Pd-Catalyzed Cross-Coupling Reactions of Pyridine Carboxylic Acid Chlorides with Alkylzinc Reagents

Abstract

The efficient cross-coupling reaction to afford ketones from pyridine carboxylic acid chlorides and alkylzinc reagents in the presence of Pd(phen)Cl₂ is reported. In the case of chloronico­tinoyl chlorides, none of Negishi cross-coupling products of 2-chloroazine moiety was formed. The catalyst loading could be reduced up to 0.01 mol%.

Key words

cross-coupling - alkylzinc reagents - palladium - pyridine - ketone

References and Notes

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15

Typical Procedure for Preparation of Alkylzinc Reagents
Under argon atmosphere, to a mixture of Zn metal (196 mg, 3.0 mmol) and DMI (0.43 mL, 4.0 mmol) in MeCN (3.0 mL) was added one drop of TMSCl at 60 ˚C and stirred for 5 min, followed by addition of 2-phenylethyl iodide (0.43 mL, 3.0 mmol), stirring at the same temperature for 2 h, and cooling to r.t.

16

Toluene-DMI was utilized instead of benzene-DMA.

18

Stylene was detected by GC-MS.

19

Typical Procedure for the Pd-Catalyzed Cross-Coupling Reaction
Under argon atmosphere, to a suspension of 6-chloro­-nicotinoyl chloride (1a, 352 mg, 2.0 mmol) and Pd(phen)Cl₂ (21 mg, 0.06 mmol) in MeCN (3.0 mL) was added alkylzinc reagent 2 and stirring at same temperature. After stirring for 2 h, sat. NH₄Cl was added to the reaction mixture and extracted with EtOAc (2 × 20 mL). The combined EtOAc extract was washed with sat. NH₄Cl, sat. NaHCO₃ and brine, and dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO₂ (hexane-EtOAc, 6:1) to give the product 3a (453 mg, 92%) as white solid.
Selected Spectra Data
Compound 3a: mp 82.9 ˚C. ^¹H NMR (300 MHz, CDCl₃):
δ = 8.91 (1 H, d, J = 2.4 Hz), 8.16 (1 H, dd, J = 8.4, 2.4 Hz), 7.42 (1 H, d, J = 8.3 Hz), 7.32-7.18 (5 H, m), 3.31-3.26 (2 H, m), 3.10-3.05 (2 H, m). ^¹³C NMR (75.5 MHz, CDCl₃):
δ = 196.63, 155.44, 149.67, 140.43, 137.87, 130.84, 128.51, 128.27, 126.25, 124.41, 40.57, 29.60. IR (KBr): 3055, 3025, 1685, 1575, 1466, 1375, 1103, 700 cm^-¹. MS (EI): m/z (relative intensity) = 245 (100) [M⁺], 140 (95). HRMS (EI): m/z calcd for C₁₄H₁₂ClNO [M⁺]: 245.0607; found: 245.0617.
Compound 3f: white solid, mp 52.8 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.97 (1 H, d, J = 2.3 Hz), 8.21 (1 H, dd, J = 8.3, 2.4 Hz), 7.45 (1 H, d, J = 8.4 Hz), 4.16 (2 H, q, J = 7.1 Hz), 3.28 (2 H, t, J = 6.5 Hz), 2.79 (2 H, t, J = 6.4 Hz), 1.27 (3 H, t, J = 7.1 Hz). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 195.84, 172.36, 155.68, 149.73, 137.93, 130.7, 124.49, 60.76, 33.58, 27.87, 14.10. IR (KBr): 3037, 2995, 1730, 1688, 1579, 1373, 1221 cm^-¹. MS (EI): m/z (relative intensity) = 241 (31) [M⁺], 196 (65), 140 (100). HRMS (EI): m/z calcd for C₁₁H₁₂ClNO₃ [M⁺]: 241.0506; found: 241.0504.

20

When excess amount of 2 (2.5 equiv) was used with Pd(Ph₃P)₄ catalyst, 4 and 6 were obtained in 45% and 38%, respectively.