Synlett 2010(2): 195-198  
DOI: 10.1055/s-0029-1218556
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3,5-Diaryl-4-fluorophthalates by [4+2]-Cycloaddition and Subsequent Site-Selective Suzuki-Miyaura Reactions

Muhammad Farooq Ibada, Obaid-Ur-Rahman Abida, Muhammad Nawaza, Muhammad Adeela,b, Alexander Villingera, Peter Langer*a,c
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, Gomal University, Dera Ismail Khan, N.W.F.P, Pakistan
c Leibniz Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: peter.langer@uni-rostock.de;
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Publikationsverlauf

Received 7 October 2009
Publikationsdatum:
11. Dezember 2009 (online)

Abstract

The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 4-fluoro-3,5-dihydroxyphthalate. Site-selective Suzuki-Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-fluorophthalates.

    References and Notes

  • 1a Fluorine in Bioorganic Chemistry   Filler R. Kobayasi Y. Yagupolskii LM. Elsevier; Amsterdam: 1993. 
  • 1b Filler R. Fluorine Containing Drugs in Organofluorine Chemicals and their Industrial Application   Pergamon; New York: 1979.  Chap. 6.
  • 1c Hudlicky M. Chemistry of Organic Compounds   Ellis Horwood; Chichester: 1992. 
  • 1d Kirsch P. Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
  • 1e Chambers RD. Fluorine in Organic Chemistry   Blackwell Publishing CRC Press; Florida: 2004. 
  • See also:
  • 1f Ryckmanns T. Balancon L. Berton O. Genicot C. Lamberty Y. Lallemand B. Passau P. Pirlot N. Quéré L. Talaga P. Bioorg. Med. Chem. Lett.  2002,  12:  261 
  • 1g Malamas MS. Sredy J. Moxham C. Katz A. Xu W. McDevitt R. Adebayo FO. Sawicki DR. Seestaller L. Sullivan D. Taylor JR. J. Med. Chem.  2000,  43:  1293 
  • 1h Ciha AJ. Ruminski PG. J. Agric. Food Chem.  1991,  39:  2072 
  • 1i Albrecht HA. Beskid G. Georgopapadakou NH. Keith DD. Konzelmann FM. Pruess DL. Rossman PL. Wei CC. Christenson JG. J. Med. Chem.  1991,  34:  2857 
  • 1j Albrecht HA. Beskid G. Christenson JG. Deitcher KH. Georgopapadakou NH. Keith DD. Konzelmann FM. Pruess DL. Wie CC. J. Med. Chem.  1994,  37:  400 
  • 1k Song CW. Lee KY. Kim CD. Chang T.-M. Chey WY. J. Pharmacol. Exp. Ther.  1997,  281:  1312 
  • 1l De Voss JJ. Sui Z. DeCamp DL. Salto R. Babe LM. Craik CS. Ortiz de Montellano PR.
    J. Med. Chem.  1994,  37:  665 
  • 1m Anjaiah S. Chandrasekhar S. Gree R. Adv. Synth. Catal.  2004,  346:  1329 
  • 1n Iorio MA. Paszkowska RT. Frigeni V. J. Med. Chem.  1987,  30:  1906 
  • 1o Popp JL. Musza LL. Barrow CJ. Rudewicz PJ. Houck DR. J. Antibiot.  1994,  47:  411 
  • 1p Chen TS. Petuch B. MacConnell J. White R. Dezeny G. J. Antibiot.  1994,  47:  1290 
  • 1q Lam KS. Schroeder DR. Veitch JMJM. Colson KL. Matson JA. Rose WC. Doyle TW. Forenza S.
    J. Antibiot.  2001,  54:  1 
  • 2 Metal-Catalyzed Cross-Coupling Reactions   de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
  • Reviews:
  • 3a Wittkopp A. Schreiner PR. The Chemistry of Dienes and Polyenes   Vol. 2:  John Wiley & Sons Ltd.; New York: 2000. 
  • 3b Schreiner PR. Chem. Soc. Rev.  2003,  32:  289 
  • See also:
  • 3c Wittkopp A. Schreiner PR. Chem. Eur. J.  2003,  9:  407 
  • 3d Kleiner CM. Schreiner PR. Chem. Commun.  2006,  4315 
  • 3e Kotke M. Schreiner PR. Synthesis  2007,  779 
  • 3f Review: Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
  • 4a Schmidbaur H. Kumberger O. Chem. Ber.  1993,  126:  3 
  • 4b Dinger MB. Henderson W. J. Organomet. Chem.  1998,  560:  233 
  • 4c Liedtke J. Loss S. Widauer C. Grützmacher H. Tetrahedron  2000,  56:  143 
  • 4d Schneider S. Tzschucke CC. Bannwarth W. Multiphase Homogeneous Catalysis   Cornils B. Herrmann WA. Horvath IT. Leitner W. Mecking S. Olivier-Booubigou H. Vogt D. Wiley-VCH; Weinheim: 2005.  Chap. 4. p.346 
  • 4e Clarke D. Ali MA. Clifford AA. Parratt A. Rose P. Schwinn D. Bannwarth W. Rayner CM. Curr. Top. Med. Chem.  2004,  7:  729 
  • 5a Shi G.-Q. Cottens S. Shiba SA. Schlosser MA. Tetrahedron  1992,  48:  10569 
  • 5b Shi G.-Q. Schlosser M. Tetrahedron  1993,  49:  1445 
  • 5c Patrick TB. Rogers J. Gorrell K. Org. Lett.  2002,  4:  3155 
  • 6 Lefebvre O. Brigaud T. Portella C. Tetrahedron  1998,  54:  5939 
  • 7 For a review of 1,3-bis(silyloxy)-1,3-butadienes in general, see: Langer P. Synthesis  2002,  441 
  • 8 For a review of [3+3] cyclizations, see: Feist H. Langer P. Synthesis  2007,  327 
  • 9a Adeel M. Reim S. Wolf V. Yawer MA. Hussain I. Villinger A. Langer P. Synlett  2008,  2629 
  • 9b Hussain I. Yawer MA. Lau M. Pundt T. Fischer C. Reinke H. Görls H. Langer P. Eur. J. Org. Chem.  2008,  503 
  • 10 For reviews of site-selective palladium(0)-catalyzed cross-coupling reactions of polyhalogenated substrates, see: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
11

Synthesis of Dimethyl 4-Fluoro-3,5-dihydroxyphthalate (2): Diene 1 (9.0 g, 30.8 mmol) was added to DMAD (6.5 g, 5.5 mL, 46.2 mmol) at -78 ˚C. The mixture(neat) was allowed to warm to 20 ˚C during 20 h with stirring. To the mixture were added hydrochloric acid (10%) and dichloromethane (50 mL each). The organic and the aqueous layer were separated and the latter was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 2 as a crystalline colorless solid (3.0 g, 40%); mp 140-142 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 3.87 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 6.15 (s, 1 H, OH), 6.60 (d, 1 H, J FH = 7.5 Hz, ArH), 10.96 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl3): δ = 52.8 (OMe), 53.0 (OMe), 104.6 (C), 108.4 (CH), 131.6 (d, J FC = 4.5 Hz, C), 140.5 (d, J FC = 239 Hz, CF), 148.3 (d, J FC = 11.7 Hz, COH), 151.1 (d, J FC = 11.0 Hz, COH), 168.6 (C=O), 168.8 (d, J FC = 3.0 Hz, C=O). ¹9F NMR (282 MHz, CDCl3): δ = -160.80 (F). IR (ATR): 3292 (m), 2962 (w), 2859 (w), 1716 (s), 1682 (s), 1621 (s), 1599 (s), 1515 (w), 1434 (s), 1325 (s), 1236 (s), 1093 (s), 933 (w) cm. GC-MS (EI, 70 eV): m/z (%) = 244 (24) [M+], 212 (53), 181 (11), 154 (100), 137 (4), 126 (12), 97 (9). HRMS (EI): m/z [M+] calcd for C10H9O6F: 244.03777; found: 244.037617.

12

Dimethyl 4-Fluoro-3,5-bis(trifluoromethylsulfonyloxy)-phthalate (3): To a solution of 2 (1.0 equiv) in CH2Cl2 (10 mL/mmol) was added pyridine (4.0 equiv) at - 78 ˚C under an argon atmosphere. After 10 min, Tf2O (2.4 equiv) was added at -78 ˚C. The mixture was allowed to warm up to 0 ˚C and stirred for 4 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The products of the reaction mixture were isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc). Starting with 2 (2.00 g, 8.0 mmol), pyridine (2.6 mL, 32.0 mmol), CH2Cl2 (80 mL), Tf2O (3.2 mL, 19.2 mmol), 3 was isolated as a viscous colorless liquid (3.54 g, 87%). ¹H NMR (300 MHz, CDCl3): δ = 3.87 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 7.96 (d, 4 J FH = 6.4 Hz, 1 H, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 52.6 (OMe), 52.7 (OMe), 117.5 (q, ¹ J CF = 321 Hz, CF3), 117.6 (q, ¹ J CF = 321 Hz, CF3), 124.3 (br s, CH), 124.9 (d, ³ J FC = 5.0 Hz, C), 130.9 (C), 133.8 (d, ² J FC = 13.2 Hz, C), 136.7 (d, ² J = 12.2 Hz, C), 148.0 (d, ¹ J = 268 Hz, CF), 161 (CO), 161.4 (d, 4 J FC = 1.6 Hz, CO). ¹9F NMR (282 MHz, CDCl3): δ = 129.34, -72.81 (d, 5 J FCF3 = 5.1 Hz, CF3), -72.51 (d, 5 J FCF3 = 14.31 Hz, CF3). IR (ATR): 2960 (w), 2922 (w), 1739 (s), 1616 (w), 1595 (w), 1502 (w), 1426 (s), 1326 (m), 1209 (s), 1128 (m), 1045 (m), 1011 (s), 971 (s), 887 (m), 821 (m), 787 (s), 750 (m), 736 (m), 650 (w), 601 (s) cm. GC-MS (70 eV): m/z (%) = 510 (1) [M+ + 2], 509 (2) [M+ + 1], 508 (12) [M+], 477 (100), 439 (5), 413 (44), 349 (52), 283 (33), 253 (6), 222 (19), 183 (16), 155 (14), 127 (4), 81 (8), 69 (63), 59 (15), 45 (4). HRMS (EI): m/z [M+] calcd for C12H7O10F7S2: 507.93634; found: 507.936470.

13

CCDC 753087 and CCDC 753088 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

14

General Procedure for Suzuki-Miyaura Reactions:
A 1,4-dioxane solution (4 mL per 3 mmol of 3 ) of 3, K3PO4, Pd(PPh3)4 and arylboronic acid 4 was stirred at 110 ˚C or 90 ˚C for 8 h. After cooling to 20 ˚C, a saturated aqueous solution of NH4Cl was added. The organic and the aqueous layers were separated and the latter was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography.

15

Dimethyl 4-Fluoro-3,5-di(4-ethylphenyl)phthalate (5e): Starting with 3 (152 mg, 0.3 mmol), K3PO4 (191 mg, 0.9 mmol), Pd(PPh3)4 (3 mol%), 4-ethylphenylboronic acid (105 mg, 0.7 mmol) and 1,4-dioxane (4 mL), 5e was isolated as a colorless solid (91 mg, 72%); mp 151-153 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.19 (t, J = 7.5 Hz, 3 H, Me), 1.20 (t, J = 7.5 Hz, 3 H, Me), 2.62 (q, J = 7.6 Hz, 2 H, CH2), 2.63 (q,
J = 7.6 Hz, 2 H, CH2), 3.56 (s, 3 H, OMe), 3.83 (s, 3 H, OMe), 7.16-7.23 (m, 9 H, ArH). ¹³C NMR (75 MHz, CDCl3):
δ = 15.3, 15.5 (2 × Me), 28.6 (2 × CH2), 52.4 (OMe), 52.6 (OMe), 123.6 (d, ³ J CF = 4.4 Hz, C), 127.7 (2 × CH), 128.2
(2 × CH), 129.0 (d, 4 J CF = 2.8 Hz, 2 × CH), 129.3 (C), 129.6 (d, 4 J FC = 1.2 Hz, 2 × CH), 130.2 (d, ² J FC = 15.9 Hz, C), 131.5 (C), 131.9 (d, ³ J FC = 5.5 Hz, CH), 136.6 (d, 4 J FC = 3.8 Hz, C), 144.7 (d, ² J FC = 23.7 Hz, C), 159.1 (d, ¹ J FC = 256 Hz, CF), 165.4 (CO), 167.9 (d, 4 J FC = 2.7 Hz, CO). ¹9F NMR (282 MHz, CDCl3): δ = -111.4. IR (ATR): 3037 (w), 3002 (w), 2961 (m), 2947 (m), 2931 (m), 2671 (w), 1739 (m), 1717 (s), 1613 (w), 1514 (m), 1429 (m), 1396 (m), 1345 (m), 1274 (m), 1247 (m), 1219 (s), 1146 (m), 1118 (m), 1069 (m), 1020 (m), 1003 (m), 968 (m), 848 (m), 835 (m), 794 (m), 683 (m), 575 (m), 531 (m) cm. GC-MS (70 eV): m/z (%) = 421 (28) [M+ + 1], 420 (100) [M+], 405 (20), 389 (52), 373 (3), 357 (18), 329 (7), 315 (2), 301 (4), 287 (5), 273 (6), 272 (5), 259 (4), 257 (6), 252 (2), 244 (3), 195 (7), 170 (2), 143 (3), 135 (3), 129 (2), 77 (1), 59 (1), 29 (2). HRMS (EI): m/z [M+] calcd for C26H25O4F: 420.17314: found: 420.173423.

16

Dimethyl 4-Fluoro-5-(3,5-dimethylphenyl)-3-(trifluoro-methylsulfonyloxy)phthalate (6e): Starting with 3 (152 mg, 0.3 mmol), K3PO4 (95 mg, 0.45 mmol), Pd(PPh3)4 (3 mol%), 3,5-dimethylphenylboronic acid (50 mg, 0.33 mmol) and 1,4-dioxane (4 mL), 6e was isolated as a colorless solid (104 mg, 75%); mp 79-80 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 2.31 (br s, 6 H, 2 × Me), 3.85 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 7.02 (s, 1 H, ArH), 7.06 (s, 2 H, ArH), 8.01 (d, 4 J FH = 6.6 Hz, 1 H, ArH). ¹³C NMR (62.90 MHz, CDCl3): δ = 20.3 (2 × Me), 52.1 (OMe), 52.3 (OMe), 117.5 (q, ¹ J CF = 321 Hz, CF3), 124.4 (d, ³ J FC = 4.4 Hz, C), 125.6 (d, 4 J FC = 2.75, 2 × CH), 128.8 (C), 130.1 (CH), 130.9 (d, ³ J FC = 4.6 Hz, CH), 131.1 (d, 4 J = 1.8 Hz, C), 131.9 (d, ² J = 13.0 Hz, C), 133.3 (d, ² J F,C = 17.0 Hz, C), 137.6 (s, 2 × C), 152.3 (d, ¹ J FC = 261 Hz, C), 162.7 (d, 4 J FC = 2.7 Hz, CO). 163.1 (CO). ¹9F NMR (282 MHz, CDCl3): δ = -72.58 (d, J = 13.4 Hz, CF3), -122.34 (q, J = 13.4 Hz, ArF). IR (ATR): 2959 (w), 2921 (w), 1737 (s), 1729 (s), 1620 (w), 1602 (w), 1495 (w), 1428 (s), 1408 (m), 1343 (m), 1275 (s), 1205 (s), 1133 (m), 1006 (m), 945 (m), 854 (m), 813 (s), 757 (m), 731 (m), 598 (s), 532 (s) cm. GC-MS (70 eV): m/z (%) = 466 (8) [M+ + 2], 465 (21) [M+ + 1], 464 (100) [M+], 433 (35), 395 (2), 369 (16), 331 (6), 303 (10), 272 (9), 242 (15), 214 (10), 185 (6), 160 (7), 99 (1), 69 (5), 59 (2). HRMS (ESI, +ve): m/z [M + H]+ calcd for C19H17F4O7S: 465.06256; found: 465.06268.

17

General Procedure for the Synthesis of 7a-c: The reaction was carried out in a pressure tube. To a dioxane suspension (4 mL) of 3 (228 mg, 0.45 mmol), Pd(PPh3)4 (3 mol%) and Ar¹B(OH)2 (0.5 mmol) was added K3PO4 (143 mg, 0.67 mmol), and the resultant solution was degassed by bubbling argon through the solution for 10 min. The mixture was heated at 90 ˚C under an argon atmosphere for 9 h. The mixture was cooled to 20 ˚C. Ar²B(OH)2 (0.6 mmol) and K3PO4 (143 mg, 0.67 mmol) were added. The reaction mixtures were heated under an argon atmosphere for 6 h at 110 ˚C. They were diluted with H2O and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc-heptanes).

18

Dimethyl 4-Fluoro-5-(2-ethoxyphenyl)-3-(4-ethylphenyl)-phthalate (7c): Starting with 3 (228 mg, 0.45 mmol), K3PO4 (286 mg, 1.34 mmol), Pd(PPh3)4 (3 mol%), 2-ethoxyphenyl-boronic acid (82 mg, 0.5 mmol), 1,4-dioxane (4 mL), and
4-ethylphenylboronic acid (85 mg, 0.6 mmol), 7c was isolated as transparent crystals (114 mg, 58%); mp 104-106 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.15-1.25 (m, 6 H, 2 × Me), 2.61 (q, J = 7.5 Hz, 2 H, CH2), 3.57 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 3.95 (q, ³ J = 7.0 Hz, 2 H, OCH2), 6.87 (d, J = 8.4 Hz, 1 H, ArH), 6.93 (dt, J = 7.5 Hz, 1 H, ArH), 7.14-7.30 (m, 6 H, ArH), 7.98 (d, 4 J FH = 6.7 Hz, 1 H, ArH). ¹³C NMR (62.90 MHz, CDCl3): δ = 14.7 (Me), 15.2 (Me), 28.6 (CH2), 52.3 (OMe), 52.5 (OMe), 64.0 (OCH2), 112.1, 120.5 (2 × CH), 123.7 (C), 127.6 (2 × CH), 127.8 (d, ² J FC = 19.0 Hz, C), 128.5 (d, ² J = 20.7 Hz, C), 129.4, 129.5, 130.1 (3 × CH), 131.0 (d, 4 J = 1.4 Hz, CH), 133.3 (d, ³ J F,C = 5.6 Hz, CH), 136.8 (d, ³ J F,C = 4.1 Hz, C), 144.3, 156.3 (2 × C), 159.6 (d, ¹ J FC = 256 Hz, CF), 165.5 (C=O), 168.1 (d, 4 J = 2.7 Hz, C=O). ¹9F NMR (282 MHz, CDCl3): δ =
-106.42 (CF). IR (ATR): 2973 (w), 2944 (w), 2929 (w), 2881 (w), 1724 (br s), 1609 (w), 1580 (w), 1563 (w), 1516 (w), 1497 (m), 1451 (m), 1428 (m), 1390 (m), 1341 (m), 1273 (s), 1249 (s), 1215 (s), 1149 (s), 1123 (m), 1067 (m), 1041 (s), 969 (m), 919 (m), 858 (w), 839 (w), 793 (m), 754 (s), 689 (m), 611 (m), 537 (w) cm. GC-MS (70 eV): m/z (%) = 438 (5) [M+ + 2], 437 (30) [M+ +1], 436 (100) [M+], 405 (19), 376 (30), 361 (16), 348 (20), 317 (20), 289 (9), 271 (9), 244 (5), 171 (3), 151 (2), 128 (2), 59 (2), 29 (4). HRMS (EI): m/z [M+] calcd for C26H25FO5: 436.16805; found: 436.168135.