Synthesis of 3,4-Diarylbenzophenones by Site-Selective Suzuki-Miyaura Reactions of 3,4-Bis(trifluoromethylsulfonyloxy)benzophenone

Abstract

The Suzuki-Miyaura reaction of the bis(triflate) of 3,4-dihydroxybenzophenone with two equivalents of boronic acids gave 3,4-diarylbenzophenones. The reaction with one equivalent of arylboronic acids resulted in site-selective attack onto carbon atom C-4. 3,4-Diarylbenzophenones containing two different aryl groups were prepared by sequential addition of two different boronic acids.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - site-selectivity - benzophenones

References and Notes

• Cytotoxic activity:
• 1a De Souza AO. Santos RR. Melo PS. Alderete JB. De Conti R. Haun M. Sato DN. Duran N. Pharmazie  2001,  56:  871 
• Antibacterial activity:
• 1b De Souza AO. Alderete JB. Schmidt F. Sato DN. Duran N. Arzneim. Forsch.  1999,  49:  1025 
• Inhibition of ^³H-progesterone binding:
• 2a Kumar S. Seth M. Bhaduri AP. Agnihotri A. Srivastava AK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1984,  23:  154 
• Inhibition of the interleukin (IL-1) biosynthesis:
• 2b Batt DG. Goodman R. Jones DG. Kerr JS. Mantegna LR. J. Med. Chem.  1993,  36:  1434 
• Inhibition of the human type-2 steroid 5α-reductase:
• 2c Holt DA. Yamashita DS. Konialian-Beck AL. Luengo JI. Abell AD. J. Med. Chem.  1995,  38:  13 
• Inhibition of COX-1:
• 2d Dannhardt G. Fiebich BL. Schweppenhaeuser J. Eur. J. Med. Chem.  2002,  147 
• Inhibition of human liver microsomes:
• 2e Lenhart A. Reinert DJ. Aebi JD. Dehmlow H. Morand OH. Schulz GE. J. Med. Chem.  2003,  46:  2083 
• 3 Appel B. Rotzoll S. Kranich R. Reinke H. Langer P. Eur. J. Org. Chem.  2006,  3638 
• 4 Guarnieri A. Burnelli S. Varoli L. Busacchi I. Barbaro AM. Arch. Pharm. (Weinheim, Ger.)  1981,  314:  703 
• 5 Aburaki S. Okuyama S. Hoshi H. Kamachi H. Nishio M. J. Antibiot.  1993,  46:  1447 
• 6a Pettit GR. Toki B. Herald DL. Verdier-Pinard P. Boyd MR. Hamel E. Pettit RK. J. Med. Chem.  1998,  41:  1688 
• 6b Liou J.-P. Chang J.-Y. Chang C.-W. Chang C.-Y. Mahindroo N. Kuo F.-M. Hsieh H.-P. J. Med. Chem.  2004,  47:  2897 
• 6c Liou J.-P. Chang C.-W. Song JS. Yang YS. Yeh CF. Tseng HY. Lo YK. Chang C.-L. Chang C.-M. Hsieh H.-P. J. Med. Chem.  2002,  45:  2556 
• 7a Cai X. Sakamoto M. Fujitsuka M. Majima T. Chem. Eur. J.  2005,  11:  6471 ; and references cited therein
• 7b Langhals H. Fuchs K. Chem. Unserer Zeit  2004,  38:  98 ; and references cited therein
• 8 Buchta E. Egger H. Chem. Ber.  1957,  90:  2760 
• 9 Shiue J.-S. Lin M.-H. Fang J.-M. J. Org. Chem.  1997,  62:  4643 
• 10 For a review of site-selective palladium(0)-catalyzed cross-coupling reactions, see: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
• 11 Nawaz M. Adeel M. Farooq M. Langer P. Synlett  2009,  2154 

12

3,4-Bis(trifluoromethylsulfonyloxy)benzophenone (2) To a CH₂Cl₂ solution (10 mL/mmol) of 1 (1.0 equiv) was added pyridine (4.0 equiv) at -78 ˚C under argon atmo-sphere. After 10 min, Tf₂O (2.4 equiv) was added at
-78 ˚C. The mixture was allowed to warm to 0 ˚C during 4 h with stirring. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The product was isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc). Starting with 1 (214 mg, 1.0 mmol), pyridine (0.32 mL, 4.0 mmol), and Tf₂O (0.38 mL, 2.4 mmol), 2 was isolated as a highly viscous oil (401 mg, 84%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.44-7.60 (m, 5 H, ArH), 7.68-7.74 (m, 2 H, ArH), 7.86 (s, 1 H, ArH). ^¹³C NMR (62.89 MHz, CDCl₃): δ = 115.9 (q, J _F,C = 320.0 Hz, CF₃), 121.1 (q, J _F,C = 321.3 Hz, CF₃), 123.6, 125.2, 128.7, 129.9, 130.9, 133.6 (CH), 135.7, 138.7, 140.2, 142.9 (C), 192.6 (C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -73.3, 72.0 (2 CF). IR (KBr): ν = 3061, (w), 1598, 1589, 1580 (m), 1496, 1431, 1414, 1319, 1291 (m), 1265 (s), 1165, 1077, 1028, 989, 976, 932 (m), 887, 787, 757 (s), 680, 595, 572 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 478 (74) [M⁺], 401 (5), 345 (08), 253 (26), 225 (32), 204 (04), 167 (22), 156 (06), 128 (27), 105 (100), 77 (43), 69 (30), 51 (14). HRMS (EI, 70 eV): m/z calcd for C₁₅H₈F₆O₇S₂ [M⁺]: 477.96101; found: 477.960958.

13

General Procedure for the Synthesis of 4a-i, 5a-e, and 6a-d
The reaction was carried out in a pressure tube. To a dioxane suspension (5 mL) of 2 or 5, Pd(PPh₃)₄, arylboronic acid, and K₃PO₄ were added. The mixture was stirred at 110 ˚C under argon atmosphere for the indicated period of time (6-8 h). The reaction mixture was 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).

14

3,4-Bis(3,5-dimethylphenyl)benzophenone (4c) Starting with 2 (220 mg, 0.46 mmol), K₃PO₄ (292 mg, 1.38 mmol), Pd(PPh₃)₄ (6 mol%), 3,5-dimethylphenylboronic acid (180 mg, 1.2 mmol), and 1,4-dioxane (5 mL per mmol of 2), 4c was isolated as a crystalline solid (134 mg, 75%); mp 140-142 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 2.09 (s, 6 H, 2 CH₃), 2.11 (s, 6 H, 2 CH₃), 6.67-6.77 (m, 5 H, ArH), 7.38-7.48 (m, 5 H, ArH), 7.68-7.78 (m, 4 H, ArH). ^¹³C NMR (75.46 MHz, CDCl₃): δ = 21.2 (2 CH₃), 21.3 (2 CH₃), 125.1, 127.5, 127.7, 128.3, 128.6, 128.8, 130.0, 130.4, 132.1, 132.3 (CH), 136.3, 137.1, 137.2, 137.8, 140.4, 140.5, 140.9, 144.9 (C), 196.4 (C=O). IR (KBr): ν = 3289, 3013, 2916, 2857, 2732 (w), 1732, (s), 1574 1505 (m), 1495, 1455, 1436, 1386, 1328, 1296 (m), 1250 (s), 1199, 1118, 1067, 1036, 959, 902 (m), 882, 842, 793, 738 (s), 695, 648, 596, 567 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 390 (100) [M⁺], 313 (29), 270 (13), 239 (7), 148 (4), 105 (22), 77 (11). HRMS (EI): m/z calcd for C₂₉H₂₆O [M⁺]: 390.19782; found: 390.197629.

15

CCDC-759141 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: [phone]; or [e-mail].

16

4-(3,4,5-Trimethoxyphenyl)-3-(trifluorosulfonyloxy)-benzophenone (5d) Starting with 2 (220 mg, 0.46 mmol), K₃PO₄ (146 mg, 0.69 mmol), Pd(PPh₃)₄ (3 mol%), 3,4,5-trimethoxyphenylboronic acid (125 mg, 0.59 mmol), and 1,4-dioxane (5mL per mmol of triflate), 5d was isolated as a viscous oil (173 mg, 76%); mp 139-140 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.82 (s, 6 H, 2 OCH₃), 3.83 (s, 3 H, OCH₃), 6.62 (s, 2 H, ArH), 7.39-7.47 (m, 3 H, ArH), 7.56 (s, 1 H, ArH), 7.68-7.78 (m, 3 H, ArH), 7.88 (d, 1 H, J = 6.4 Hz, ArH). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 56.2 (2 OCH₃), 61.0 (OCH₃), 106.8 (CH), 120 (q, J _F,C = 320 Hz, CF₃), 122.0, 128.5, 130.0, 130.4, 133.1, 133.3 (CH), 135.8, 136.7, 137.7, 138.6, 149.0, 153.3 (C), 194.8 (C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -73.8 (CF₃). IR (KBr): ν = 3065, 2999, 2936 (w), 1660, 1609 (s),1584, 1514, 1488 (m), 1463, 1418, 1393, 1317, 1291, 1278 (m), 1241 (s), 1170, 1104, 1063, 1001, 978 (m), 889, 831, 790, 745 (s), 675, 630, 598, 569 (m) cm^-¹. GC-MS (EI, 70 eV):
m/z (%) = 496 (92) [M⁺], 363 (26), 332 (100), 317 (17), 255 (12), 227 (07), 185 (05), 105 (57), 77 (19). HRMS (EI): m/z calcd for C₂₃H₁₉F₃O₇S [M⁺]: 496.07981; found: 496.079887.