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DOI: 10.1055/s-2004-832805
Preparation and Acylation of Highly Functionalized Copper Derivatives of 3-Iodoindazoles Leading to Polyfunctional 3-Acylindazoles
Publication History
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).
Key words
polyfunctional heterocycles - cuprates - acylation - indazole - iodine-copper exchange reaction
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References
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.