Nucleophilic Addition of Alkanenitriles to Aldehydes via N-Silyl Ketene Imines Generated In Situ

Abstract

Upon treatment with triisopropylsilyl trifluoromethanesulfonate and 2,2,6,6-tetramethylpiperidine, alkanenitriles undergo direct addition to aldehydes under mild non-basic neutral conditions to provide triisopropylsilyl ethers of β-hydroxy nitriles in good yield. The reaction proceeds through generation of an N-silyl ketene imine intermediate in situ from the alkanenitrile followed by nucleophilic addition of the intermediate to the aldehyde.

Key words

nitriles - nitrile aldol reaction - nucleophilic addition - N-silyl ketene imines - aldehydes

• References and Notes


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• 12 The combination of TIPSOTf and PMP smoothly promoted hydrosilylation of benzaldehyde (6) to afford TIPS ether 13 in 82% yield (Scheme 6).
• 13 A deuterium-labeling experiment proved that PMP acts as the hydride source (Scheme 7).
• 14 The reason for the superior reactivity of TMP is not yet clear. Very low solubility of 2,2,6,6-tetramethylpiperidinium triflate (TfOH·TMP) in DCE might cause the equilibrium to shift slightly toward the N-silyl ketene imine.
• 15 When DCE was used as the solvent, a significant amount of inseparable double aldol type addition product accompanied 15f. Solvent screening revealed that toluene could suppress such side reactions, although it required heating of the reaction mixture to 100 °C.
• 16 General Procedure (Table [1], Entry 5): To a mixture of benzaldehyde (6; 40.8 μL, 0.400 mmol), 2-methoxy-2-phenylacetonitrile (11; 55.5 μL, 0.400 mmol), and 2,2,6,6-tetramethylpiperidine (136 μL, 0.800 mmol) in DCE (2.0 mL) was added TIPSOTf (215 μL, 0.800 mmol), and the mixture was stirred at room temperature for 22 h, at which point the consumption of starting materials 6 and 11 was complete (as determined by TLC analysis, hexane/EtOAc = 4:1). After cooling to 0 °C, the reaction was quenched by slow addition of saturated aqueous NaHCO₃ (1 mL), and the resulting mixture was filtered through a cotton plug to remove the precipitate (rinsed with CH₂Cl₂). The filtrate was extracted with CH₂Cl₂ (3 × 1 mL). The combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂; hexane/EtOAc = 50:1) to give nitrile 12 (139.6 mg, 0.341 mmol, 85% yield) as an inseparable 55:45 mixture of diastereomers. Compound 12: Colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.53–7.51 (m, 1 H), 7.40–7.36 (m, 3 H), 7.31–7.27 (m, 2 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.13–7.04 (m, 2 H), 6.92 (m, 1 H), 4.98 (s, 0.55 H), 4.97 (s, 0.45 H), 3.34 (s, 0.45 × 3 H), 3.18 (s, 0.55 × 3 H), 1.15–1.09 (m, 0.45 × 3 H), 1.06 (d, J = 6.9 Hz, 0.45 × 9 H), 1.00 (d, J = 7.5 Hz, 0.45 × 9 H), 0.81–0.74 (m, 0.55 × 21 H). ¹³C NMR (125 MHz, CDCl₃): δ = 139.08, 137.95, 134.79, 133.93, 129.21, 128.99, 128.51, 128.45, 128.18, 128.09, 127.96, 127.86, 127.76, 127.41, 127.20, 127.07, 117.15, 116.89, 88.12, 86.64, 81.44, 81.06, 54.03, 53.97, 17.87, 17.82, 17.70, 17.63, 12.44, 12.40. IR (ATR): 2943, 2867, 2365, 1122, 1069 cm^–1. HRMS (FD): m/z [M+H]⁺ calcd for C₂₅H₃₆NO₂Si: 410.2515; found: 410.2484.
• 17 Attempts to detect N-silyl ketene imine intermediates by ¹H or ¹³C NMR spectroscopic analysis were unsuccessful, suggesting that these reactive species in equilibrium with the corresponding nitriles exist only in low concentration. The reaction of 6 with 11 did not proceed in the absence of either TIPSOTf or TMP. The alkanenitrile underwent isomerization at the α-position of the cyano group upon treatment with TIPSOTf/TMP (i.e., nitrile 28 in Scheme S2). These results support the conclusion that the nucleophilic addition proceeds via the N-silyl ketene imine intermediate. For details, see Scheme S2 in the Supporting Information.