Synlett, Table of Contents Synlett 2023; 34(20): 2515-2519DOI: 10.1055/a-2093-9069 cluster Special Issue Dedicated to Prof. Hisashi Yamamoto Asymmetric α-Cyanation of β-Keto Esters Catalyzed by Chiral Tin Alkoxides Akira Yanagisawa∗ a Molecular Chirality Research Center, Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan , Yuki Hinata a Molecular Chirality Research Center, Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan , Koji Midorikawa b Nippoh Chemicals Co., Ltd., 1240, Matsumaru, Isumi-shi, Chiba 298-0104, Japan , Takamichi Watanabe b Nippoh Chemicals Co., Ltd., 1240, Matsumaru, Isumi-shi, Chiba 298-0104, Japan › Author Affiliations Recommend Article Abstract Buy Article All articles of this category This letter is dedicated to Professor Hisashi Yamamoto on the occasion of his 80th 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 Key wordsasymmetric catalysis - cyanating reagent - cyanation - keto esters - tin catalysis Full Text References References and Notes For a review see: 1a Kiyokawa K, Nagata T, Minakata S. Synthesis 2018; 50: 485 For an example of electrophilic cyanation of β-keto esters and amides, see 1b Wang Y.-F, Qiu J, Kong D, Gao Y, Lu F, Karmaker PG, Chen F.-X. Org. Biomol. Chem. 2015; 13: 365 For examples of transformations of α-cyano carbonyl compounds into heterocycles, see: 2a Pask CM, Camm KD, Kilner CA, Halcrow MA. Tetrahedron Lett. 2006; 47: 2531 2b Puterová Z, Andicsová A, Végh D. Tetrahedron 2008; 64: 11262 2c Gudmundsson KS, Johns BA, Weatherhead J. Bioorg. Med. Chem. Lett. 2009; 19: 5689 2d Surmont R, Verniest G, De Kimpe N. Org. Lett. 2010; 12: 4648 2e Kim BR, Sung GH, Ryu KE, Lee S.-G, Yoon HJ, Shin D.-S, Yoon Y.-J. Chem. Commun. 2015; 51: 9201 For examples of transformations of α-cyano carbonyl compounds into β-hydroxynitriles, see: 3a Soltani O, Ariger MA, Vázquez-Villa H, Carreira EM. Org. Lett. 2010; 12: 2893 3b Schranck J, Burhardt M, Bornschein C, Neumann H, Skrydstrup T, Beller M. Chem. Eur. J. 2014; 20: 9534 . For an example of transformations of α cyano carbonyl compounds into β-aminonitriles, see 3c Malapit CA, Caldwell DR, Luvaga IK, Reeves JT, Volchkov I, Gonnella NC, Han ZS, Busacca CA, Howell AR, Senanayake CH. Angew. Chem. Int. Ed. 2017; 56: 6999 4 Chowdhury R, Schörgenhumer J, Novacek J, Waser M. Tetrahedron Lett. 2015; 56: 1911 5a Chen M, Huang Z.-T, Zheng Q.-Y. Org. Biomol. Chem. 2015; 13: 8812 5b Karmaker PG, Qiu J, Wu D, Reng M, Yang Z, Yin H, Chen F.-X. Org. Biomol. Chem. 2017; 15: 7753 6a Buttke K, Niclas H.-J. J. Prakt. Chem. 1998; 340: 669 6b Kiyokawa K, Nagata T, Minakata S. Angew. Chem. Int. Ed. 2016; 55: 10458 6c Nagata T, Tamaki A, Kiyokawa K, Tsutsumi R, Yamanaka M, Minakata S. Chem. Eur. J. 2018; 24: 17027 . For a related reaction, see 6d Vita MV, Caramenti P, Waser J. Org. Lett. 2015; 17: 5832 7 Yanagisawa A, Uchiyama C, Takagi K. Synlett 2021; 32: 2085 8a Yanagisawa A, Satou T, Izumiseki A, Tanaka Y, Miyagi M, Arai T, Yoshida K. Chem. Eur. J. 2009; 15: 11450 8b Yanagisawa A, Yoshida K. Chem. Rec. 2013; 13: 117 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. Supplementary Material Supplementary Material Supporting Information
