Synlett 2004(13): 2303-2306  
DOI: 10.1055/s-2004-832805
LETTER
© Georg Thieme Verlag Stuttgart · New York

Preparation and Acylation of Highly Functionalized Copper Derivatives of 3-Iodoindazoles Leading to Polyfunctional 3-Acylindazoles

Xiaoyin Yang, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax: +49(89)218077680; e-Mail: knoch@cup.uni-muenchen.de;
Further Information

Publication History

Received 2 August 2004
Publication Date:
08 September 2004 (online)

Abstract

The reaction of functionalized 3-iodoindazoles with (Nphyl)2CuLi provides polyfunctional 3-cuprated indazoles which are readily acylated in THF-NMP mixtures with various acid chlorides providing 3-ketoindazoles in excellent yields. These heterocyclic cuprates tolerate the presence of most important functional groups (ketone, ester and cyanide).

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Typical Procedure: Preparation of the Benzyl 3-Cyclopentanecarbonyl-1 H -indazole-4-carboxylic Acid Ethyl Ester (5): To a solution of 1-benzyl-3-iodo-1H-indazole-4-carboxylic acid ethyl ester (203 mg, 0.5 mmol, 1.0 equiv) in dry THF (2 mL) at -78 °C was added dropwise freshly prepared (Nphyl)2CuLi solution (0.6 mmol, 1.2 equiv). The resulting solution was warmed to r.t. and kept stirring for 30 min. Dry N-methyl-2-pyrrolidinone (NMP, 0.2 mL) and cyclopentanecarbonyl acid chloride (198 mg, 1.5 mmol, 3.0 equiv) were added successively at r.t. and the resulting solution was kept stirring for 1 h. The reaction mixture was quenched with sat. aq NH4Cl solution (3 mL) and aq NH3 solution (25%, 1 mL) and poured into H2O (10 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The organic fractions were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (n-pentane-Et2O = 1:1) gave the desired product 5 (165 mg, 88% yield). IR (film): 3402 (m, br), 2982 (m), 1720 (vs), 1661 (vs), 1597 (m), 1579 (w), 1448 (m), 1405 (s), 1356 (s), 1369 (s), 1317 (s), 1275 (vs), 1105 (vs), 1020 (m), 939 (m), 927 (m), 851 (w), 769 (w), 715 (s), 698 (m), 657 (m) cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.07 (dd, J = 8.4 and 1.8 Hz, 2 H), 7.73 (m, 4 H), 7.53 (m, 1 H), 7.40 (t, J = 8.0 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 195.0, 164.8, 140.2, 136.0, 132.6, 131.9, 129.1, 128.7, 128.4, 127.4, 126.2, 60.4, 13.3. MS (EI, 70 eV): m/z (%) = 254 (48) [M+], 226 (14), 209 (45), 181 (18), 177 (57), 152 (10), 149 (14), 130 (20), 118 (17), 104 (100). HRMS (EI): m/z calcd for C16H14O3 [M+]: 527.7580; found: 527.7579.