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Synlett 2016; 27(01): 75-79
DOI: 10.1055/s-0035-1560211
letter
© Georg Thieme Verlag Stuttgart · New York

Regioselective Suzuki–Miyaura Cross-Coupling Reactions of the Bis(triflate) of 1,4-Dihydroxy-9H-fluoren-9-one

Marcel Sonneck
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
,
David Kuhrt
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
,
Krisztina Kónya
c   Department of Organic Chemistry, University of Debrecen, 4032 Debrecen, Egyetem tér 1, Hungary
,
Tamás Patonay
c   Department of Organic Chemistry, University of Debrecen, 4032 Debrecen, Egyetem tér 1, Hungary
,
Alexander Villinger
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Langer*
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
› Author Affiliations
Further Information

Publication History

Received: 24 June 2015

Accepted after revision: 08 August 2015

Publication Date:
23 September 2015 (online)

 
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Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday

Abstract

1,4-Diaryl-9H-fluoren-9-ones were prepared by regioselective Suzuki–Miyaura cross-coupling reaction of the bis(triflate) of 1,4-dihydroxy-9H-fluoren-9-one. The reactions proceeded with excellent site selectivity. The first attack occurs at position 1, due to electronic reasons.


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Key words

Catalysis - Suzuki–Miyaura reaction - regioselectivity - palladium - heterocycles

Fluorenones from natural and synthetic sources show a wide spectrum of biological properties.[1] Amidofluorenones[2] are inhibitors of telomerase enzyme, kinamycin derivatives show antitumor and antimicrobial activity against Gram-positive bacteria.[3] Other fluorenone derivatives also exhibit pharmaceutical properties and are important components of many naturals products.[4] [5] [6] [7] Dendroflorin (A), denchrysan A (B), and 1,4,5-trihydroxy-7-methoxyfluoren-9-one (C) are natural products (Figure [1]) that have been isolated from the orchid Dendrobium chrysotoxum and show a wide range of biological activities.[6]

Zoom Image
Figure 1 Structure of biologically active dendroflorin (A), denchrysan A (B), and 1,4,5-trihydroxy-7-methoxyfluoren-9-one (C)

These natural products were examined for their inhibitory activity against the growth of human lung adenocarcinoma and human stomach cancer. Furthermore, they are used as drugs for the treatment of viral diseases, such as diarrhea, herpes, and hepatitis.[8] [9] Fluorenes, arylated fluorenones, and benzofluorenones have been incorporated in oligomers and polymers which have been examined widely for potential applications as organic light-emitting devices (OLED).[10]

We have reported a synthetic approach to functionalized fluorenones based on formal [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-butadienes.[11] Since the importance of fluorenones and benzofluorenones are obvious, the development of efficient and regioselective methods for the synthesis of aryl-substituted derivatives is of actual importance. Herein, we show a convenient pathway to 1,4-diaryl-9H-fluoren-9-one by site-selective[12] Suzuki–Miyaura reactions of the bis(triflate)[13] of 1,4-dihydroxy-9H-fluoren-9-one (1). The preparation of these products is difficult by other methods.

The reaction of 1,4-dihydroxy-9H-fluoren-9-one (1) with triflic anhydride provided bis(triflate) 2 (Scheme [1]).[14] The Suzuki–Miyaura reaction of 2 with arylboronic acids 3a–h (2.4 equiv) gave 1,4-diaryl-9H-fluoren-9-ones 4a–h in 86–98% yield (Scheme [2,]Table [1]).[15] [16] In addition, the application of DMF (instead of dioxane) was important in the case of 4g due to the low solubility of the starting material. Both electron-rich and electron-poor arylboronic acids were successfully employed in these transformations.

Zoom Image
Scheme 1 Synthesis of 2. Reagents and conditions: i) 1 (1.0 equiv), abs. pyridine, CH2Cl2, Tf2O (2.4 equiv), 20 °C, 20 h.
Zoom Image
Scheme 2 Synthesis of 4a–h. Reagents and conditions: i) 2 (1.0 equiv), 3a–d,f–h (2.4 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (3.0 equiv), 1,4-dioxane, 100 °C, 12 h.

Table 1 Synthesis of Compounds 4a–h

Entry

3

Ar

Yield of 4 (%)a

1

3a

3,4-(MeO)2C6H3

4a 97

2

3b

4-MeOC6H4

4b 98

3

3c

4-MeC6H4

4c 97

4

3d

Ph

4d 98

5

3f

4-HOC6H4

4f 98

6

3g

5-F-2-MeOC6H3

4g 86b

7

3h

4-F3CC6H4

4h 87

a Yield of isolated products.

b DMF was used as solvent.

The Suzuki–Miyaura reaction of 2 with one equivalent of arylboronic acids 3a–h gave 1-aryl-4-(trifluoromethane-sulfonyloxy)-9H-fluoren-9-ones 5a–h in 66–92% yield (Scheme [3,]Table [2]).[17] [18] The reactions proceeded by regioselective attack onto the 1-position. During the optimization, it proved to be important to perform the reaction at lower temperature (60 °C) with lower catalyst amount as compared to the synthesis of 1,4-diarylated-9H-fluoren-9-ones. Repeatedly, both electron-rich and electron-poor arylboronic acids afforded the corresponding compounds in good yields. The structure of 5b was independently confirmed by X-ray crystal-structure analyses[19] (Figure [3]) and by 2D-NMR measurements.

Zoom Image
Scheme 3 Synthesis of 5a–h. Reagents and conditions: i) 2 (1.0 equiv), 3a–h (1.2 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (2.0 equiv), 1,4-dioxane, 60 °C, 12 h.

Table 2 Synthesis of Compounds 5a–h

Entry

3

Ar

Yield of 5 (%)a

1

3a

3,4-(MeO)2C6H3

5a 66

2

3b

4-MeOC6H4

5b 84

3

3c

4-MeC6H4

5c 85

4

3d

Ph

5d 92

5

3e

3-(CH2=CH)C6H4

5e 85

6

3f

4-HOC6H4

5f 86

7

3g

5-F-2-MeOC6H3

5g 83

8

3h

4-F3CC6H4

5h 73

a Yield of isolated products.

Zoom Image
Figure [ 2 ] ORTEP plot for compound 5b [19]

The reaction of 5 with different arylboronic acids 3a–g provided 1,4-diarylated 9H-fluoren-9-ones 6a–g in high yields (Scheme [4,]Table [3]).[20] [21] These transformations were successful even at lower temperature and with shorter reaction time.

Zoom Image
Scheme 4 Synthesis of 6a–g. Reagents and conditions: i) 5 (1.0 equiv), 3a–g (1.2 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (2.0 equiv), 1,4-dioxane, 100 °C, 12 h.

In conclusion, we have report the first Suzuki–Miyaura reactions of 1,4-bis(trifluoromethylsulfonyl-oxy)-9H-fluoren-9-one. These reactions provide a convenient access to a variety of 1,4-diarylated 9H-fluoren-9-ones. The reactions showed a very good regioselectivity in favor of the 1-position. Palladium-catalyzed cross-coupling reactions of polyhalogenated substrates and of bis(triflates) usually proceed in favor of the sterically less hindered and electronically more deficient position. The first attack of palladium(0)-catalyzed cross-coupling reactions generally occurs at the electronically more deficient and sterically less hindered position.[22] Position 1 of bis(triflate) 2 is sterically more hindered compared to position 4, because of the neighbourhood of the carbonyl group (Figure [3]). Therefore, the site-selective formation of 5a–h and 6a–g can be interpreted by electronic reasons. In addition, chelation of the palladium catalyst by the carbonyl group might play a role. The selectivity can be explained by the highly electron-deficient nature of the 1-position of the 9H-fluoren-9-one moiety (due to the electron-withdrawing effect of the carbonyl group).

Zoom Image
Figure 3 Possible explanation for the regioselectivity of the reactions of bis(triflate) 2

Table 3 Synthesis of Compounds 6a–g

Entry

5

3

Ar

Ar1

Yield of 6 (%)a

1

5g

3b

5-F-2-MeOC6H3

4-MeOC6H4

6a 99

2

5g

3c

5-F-2-MeOC6H3

4-MeC6H4

6b 99

3

5b

3a

4-MeOC6H4

3,4-(MeO)2C6H3

6c 97

4

5e

3b

3-CH2=CHC6H4

4-MeOC6H4

6d 42

5

5a

3f

3,4-(MeO)2C6H3

4-HOC6H4

6e 94

6

5d

3a

Ph

3,4-(MeO)2C6H3

6f 99

7

5c

3g

4-MeC6H4

5-F-2-MeOC6H3

6g 96b

a Yield of isolated products.

b DMF was used as solvent.


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Acknowledgement

Financial support from the Hungarian Scientific Research Fund – OTKA (grant number PD 106244) is gratefully acknowledged. Financial support by the Alexander von Humboldt foundation (Institute Partnership Program Debrecen-Rostock) is gratefully acknowledged. Financial support by the European Social Fund (EFRE program) is also acknowledged.

  • References and Notes

  • 1 Campo MA, Larock RC. J. Org. Chem. 2002; 67: 5616 ; and references cited therein
    CrossrefPubMedSearch in Google Scholar
  • 2 Perry PJ, Read MA, Davies RT, Gowan SM, Reszka AP, Wood AA, Kelland LR, Neidle S. J. Med. Chem. 1999; 42: 2679
    CrossrefSearch in Google Scholar
  • 8 Burke SM, Joullie MM. Synth. Commun. 1976; 6: 371
    CrossrefSearch in Google Scholar
  • 10 Goel A, Chaurasia S, Dixit M, Kumar V, Parakash S, Jena B, Verma JK, Jain M, Anand RS, Manoharan S. Org. Lett. 2009; 11: 1289 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 11 Reim S, Lau M, Adeel M, Hussain I, Yawer MA, Riahi A, Ahmed Z, Fischer C, Reinke H, Langer P. Synthesis 2009; 445
    Thieme Connect

      • For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
    • 12a Schröter S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
      Search in Google Scholar
    • 12b Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P. Eur. J. Org. Chem. 2006; 3283

      For Suzuki–Miyaura reactions of bis(triflates) from our laboratory, see, for example:
    • 13a Methyl 2,5-dihydroxybenzoate: Nawaz M, Ibad MF, Abid O.-U.-R, Khera RA, Villinger A, Langer P. Synlett 2010; 150
      Thieme Connect
    • 13b Alizarin: Mahal A, Villinger A, Langer P. Synlett 2010; 1085 3,4
    • 13c Dihydroxybenzophenone: Nawaz M, Khera RA, Malik I, Ibad MF, Abid O.-UR, Villinger A, Langer P. Synlett 2010; 979
      Thieme Connect
    • 13d Phenyl 1,4-dihydroxynaphthoate: Abid O.-U.-R, Ibad MF, Nawaz M, Ali A, Sher M, Rama NH, Villinger A, Langer P. Tetrahedron Lett. 2010; 51: 1541
      CrossrefSearch in Google Scholar
    • 13e 5,10-Dihydroxy-11H-benzo[b]fluoren-11-one: Ali A, Hussain MA, Villinger A, Langer P. Synlett 2010; 3031
      Thieme Connect
  • 14 Synthesis of 9-Oxo-9H-fluorene-1,4-diaryl-bis(trifluoromethanesulfonate) (2) To a CH2Cl2 solution (150 mL) of 1 (1.8 g, 8.543 mmol) was added dry pyridine (10 mL), and the solution was cooled to –78 °C under argon atmosphere. Then Tf2O (5.785 g, 20.503 mmol, 2.4 equiv) was added dropwise to the solution and stirred for 20 h at r.t. After removal of the solvent with reduced pressure H2O (100 mL) was added to the resulting oil, and the precipitate was filtered off and recrystallized with hot heptane. After cooling to r.t., the precipitated pure product 2 was filtered and washed with heptane. To obtain the residual product, the heptane was concentrated under vacuum, and the product 2 was isolated by column chromatography (silica gel; heptane–EtOAc, 3:1) as a yellow fluffy solid (3.318 g, 82%); mp 131–133 °C. 1H NMR (300 MHz, CDCl3): δ = 7.88 (d, 3 J = 7.6 Hz, 1 H, ArH), 7.78 (d, 3 J = 7.4 Hz, 1 H, ArH), 7.64 (dt, 3 J = 7.6 Hz, 4 J = 1.2 Hz, 1 H, ArH), 7.53 (d, 3 J = 9.1 Hz, 1 H, ArH), 7.48 (dt, 3 J = 7.5 Hz, 4 J = 0.9 Hz, 1 H, ArH), 7.21 (d, 3 J = 9.1 Hz, 1 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 187.40 (CO), 144.29, 143.06, 139.32, 138.13 (C), 136.09 (CH), 133.49 (C), 131.48 (CH), 129.39 (C), 127.62 (CH), 125.70, 124.5, 124.38 (C), 118.85 (q, J F,C = 321.00 Hz, CF3), 118.66 (q, J F,C = 321.00 Hz, CF3). 19F NMR (282 MHz, CDCl3): δ = –73.02 (CF3), –73.17 (CF3). IR (ATR): ν = 3104.6 (w), 3089 (w), 2921 (w), 2849 (w), 1726 (s), 1427 (s), 1224 (s), 1207 (s), 1166 (m), 1134 (s), 1104 (m), 905 (s), 886 (s), 845 (s), 812 (m), 803 (s), 762 (m), 754 (s), 598 (s) cm–1. MS (EI, 70eV): m/z = 476 (52) [M+], 343 (13), 279 (100), 251 (49), 223 (35), 185 (14), 154 (16), 128 (33), 100 (12), 69 (43). HRMS (EI): m/z calcd for C15H6F6O7S2 [M+]: 475.94536; found: 475.94491. Anal. Calcd for C15H6F6O7S2 (476.32): C, 37.82; H, 1.27. Found: C, 37.92; H, 1.08.
  • 15 General Procedure for the Synthesis of 4a–h In a pressure tube 2 (0,315 mmol), K3PO4 (3.0 equiv), Pd(PPh3)4 (6.0 mol%), and arylboronic acid (2.4 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the bis-substituted fluorenone 4a–h in good yields.
  • 16 1,4-Bis-(3,4-dimethoxyphenyl)-9H-fluoren-9-one (4a) Starting with 2 (150 mg, 0.315 mmol), 3a (138 mg, 0.756 mmol, 2.4 equiv), Pd(PPh3)4 (22 mg, 0.018 mmol, 6 mol%), K3PO4 (200 mg, 0.945 mmol, 3.0 equiv), and 1,4-dioxane (5 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 1:1) 4a was isolated as an orange solid (138 mg, 97%); mp 192–194 °C. 1H NMR (300 MHz, CDCl3): δ = 7.62–7.58 (m, 1 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.23 (d, J = 7.9 Hz, 1 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.15–7.11 (m, 2 H, ArH), 7.02 (s, 2 H, ArH), 6.97 (d, J = 9.2 Hz, 2 H, ArH), 6.81–6.75 (m, 1 H, ArH), 4.00 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3). 13C NMR (75 MHz, CDCl3): δ = 193.09 (CO), 149.35, 149.18, 149.11, 148.43, 143.72, 142.41, 141.17, 136.87 (C), 136.41 (CH), 134.80 (C), 134.20 (CH), 132.29 (C), 131.35 (CH), 130.18 (C), 128.85, 124.03, 123.30, 121.88, 121.20, 113.09, 112.26, 111.57, 110.82 (CH), 56.15, 5615 (OCH3), 56.06, 56.06 (OCH3). IR (ATR): ν = 3008 (w), 2955 (w), 2933 (w), 2905 (w), 2838 (w), 2627 (w), 2577 (w), 1701 (m), 1519 (m), 1441 (s), 1251 (s), 1222 (s), 1146 (s), 1020 (s), 746 (s) cm–1. MS (EI, 70 eV): m/z = 452 (100) [M+], 437 (9), 263 (4); 250 (4), 226 (5), 132 (4). HRMS (ESI-TOF/MS): m/z calcd for C29H24O5 [M + H]+: 453.16965; found: 453.16995; m/z calcd for C29H24O5 [M + Na]+: 475.15159; found: 475.15191.
  • 17 General Procedure for the Synthesis of 5a–h In a pressure tube 2 (0.525 mmol), K3PO4 (2.0 equiv), Pd(PPh3)4 (3.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 60 °C. After cooling to r.t., the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the monosubstituted fluorenone 5a–h in good yields.
  • 18 1-(4′-Hydroxyphenyl)-9-oxo-9H-fluoren-4-yl-trifluoromethanesulfonate (5f) Starting with 2 (150 mg, 0.315 mmol), 3f (53 mg, 0.378 mmol, 1.2 equiv), Pd(PPh3)4 (11 mg, 0.009 mmol, 3 mol%), K3PO4 (134 mg,0.63 mmol, 2.0 equiv), and 1,4-dioxane (9 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 6:1) 5f was isolated as deep yellow solid (112 mg, 86%); mp 194–196 °C. 1H NMR (300 MHz, DMSO): δ = 9.75 (s, 1 H, OH), 7.80–7.69 (m, 2 H, ArH), 7.64 (t, J = 7.2 Hz, 2 H, ArH), 7.51 (t, J = 7.2 Hz, 1 H, ArH), 7.40 (m, 3 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH). 13C NMR (63 MHz, CDCl3): δ = 190.03 (CO), 158.21, 142.34, 141.91, 138.63, 135.74 (C), 135.49, 134.00 (CH), 133.54, 133.58 (C), 130.81, 130.81, 130.68, 127.34 (CH), 126.01 (C), 124.47, 123.03 (CH), 118.06 (q, J F,C = 320.70 Hz, CF3), 114.73, 114.73 (CH). 19F NMR (282 MHz, CDCl3): δ = –73.13 (CF3). IR (ATR): ν = 3320 (w), 3019 (w), 2920 (w), 2850 (w), 1699 (m), 1422 (s), 1205 (s), 1137 (s), 825 (s), 608 (s), 585 (s), 567 (s), 547 (m), 527 (s) cm–1. MS (EI, 70eV): m/z = 420 (28) [M+], 287 (100), 259 (22), 231 (7), 202 (22), 176 (4), 150 (2), 101 (5), 69 (8). HRMS (EI): m/z calcd for C20H11F3O5S1 [M+]: 420.02738; found: 420.02764. Anal. Calcd for C20H11F3O5S (420.36): C, 57.15; H, 2.64. Found: C, 57.23; H, 2.52.
  • 19 CCDC-1416855 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +44(1223)336033; or deposit@ccdc.cam.ac.uk.
  • 20 General Procedure for the Synthesis of 6a–g In a pressure tube 5a–e,g, K3PO4 (2.0 equiv), Pd(PPh3)4 (5.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon and stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the cross-substituted fluorenone 6a–g in good yields.
  • 21 1-(5′-Fluoro-2′-methoxyphenyl)-4-(4′′-methoxyphenyl)-9H-fluoren-9-one (6a) Starting with 5g (75 mg, 0.166 mmol), 3b (30 mg, 0.199 mmol, 1.2 equiv), Pd(PPh3)4 (9 mg, 0.008 mmol, 5 mol%), K3PO4 (67 mg, 0.315 mmol, 2.0 equiv), and 1,4-dioxane (3 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 4:1) 6a was isolated as a deep yellow solid (67 mg, 99%); mp 193–195 °C. 1H NMR (300 MHz, CDCl3): δ = 7.58–7.52 (m, 1 H, ArH), 7.45–7.39 (m, 2 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.20–7.14 (m, 3 H, ArH), 7.13–7.03 (m, 3 H, ArH), 7.01 (dd, J = 8.7, 3.1 Hz, 1 H, ArH), 6.93 (dd, J = 9.0, 4.4 Hz, 1 H, ArH), 6.84–6.78 (m, 1 H, ArH), 3.92 (OCH3), 3.74 (OCH3). 13C NMR (75 MHz, CDCl3): δ = 192.72 (CO), 159.71 (OCH3), 156.92 (d, 2 J F,C = 238.5 Hz, CF), 153.52 (d, 4 J = 2.0 Hz, COCH3), 144.11, 137.45 (C), 136.57 (CH), 135.42 (d, 4 J F,C = 3.1 Hz, CH), 134.72 (C), 134.16 (CH), 131.95, 131.61 (C), 131.25, 130.22, 130.22 (CH), 128.68 (d, J = 6.6 Hz, CH), 123.94, 123.24 (CH), 117.23 (d, 2 J F,C = 23.7 Hz, CH), 115.33 (d, 2 J F,C = 22.6 Hz, CH), 114,29 (CH), 111.67 (d, 3 J F,C = 8.2 Hz, CH), 56.33 (OCH3), 55.52 (OCH3). 19F NMR (282 MHz, CDCl3): δ = –124.53 (CF). IR (ATR): ν = 3392 (w), 3068 (w), 3000 (w), 2957 (w), 2945 (w), 2914 (w), 2835 (w), 1704 (s), 1483 (s), 1469 (s), 1175 (s), 1026 (s), 940 (s), 764 (s) cm–1. MS (EI, 70eV): m/z = 410 (35) [M+], 379 (100), 294 (6), 190 (8), 153 (5). HRMS (EI): m/z calcd for C27H19F1O3 [M+]: 410.13127; found: 410.13077.
  • 22 Handy ST, Zhang Y. Chem. Commun. 2006; 299

  • References and Notes

  • 1 Campo MA, Larock RC. J. Org. Chem. 2002; 67: 5616 ; and references cited therein
    CrossrefPubMedSearch in Google Scholar
  • 2 Perry PJ, Read MA, Davies RT, Gowan SM, Reszka AP, Wood AA, Kelland LR, Neidle S. J. Med. Chem. 1999; 42: 2679
    CrossrefSearch in Google Scholar
  • 8 Burke SM, Joullie MM. Synth. Commun. 1976; 6: 371
    CrossrefSearch in Google Scholar
  • 10 Goel A, Chaurasia S, Dixit M, Kumar V, Parakash S, Jena B, Verma JK, Jain M, Anand RS, Manoharan S. Org. Lett. 2009; 11: 1289 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 11 Reim S, Lau M, Adeel M, Hussain I, Yawer MA, Riahi A, Ahmed Z, Fischer C, Reinke H, Langer P. Synthesis 2009; 445
    Thieme Connect

      • For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
    • 12a Schröter S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
      Search in Google Scholar
    • 12b Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P. Eur. J. Org. Chem. 2006; 3283

      For Suzuki–Miyaura reactions of bis(triflates) from our laboratory, see, for example:
    • 13a Methyl 2,5-dihydroxybenzoate: Nawaz M, Ibad MF, Abid O.-U.-R, Khera RA, Villinger A, Langer P. Synlett 2010; 150
      Thieme Connect
    • 13b Alizarin: Mahal A, Villinger A, Langer P. Synlett 2010; 1085 3,4
    • 13c Dihydroxybenzophenone: Nawaz M, Khera RA, Malik I, Ibad MF, Abid O.-UR, Villinger A, Langer P. Synlett 2010; 979
      Thieme Connect
    • 13d Phenyl 1,4-dihydroxynaphthoate: Abid O.-U.-R, Ibad MF, Nawaz M, Ali A, Sher M, Rama NH, Villinger A, Langer P. Tetrahedron Lett. 2010; 51: 1541
      CrossrefSearch in Google Scholar
    • 13e 5,10-Dihydroxy-11H-benzo[b]fluoren-11-one: Ali A, Hussain MA, Villinger A, Langer P. Synlett 2010; 3031
      Thieme Connect
  • 14 Synthesis of 9-Oxo-9H-fluorene-1,4-diaryl-bis(trifluoromethanesulfonate) (2) To a CH2Cl2 solution (150 mL) of 1 (1.8 g, 8.543 mmol) was added dry pyridine (10 mL), and the solution was cooled to –78 °C under argon atmosphere. Then Tf2O (5.785 g, 20.503 mmol, 2.4 equiv) was added dropwise to the solution and stirred for 20 h at r.t. After removal of the solvent with reduced pressure H2O (100 mL) was added to the resulting oil, and the precipitate was filtered off and recrystallized with hot heptane. After cooling to r.t., the precipitated pure product 2 was filtered and washed with heptane. To obtain the residual product, the heptane was concentrated under vacuum, and the product 2 was isolated by column chromatography (silica gel; heptane–EtOAc, 3:1) as a yellow fluffy solid (3.318 g, 82%); mp 131–133 °C. 1H NMR (300 MHz, CDCl3): δ = 7.88 (d, 3 J = 7.6 Hz, 1 H, ArH), 7.78 (d, 3 J = 7.4 Hz, 1 H, ArH), 7.64 (dt, 3 J = 7.6 Hz, 4 J = 1.2 Hz, 1 H, ArH), 7.53 (d, 3 J = 9.1 Hz, 1 H, ArH), 7.48 (dt, 3 J = 7.5 Hz, 4 J = 0.9 Hz, 1 H, ArH), 7.21 (d, 3 J = 9.1 Hz, 1 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 187.40 (CO), 144.29, 143.06, 139.32, 138.13 (C), 136.09 (CH), 133.49 (C), 131.48 (CH), 129.39 (C), 127.62 (CH), 125.70, 124.5, 124.38 (C), 118.85 (q, J F,C = 321.00 Hz, CF3), 118.66 (q, J F,C = 321.00 Hz, CF3). 19F NMR (282 MHz, CDCl3): δ = –73.02 (CF3), –73.17 (CF3). IR (ATR): ν = 3104.6 (w), 3089 (w), 2921 (w), 2849 (w), 1726 (s), 1427 (s), 1224 (s), 1207 (s), 1166 (m), 1134 (s), 1104 (m), 905 (s), 886 (s), 845 (s), 812 (m), 803 (s), 762 (m), 754 (s), 598 (s) cm–1. MS (EI, 70eV): m/z = 476 (52) [M+], 343 (13), 279 (100), 251 (49), 223 (35), 185 (14), 154 (16), 128 (33), 100 (12), 69 (43). HRMS (EI): m/z calcd for C15H6F6O7S2 [M+]: 475.94536; found: 475.94491. Anal. Calcd for C15H6F6O7S2 (476.32): C, 37.82; H, 1.27. Found: C, 37.92; H, 1.08.
  • 15 General Procedure for the Synthesis of 4a–h In a pressure tube 2 (0,315 mmol), K3PO4 (3.0 equiv), Pd(PPh3)4 (6.0 mol%), and arylboronic acid (2.4 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the bis-substituted fluorenone 4a–h in good yields.
  • 16 1,4-Bis-(3,4-dimethoxyphenyl)-9H-fluoren-9-one (4a) Starting with 2 (150 mg, 0.315 mmol), 3a (138 mg, 0.756 mmol, 2.4 equiv), Pd(PPh3)4 (22 mg, 0.018 mmol, 6 mol%), K3PO4 (200 mg, 0.945 mmol, 3.0 equiv), and 1,4-dioxane (5 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 1:1) 4a was isolated as an orange solid (138 mg, 97%); mp 192–194 °C. 1H NMR (300 MHz, CDCl3): δ = 7.62–7.58 (m, 1 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.23 (d, J = 7.9 Hz, 1 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.15–7.11 (m, 2 H, ArH), 7.02 (s, 2 H, ArH), 6.97 (d, J = 9.2 Hz, 2 H, ArH), 6.81–6.75 (m, 1 H, ArH), 4.00 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3). 13C NMR (75 MHz, CDCl3): δ = 193.09 (CO), 149.35, 149.18, 149.11, 148.43, 143.72, 142.41, 141.17, 136.87 (C), 136.41 (CH), 134.80 (C), 134.20 (CH), 132.29 (C), 131.35 (CH), 130.18 (C), 128.85, 124.03, 123.30, 121.88, 121.20, 113.09, 112.26, 111.57, 110.82 (CH), 56.15, 5615 (OCH3), 56.06, 56.06 (OCH3). IR (ATR): ν = 3008 (w), 2955 (w), 2933 (w), 2905 (w), 2838 (w), 2627 (w), 2577 (w), 1701 (m), 1519 (m), 1441 (s), 1251 (s), 1222 (s), 1146 (s), 1020 (s), 746 (s) cm–1. MS (EI, 70 eV): m/z = 452 (100) [M+], 437 (9), 263 (4); 250 (4), 226 (5), 132 (4). HRMS (ESI-TOF/MS): m/z calcd for C29H24O5 [M + H]+: 453.16965; found: 453.16995; m/z calcd for C29H24O5 [M + Na]+: 475.15159; found: 475.15191.
  • 17 General Procedure for the Synthesis of 5a–h In a pressure tube 2 (0.525 mmol), K3PO4 (2.0 equiv), Pd(PPh3)4 (3.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 60 °C. After cooling to r.t., the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the monosubstituted fluorenone 5a–h in good yields.
  • 18 1-(4′-Hydroxyphenyl)-9-oxo-9H-fluoren-4-yl-trifluoromethanesulfonate (5f) Starting with 2 (150 mg, 0.315 mmol), 3f (53 mg, 0.378 mmol, 1.2 equiv), Pd(PPh3)4 (11 mg, 0.009 mmol, 3 mol%), K3PO4 (134 mg,0.63 mmol, 2.0 equiv), and 1,4-dioxane (9 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 6:1) 5f was isolated as deep yellow solid (112 mg, 86%); mp 194–196 °C. 1H NMR (300 MHz, DMSO): δ = 9.75 (s, 1 H, OH), 7.80–7.69 (m, 2 H, ArH), 7.64 (t, J = 7.2 Hz, 2 H, ArH), 7.51 (t, J = 7.2 Hz, 1 H, ArH), 7.40 (m, 3 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH). 13C NMR (63 MHz, CDCl3): δ = 190.03 (CO), 158.21, 142.34, 141.91, 138.63, 135.74 (C), 135.49, 134.00 (CH), 133.54, 133.58 (C), 130.81, 130.81, 130.68, 127.34 (CH), 126.01 (C), 124.47, 123.03 (CH), 118.06 (q, J F,C = 320.70 Hz, CF3), 114.73, 114.73 (CH). 19F NMR (282 MHz, CDCl3): δ = –73.13 (CF3). IR (ATR): ν = 3320 (w), 3019 (w), 2920 (w), 2850 (w), 1699 (m), 1422 (s), 1205 (s), 1137 (s), 825 (s), 608 (s), 585 (s), 567 (s), 547 (m), 527 (s) cm–1. MS (EI, 70eV): m/z = 420 (28) [M+], 287 (100), 259 (22), 231 (7), 202 (22), 176 (4), 150 (2), 101 (5), 69 (8). HRMS (EI): m/z calcd for C20H11F3O5S1 [M+]: 420.02738; found: 420.02764. Anal. Calcd for C20H11F3O5S (420.36): C, 57.15; H, 2.64. Found: C, 57.23; H, 2.52.
  • 19 CCDC-1416855 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +44(1223)336033; or deposit@ccdc.cam.ac.uk.
  • 20 General Procedure for the Synthesis of 6a–g In a pressure tube 5a–e,g, K3PO4 (2.0 equiv), Pd(PPh3)4 (5.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon and stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH2Cl2, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the cross-substituted fluorenone 6a–g in good yields.
  • 21 1-(5′-Fluoro-2′-methoxyphenyl)-4-(4′′-methoxyphenyl)-9H-fluoren-9-one (6a) Starting with 5g (75 mg, 0.166 mmol), 3b (30 mg, 0.199 mmol, 1.2 equiv), Pd(PPh3)4 (9 mg, 0.008 mmol, 5 mol%), K3PO4 (67 mg, 0.315 mmol, 2.0 equiv), and 1,4-dioxane (3 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 4:1) 6a was isolated as a deep yellow solid (67 mg, 99%); mp 193–195 °C. 1H NMR (300 MHz, CDCl3): δ = 7.58–7.52 (m, 1 H, ArH), 7.45–7.39 (m, 2 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.20–7.14 (m, 3 H, ArH), 7.13–7.03 (m, 3 H, ArH), 7.01 (dd, J = 8.7, 3.1 Hz, 1 H, ArH), 6.93 (dd, J = 9.0, 4.4 Hz, 1 H, ArH), 6.84–6.78 (m, 1 H, ArH), 3.92 (OCH3), 3.74 (OCH3). 13C NMR (75 MHz, CDCl3): δ = 192.72 (CO), 159.71 (OCH3), 156.92 (d, 2 J F,C = 238.5 Hz, CF), 153.52 (d, 4 J = 2.0 Hz, COCH3), 144.11, 137.45 (C), 136.57 (CH), 135.42 (d, 4 J F,C = 3.1 Hz, CH), 134.72 (C), 134.16 (CH), 131.95, 131.61 (C), 131.25, 130.22, 130.22 (CH), 128.68 (d, J = 6.6 Hz, CH), 123.94, 123.24 (CH), 117.23 (d, 2 J F,C = 23.7 Hz, CH), 115.33 (d, 2 J F,C = 22.6 Hz, CH), 114,29 (CH), 111.67 (d, 3 J F,C = 8.2 Hz, CH), 56.33 (OCH3), 55.52 (OCH3). 19F NMR (282 MHz, CDCl3): δ = –124.53 (CF). IR (ATR): ν = 3392 (w), 3068 (w), 3000 (w), 2957 (w), 2945 (w), 2914 (w), 2835 (w), 1704 (s), 1483 (s), 1469 (s), 1175 (s), 1026 (s), 940 (s), 764 (s) cm–1. MS (EI, 70eV): m/z = 410 (35) [M+], 379 (100), 294 (6), 190 (8), 153 (5). HRMS (EI): m/z calcd for C27H19F1O3 [M+]: 410.13127; found: 410.13077.
  • 22 Handy ST, Zhang Y. Chem. Commun. 2006; 299

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Figure 1 Structure of biologically active dendroflorin (A), denchrysan A (B), and 1,4,5-trihydroxy-7-methoxyfluoren-9-one (C)
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Scheme 1 Synthesis of 2. Reagents and conditions: i) 1 (1.0 equiv), abs. pyridine, CH2Cl2, Tf2O (2.4 equiv), 20 °C, 20 h.
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Scheme 2 Synthesis of 4a–h. Reagents and conditions: i) 2 (1.0 equiv), 3a–d,f–h (2.4 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (3.0 equiv), 1,4-dioxane, 100 °C, 12 h.
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Scheme 3 Synthesis of 5a–h. Reagents and conditions: i) 2 (1.0 equiv), 3a–h (1.2 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (2.0 equiv), 1,4-dioxane, 60 °C, 12 h.
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Figure [ 2 ] ORTEP plot for compound 5b [19]
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Scheme 4 Synthesis of 6a–g. Reagents and conditions: i) 5 (1.0 equiv), 3a–g (1.2 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (2.0 equiv), 1,4-dioxane, 100 °C, 12 h.
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Figure 3 Possible explanation for the regioselectivity of the reactions of bis(triflate) 2