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

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

References

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10

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.