Asymmetric α-Cyanation of β-Keto Esters Catalyzed by Chiral Tin Alkoxides

This letter is dedicated to Professor Hisashi Yamamoto on the occasion of his 80^th birthday.

Abstract

A catalytic enantioselective α-cyanation reaction of β-keto esters with p-toluenesulfonyl cyanide (TsCN) as a cyanating reagent was achieved using an (R)-BINOL-derived chiral tin dibromide possessing 4-tert-butylphenyl groups at the 3- and 3′-positions as a chiral precatalyst in the presence of sodium ethoxide in ethanol. Optically active α-cyano-β-keto esters having a chiral quaternary carbon were obtained in good to high yields under the influence of the chiral tin diethoxide generated in situ.

Key words

asymmetric catalysis - cyanating reagent - cyanation - keto esters - tin catalysis

Publication History

Received: 24 April 2023

Accepted after revision: 15 May 2023

Accepted Manuscript online:
15 May 2023

Article published online:
19 June 2023

• References and Notes


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• 9 tert-Butyl 2-Cyano-4-methoxy-1-oxoindane-2-carboxylate (3g: Table [4], Entry 7); Typical ProcedureA 20% solution of NaOEt in EtOH (16.8 μL, 0.04 mmol) was added to a suspension of the chiral tin dibromide (R)-4a ⁸ (0.02 mmol) in anhyd THF (12 mL) under argon and the mixture was stirred at r.t. for 30 min. β-keto ester 1g (66.1 mg, 0.25 mmol) and TsCN (2b, 72.0 mg, 0.375 mmol) were added successively at r.t., and the resulting mixture was heated to 50 °C with stirring for 2 h. The mixture was then cooled to r.t. and treated with solid KF (0.5 g) and brine (1 mL) for 5 min. The resulting precipitate was removed by filtration, and the filtrate was extracted with CHCl₃ (×3). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. The residual crude product was purified by column chromatography (silica gel) to give a white solid; yield: 66.2 mg (98%, 83% ee); mp 89–93 °C, [α]_D ^{20. 8} +22.9 (c 1.0, CHCl₃).HPLC [Daicel Chiralcel OJ-H, hexane–i-PrOH (10:1), 1.0 mL/min]; t _R (major) = 23.3 min, t _R (minor) = 50.5 min. IR (neat): 2980, 2941, 2843, 2247, 1728, 1602, 1490, 1458, 1441, 1395, 1371, 1295, 1267, 1251, 1209, 1147, 1076, 979, 950 cm^–1. ¹H NMR (392 MHz, CDCl₃): δ = 1.50 (s, 9 H), 3.54 (d, J = 17.6 Hz, 1 H), 3.77 (d, J = 18.0 Hz, 1 H), 3.93 (s, 3 H), 7.14 (dd, J = 1.6, 7.1 Hz, 1 H), 7.40–7.47 (m, 2 H). ¹³C NMR (99 MHz, CDCl₃): δ = 27.6 (3 C), 34.6, 55.0, 55.6, 85.7, 116.1, 116.7, 117.2, 130.4, 133.7, 140.6, 156.6, 162.9, 191.5. MS (ESI): m/z [M–H]^– calcd for C₁₆H₁₆NO₄: 286.1074, found: 286.1069.
• 10 Although the formation of p-TolSO₂H was not confirmed by NMR, we propose a catalytic cycle similar to Scheme 3, which produces p-TolSO₂H as a byproduct, as a possible catalytic cycle in the initial stage of this reaction. As the reaction progresses, it is assumed that the formation of the chiral tin enolate 5 is inhibited by the acidic sulfinic acid or that the formed chiral tin enolate 5 is protonated. We believe that these factors are among the causes of a lower yield of the reaction product.