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Synlett 2009(7): 1091-1094  
DOI: 10.1055/s-0028-1088113
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Toshiyuki Iwai*, Takeo Nakai, Masatoshi Mihara, Takatoshi Ito, Takumi Mizuno, Toshinobu Ohno*
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax: +81(6)69638049; e-Mail: iwai@omtri.city.osaka.jp; e-Mail: ohno@omtri.city.osaka.jp;
Further Information

Publication History

Received 2 February 2009
Publication Date:
26 March 2009 (online)

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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

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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.