Synthesis of Trifluoromethyl-Substituted
Di- and Terphenyls by Site-Selective Suzuki-Miyaura Reactions
of 1,4-Dibromo-2-trifluoromethyl-benzene

Ihsan Ullah; Muhammad Nawaz; Alexander Villinger; Peter Langer

doi:10.1055/s-0030-1260956

LETTER

Synthesis of Trifluoromethyl-Substituted Di- and Terphenyls by Site-Selective Suzuki-Miyaura Reactions of 1,4-Dibromo-2-trifluoromethyl-benzene

Ihsan Ullah^a, Muhammad Nawaz, Alexander Villinger^a, Peter Langer*^a,b
^a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
^b 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;

Abstract

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Abstract

The Suzuki-Miyaura reaction of 1,4-dibromo-2-(trifluoromethyl)benzene provides a convenient route for the synthesis of various trifluoromethylated di- and terphenyls. The reactions proceed with excellent site selectivity in favor of the 4-position due to steric and electronic reasons.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - site selectivity - organofluorine compounds

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References

References and Notes

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Typical Procedure for Suzuki-Miyaura Reactions
The reaction was carried out in a pressure tube. To a dioxane suspension (5 mL) of 1, Pd(PPh₃)₄ (3-5 mol%), and of the arylboronic acid 2a-o was added an aq solution of K₂CO₃ (2 M, 1-2 mL). The mixture was heated at 70 ˚C (3a-o) or 90 ˚C (4a-o) under argon for 8 h. The solution was cooled to 20 ˚C, poured into H₂O and CH₂Cl₂ (5 mL each), and the organic and the aqueous layers were separated. The latter was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with H₂O (3 × 10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc).

4-Bromo-4′- tert -butyl-3-(trifluoromethyl)biphenyl (3g)
Starting with 1 (150 mg, 0.5 mmol) and 2g (90 mg, 0.5 mmol), 3g was isolated as a colorless viscous oil (158 mg, 88%). ^¹H NMR (300 MHz, 298 K, CDCl₃): δ = 1.28 [s, 9 H, (CH₃)₃], 7.42 (s, 4 H, H_Ar), 7.50 (dd, J = 2.1, 8.3 Hz, 1 H, H_Ar), 7.67 (d, J = 8.2 Hz, 1 H, H_Ar), 7.80 (d, J = 2.1 Hz, 1 H, H_Ar). ^¹9F NMR (282 MHz, 298 K, CDCl₃): δ = -62.61. ^¹³C NMR (75 MHz, 298 K, CDCl₃): δ = 31.2 [(CH₃)₃], 34.6 [C(CH₃)₃], 118.3 (J _C-F = 1.9 Hz, C_Ar), 123.0 (J _C-F = 272 Hz, CF₃), 126.1, 126.3 (J _C-F = 5.4 Hz), 126.6 (CH_Ar), 130.4
(J _C-F = 31.7 Hz, C_Ar), 131.1, 135.2 (CH_Ar), 135.7, 140.6, 151.6 (C_Ar). IR (neat): 3034, 2961, 2868, 1601 (w), 1473, 1418 (m), 1325 (s), 1251, 1172 (m), 1129, 1100 (s), 1021 (m), 962 (w), 902 (m), 818 (s), 743, 697, 659 (m), 603 (w), 566 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 358 (28) [M⁺, ^8¹Br], 344 (18), 343 (98), 342 (19), 341 (100), 315 (20), 313 (20), 262 (10), 233 (7), 222 (8), 165 (7), 157 (8), 156 (9). HRMS (EI): m/z calcd for C₁₇H₁₆ ^8¹BrF₃ [M]⁺: 358.036150; found: 358.036852.

2-Trifluoromethyl-1,4-bis(4-methoxyphenyl)benzene (4h) Starting with 1 (150 mg, 0.5 mmol) and 2t (190 mg, 1.25 mmol), 4h was isolated as a viscous oil (167 mg, 93%). ^¹H NMR (300 MHz, 298 K, CDCl₃): δ = 3.77, 3.78 (s, 6 H, 2 OCH₃), 6.86 (d, J = 8.7 Hz, 2 H, H_Ar), 6.93 (d, J = 8.7 Hz, 2 H, H_Ar), 7.18-7.27 (m, 3 H, H_Ar), 7.48 (d, J = 8.8 Hz, 2 H, H_Ar), 7.62 (dd, J = 8.8, 1.6 Hz, 1 H, H_Ar), 7.82 (d, J = 1.6 Hz, 1 H, H_Ar). ^¹9F NMR (282 MHz, 298 K, CDCl₃): δ = -56.83. ^¹³C NMR (75 MHz, 298 K, CDCl₃): δ = 55.2, 55.4 (OCH₃), 113.3, 114.5, 124.2 (J _C-F = 4.5 Hz) (CH_Ar) 124.3 (J _C-F = 275 Hz, CF₃), 128.1, 129.2, 130.1 (J _C-F = 1.4 Hz, CH_Ar), 130.8 (J _C-F = 30.9 Hz, C_Ar), 132.0 (CH_Ar), 132.8, 139.2, 139.3, 139.8 (J _C-F = 1.9 Hz), 159.1, 159.7 (C_Ar). IR (neat): 3028, 2922 (w), 1605, 1475 (m), 1395 (w), 1321, 1270, 1241, 1165 (m), 1118 (s), 1074, 1050, 1032 (m), 972 (w), 895, 839 (m), 778, 705 (s), 663, 607 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 359 (22) [M + 1], 358 (100) [M⁺], 344 (12), 243 (32), 315 (14), 300(14), 271 (17), 251 (41), 207 (15), 202 (22), 179 (49), 157 (28). HRMS (EI): m/z calcd for C₂₁H₁₇O₂F₃ [M]⁺: m/z = 358.117520; found: 358.116620.

1-(3′,4′-Dimethoxy)-phenyl-4-naphthyl-2-trifluoromethyl-benzene (5b)
Starting with 3j (88 mg, 0.25 mmol) and 2m (45 mg, 0.25 mmol), 5b was obtained as a yellowish crystalline solid (87 mg, 85%). ^¹H NMR (300 MHz, 298 K, CDCl₃): δ = 3.81, 3.84 (s, 6 H, 2 OCH₃), 6.82-6.86 (m, 3 H, H_Ar), 7.36-7.45 (m, 3 H, H_Ar), 7.67 (dd, J = 8.5, 1.8 Hz, 1 H, H_Ar), 7.77-7.87 (m, 4 H, H_Ar), 8.00 (s, 2 H, H_Ar). ^¹9F NMR (282 MHz, 298K, CDCl₃): δ = -56.72. ^¹³C NMR (75 MHz, 298K, CDCl₃): δ = 55.9, 56.0 (OCH₃), 110.4, 112.6, 121.4 (CH_Ar), 122.8 (J _C-F = 275.2 Hz, CF₃), 125.0, 125.1, 126.0, 126.4, 126.6 (CH_Ar), 127.1, 127.3 (C_Ar), 127.7, 128.3 (CH_Ar), 128.5
(J _C-F = 29.7 Hz, C_Ar), 128.8, 129.9 (CH_Ar), 132.1 (C_Ar), 132.9 (CH_Ar), 133.6, 136.7, 140.0, 140.2, 148.2, 148.7 (C_Ar). IR (neat): 3052, 2954, 2834, 1602 (w), 1495, 1462, 1407 (m), 1369 (w), 1314 (m), 1244, 1217, 1164, 1118 (s), 1071 (m), 1022 (s), 952, 886, 857 (m), 811, 748 (s), 719, 644, 607, 553 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) 409 (27) [M + 1], 408 (100) [M⁺], 393 (13), 365 (32), 350 (29), 326 (23), 325 (47), 322 (30), 305 (14), 297 (16), 296 (44), 253 (14), 252 (39), 204 (59), 163 (52), 162 (36). HRMS (EI): m/z calcd for C₂₅H₁₉O₂F₃ [M]⁺: 408.133170; found: 408.133547.

CCDC-822983 (3j) and CCDC-822984 (4i) contain 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, GB-Cambridge CB21EZ; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.

<A NAME="RD09511ST-15">15</A> For a simple guide for the prediction of the site selectivity of palladium(0)-catalyzed cross-coupling reactions based on the ^¹H NMR chemical shift values, see: Handy ST. Zhang Y. Chem. Commun. 2006, 299