Chiral Sulfoxide Ligands in Catalytic Asymmetric Cyanohydrin Synthesis

Abstract

A novel chiral sulfoxide-containing ligand for the catalytic addition of trimethylsilylcyanide to aldehydes is reported. The sulfoxide moiety was found to be vital for reactivity.

aldehydes - catalysis - cyanohydrins - chiral sulfoxides

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<A NAME="RD26802ST-27">27</A>

Sulfoxide (S _S)-7: ¹H NMR (300 MHz, CDCl₃) 12.21 (1 H, br s,), 7.53 (1 H, d, J = 1.5 Hz), 7.44 (1 H, d, J = 2.5 Hz), 4.93-4.82 (1 H, m), 4.61 (1 H, t, J = 9.5 Hz), 4.29 (1 H, t, J 9.0 Hz), 2.84 (1 H, dd, J = 12.5 Hz, 6.5 Hz), 2.68 (1 H, dd, J = 12.5 Hz, 7.5 Hz), 1.42 (9 H, s), 1.28 (9 H, s), 1.26 (9 H, s); ¹³C NMR (75 MHz, CDCl₃) 167.7 (C), 157.3 (C), 140.7 (C), 137.0 (C), 128.9 (CH), 122.8 (CH), 109.7 (C), 71.9 (CH₂), 62.2 (CH), 53.8 (C), 51.4 (CH₂), 35.5 (C), 34.7 (C), 31.9 (CH₃), 29.8 (CH₃), 23.2 (CH₃); MS (EI) m/z = 393, 337, 322, 274, 250, 217, 205, 149, 57.
Sulfoxide (R _S)-7: ¹H NMR (300 MHz, CDCl₃) 12.15 (1 H, s), 7.52 (1 H, d, J = 2.5 Hz), 7.42 (1 H, d, J = 2.5 Hz), 4.91-4.81 (1 H, m), 4.58 (1 H, t, J = 9.0 Hz), 4.40 (1 H, dd, J = 9.0 Hz, 7.0 Hz), 3.00 (1 H, dd, J = 12.5 Hz, 3.5 Hz), 2.59 (1 H, dd, J = 12.5 Hz, 10.0 Hz), 1.40 (9 H, s), 1.27 (9 H, s), 1.25 (9 H, s); ¹³C NMR (75 MHz, CDCl₃) 167.9 (C), 157.2 (C), 140.7 (C), 137.1 (C), 128.9 (CH), 122.7 (CH), 109.5 (C), 71.0 (CH₂), 61.4 (CH), 54.1 (C), 51.1 (CH₂), 35.5 (C), 34.7 (C), 31.9 (CH₃), 29.8 (CH₃), 23.1 (CH₃).

<A NAME="RD26802ST-28">28</A>

Typical procedure: Ti(i-PrO)₄ (0.013 mL, 0.04 mmol, 0.09 equiv) was added to a solution of (S _S)-7 (0.018 g, 0.05 mmol, 0.1 equiv) in CH₂Cl₂ (0.78 mL) at room temperature. The resultant pale yellow solution was stirred at room temperature for 1 hour whereupon it was cooled to -78 °C. Benzaldehyde (0.049 mL, 0.47 mmol, 1.0 equiv) was added and the solution stirred for a further 30 min. TMSCN (0.095 mL, 0.71 mmol, 1.5 equiv) was then added and the reaction vessel transferred to a -84 °C freezer for 60 h. HCl_(aq) (3 M; 3 mL) was added and the mixture vigorously stirred at room temperature for 2 h. The layers were separated and the aqueous phase extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried (MgSO₄) and concentrated. The cyanohydrin 9 was isolated by column chromatography (petroleum ether:ether, 3:1).

<A NAME="RD26802ST-29">29</A>

At -84 °C there was no reaction between benzaldehyde and TMSCN in the presence of either 10% Ti(i-PrO)₄ or 10% Ti(i-PrO)₄ + 10% DMSO after 48 h. On warming to -20 °C complete reaction was observed in the presence of just 10% Ti(i-PrO)₄ in 12 h whilst the reaction had only gone to 60% completion in the presence of 10% Ti(i-PrO)₄ + 10% DMSO over the same period. Again this indicates that the ligand is essential for activity. The decrease in the rate of reaction in the presence of DMSO could possibly be the result of the formation of a coordinatively saturated octahedral complex with resultant loss in Lewis acidity. This would require two equivalents of DMSO per titanium centre thus resulting in only 5% active catalyst being present. Stoichiometry of the catalyst has already been shown to effect the rate (Table [1] ; entry 6).

<A NAME="RD26802ST-30">30</A>

Three aluminium complexes were studied in cyanosilylation reaction of benzaldehyde. One formed from 2,2′-biphenol gave 58% conversion, one with a phenyl sulfone substituent in the ortho position of 2,2′-biphenol gave 75% conversion whilst the phenyl sulfoxide substituted 2,2′-biphenol gave 92% conversion. This suggests that the sulfoxide is activating the TMSCN and that it is not purely an electronic effect making the aluminium centre more Lewis acidic. Work to convert this to a chiral system is currently underway.

<A NAME="RD26802ST-31">31</A> Braunstein P. Naud F. Angew. Chem. Int. Ed.  2001,  40:  680 

<A NAME="RD26802ST-32">32</A> The use of sulfoxides as Lewis base catalysts for allylations: Kentish-Barnes W. D. Phil. Thesis   The University of Sussex; UK: 2002.