Supporting Information

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1 Supporting Information Titanocene-Catalyzed Conjugate Reduction of α,β -Unsaturated Carbonyl Derivatives Andrew D. Kosal and Brandon L. Ashfeld* Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN Contents 1. General S-2 2. Titanium-mediated reduction of carbonyl derivatives S-2 3. Spectral data of compounds S-4 S 1

2 1. General Solvents and reagents were reagent grade and used without purification unless otherwise noted. Tetrahydrofuran (THF) and dichloromethane (DCM) was degassed, passed through a column of molecular sieves, and stored under argon. Zn (0) dust was rinsed with 1M HCl, filtered and washed thoroughly with water, acetone and ether and dried under vacuum. All reactions were carried out in oven dried glassware under nitrogen unless otherwise specified. 1 H nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz. 13 C NMR were obtained at 100 MHz. Chemical shifts are reported in parts per million (ppm, δ), and referenced from the solvent. Coupling constants are reported in Hertz (Hz). Spectral splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; comp, complex; app, apparent; and br, broad. Infrared (IR) spectra were obtained using a silicon (Si) crystal in an attenuated total reflectance (ATR) tower and reported as wavenumbers (cm -1 ). High and Low resolution mass spectrometry was obtained via electronspray ionization (ESI) technique. Analytical thin layer chromatography (TLC) was visualized with UV light and stained with either p-anisaldehyde, ceric ammonium nitrate or potassium permanganate solutions. Flash column chromatography was performed according to Still s procedure (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923). Percent yields were verified by 1 H NMR or gas chromatography (GC) with naphthalene as the internal standard. 1 H and 13 C NMR data for the known compounds 2a 1, 2c 2, 2d 3, 2e 4, 2f 5, 2g 6, 2h 7, 2i 8, 2j 9, 2m 3, 2o 10, 2q 11 and 2t 12 was consistent with the literature reported values. Aldehyde 2b and ketones 2k and 2l were commercially available. Spectral and physical properties of these ketones and aldehyde were identical with those of authentic samples. 2. Catalytic titanium reduction procedure 1 Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem., 2002, 67, Nestl, B. M.; Glueck, S. M.; Hall, M.; Kroutil, W.; Stuermer, R.; Hauer, B.; Faber, K. Eur. J. Org. Chem. 2006, Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M. Org. Lett., 2007, 9, Condon, S.; Dupre, D.; Nedelec, J. Y. Org. Lett., 2003, 5, Fox, D. J.; Pedersen, D. S.; Warren, S. Org. Biomol. Chem., 2006, 4, Purohit, A.; Radeke, H.; Azure, M.; Hanson, K.; Benetti, R. ; Su, F.; Yalamanchili, P. ; Yu, M.; Hayes, M.; Guaraldi, M.; Kagan, M.; Robinson, S.; Casebier, D. J. Med. Chem., 2008, 51, Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, Condon, S.; Dupre, D.; Falgayrac, G.; Ne de lec, J. Y. Eur. J. Org. Chem. 2002, Khanova, M. D.; Sultanova, R. M.; Zlotskii, S. S.; Dokichev, V. A.; Tomilov, Y. V. Russ. Chem. Bull. 2005, Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org. Chem. 2004, Taylor, S.K.; Bischoff, D.S.; Blankespoor, C.L.; Deck, P.A.; Harvey, S.M.; Johnson, P.L.; Marolewski, A.E.; Mork, S.W.; Motry, D.H.; Von Eenenaam, R. J. Org. Chem. 1990, Kuwajima, I.; Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1982, 104, S 2

3 Representative Procedure: 4-phenyl butan-2-one (1a). A mixture of Cp 2 TiCl 2 (2.6 mg, mmol, 5 mol%), zinc dust (33.5 mg, 0.51 mmol, 2.5 equiv.), and triethylamine hydrochloride (139 mg, 1.0 mmol, 5 equiv.) was stirred in CH 2 Cl 2 (1.5 ml) for 10. A solution of trans-4- phenyl-3-butene-2-one (30 mg, mmol) in CH 2 Cl 2 (2.5 ml) was then added via syringe. The reaction was stirred until starting material consumed as monitored by TLC (p-anisaldehyde). The mixture was quenched with saturated aqueous NH 4 Cl (10 ml). The solution was passed through celite, extracted with Et 2 O (3 x 10 ml), and the combined organic fractions were washed with saturated aqueous NaCl (30 ml), dried (MgSO 4 ) and concentrated under reduced pressure. The crude residue was purified by flash chromatography, eluting with hexanes/etoac (4:1) to give 16.7 mg (55%) of 2a as a clear colorless oil. H 1 NMR and C 13 NMR data consistent with literature values 1. Methyl 4-(3-ethoxy-3-oxopropyl) benzoate (2n). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (dt, J = 8.2, 1.8 Hz, 2 H), 7.28 (bdt, J = 8.2, 2 H), 4.13 (q, 7.1 Hz, 2 H), 3.91 (s, 3 H), 3.01 (t, 7.8 Hz, 2 H), 2.65 (t, 7.5 Hz, 2 H), 1.24 (t, 7.2 Hz, 3 H); 13 C NMR (125 MHz, CDCl 3 ) δ 172.8, 167.3, 146.3, 130.1, 128.6, 60.8, 52.3, 35.7, 31.2, 14.5; IR (neat) 3011, 2927, 1723, 1612, 1436, 1281, 1180, 1110 cm -1 ; HRMS (ESI + ); Calc d for C 13 H 16 O 4 Na: ; found: S 3

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