 146.8, 145.3, 140.9, 140.3, 138.7, 136.1, 134.0, 128.4, 128.2, 127.7, 126.8, 124.9, 121.1, 110.4, 107.5, 60.7, 36.5, 21.1, 12.9. IR (KBr) υ_O–H 3460–3200 (br), υ_C=O 1654 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₃H₂₁O₃: 345.1485. Found: 345.1474.

Ethyl 3-hydroxy-1-(o-tolyl)-9H-fluorene-2-carboxylate (4f). Pale yellow oil. R_f = 0.35 (hexane/EA = 19:1); (82.1 mg, 45%). ¹H-NMR (400 MHz, CDCl₃): δ 11.5 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.49–7.18 (m, 7H), 7.04 (d, J = 7.4 Hz, 1H), 4.06–3.90 (m, 2H), 3.46 (d, J = 22.0 Hz, 1H), 3.31 (d, J = 22.0 Hz, 1H), 2.04 (s, 3H), 0.74 (t, J = 7.1 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 171.3, 162.6, 147.3, 145.2, 141.3, 140.4, 134.7, 133.6, 129.4, 128.3, 127.4, 126.9, 126.8, 125.4, 125.0, 121.2, 110.1, 107.7, 60.7, 36.3, 19.6, 12.9. IR (KBr) υ_O–H 3480–3200 (br), υ_C=O 1654 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₃H₂₁O₃: 345.1485. Found: 345.1479.

Ethyl 3-hydroxy-1-(4-methoxyphenyl)-9H-fluorene-2-carboxylate (4g). Light yellow solid. R_f = 0.20 (hexane/EA = 19:1); mp 120–121 °C. (89.3 mg, 45%). ¹H-NMR (400 MHz, CDCl₃): δ 11.3 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.45–7.26 (m, 4H), 7.10 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.50 (s, 2H), 0.79 (t, J = 7.2 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 171.4, 162.1, 158.5, 146.8, 145.2, 140.6, 140.3, 134.2, 134.1, 128.9, 128.2, 126.8, 124.9, 121.1, 113.3, 110.5, 107.5, 60.7, 55.3, 36.5, 13.1. IR (KBr) υ_O–H 3500–3200 (br), υ_C=O 1653 cm⁻¹. ESI-HRMS (TOF) m/z [M+Na]⁺ Calcd. for C₂₃H₂₀O₄Na: 383.1254. Found: 383.1264.

Ethyl 3-hydroxy-1-(naphthalen-1-yl)-9H-fluorene-2-carboxylate (4i). Light yellow solid. R_f = 0.35 (hexane/EA = 19:1); mp 129–130 °C. (40.4 mg, 21%). ¹H-NMR (400 MHz, CDCl₃): δ 11.5 (s, 1H), 7.92–7.80 (m, 3H), 7.53–7.48 (m, 2H), 7.46–7.35 (m, 3H), 7.33–7.25 (m, 4H), 3.74–3.61 (m, 3H), 3.47 (d, J = 22.0 Hz, 1H), 3.21(d, J = 22.1 Hz, 1H), 0.17 (t, J = 7.1 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 171.1, 162.6, 147.2, 145.2, 140.3, 139.4, 138.9, 134.7, 133.4, 131.7, 128.3, 128.0, 126.9, 126.8, 125.9, 125.6, 125.3, 125.2, 124.9, 124.8, 121.2, 110.9, 108.0, 60.5, 36.2, 12.2. IR (KBr) υ_O–H 3420–3200 (br), υ_C=O 1653 cm⁻¹. ESI-HRMS (TOF) m/z [M+Na]⁺ Calcd. for C₂₆H₂₀O₃Na: 403.1305. Found: 403.1303.

Ethyl 3-hydroxy-1-propyl-9H-fluorene-2-carboxylate (4j). Light yellow solid. R_f = 0.34 (hexane/EA = 19:1); mp 103–104 °C. (62.5 mg, 41%). ¹H-NMR (400 MHz, CDCl₃): δ 11.5 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 6.4 Hz, 1H), 7.40–7.29 (m, 2H), 7.23 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3.07- 2.88 (m, 2H), 1.69–1.54 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H). ¹³C-NMR (100 MHz, CDCl₃): δ 171.9, 162.9, 146.9, 144.6, 141.4, 140.6, 133.6, 128.1, 126.8, 124.9, 121.0 110.1, 106.5, 61.4, 35.8, 35.1, 23.9, 14.6, 14.0. IR (KBr) υ_O–H 3400–3200 (br), υ_C=O 1646 cm⁻¹. ESI-HRMS (TOF) m/z [M+Na]⁺ Calcd. for C₁₉H₂₀O₃Na: 319.1305. Found: 319.1308.

Ethyl 1-(3,4-dimethoxyphenyl)-3-hydroxy-9H-fluorene-2-carboxylate (4k). Light yellow oil. R_f = 0.09 (hexane/EA = 9:1); (82.3 mg, 42%). ¹H NMR (400 MHz, CDCl₃): δ 11.3 (s, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.50–7.29 (m, 4H), 6.95 (d, J = 8.6 Hz, 1H), 6.84–6.71 (m, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 3.60 (s, 2H), 0.84 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.3, 162.0, 148.5, 147.8, 146.8, 145.2, 140.5, 140.2, 134.3, 134.1, 128.2, 126.8, 124.9, 121.1, 120.0, 111.5, 110.7, 110.4, 107.5, 60.7, 55.9, 55.8, 36.5, 13.2. IR (KBr) υ 3100–3440 (br), 1655 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₄H₂₃O₅: 391.1540. Found: 391.1527.

Isopropyl 3-hydroxy-1-phenyl-9H-fluorene-2-carboxylate (4l). Light yellow solid. R_f = 0.37 (hexane/EA = 19:1); mp 114–115 ℃. (114.2 mg, 64%). ¹H NMR (400 MHz, CDCl₃): δ 11.5 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.50–7.32 (m, 7H), 7.24 (d, J = 7.8 Hz, 2H), 4.99 (sep, J = 6.2 Hz, 1H), 3.52 (s, 2H), 0.88 (d, J = 6.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 170.7, 162.2, 146.8, 145.2, 141.9, 140.8, 140.3, 133.9, 128.2, 127.9, 126.8, 126.5, 124.9, 121.2, 110.5, 107.6, 68.6, 36.5, 20.9. IR (KBr) υ 3200–3500 (br), 1654 cm⁻¹. ESI-HRMS (TOF) m/z [M+H]⁺ Calcd. for C₂₃H₂₁O₃: 345.1485. Found: 345.1477.

2.4. Crystallogarphy

A crystal of 2a suitable for X-ray determination was obtained from hexane/dichloromethane. The structure was solved using the SHELXS-97 program [21] and refined using the SHELXL-97 program [22] by full-matrix least-squares on F2 values. CCDC 2193935 contains the supplementary crystallographic data for 2a. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, (accessed on 1 August 2022) or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

3. Results and Discussion

3.1. Preliminary study and Optimization

Substrate 1 for this investigation was prepared according to the reported method [20]. After several screenings of reaction conditions, we found that reaction of 1a with excess of ethyl acetoacetate in the presence of one equivalent of potassium t-butoxide in dioxane reached a full conversion of 1a, but giving two cyclized products 2a and 3a in a ratio of 1:1, which is quite different to that reported previously [19]. Scheme 4 illustrates the reaction and intermediates of Michael adduct (A) and annulation intermediate (B) leading to the products. Both 2a and 3a are isomers, which are resulted from the dehydration of B via two different β-hydrogens. Another finding is that both 2a and 3a did not interconvert to each other under the conditions of (i) t-BuOK (1 eq.) in dioxane at 80 °C for 24 h, and (ii) HBF₄ in dioxane at 80 °C for 24h, (iii) H₂SO₄ (1 eq) in dioxane at 80 °C for 24 h. Characterization of compounds 2a and 3a were performed by NMR and mass spectroscopy.

¹H NMR spectrum of 2a shows two sets of AB splitting patterns, at δ 3.59 and 3.48 (J² = 22 Hz); δ 3.21 and 2.97 (J² = 22 Hz), for two distinct -CH₂- units at C(4) and C(9) due to the diastereotopic nature of these methylene protons. ¹³C NMR spectral data and HRMS of 2a are also consistent with the proposed structure. However, single crystal determination of 2a confirms its structural details (Figure 2). As expected, bond lengths of both C1-C2 [1.355(2) Å] and C4-C12 [1.343(2) Å] are in the typical range for C=C. For 3a, a characteristic shift for the vinylic proton of C(4)-H appears at δ 6.43 as a doublet due to the long range allylic coupling with C-H’. A signal at δ 3.74 as doublet for the C(2)-H indicates that 3a does not enolize and retains the β-keto ester form, unlike 2a. Other spectral data and HRMS of 3a are all in agreement with the structure (see experimental section).

3.2. Reaction of 1a with Acetoacetate—Selectivity of Formation of 2a Versus 3a

Next, we examined this reaction under various conditions to improve the selectivity of products.

Table 1. Optimization for reaction of 1a with ethyl acetoacetate leading to 2a and 3a ¹.

Entry	Base	Solvent	Temp	Time	2a 2	3a 2
1	DABCO	Dioxane	80 °C	24 h	0	0
2	DBU	Dioxane	80 °C	24 h	complex mixture
3	t-BuOK	Dioxane	80 °C	24 h	52%	48%
4	t-BuOK	Dioxane	50 °C	24 h	7%	48%
5	t-BuOK	Dioxane	50 °C	48 h	24%	75%
6	t-BuOK	Dioxane	40 °C	48 h	6%	45%
7 3	t-BuOK	Dioxane	80 °C	24 h	Trace	Trace
8	t-BuOK	Toluene	80 °C	24 h	60%	40%
9	t-BuOK	THF	50 °C	48 h	20%	40%
10	t-BuOK	t-BuOH	50 °C	48 h	30%	55%

¹ Reaction conditions: 1a (220.3 mg, 0.5 mmol), ethyl acetoacetate (220.3 mg, 2.5 mmol) and base in solvent (5 mL) under N₂ atmosphere. ² NMR yields. ³ addition of LiCl (1 eq.).

summarizes the results. The use of DBU and DABCO as bases did not render good production of the desired products. The basicity of DABCO is too weak for the reaction to proceed with the reactant recovered, whereas the DBU causes the decomposition of the reactants (Entries 1 and 2). The lower reaction temperature gave a lower conversion (Entries 3–6). The formation of 3a is preferred at 50 °C, but the reaction still provides 25% production of 2a (Entry 5). For solvents, both dioxane and toluene are good choice to have full conversion (entries 3 and 8, respectively), however, the selectivity of 2a versus 3a remains as ca. 1:1. It seems unable to reach the selectivity for a single product.

With 2a and 3a in hand, oxidation of these compounds leading to the desired fluorene product 4a was examined (Scheme 5). Air-oxidation of both compounds leading to 4a proceeded very slowly. Hence, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was chosen as the reagent for this oxidation. It appeared that compound 2a was completely converted into 4a under the condition of the substrate in dioxane with DDQ (1.1 eq) at 100 °C for 3 h. By exposing a solution of 3a in dioxane to DDQ, the desired oxidation compound 4a was obtained, but not in full conversion. Other oxidants such as MnO₂ did not provide a better result. Table S2 summarizes the results of oxidations of 2a and 3a under various conditions (see supporting information).

3.3. Preparation of Fluorenes via a Two-Step Reaction without Isolation of 2 and 3

Since oxidation of 2a and 3a yields the same product 4a, we envisioned that we should investigate the direct preparation of fluorenes from reaction 2-benzylideneindan-l-one with acetoacetate without purification of 2a and 3a, i.e., carrying out the oxidation of a mixture 2a and 3a from the first step without a purification procedure. First, a reaction mixture obtained according the conditions shown in Table 1 entry 3 was acidified with 2 M H₂SO_4(aq) and then treated with DDQ (1.1 eq.) at 100 °C. Upon workup, the desired product 4a was obtained in 48% yield accompanied with 2a and 3a. Under the similar procedure, the use of 2 equivalent of DDQ did improve the yield up to 60%, but a larger amount of DDQ resulted in the formation of complicated reaction mixture. By switching to other oxidants such as MnO₂, production of 4a did not get better. As shown in Table 1 entry 8, toluene is another good solvent for a full conversion, but the use of toluene as the solvent for this two-step treatment did not provide a better improvement. Apparently, the unreacted substrates or reagents caused the complication in having a better production of 4a. Thus, we modified the procedure by a simple extraction of reaction mixture in the first step and then change the solvent for oxidation.

Typically, a solution of 2-benzylidene-1-indanone derivatives with ethyl acetoacetate and t-BuOK in dioxane was heated at 80 °C under inert atmosphere for 24 h. Then, the reaction mixture was quenched with saturated NH₄Cl aqueous solution and extracted with ethyl acetate. Upon concentration, the residue was re-dissolved in dioxane and treated with oxidant for another 24 h. After purification, 4a was obtained in various amounts based on the oxidants as illustrated in

Table 2. Oxidation study of conversion of 2a and 3a into 4a ¹.

Entry	Oxidant	Temp	Yield
1	O2/CF3COOH	100 °C	trace
2	H2O2 (1.0 eq)	80 °C	trace
3	Cu(OTf)(10 mol%)/bipy/NHPI/KI (1.0 eq) 2	80 °C	trace
4	CuBr(10 mol%)/LiBr(2.0 eq) 2	80 °C	56%
5	DDQ (1.1 eq)	RT	41%
6 3	DDQ (1.1 eq)	100 °C	75%

¹ Reaction conditions: (i) 1a (220.3 mg, 0.5 mmol), ethyl acetate (220.3 mg, 2.5 mmol) and t-BuOK (0.5 mmol) in dioxane (5 mL) was heated 80 °C for 24 h, (ii) Quench with saturated NH₄Cl and extraction with ethyl acetate, (iii) Concentration and re- dissolution in dioxane (5 mL), (iv) addition of oxidant and stirring for 24 h. in isolated yields. ² Cu-catalyzed oxidation. ³ toluene used as the solvent in the first step.

. It showed that, in order to have a better yield of 4a, reaction has to run in toluene as solvent in the first step and then oxidation in dioxane (Table 2, entry 6). Thus, this standard procedure was established for the further investigation.

With the optimized protocol, we screened various substituted 2-benzylidene-1-indanones as substrates for the preparation of fluorenes (Scheme 6). All desired products were isolated in moderate to good yields. For the aryl ring with electron-withdrawing substituents at para position, the yields were slightly better than those with electron-donating groups (4c and 4d vs. 4e and 4g). Compound 4i was received in 21% yield presumably due to the steric hindrance of 1-naphthyl group. Alkylidene-1-indanone was also applicable to the reaction to give ethyl 3-hydroxy-1-propyl-9H-fluorene-2-carboxylate 4j (41%). However, a tertiaryamino-substituted substrate did not deliver the expected product 4h, which is unexpected, presumably due to the basic nature of dimethylamino group. It was noticed that isopropyl acetoacetate is also a suitable reagent for this methodology, giving 4l in 64% yield.

4. Conclusions

In summary, a two-step design for synthsis of 3-hydroxy-9H-fluorene-2-carboxylates was reported. In this work, the Robinson annulation from the intermediate A was studied, offering an understanding of the regiochemistry of dehydration. This method offers a simple and facile manipulation for the desired fluorene. These obtained compounds are expected to be valuable for pharmacophores and synthetic intermediates.