Chemoselective Aromatic C-H Insertion of α-diazo-β-ketoesters Catalyzed by Dirhodium(II) Carboxylates Esdrey Rodriguez-Cárdenas, a Rocío Sabala, b Moisés Romero-rtega, a Aurelio rtiz, b and Horacio F. livo* a Division of Medicinal and Natural Products Chemistry The University of Iowa, Iowa City, IA 52242 Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Pue. 72570, México. SUPPRTING INFRMATIN General Information. All moisture-sensitive reactions were carried out in oven-dried glassware under argon atmosphere. Reagents were purchased from Aldrich and used without any further purification. Dichloromethane was distilled from CaH 2 under argon. THF was distilled from Na/benzophenone under argon. ptical rotations were measured in a JASC P-1020 or a Perkin-Elmer-341 polarimeter with sodium D-line (589 nm) and are reported on a concentration (c) of grams/100 ml of solvent. Nuclear Magnetic Resonance (NMR) spectra were measured at 300 MHz on a Bruker Avance 300 or at 500 MHz on a Varian spectrometer. 1 H-NMR chemical shifts (δ) are reported in parts per million (ppm) relative to Me 4 Si (δ = 0.0 ppm) with coupling constants (J) reported in Hertz (Hz). Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad singlet (bs). 13 C-NMR are reported using 77.0 ppm (CDCl 3 ) as internal reference. Carbon signal multiplicities were determined by DEPT. High resolution mass spectra were performed at the University of Iowa Mass Spectrometry Facility. Ethyl-3-oxo-5-phenyl-pentanoate (4a) 1 : yellow oil. Rf 0.6 (8:2, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.32-7.12 (5H, m), 4.16 (2H, q, J = 7.2 Hz), 3.41 (2H, s), 2.95-2.82 (4H, m), 1.25 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 202.0 (C), 167.1 (C), 145.8 (C), 128.6 (2CH), 128.4 (2CH), 126.3 (CH), 61.4 (CH 2 ), 49.5 (CH 2 ), 44.5 (CH 2 ), 29.5 (CH 2 ), 14.1 (CH 3 ). 1 Schweizer, E. E.; Lee, K.-J. J. rg. Chem. 1982, 47, 2768-2773. S1
General procedure for the displacement of the 1,3-oxazolidin-2-thione auxiliary. 2 To a stirred mixture containing N-acyl oxazolidinethione (1 mmol) and ethyl malonate potassium salt (680 mg, 4 mmol) in anhydrous THF (10 ml) was added magnesium chloride (190 mg, 2 mmol) in one portion. Imidazole (136 mg, 2 mmol) was added and stirred at room temperature for 16 h. The reaction was diluted with Ac (15 ml) and quenched by the addition 0.5 N HCl solution (15 ml). The aqueous layer was extracted with more Ac. The organic layer was washed with a solution of aqueous sodium bicarbonate. The organic layer was dried over Na 2 S 4, filtered and concentrated under reduced pressure. The oily residue was purified by flash gel column chromatography eluting with petroleum ether ethyl acetate (4:1). (S)-Ethyl-3-oxo-5-phenyl-hexanoate (4b): amber oil, yield 76%. Rf 0.6 (8:2, petroleum ether ethyl acetate); [α] 25 D = - 41.0 (c 1.0, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.33-7.10 (5H, m), 4.2 (2H, q, J = 7.2 Hz), 3.3 (2H,s), 3.36-3.27 (1H, m), 2.85 (1H, dd, J = 17.0, 6.3 Hz), 2.76 (1H, dd, J = 17.0, 7.8 Hz), 1.24 (3H, t, J = 6.9 Hz), 1.22 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 201.6 (C), 167.1 (C), 145.8 (C), 128.6 (2CH), 126.5 (2CH), 126.3 (CH), 61.4 (CH 2 ), 51.2 (CH 2 ), 49.8 (CH 2 ), 35.1 (CH), 21.9 (CH 3 ), 14.1 (CH 3 ). (S)-Ethyl-3-oxo-5-p-tolyl-hexanoate (4c): amber oil, yield 79%. Rf 0.6 (8:2, petroleum ether ethyl acetate); [α] 25 D = - 15.0 (c 1.0, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.1 (4H, s), 4.2 (2H, q, J = 7.2 Hz), 3.3 (2H,s), 3.29 (1H, sext, J = 6.9 Hz ), 2.85 (1H, dd, J = 17.1, 6.3 Hz), 2.76 (1H, dd, J = 16.8, 7.8 Hz), 2.3 (3H, s), 1.25 (3H, d, J = 7.2 Hz), 1.23 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 201.6 (C), 166.9 (C), 142.6 (C), 135.7 (C), 129.1 (2CH), 126.5 (2CH), 61.2 (CH 2 ), 51.1 (CH 2 ), 49.7 (CH 2 ), 34.6 (CH), 21.8 (CH 3 ), 20.8 (CH 3 ), 13.9 (CH 3 ). Ethyl-3-oxo-5-phenyl-heptanoate (4d): amber oil, yield 79%. Rf 0.6 (8: 2, petroleum ether ethyl acetate). 1 H NMR (300 MHz, CDCl3) δ 7.35-7.10 (5H, m), 4.13 (2H, q, J = 7.2 Hz), 3.28 (2H, s), 3.05 (1H, quintet, J = 7.2 2 Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.; Carroll, K. A.; van Alpen, S. rg. Lett. 2004, 6, 2317-2320. S2
Hz), 2.84 (2H, d, J = 7.5 Hz), 1.8-1.48 (2H, m), 1.22 (3H, t, J = 7.5 Hz), 0.77 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 201.6 (C), 166.9 (C), 143.8 (C), 128.3 (2CH), 127.4 (2CH), 126.3 (CH), 61.1 (CH 2 ), 49.7 (CH 2 ), 49.6 (CH 2 ), 42.4 (CH), 29.07 (CH 2 ), 13.9 (CH 3 ), 11.8 (CH 3 ). Ethyl-3-oxo-6-methyl-5-phenyl-heptanoate (4e): oil, yield 80%. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.28-7.24 (2H, m), 7.18 (1H, tt, J = 7.3, 2.0 Hz), 7.14-7.10 (2H, m), 4.12 (2H, q, J = 7.0 Hz), 3.23 (2H, s), 2.98-2.87 (3H, m), 1.92-1.80 (1H, m), 1.22 (3H, t, J = 7.2 Hz), 0.93 (3H, d, J = 6.4 Hz), 0.74 (3H, d, J = 6.8 Hz); 13 C-NMR (125 MHz, CDCl 3 ) δ 202.0 (C), 167.0 (C), 142.9 (C), 128.2 (4CH), 126.4 (CH), 61.2 (CH 2 ), 49.9 (CH 2 ), 47.7 (CH), 46.9 (CH 2 ), 33.1 (CH), 20.7 (CH 3 ), 20.2 (CH 3 ), 14.0 (CH 3 ). Ethyl-3-oxo-5,5-diphenylpentanoate (4f): oil, yield 79%. Rf 0.6 (8:2, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.36-7.08 (10H, m), 4.6 (1H, t, J = 7.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 3.32 (2H, s), 3.3 (2H, d, J = 7.8 Hz), 1.21 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 200.6 (C), 166.8 (C), 143.4 (2C), 128.5 (4CH), 127.6 (4CH), 126.4 (2CH), 61.3 (CH 2 ), 49.74 (CH 2 ), 48.7 (CH 2 ), 45.6 (CH), 13.9 (CH 3 ). General Procedure for the Regitz Reaction. To a solution of β-ketoester (1.5 mmol) in acetonitrile (10 ml) was added p-acetoamidenbenzensulfonyl azide (0.405 g, 1 mmol) and 1,8-diazabicyclo[5.4.0]- undec-7-ene (25 L, 0.1 mmol). The resulting orange slurry was stirred for 4 h at room temperature. The oily residue was purified by flash gel column chromatographic eluting with petroleum ether ethyl acetate (9:1). Ethyl-2-diazo-3-oxo-5-phenyl-pentanoate (5a): yellow oil, yield 87%. Rf 0.36 (9:1, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.33-7.15 (5H, m), 4.28 (2H, q, J = 7.2 Hz), 3.18 (2H, t, J = 7.2 Hz), 2.96 (2H, t, 7.5 Hz), 1.31 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 192.05 (C), 161.4 (C), 140.9 (C), 128.6 (2CH), 128.5 (2CH), 126.2 (CH), 76.1 (C), 61.5 (CH 2 ), 41.9 (CH 2 ), 30.3 (CH 2 ), 14.5 (CH 3 ). S3
(S)-Ethyl-2-diazo-3-oxo-5-fenyl-hexanoate (5b): oil, yield 79%. Rf 0.37 (9:1, petroleum ether ethyl acetate); [α] 25 D = - 68 (c 1.00, CHCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 7.33-7.12 (5H, m), 4.26 (2H, q, J = 7.2 Hz), 3.4 (1H, sext, J = 6.9 Hz), 3.26 (1H, dd, J = 16.0, 6.6 Hz), 3.07 (1H, dd, J = 16.0, 7.8 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.29 (3H, d, J = 6.9 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 191.6 (C), 161.3 (C), 146.1 (C), 128.4 (2CH), 126.9 (2CH), 126.3 (CH), 76.1 (C), 61.4 (CH 2 ), 47.9 (CH 2 ), 35.7 (CH), 21.9 (CH 3 ), 14.4 (CH 3 ). (S)-Ethyl-2-diazo-3-oxo-5-p-tolyl-hexanoate (5c): oil, yield 95%. Rf 0.4 (9:1, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.12 (4H, q, J = 8.1Hz), 4.28 (2H, q, J = 7.2 Hz), 3.35 (1H, sext, J = 6.9 Hz), 3.24 (1H, dd, J = 16.2, 6.9 Hz), 3.05 (1H, dd, J = 15.6, 7.2 Hz), 2.3 (1H, s), 1.4 (3H, d, J = 7.2 Hz), 1.27 (3H, t, J = 7.5 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 191.6 (C), 161.3 (C), 143.1 (C), 135.7 (C), 129.1 (2CH), 126.8 (2CH), 76.3 (C), 61.4 (CH 2 ), 47.9 (CH 2 ), 35.4 (CH), 22.1 (CH 3 ), 21.0 (CH 3 ),14.3 (CH 3 ). Ethyl-2-diazo-3-oxo-5-phenylheptanoate (5d): oil, yield 92%. Rf 0.41 (9:1, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.13 (5H, m), 4.27 (2H, q, J = 7.2 Hz), 3.29 (1H, dd, J = 18.0, 10.2 Hz ), 3.11 (1H, dd, J = 18.0, 6.0 Hz), 3.19 3.08 (1H, m), 1.79-1.53 (2H, m), 1.30 (3H, t, J = 7.5 Hz), 0.77 (3H, t, J = 6.9 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 191.5 (C), 161.2 (C), 144.2 (C), 128.2 (2CH), 127.6 (2CH), 126.2 (CH), 76.2 (C), 61.2 (CH 2 ), 46.3 (CH 2 ), 43 (CH), 29.2 (CH 2 ), 14.2 (CH 3 ), 11.9 (CH 3 ). Ethyl-2-diazo-3-oxo-6-methyl-5-phenyl-heptanoate (5e): oil, yield 94%. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.26-7.11 (5H, m), 4.27 (2H, q, J = 7.0 Hz), 3.45 (1H, dd, J = 16.2, 9.8 Hz), 3.16 (1H, dd, J = 16.2, 4.9 Hz), 3.06 (1H, ddd, J = 9.8, 7.4, 4.9 Hz), 1.88 (1H, sept, J = 6.5 Hz), 1.30 (3H, t, J = 7.0 Hz), 0.95 (3H, d, J = 6.8 Hz), 0.76 (3H, d, J = 6.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ) δ 191.7 (C), 161.2 (C), 143.0 (C), 128.3 (2CH), 127.8 (2CH), 126.0 (CH), 76.1 (C), 61.1 (CH 2 ), 47.8 (CH 2 ), 43.1 (CH), 33.1 (CH), 20.6 (CH 3 ), 20.2 (CH 3 ), 14.2 (CH 3 ). S4
61.3 (CH 2 ), 46.02 (CH), 45.3 (CH 2 ), 14.3 (CH 3 ). Ethyl-2-diazo-3-oxo-5,5-diphenylpentanoate (5f): white solid, yield 91.4%. Rf 0.36 (9:1, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 7.37-7.06 (10H, m), 4.71 (1H, t, J = 7.5 Hz), 4.26 (2H, q, J = 7.2 Hz), 3.67 (2H, d, J = 6.9), 1.28 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 190.6 (C), 161.2 (C), 143.4 (2C), 128.4 (4CH), 127.7 (4CH), 126.3 (2CH), 76.4 (C), General Procedure for the aromatic C-H insertion. A solution of α-diazo-β-ketoester (0.5 mmol) in CH 2 Cl 2 (5 ml) is added via syringe pump at a rate of 5-10 ml/h to a stirred solution of rhodium (II) catalyst (5 mg) in anhydrous CH 2 Cl 2 (5 ml) at room temperature under a nitrogen atmosphere. After the addition is complete, the reaction mixture is stirred for 3 h. The solution is concentrated under reduced pressure. A sample of the crude reaction mixture is analyzed by NMR. Products are purified by silica gel chromatography eluting with petroleum ether ethyl acetate, 98:2. Ethyl 3,4-dihydro-2-hydroxy-naphthalene-1-carboxylate (6a): yellow oil. Rf 0.65 (8:2, petroleum ether ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 13.43 (1H, s), H 7.72 (1H, d, J = 8 Hz), 7.33-7.15 (3H, m), 4.39 (2H, q, J = 7.2 Hz), 2.82 (2H, t, J = Et 7.2 Hz), 2.54 (2H, t, J = 7.2 Hz), 1.41 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 178.3 (C), 172.1 (C), 133.2 (C), 131.5 (C), 127.1 (CH), 126.3 (CH), 125.8 (CH), 124.9 (CH), 100 (C), 61.0 (CH 2 ), 29.5 (CH 2 ), 27.7 (CH 2 ), 14.2 (CH 3 ); EI-HRMS calc. for C 13 H 13 3 : 217.0859. Found 217.0858. Ethyl-3,4-dihydro-2-hydroxy-4-methylnaphtalene-1-carboxylate (6b): Rf 0.38 (95:5, petroleum ether-ethyl acetate); [α] D = - 38 (c 0.25, CHCl 3 ); 1 H NMR (300 H MHz, CDCl 3 ) δ 13.42 (1H, s), 7.75 (1H, d, J = 7.8 Hz), 7.23-7.06 (3H, m), 4.48 - Et 4.31 (2H, m), 2.97 (1H, sext, J = 6.9 Hz), 2.68 (1H, dd, J = 16.5, 6.0 Hz), 2.32 (1H, dd, J = 16.5, 7.0 Hz), 1.4 (3H, t, J = 7.2 Hz), 1.25 (3H, d, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 176.9 (C), 172.0 (C), 137.8 (C), 130.6 (C), 126.2 (CH), 126.0 (CH), 125.7 (CH), 125.2 (CH), 99.3 (C), 61.0 (CH 2 ), 36.8 (CH 2 ), 32.1 (CH), 19.1 (CH 3 ), 14.2 (CH 3 ). S5
Ethyl-3,4-dihydro-2-hydroxy-4,7-dimethylnaphtalene-1-carboxylate (6c): oil. Rf 0.4 (95:5, petroleum ether-ethyl acetate); [α] D = - 45.9 (c 1.0, CHCl 3 ); 1 H NMR H (300 MHz, CDCl 3 ) δ 13.4 (1H, s), 7.58 (1H, s), 7.05 (1H, d, J = 7.8 Hz), 6.9 (1H, d, Et J = 7.5 Hz), 4.48 4.30 (2H, m), 2.94 (1H, sext, J = 6.9 Hz), 2.66 (1H, dd, J = 5.7, 16.8 Hz), 2.32 (3H, s); 2.3 (1H, dd, J = 6.9, 17.7 Hz), 1.42 (3H, t, J = 7.2 Hz), 1.25 (3H, d, J = 6.9 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 177.0 (C), 172.0 (C), 135.6 (C), 135.0 (C), 130.6 (C), 126.9 (CH), 125.8 (CH), 125.6 (CH), 99.3 (C), 61.0 (CH 2 ), 37.1 (CH 2 ), 31.8 (CH), 21.5 (CH 3 ), 19.2 (CH 3 ), 14.2 (CH 3 ); IR υ max. : 2963, 2925, 1720, 1632, 1599, 1319, 1227, 1045 cm -1 ; EI-HRMS Calc. for C 15 H 18 3 : 246.1256, Found: 246.1277. Ethyl-3,4-dihydro-2-hydroxy-4-ethylnaphtalene-1-carboxylate (6d): Rf 0.41 (95:5, petroleum ether-ethyl acetate); [α] D = - 27.0 (c 0.2, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ 13.46 (1H, s), 7.76 (1H, d, J = 7.8 Hz), 7.22-7.15 (2H, m), 7.10 (1H, ), 4.51 H - 4.27 (2H, m), 2.78 (1H, dd, J = 16.5, 6.3 Hz), 2.70 2.60 (1H, m), 2.43 (1H, dd, J = Et 16.5, 3.6 Hz), 1.71 1.48 (2H, m), 1.42 (3H, t, J = 7.2 Hz), 0.92 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 176.9 (C), 170.5 (C), 136.7 (C), 130.6 (C), 127.4 (CH), 126.3 (CH), 126.1 (CH), 124.8 (CH), 99.1 (C), 60.9 (CH 2 ), 39.5 (CH), 34.2 (CH 2 ), 25.8 (CH 2 ), 14.3 (CH 3 ), 11.9 (CH 3 ). Ethyl-3,4-dihydro-2-hydroxy-4-i-propylnaphtalene-1-carboxylate (6e): [α] D = - 33 (c 0.2, CHCl 3 ); 1 H-NMR (500 MHz, CDCl 3 ) δ 13.42 (1H, s), 7.75 (1H, d, J = 8 Hz), 7.25-7.14 (2H, m), 7.06 (1H, d, J = 6.8 Hz), 4.45 (1H, dq, J = 10.8, 7.2 Hz), 4.32 (1H, dq, H J = 10.8, 7.2 Hz), 2.71 (1H, dd, J = 16.6, 6.3 Hz), 2.61 (1H, dd, J = 16.6, 2.8 Hz), 2.38 C 2 Et (1H, ddd, J = 6.3, 6.0, 2.8 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.91-1.82 (1H, m), 0.97 (3H, d, J = 7.0 Hz), 0.85 (3H, t, J = 7.0 Hz); 13 C-NMR (75 MHz, CDCl 3 ) δ 177.2 (C), 171.9 (C), 136.2 (C), 131.0 (C), 128.6 (CH), 126.3 (CH), 126.1 (CH), 124.4 (CH), 99.5 (C), 60.9 (CH 2 ), 44.9 (CH), 32.4 (CH 2 ), 29.1 (CH), 21.6 (CH 3 ), 20.2 (CH 3 ), 14.2 (CH 3 ). S6
(±)-Ethyl-3,4-dihydro-2-hydroxy-4-phenylnaphtalene-1-carboxylate (6f): oil. Rf 0.36 (95:5, petroleum ether-ethyl acetate); 1 H NMR (300 MHz, CDCl 3 ) δ 13.4 (1H, s), 7.81 (1H, d, J = 8.1 Hz), 7.39-7.11 (6H, m), 7.04 (1H, td, J = 7.5, 1.5 Hz), 6.84 (1H, d, J = 7.2 Hz), 4.46-4.33 (2H, m), 4.15 (1H, t, J = 7.5 Hz), 2.87 (2H, q, J = 3.3 Hz), H 1.42 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 176.5 (C), 171.8 (C), 141.7 Et (C), 135.7 (C), 131.5 (C), 128.5 (2CH), 128.1 (2CH), 127.4 (CH), 126.8 (CH), 126.6 (CH), 126.0 (CH), 125.1 (CH), 100.0 (C), 61.1 (CH 2 ), 43.2 (CH), 36.6 (CH 2 ), 14.2 (CH 3 ). Dimer 7. 1 H-NMR (CDCl 3, 300 MHz, mixture of diastereomers) δ 7.29 7.15 (10H, m), 4.6 (2H, s), 4.20 (4H, q, J = 7.2 Hz), 3.18-2.83 (8H, m), Et 1.23 (6H, t, J = 7.2 Hz); 13 C-NMR (CDCl 3, 75 MHz, major diastereomer is reported) δ 201.1 (2C), 166.2 (2C), 140.5 (2C), 128.4 (4CH), 128.3 (4CH), 126.2 (2CH), 83.6 (2CH), 62.3 (2CH 2 ), 40.7 (2CH 2 ), 28.9 (2CH 2 ), 13.9 (2CH 3 ). C 2 Et Ethyl (4R, 5S)-5-methyl-2-oxo-4-phenyl-cyclopentane carboxylic acid (8): 1 H-NMR (CDCl 3, 300 MHz) δ 7.39 7.14 (5H), 4.26 (2H, q, J = 7.0 Hz), 3.00 (1H, d, J = 12.2 Hz), 2.90 2.50 (4H, m), 1.32 (3H, t, J = 7.1 Hz), 1.07 (3H, d, J = 6.2 Hz); 13 C-NMR (CDCl 3, 75 MHz) δ 209.3 (C), 168.8 (C), 140.3 (C), 128.8 (2CH), 127.4 (2CH), 127.2 (CH), 63.8 (CH), 61.5 (CH 2 ), 48.4 (CH), 47.3 (CH 2 ), 43.2 (CH), 16.8 (CH 3 ), 14.2 (CH 3 ). S7