Protected Indazole Boronic Acid Pinacolyl Esters: Facile Syntheses and Studies of Reactivities in Suzuki-Miyaura Cross-Coupling and Hydroxydeboronation Reactions

Abstract

The paper describes a rapid and efficient synthesis for the isolation of protected indazolylboronic esters. These compounds were synthesized by reaction between prepared protected haloindazoles and bis(pinacolato)diboron. The effects of solvent, temperature, reaction time, and the nature of halogen atom as well as protecting group were investigated. Additionaly, these compounds reacted either with aryl halides in a Suzuki-Miyaura cross-coupling reaction or with hydrogen peroxide in a hydroxydeboronation reaction showing the potential access to new aryl and hydroxyindazole libraries.

Key words

indazole boronic acid pinacolyl esters - Suzuki-Miyaura cross-coupling reaction - palladium-mediated reaction - protected halo-1H-indazoles - hydroxydeboronation

References and Notes

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25

Typical Experimental Procedure for the Synthesis of Indazolylboronic Esters
To a solution of 1-(4-bromoindazol-1-yl)ethanone (3a, 1.5 g, 6.3 mmol) in 1,4-dioxane (25 mL) were added successively bis(pinacolato)diboron (1.8 g, 7.2 mmol, 1.15 equiv) and KOAc (2.8 g, 23.8 mmol, 4.6 equiv) at r.t. The reaction mixture was degassed under vacuum with argon replacement three times, then PdCl_{2 (}dppf)-CH₂Cl₂ (0.3 g, 0.5 mmol, 0.08 equiv) was added, and the degassing procedure was repeated twice. The reaction was heated under reflux conditions for 15 min then concentrated in vacuo. After the addition of EtOAc, the organic layer was washed successively with H₂O and brine, dried over MgSO₄, and the solvent evaporated in vacuo. The crude material was purified by flash column chromatography on SiO₂ (EtOAc-cyclohexane, 1:3) to give 1-[4-(4,4,5,5-tetramethyl[1,3,2]-
dioxaborolan-2-yl)indazol-1-yl)ethanone (7a); yield 1.8 g (98%); pink solid; mp 128 ˚C. TLC: R _f  = 0.6 (EtOAc-cyclohexane, 1:4). IR (KBr): 2976, 1713, 1601, 1415, 1349, 1325, 1174, 1151, 932, 756 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.42 (s, 12 H), 2.80 (s, 3 H), 7.55 (t, J = 8.3 Hz, 1 H), 7.82 (d, J = 7.1 Hz, 1 ), 8.54 (d, J = 7.1 Hz, 1 H), 8.55 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.1, 25.0, 84.2, 118.3, 128.6, 130.6, 132.0, 138.3, 141.7, 171.1. MS (EI): m/z (%) = 286 (53) [M⁺], 244 (100), 243 (39), 229 (14), 158 (70), 145 (34), 144 (68), 134 (67). Anal. Calcd for C₁₅H₁₉BN₂O₃: C, 62.96; H, 6.69; N, 9.79. Found: C, 62.39; H, 6.48; N, 9.23.

28

7-(4-Methoxyphenyl)-1-(tetrahydro-2 H -pyran-2-yl)-1 H -indazole (17)
Yield 0.3 g (73%); white solid. TLC: R _f  = 0.1 (EtOAc-cyclohexane, 1:10). IR (KBr): 3428, 2932, 1611, 1497, 1245, 1078, 1032, 824 cm^-¹. ^¹H NMR (400 MHz, CDCl₃):
δ = 1.37-1.42 (m, 2 H), 1.76-1.78 (m, 1 H), 1.90-1.95 (m,
1 H), 2.56-2.58 (m, 1 H), 2.91-2.96 (m, 1 H), 3.74-3.80 (m, 1 H), 3.91 (s, 3 H), 4.04-4.07 (m, 1 H), 5.00 (dd, J = 12.7, 2.2 Hz, 1 H), 7.02 (dd, J = 7.3, 1.4 Hz, 2 H), 7.18-7.19 (m, 2 H), 7.23-7.26 (m, 2 H), 7.64-7.70 (m, 1 H), 8.12 (s, 1 H). MS (EI): m/z (%) = 308 (22) [M ⁺ ], 224 (100), 209 (26), 192 (2), 182 (8), 154 (7), 85 (8). Anal. Calcd for C₁₉H₂₀N₂O₂: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.30; H, 6.74; N, 9.28.

30

The use of Oxone^® (2KHSO₅-KHSO₄-K₂SO₄) as oxidative reagent in the presence of Na₂CO₃ in a mixture of H₂O-acetone (1:1) at 0 ˚C led to the desired compounds but in lower yields.