Synlett, Inhaltsverzeichnis Synlett 2024; 35(09): 952-956DOI: 10.1055/a-2201-7141 cluster Chemical Synthesis and Catalysis in Germany Chemoselective Reduction of Barbiturates by Photochemically Excited Flavin Catalysts Richard Foja , Alexandra Walter , Golo Storch ∗ Artikel empfehlen Abstract Artikel einzeln kaufen Alle Artikel dieser Rubrik Abstract Photocatalytic reductive cyclizations are powerful methods for obtaining structurally complex molecules. Achieving noninherent reactivity in substrates with more than one potential site of reduction is a difficult challenge. We disclose the use of flavin catalysis for the chemoselective reductive cyclization of barbiturates with additional reactive functional groups. Our method provides orthogonal selectivity in comparison to the well-established reductant samarium(II) iodide, which preferentially reduces substrate ketone groups. Flavin catalysis first leads to barbiturate reduction and allows a complete change of chemoselectivity in barbiturates with appended ketones. Additionally, flavin photocatalysis enables the reductive cyclization of substrates with appended oxime ethers in >99% yield, which is not possible with SmI2. Key words Key wordsflavin catalysis - photochemistry - chemoselectivity - reductive catalysis - barbiturates Volltext Referenzen References and Notes 1 Péter Á, Agasti S, Knowles O, Pye E, Procter DJ. Chem. Soc. Rev. 2021; 50: 5349 2 Streuff J. Synthesis 2013; 45: 281 3a Nicolaou KC, Ellery SP, Chen JS. Angew. Chem. Int. Ed. 2009; 48: 7140 3b Szostak M, Spain M, Procter DJ. Chem. Soc. Rev. 2013; 42: 9155 3c Szostak M, Fazakerley NJ, Parmar D, Procter DJ. Chem. Rev. 2014; 114: 5959 3d Heravi MM, Nazari A. RSC Adv. 2022; 12: 9944 4 Mechanistic switching was also observed when coordinating additives were used: Szostak M, Spain M, Sautier B, Procter DJ. Org. 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Tetrahedron Lett. 2016; 57: 1790 22 Analytical Data for Compound 8 White solid (25.6 mg, 94 μmol, 94% (quant. NMR yield)). TLC: Rf = 0.37 (n-pentane/EtOAc, 50/50) [KMnO4]. 1H NMR (400 MHz, acetone-d 6, 298 K): δ = 5.35 (s, 1 H, O-H3), 5.16 (s, 1 H, O-H9), 3.08 (s, 3 H, H5), 3.00 (s, 3 H, H2), 2.47–2.29 (m, 1 H, H11a), 1.88–1.77 (m, 1 H, H10a), 1.74–1.67 (m, 2 H, H6), 1.66–1.55 (m, 2 H, H10b,11b), 1.27–1.19 (m, 1 H, H7a), 1.07 (s, 4 H, H7b,12), 0.82 (t, 3 J H–H = 7.3 Hz, 3 H, H8) ppm. 13C{1H} NMR (101 MHz, acetone-d 6, 298 K): δ = 173.9 (C6), 152.7 (C1), 91.6 (C3), 82.7 (C9), 55.1 (C4), 38.4 (C6), 37.1 (C10), 30.1 (C11), 28.8 (C2), 28.1 (C5), 24.9 (C12), 18.4 (C7), 14.7 (C8) ppm. HRMS (ESI+): m/z calcd for [M + H]+ = [C13H23N2O4]+: 271.1652; found: 271.1635. IR: (ATR): ν = 3400 (br OH), 2960, 2874, 2034, 1854, 1732, 1703, 1648 (C=O), 1587, 1549, 1513, 1450, 1415, 1377, 1333, 1309, 1246, 1129, 1080, 1062, 1028, 1013, 972, 942, 882, 861, 836, 795, 755, 743, 721, 698, 656 cm–1. 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Subsequently, N,N-dimethylformamide (anhydrous, 250 μL, 0.2 M) and γ-terpinene (16 μL, 100 μmol, 2.00 equiv.) were added, and the vial was irradiated at λmax = 365 nm and a controlled reaction temperature of 15 °C for 16 h. The vial was then opened, the solution was transferred to a flask (rinsed with acetone thrice), and all volatiles were removed in vacuo. 1,3,5-Benzene tricarboxylic acid trimethyl ester (10 μmol) was added as an internal standard and the NMR spectrum was recorded. The crude compound was purified by column chromatography to afford product 7. 28 Analytical Data for Compound 7 White solid (11.1 mg, 40 μmol, 79% (96% NMR-yield)); TLC: Rf = 0.23 (n-pentane/EtOAc, 60/40) [KMnO4]. The compound was isolated as a single diastereomer. However, compound 7 was observed to contain two isomers which are assigned to an open chain (major) ‘Ha’ and lactol (minor) ‘Hb’ form. 1H NMR (400 MHz, CD2Cl2, 298 K): δ = 4.69 (br s, 1 H, C3-OH), 3.16 (s, 3 H, H6a), 3.14 (s, 3 H, H6b), 2.97 (s, 3 H, H2b), 2.88 (s, 3 H, H2a), 2.51–2.40 (m, 3 H, H8,14-1), 2.37–2.26 (m, 1 H, H11), 2.18–2.10 (m, 1 H, H7-1), 2.08 (s, 3 H, H10a), 2.05–1.93 (m, 1 H, H13-1), 1.83–1.75 (m, 1 H, H7-2), 1.73–1.63 (m, 1 H, H14-2), 1.42 (s, 3 H, H10b), 1.18–1.02 (m, 1 H, H13-2), 0.69 (d, 3 J H–H = 7.5 Hz, 3 H, H12a), 0.63 (d, 3 J H–H = 7.5 Hz, 3 H, H12b) ppm. 13C{1H} NMR (101 MHz, CD2Cl2, 298 K): δ = 210.9 (C9a), 175.1 (C5b), 172.9 (C5a), 152.3 (C1), 95.6 (C9b), 94.2 (C3b), 92.8 (C3a), 55.8 (C4a), 47.7 (C4b), 45.4 (C11b), 44.6 (C11a), 38.9 (C8a), 33.5 (C14a), 30.5 (C13b), 30.2 (C14b), 30.1 (C2b), 29.8 (C10b), 29.7 (C10a), 28.8 (C13a), 28.6 (C2a), 28.1 (C6b), 27.8 (C7b), 27.8 (C6a), 27.1 (C8b), 26.2 (C7a), 17.2 (C12a), 14.5 (C12b) ppm. HRMS (ESI+): m/z calcd for [M + H]+ = [C14H23N2O4]+: 283.1652; found: 283.1658. IR (ATR): 3346 (OH), 2960, 2877, 1733, 1684, 1649 (C=O), 1549, 1449, 1414, 1382, 1340, 1308, 1259, 1172, 1153, 1122, 1094, 1061, 1002, 961, 929, 885, 843, 755, 735, 722, 661.9 cm–1. 29a Singh AK, Bakshi RK, Corey EJ. J. Am. Chem. Soc. 1987; 109: 6187 29b Hasegawa E, Curran DP. J. Org. Chem. 1993; 58: 5008 30 For the related SmI2-mediated reduction of γ-indolylketones, see: Beemelmanns C, Nitsch D, Bentz C, Reissig H.-U. Chem. Eur. J. 2019; 25: 8780 For the related SmI2-mediated reduction of α,β-unsaturated esters in cyclic imide substrate side chain, see: 31a Shi S, Szostak M. Org. Lett. 2015; 17: 5144 31b Shi S, Lalancette R, Szostak R, Szostak M. Chem. Eur. J. 2016; 22: 11949 32 Computational study of a SmI2-mediated reduction with chelate complex intermediates: Achazi AJ, Andrae D, Reissig H.-U, Paulus B. J. Comput. Chem. 2017; 38: 2693 33a Chiara JL, Marco-Contelles J, Khiar N, Gallego P, Destabel C, Bernabe M. J. Org. Chem. 1995; 60: 6010 33b Marco-Contelles J, Gallego P, Rodríguez-Fernández M, Khiar N, Destabel C, Bernabé M, Martínez-Grau A, Chiara JL. J. Org. Chem. 1997; 62: 7397 34 On the reduced reactivity of SmI2 towards oxime ethers, see: Ning L, Li H, Lai Z, Szostak M, Chen X, Dong Y, Jin S, An J. J. Org. Chem. 2021; 86: 2907 Zusatzmaterial Zusatzmaterial Supporting Information