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Synlett 2009(4): 615-619  
DOI: 10.1055/s-0028-1087922
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

François Crestey, Elodie Lohou, Silvia Stiebing, Valérie Collot*, Sylvain Rault
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Études et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen Cedex, France
Fax: +33(2)31931188; e-Mail: valerie.collot@unicaen.fr;
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Publication History

Received 8 October 2008
Publication Date:
16 February 2009 (online)

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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

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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 PdCl2 (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.