Zinc Metal-Promoted Cross-Coupling Reaction of Non-Activated Alkyl Halides with Aldehydes in the Presence of Chlorotrimethylsilane

Abstract

Treatment of non-activated alkyl halides 1 with aldehydes 3 in the presence of zinc metal and chlorotrimethylsilane (TMSCl), DMA and/or NMP in THF brought about highly facile and effective cross-coupling to give the corresponding alcohols in good yield. These reactions are assumed to proceed through zinc reagent intermediates generated in situ.

addition reactions - non-activated alkyl halides - zinc - TMSCl - aldehydes

References

For review see:

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11

Generation of alkylzinc reagents 2 was checked by GLC after hydrolysis with H₂O.

12

The representative procedure is as follow: Under an argon atmosphere, to a mixture of zinc metal (278 mg, 4.25 mmol) and methyl 5-iodovalelerate(1a) (1.0 g, 4.13 mmol) in THF (4 mL) was added NMP (545 mg, 5.50 mmol), followed by heating at 60 °C for 1 h. After cooling to r.t., benzalde-hyde(3a) (877 mg, 8.26 mmol) and TMSCl (898 mg, 8.26 mmol) were added and stirred at the same temperature for 16 h. After the usual work-up and flash column chromato-graphy of the resulting oil, methyl 6-hydroxy-6-phenyl-hexanoate(4a) (643 mg, 2.89 mmol) was obtained in 70% yield. All new compounds were fully characterized by ¹H, ¹³C NMR and MS spectrometry. Selected spectra data: 4a, ¹H NMR (300 MHz, CDCl₃): δ = 7.33-7.20 (m, 5 H), 4.64 (t, 1 H, J = 6.5 Hz), 3.63 (s, 3 H), 2.28 (t, 2 H, J = 7.4 Hz), 1.86-1.58 (m, 4 H), 1.51-1.22 (m, 2 H). ¹³C NMR (75.57 MHz, CDCl₃): δ = 174.08, 144.71, 128.37, 127.46, 125.79, 74.22, 51.40, 38.56, 33.88, 25.27, 24.69. MS (EI): m/z (relative intensity) = 222 (M⁺, 32), 204 (7), 116 (40), 107 (100), 87 (79). HRMS: calcd for C₁₃H₁₈O₃: 222.1256. Found: 222.1243. Methyl 6-hydroxy-6-(4′-methyl-phenyl)hexanoate(4f): ¹H NMR (300 MHz, CDCl₃): δ = 7.16 (dd, 4 H, J = 8.0 Hz, J = 21.1 Hz), 4.59 (t, 1 H, J = 6.6 Hz), 3.62 (s, 3 H), 2.33 (s, 3 H), 2.27 (t, 2 H, J = 7.5 Hz), 1.80-1.57 (m, 4 H), 1.48-1.21(m, 2 H). ¹³C NMR (75.57 MHz, CDCl₃): δ = 177.08, 141.74, 137.03, 129.00, 125.73, 74.00, 51.37, 38.46, 33.86, 25.29, 24.67, 20.99. MS (EI): m/z (relative intensity) = 236 (M⁺, 44), 221 (7), 121 (100), 93 (14), 91 (7). HRMS: calcd for C₁₄H₂₀O₃: 236.1412. Found: 236.1390.

13 Reaction of α-bromo esters with TMSCl in the presence of zinc metal has been reported to form a mixture of O-silylated and C-silylated products: Slougui N. Rousseau G. Synth. Commun.  1987,  17:  1 

14

In this reaction, the role of TMSCl may be postulated mainly to be the activation of aldehydes 3 by coordination of the Si atom to the carbonyl group.