Ruthenium-Catalyzed C H Oxygenation on Aryl Weinreb Amides

Transcription

1 Supporting Information Ruthenium-Catalyzed C H xygenation on Aryl Weinreb Amides Fanzhi Yang and Lutz Ackermann* Institut für rganische und Biomolekulare Chemie Georg-August-Universität Tammannstrasse 2, Göttingen, Germany Lutz.Ackermann@chemie.uni-goettingen.de Contents General Remarks S-2 Representative Procedure S-2 Preparation and Characterization Data for Compounds 2 S-3 Competition Experiments S-10 Studies with Labeled Substrate [D 5 ]-1a S-13 Synthesis of ortho-hydroxybenzaldehyde 3a S-14 References S-15 1 H-, and 13 C-Spectra for Compounds 2 and 3 S-16 1

2 General Remarks Catalytic reactions were carried out under an ambient atmosphere of air using pre-dried glassware. The following starting materials were synthesized according to previously described methods: 1a, 1 1b 1h, 2 and 1i 1q. 1 ther chemicals were obtained from commercial sources, and were used without further purification. Yields refer to isolated compounds, estimated to be > 95% pure as determined by 1 H-MR. TLC: Macherey- agel, TLC plates Alugram Sil G/UV254. Detection under UV light at 254 nm. Chromatography: Separations were carried out on rck Silica 60 ( mm, mesh ASTM). All IR spectra were recorded on a Bruker FT-IR Alpha device. MS: EI-MS: Finnigan MAT 95, 70 ev; DCI-MS: Finnigan MAT 95, 200 ev, reactant gas H 3 ; ESI-MS: Finnigan LCQ. High resolution mass spectrometry (HRMS): APEX IV 7T FTICR, Bruker Daltonic. M.p.: Stuart SMP3 melting point apparatus, all values are uncorrected. 1 H-, 13 C- and 19 F-MR spectra were recorded at 300 ( 1 H), 75 { 13 C, APT (Attached Proton Test)} and 283 MHz ( 19 F), respectively, on Varian Unity-300 and AMX 300 instruments in CDCl 3 solutions, chemical shifts (δ) are given in ppm. Representative Procedure: Ruthenium-Catalyzed C H xygenation on Aryl Weinreb Amides: -thoxy--methylbenzamide (1a) (83 mg, 0.50 mmol), [RuCl 2 (p-cymene)] 2 (7.7 mg, 2.5 mol %), PhI(Ac) 2 (161 mg, 0.50 mmol), and TFA/TFAA (2.0 ml, 3/1) were placed in a 25 ml-schlenk tube under an ambient atmosphere of air. The tube was sealed tightly and the reaction mixture was stirred at 50 C for 16 h. At ambient temperature, aqueous ahc 3 (25 ml) was added and the mixture was extracted with EtAc (3 25 ml). The combined organic phase was washed with brine (50 ml) and dried over a 2 S 4. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel (n pentane/etac: 5/1) to yield 2a (76 mg, 84%) as a pale green liquid. 2

3 H 2-Hydroxy--methoxy--methylbenzamide (2a): 1 H-MR δ = (s, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.36 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.84 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 3.64 (s, 3H), 3.40 (s, 3H). 13 C-MR δ = (C q ), (C q ), (CH), (CH), (CH), (CH), (C q ), 61.3 (CH 3 ), 34.2 (CH 3 ). IR (neat): 2935, 1625, 1589, 1452, 755 cm -1. MS (EI) m/z (relative intensity): 181 ([M + ] 27), 121 (100), 93 (30), 65 (30). HR-MS (EI) m/z calcd for C 9 H , found The spectral data are in accordance with those reported in the literature. 3 H Et -Ethyl-2-hydroxy--methoxybenzamide (2b): The representative procedure was followed using -ethyl--methoxybenzamide (1b) (90 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 5/1) yielded 2b (77 mg, 78%) as a colorless liquid. 1 H MR δ = (s, 1H), 7.91 (dd, J = 7.9, 1.5 Hz, 1H), 7.37 (ddd, J = 8.3, 7.3, 1.7 Hz, 1H), (m, 1H), (m, 1H), 3.84 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13 C MR δ = (C q ), (C q ), (CH), (CH), (CH), (CH), (C q ), 61.8 (CH 3 ), 42.0 (CH 2 ), 12.4 (CH 3 ). IR (neat): 2933, 1626, 1582, 1452, 1010, 756 cm -1. MS (EI) m/z (relative intensity): 195([M + ] 25), 121 (100), 93 (28), 65 (28). HR MS (EI) m/z calcd for C 10 H , found Ethyl-2-hydroxy--methoxy-4-methylbenzamide (2c): The representative procedure was followed using -ethyl--methoxy-4-methylbenzamide (1c) (97 mg, 0.50 mmol). Purification by column chromatography (n-pentane/etac: 10/1) yielded 2c (81 mg, 3

4 77%) as a colorless liquid. 1 H-MR δ = (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), (m, 1H), 6.65 (ddd, J = 8.3, 1.8, 0.5 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 2.32 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13 C-MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (C q ), 61.7 (CH 3 ), 42.0 (CH 2 ), 21.6 (CH 3 ), 12.4 (CH 3 ). IR (neat): 2936, 1633, 1582, 1447, 1253, 807 cm -1. MS (EI) m/z (relative intensity): 209 ([M + ] 9), 135 (100), 107 (12), 77 (27). HR-MS (EI) m/z calcd for C 11 H , found F H Et -Ethyl-4-fluoro-2-hydroxy--methoxybenzamide (2d): The representative procedure was followed using -ethyl-4-fluoro--methoxybenzamide (1d) (99 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 10/1) yielded 2d (80 mg, 75%) as a colorless liquid. 1 H MR δ = (s, 1H), 8.02 (dd, J = 9.1, 6.7 Hz, 1H), 6.67 (dd, J = 10.4, 2.7 Hz, 1H), 6.55 (ddd, J = 9.1, 8.0, 2.7 Hz, 1H), 3.83 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13 C MR (75 MHz, CDCl 3 ) δ = (C q ), (C q, J = Hz), (C q, J = 13.6 Hz), (CH, J = 10.9 Hz), (C q, J = 2.9 Hz), (CH, J = 22.1 Hz), (CH, J = 23.7 Hz), 61.7 (CH 3 ), 41.6 (CH 2 ), 12.3 (CH 3 ). 19 F MR (283 MHz, CDCl 3 ) δ = (ddd, J = 10.4, 8.0, 6.8 Hz). IR (neat): 2938, 1598, 1451, 1262, 977 cm -1. MS (EI) m/z (relative intensity): 213 ([M + + ] 7), 139 (100), 111 (8), 83 (12). HR MS (EI) m/z calcd for C 10 H 12 F , found H n-pr 2-Hydroxy--methoxy--n-propylbenzamide (2e): The representative procedure was followed using -methoxy--n-propylbenzamide (1e) (97 mg, 0.50 mmol). Purification by column chromatography (n-pentane/etac: 10/1) yielded 2e (77 mg, 74%) as a colorless liquid. 1 H-MR δ = (s, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 4

5 1H), 7.37 (ddd, J = 8.4, 7.2, 1.7 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.84 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), (m, 2H), 3.61 (s, 3H), (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13 C-MR δ = (C q ), (C q ), (CH), (CH), (CH), (CH), (C q ), 61.6 (CH 3 ), 48.1 (CH 2 ), 20.5 (CH 2 ), 11.2 (CH 3 ). IR (neat): 2965, 2934, 1626, 1583, 1452, 756 cm -1. MS (EI) m/z (relative intensity): 209 ([M + ] 25), 121 (100), 93 (22), 65 (27). HR-MS (EI) m/z calcd for C 11 H , found H n-bu -n-butyl-2-hydroxy--methoxybenzamide (2f): The representative procedure was followed using -n-butyl--methoxybenzamide (1f) (104 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 10/1) yielded 2f (84 mg, 75%) as a pale yellow liquid. 1 H MR δ = (s, 1H), 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.37 (ddd, J = 8.3, 7.2, 1.7 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.84 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 3.79 (t, J = 7.3 Hz, 2H), 3.61 (s, 3H), (m, 2H), (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13 C MR δ = (C q ), (C q ), (CH), (CH), (CH), (CH), (C q ), 61.6 (CH 3 ), 46.2 (CH 2 ), 29.1 (CH 2 ), 19.9 (CH 2 ), 13.7 (CH 3 ). IR (neat): 2958, 2933, 1627, 1584, 1454, 756 cm -1. MS (EI) m/z (relative intensity): 223 ([M + ] 10), 121 (100), 93 (12), 65 (11). HR MS (EI) m/z calcd for C 12 H , found Benzyl-2-hydroxy--methoxybenzamide (2g): The representative procedure was followed using -benzyl--methoxybenzamide (1g) (121 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 10/1) yielded 2g (83 mg, 64%) as a colorless liquid. 1 H MR δ = (s, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), (m, 6H), (m, 1H), 6.84 (ddd, J = 8.2, 7.3, 1.3 Hz, 1H),

6 (s, 2H), 3.58 (s, 3H). 13 C MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (C q ), 62.2 (CH 3 ), 50.5 (CH 2 ). IR (neat): 2926, 1626, 1582, 1447, 1249, 756 cm -1. MS (EI) m/z (relative intensity): 257 ([M + ] 13), 226 (15), 121 (100), 91 (48), 65 (35). HR MS (EI) m/z calcd for C 15 H , found H Et Et -Ethoxy--ethyl-2-hydroxybenzamide (2h): The representative procedure was followed using -ethoxy--ethylbenzamide (1h) (97 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 10/1) yielded 2h (80 mg, 76%) as a colorless liquid. 1 H MR δ = (s, 1H), 7.96 (dd, J = 8.1, 1.7 Hz, 1H), 7.36 (ddd, J = 8.4, 7.2, 1.7 Hz, 1H), (m, 1H), 6.83 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 3.82 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13 C MR δ = (C q ), (C q ), (CH), (CH), (CH), (CH), (C q ), 70.2 (CH 2 ), 42.3 (CH 2 ), 13.3 (CH 3 ), 12.5 (CH 3 ). IR (neat): 2980, 2925, 1627, 1582, 1451, 1251, 1019, 756 cm -1. MS (EI) m/z (relative intensity): 209 ([M + ] 18), 121 (100), 93 (22), 65 (30). HR MS (EI) m/z calcd for C 11 H , found H 2-Hydroxy--methoxy-,4-dimethylbenzamide (2i): The representative procedure was followed using -methoxy-,4-dimethylbenzamide (1i) (90 mg, 0.50 mmol). Purification by column chromatography (n-pentane/etac: 10/1) yielded 2i (74 mg, 76%) as a pale yellow liquid. 1 H-MR δ = (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 0.7 Hz, 1H), (m, 1H), 3.64 (s, 3H), 3.39 (s, 3H), 2.32 (s, 3H). 13 C-MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (C q ), 61.2 (CH 3 ), 34.2 (CH 3 ), 21.8 (CH 3 ). IR (neat): 2922, 1633, 6

7 1583, 1430, 808 cm -1. MS (EI) m/z (relative intensity): 195 ([M + ] 23), 169 (20), 135 (100), 107 (26), 77 (30). HR-MS (EI) m/z calcd for C 10 H , found Et H 4-Ethyl-2-hydroxy--methoxy--methylbenzamide (2j): The representative procedure was followed using 4-ethyl--methoxy--methylbenzamide (1j) (97 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 6/1) yielded 2j (81 mg, 78%) as a pale yellow liquid. 1 H MR δ = (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 6.68 (dd, J = 8.3, 1.5 Hz, 1H), 3.65 (s, 3H), 3.39 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13 C MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (C q ), 61.1 (CH 3 ), 34.1 (CH 3 ), 28.8 (CH 2 ), 14.7 (CH 3 ). IR (neat): 2966, 2932, 1631, 1583, 973cm -1. MS (EI) m/z (relative intensity): 209 ([M + ] 6), 149 (100), 91 (8), 77 (9). HR MS (EI) m/z calcd for C 11 H , found (Trifluoromethyl)-2-hydroxy--methoxy--methylbenzamide (2k): The representative procedure was followed using 4-(trifluoromethyl)--methoxy-methylbenzamide (1k) (117 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 4/1) yielded 2k (91 mg, 73%) as a green solid. M. p. = C. 1 H MR δ = (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), (m, 1H), (m, 1H), 3.65 (s, 3H), 3.43 (s, 3H). 13 C MR δ = (C q ), (C q ), (C q, J = 32.8 Hz), (CH), (C q, J = Hz), (C q ), (CH, J = 3.9 Hz), (CH, J = 3.6 Hz), 61.5 (CH 3 ), 33.7 (CH 3 ). 19 F MR (283 MHz, CDCl 3 ) δ = (S). IR (neat): 2923, 1593, 1425, 1329, 925 cm -1. 7

8 MS (EI) m/z (relative intensity): 249 ([M + ] 27), 189 (100), 161 (40), 113 (19), 61 (19). HR MS (EI) m/z calcd for C 10 H 10 F , found Fluoro-2-hydroxy--methoxy--methylbenzamide (2l): The representative procedure was followed using 4-fluoro--methoxy--methylbenzamide (1l) (92 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 5/1) yielded 2l (79 mg, 79%) as a pale green solid, M. p. = C. 1 H MR δ = (s, 1H), 8.05 (dd, J = 9.1, 6.7 Hz, 1H), 6.67 (dd, J = 10.4, 2.7 Hz, 1H), 6.55 (ddd, J = 9.1, 8.1, 2.7 Hz, 1H), 3.65 (s, 3H), 3.40 (s, 3H). 13 C MR δ = (C q ), (C q, J = Hz), (C q, J = 13.8 Hz), (CH, J = 11.0 Hz), (C q, J = 2.8 Hz), (CH, J = 22.1 Hz), (CH, J = 23.8 Hz), 61.1 (CH 3 ), 33.8 (CH 3 ). 19 F MR (283 MHz, CDCl 3 ) δ = - ( ) (m). IR (neat): 2938, 1622, 1597, 1265, 967 cm -1. MS (EI) m/z (relative intensity): 199 ([M + ] 22), 139 (100), 111 (27), 83 (30), 57 (20). HR MS (EI) m/z calcd for C 9 H 10 F , found Chloro-2-hydroxy--methoxy--methylbenzamide (2m): The representative procedure was followed using 4-chloro--methoxy--methylbenzamide (1m) (100 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 5/1) yielded 2m (92 mg, 85%) as an off-white solid. M. p. = C. 1 H MR δ = (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 8.7, 2.2 Hz, 1H), 3.64 (s, 3H), 3.40 (s, 3H). 13 C MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (C q ), 61.4 (CH 3 ), 34.0 (CH 3 ). IR (neat): 2934, 1621, 1572, 1458, 915 cm -1. MS (EI) m/z (relative intensity): 215 ([M + ] 10), 155 (100), 127 (12), 99 (15). HR MS (EI) m/z calcd for C 9 H 10 Cl , found

9 2-Hydroxy-4-iodo--methoxy--methylbenzamide (2n): The representative procedure was followed using 4-iodo--methoxy--methylbenzamide (1n) (146 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 5/1) yielded 2n (123 mg, 80%) as a pale yellow liquid. 1 H MR δ = (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.6, 1.8 Hz, 1H), 3.64 (s, 3H), 3.39 (s, 3H). 13 C MR δ = (C q ), (C q ), (CH), (CH), (CH), (C q ), (C q ), 61.3 (CH 3 ), 33.8 (CH 3 ). IR (neat): 2925, 1617, 1570, 853 cm -1. MS (EI) m/z (relative intensity): 307 ([M + ] 26), 247 (100), 120 (30), 63 (21). HR MS (EI) m/z calcd for C 9 H 10 I , found (Chloromethyl)-2-hydroxy--methoxy--methylbenzamide (2o): The representative procedure was followed using 4-(chloromethyl)--methoxy-methylbenzamide (1o) (107 mg, 0.50 mmol). Purification by column chromatography (n pentane/etac: 4/1) yielded 2o (70 mg, 61%) as a pale green liquid. 1 H MR (300 MHz, CDCl 3 ) δ = (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.01 (s, 1H), (m, 1H), 4.52 (s, 2H), 3.65 (s, 3H), 3.41 (s, 3H). 13 C MR δ = (C q ), (C q ), (C q ), (CH), (CH), (CH), (C q ), 61.3 (CH 3 ), 45.3 (CH 2 ), 33.9 (CH 3 ). IR (neat): 2936, 1632, 1584, 1425, 714 cm -1. MS (EI) m/z (relative intensity): 229 ([M + ] 20), 169 (100), 134 (38), 105 (30), 77 (28). HR MS (EI) m/z calcd for C 10 H 12 Cl , found

10 Intramolecular Competition Experiment: Site-selectivity with meta-substituted Weinreb Amides 1. 2-Hydroxy--methoxy-,5-dimethylbenzamide (2p') and 2-Hydroxy--methoxy-,3-dimethylbenzamide (2p''): The representative procedure was followed using - methoxy-,3-dimethylbenzamide (1p) (90 mg, 0.50 mmol). Purification by column chromatography (n-pentane/etac: 6/1) yielded 2p' (76 mg, 78%) and 2p'' (3 mg, 3%) both as colorless liquids. 2-Hydroxy--methoxy-,5-dimethylbenzamide (2p'): 1 H MR δ = (s, 1H), 7.71 (s, 1H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.40 (s, 3H), 2.28 (s, 3H). 13 C MR δ = (C q ), (C q ), (CH), (CH), (C q ), (CH), (C q ), 61.3 (CH 3 ), 34.3 (CH 3 ), 20.8 (CH 3 ). IR (neat): 2928, 1632, 1579, 1485, 1247, 822 cm -1. MS (EI) m/z (relative intensity): 195 ([M + ] 29), 135 (100), 107 (30), 77 (31). HR MS (EI) m/z calcd for C 10 H , found Hydroxy--methoxy-,3-dimethylbenzamide (2p''): 1 H-MR δ = (s, 1H), 7.78 (dd, J = 8.2, 1.1 Hz, 1H), (m, 1H), (m, 1H), 3.64 (s, 3H), 3.41 (s, 3H), 2.26 (s, 3H). 13 C-MR δ = (C q ),

11 (C q ), (CH), (CH), (C q ), (CH), (C q ), 61.2 (CH 3 ), 34.3 (CH 3 ), 16.0 (CH 3 ). IR (neat): 2921, 1603, 1425, 1253, 1014, 802 cm -1. MS (EI) m/z (relative intensity): 195 ([M + + ] 9), 135 (100), 77 (14). HR-MS (EI) m/z calcd for C 10 H , found Fluoro-2-hydroxy--methoxy--methylbenzamide (2q') and 3-Fluoro-2-hydroxy- -methoxy--methylbenzamide (2q''): The representative procedure was followed using 3-fluoro--methoxy--methylbenzamide (1q) (92 mg, 0.50 mmol). Purification by column chromatography (n-pentane/etac: 5/1) yielded 2q' (51 mg, 51%) and 2q'' (24 mg, 24%) both as colorless liquids. H F 5-Fluoro-2-hydroxy--methoxy--methylbenzamide (2q'): 1 H MR (300 MHz, CDCl 3 ) δ = (s, 1H), 7.72 (dd, J = 10.1, 3.1 Hz, 1H), 7.12 (ddd, J = 9.1, 7.7, 3.1 Hz, 1H), 6.94 (dd, J = 9.1, 4.9 Hz, 1H), 3.66 (s, 3H), 3.40 (s, 3H). 13 C MR δ = (C q, J = 2.5 Hz), (C q, J = 1.7 Hz), (C q, J = Hz), (CH, J = 23.4 Hz), (CH, J = 7.7 Hz), (CH, J = 25.6 Hz), (C q, J = 7.7 Hz), 61.5 (CH 3 ), 33.9 (CH 3 ). 19 F MR (283 MHz, CDCl 3 ) δ = (ddd, J = 10.0, 7.7, 4.9 Hz). IR (neat): 2938, 1631, 1582, 1480, 1180, 789 cm -1. MS (EI) m/z (relative intensity): 199 ([M + + ] 30), 139 (100), 111 (34), 83 (31), 57 (22). HR MS (EI) m/z calcd for C 9 H 10 F , found

12 H F 3-Fluoro-2-hydroxy--methoxy--methylbenzamide (2q''): 1 H-MR (300 MHz, CDCl 3 ) δ = (s, 1H), 7.76 (dd, J = 8.3, 1.3 Hz, 1H), (m, 1H), (m, 1H), 3.65 (s, 3H), 3.41 (s, 3H). 13 C-MR δ = (C q, J = 3.2 Hz), (C q, J = Hz), (C q, J = 12.9 Hz), (CH, J = 3.9 Hz), (CH, J = 17.4 Hz), (CH, J = 6.8 Hz), (C q, J = 3.0 Hz), 61.4 (CH 3 ), 33.9 (CH 3 ). 19 F-MR (283 MHz, CDCl 3 ) δ = (ddd, J = 10.5, 4.9, 1.4 Hz). IR (neat): 2929, 1638, 1580, 1447, 1235, 743 cm -1. MS (EI) m/z (relative intensity): 199 ([M + ] 9), 139 (100), 111 (10), 83 (13), 57 (7). HR-MS (EI) m/z calcd for C 9 H 10 F , found Intermolecular Competition Experiment between Weinreb Amides 1i and 1l: F [RuCl 2 (p-cymene)] 1i (2.0 equiv) 2 (2.5 mol %) + PhI(Ac) 2 TFA/TFAA, 50 C 23% 2i/2l = 84/16 1l (2.0 equiv) ( 1 HMR) F H 2i + H 2l -thoxy-,4-dimethylbenzamide (1i) (179 mg, 1.00 mmol), 4-fluoro--methoxy-methylbenzamide (1l) (183 mg, 1.00 mmol), [RuCl 2 (p-cymene)] 2 (7.7 mg, 2.5 mol %), PhI(Ac) 2 (161 mg, 0.50 mmol), and TFA/TFAA (2.0 ml, 3/1) were reacted according to the representative procedure at 50 C for 16 h. Purification by column chromatography on silica gel (n pentane/etac: 5/1) yielded a mixture of 2i and 2l as a pale green liquid (90 mg, 23%). The ratio of product 2i and 2l was found to be 84/16 by 1 H MR spectroscopy. 12

13 Ruthenium-Catalyzed Reaction with Labled Substrate [D 5 ]-1a: [D 5 ]--thoxy--methylbenzamide ([D 5 ]-1a) (85 mg, 0.50 mmol), [RuCl 2 (p-cymene)] 2 (7.7 mg, 2.5 mol %), PhI(Ac) 2 (161 mg, 0.50 mmol), and TFA/TFAA (2.0 ml, 3/1) were reacted according to the representative procedure at 50 C for 3 h. Purification by column chromatography on silica gel (n pentane/etac: 5/1) yielded [D 4 ]-2a as a colorless liquid (19 mg, 20%) as a colorless liquid. The D/H ratios at ortho positions of both [D 4 ]-2a and retrieved [D 5 ]-1a (46 mg, 54%) were greater than 99/1 as estimated by 1 H-MR spectroscopy. An additional reaction was performed at 50 C for 16 h and yielded [D 4 ]-2a (66 mg, 71%) as a colorless liquid. The D/H ratio at ortho position of [D 4 ]-2a was 95/5 as estimated by 1 H MR spectroscopy. [D 4 ]-2a: 1 H-MR δ = (s, 1H), 3.64 (s, 3H), 3.40 (s, 3H). 13 C-MR δ = (C q ), (C q ), (C q ), (C q ), (C q ), (C q ), (C q ), 61.2 (CH 3 ), 34.0 (CH 3 ). IR (neat): 2935, 1617, 1567, 1390, 770 cm -1. MS (EI) m/z (relative intensity): 185 ([M + ] 10), 125 (100), 97 (16), 69 (20), 43(18). HR-MS (EI) m/z calcd for C 9 H 7 D , found

14 Intermolecular Competition Experiment between 1a and [D 5 ]-1a: H 5 /D 5 [RuCl 2 (p-cymene)] 2 (2.5 mol %) PhI(Ac) 2 TFA/TFAA [D n ]-1a 50 C, 16 h [D n ]-2a 22% k H /k D H 4 /D 4 H -thoxy--methylbenzamide (1a) (165 mg, 1.00 mmol), [D 5 ]--methoxy-methylbenzamide ([D 5 ]-1a) (170 mg, 1.00 mmol), [RuCl 2 (p-cymene)] 2 (7.7 mg, 2.5 mol %), PhI(Ac) 2 (161 mg, 0.50 mmol), and TFA/TFAA (2.0 ml, 3/1) were reacted according to the representative procedure at 50 C for 16 h. Purification by column chromatography on silica gel (n pentane/etac: 5/1) yielded a mixture of 2a and [D 4 ]-2a as a pale green liquid (81 mg, 22%). The kinetic isotope effect of this reaction was determined to be k H /k D 3.0 as estimated by 1 H-MR spectroscopy. Synthesis of ortho-hydroxybenzaldehyde 3a: In a 100 ml flame dried Schlenk flask was added 2a (181 mg, 1.0 mmol) and THF (30 ml) under 2. At -78 C, LiAlH 4 (38 mg, 1.0 mmol, 1M in Et 2 ) was added dropwise. The mixture was stirred for 15 min at -78 C. Then LiAlH 4 (114 mg, 3.0 mmol, 1M in Et 2 ) was added, and the reaction mixture was allowed to warm up to 0 C in 2 h. Aqueous ahs 4 (2 ml, 10%) was carefully added, followed by HCl (20 ml, 1). The reaction mixture was extracted with Et 2 (50 ml) and n-pentane (50 ml). The organic phase was washed with brine (50 ml), dried over sodium sulfate, and evaporated at ambient temperature. The crude product was purified by Kugelrohr distillation (80 ± 5 C, 10 mbar) to yield 3a (100 mg, 82%) as a colorless liquid. 14

15 H H 2-Hydroxybenzaldehyde (3a): 1 H MR δ = (d, J = 0.4 Hz, 1H), 9.89 (d, J = 0.6 Hz, 1H), (m, 2H), 7.00 (dddd, J = 7.8, 4.3, 1.5, 0.8 Hz, 2H). 13 C MR δ =196.6 (CH), (C q ), (CH), (CH), (C q ), (CH), (CH). IR (neat): 2847, 1662, 1275, 760 cm -1. MS (EI) m/z (relative intensity): 122 ([M + ] 100), 121 (97), 93 (30), 65 (42). HR MS (EI) m/z calcd for C 7 H , found The spectral data are in accordance with those reported in the literature. 4 References: 1. Uehara, K.; Wagner, C. B.; Vogler, T.; Luftmann, H.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, Miyata,.; Koizumi, T.; Asai, H.; Iba, R.; aito, T. Tetrahedron 2004, 60, Silva, F.; Reiter, M.; Mills-Webb, R.; Sawicki, M.; Klär, D.; Bensel,.; Wagner, A.; Gouverneur, V. J. rg. Chem. 2006, 71, Janeš, D.; Kreft, S. Food Chemistry 2008, 109,

16 H 2a H 2a 16

17 H Et 2b H Et 2b 17

18 H Et 2c H Et 2c 18

19 F H Et 2d F H Et 2d 19

20 H n-pr 2e H n-pr 2e 20

21 H n-bu 2f H n-bu 2f 21

22 H Bn 2g H Bn 2g 22

23 H Et Et 2h H Et Et 2h 23

24 H 2i H 2i 24

25 H Et 2j H Et 2j 25

26 H F 3 C 2k H F 3 C 2k 26

27 H F 2l H F 2l 27

28 H Cl 2m H Cl 2m 28

29 H I 2n I H 2n 29

30 Cl H 2o Cl H 2o 30

31 H 2p' H 2p' 31

32 H 2p'' H 2p'' 32

33 H F 2q' H F 2q' 33

34 H F 2q'' H F 2q'' 34

35 D D H D D/H [D 4 ]-2a H D D D/H D [D 4 ]-2a 35

36 H H 3a H H 3a 36

37 37