S1

Aromatic N-heterocycles in Mn-mediated radical additions to N-acylhydrazones

Manshu Li, Levi Goff, and Gregory K. Friestad* Department of Chemistry, University of Iowa, Iowa City, Iowa 52245 USA

Supporting Information

Contents

General Information S1

Preparative Procedures and Characterization Data for Compounds S1,9,10,12–14,16,17 S2 1H NMR and 13C NMR Spectra for Compounds S1,9,10,12–14,16,17 S8

General information. Reactions employed oven- or flame-dried glassware under nitrogen unless otherwise noted. Toluene, tetrahydrofuran (THF) and CH2Cl2 were purchased inhibitor-free, sparged with argon, and passed through columns of activated alumina under an argon atmosphere prior to use. Nitrogen was passed successively through columns of anhydrous CaSO4 and R3-11 catalyst for removal of water and oxygen, respectively. All other materials were used as received from commercial sources unless otherwise noted. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates with a UV indicator. Flash chromatography columns were packed with 230-400 mesh silica gel as a slurry in the initial elution solvent. Gradient flash chromatography was conducted by adsorption of product mixtures on silica gel, packing over a short pad of clean silica gel as a slurry in hexane, and eluting with a continuous gradient as indicated. Radial chromatography refers to centrifugally accelerated thin-layer chromatography performed using commercially supplied rotors. Nuclear magnetic resonance (NMR) data were obtained at operating frequencies indicated in the text and are reported in units of ppm. Infrared spectra were recorded using a single beam FT-IR spectrophotometer by standard transmission method. Low and high resolution mass spectra (TOF) were obtained from local instrumentation facilities services.

* Corresponding author. e-mail: gregory-friestad@uiowa.edu

S2

Ethyl 2-(1-hydroxybut-3-enyl)thiazole-4-carboxylate (12). To a mixture of ZnCl2 (5.90 g, 43.3 mmol) and THF (120 mL) was added allylmagnesium chloride (2 M in THF, 19.7 mL, 39.4 mmol) slowly via syringe. After stirring for 0.5 h, this mixture was transferred into formyl thiazole 11 (7.20 g, 39.4 mmol, in 150 mL THF) via cannula. After 3 h, reaction was quenched with water (20 mL) then extracted with EtOAc.

The organic phase was dried over Na2SO4. Concentration and gradient flash chromatography (25% EtOAc in petroleum ether to 50% EtOAc in petroleum ether) afforded homoallylic alcohol 12 (5.27 g, 60% yield) as a pale yellow solid: mp 46.0 – 46.5 °C; IR (film) 3411, 2983, 1725, 1489, 1215 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 5.90-5.76 (m, 1H), 5.27-5.20 (m, 2H), 5.11 (dd, J = 7.9, 4.0 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2 H), 2.91-2.82 (m, 1H), 2.79 (br s, 1H), 2.66-2.55 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 175.9, 161.5, 146.9, 132.8, 127.5, 119.7, 71.0, 61.6, 42.4, 14.4; HRMS (ESI) calcd for C10H14NO3S ([M+H]+) m/z 228.0694, found 228.0686.

Ethyl 2-(1-(benzyloxy)but-3-enyl)thiazole-4-carboxylate) (10). To a solution of homoallylic alcohol 12 (1.16 g, 5.12 mmol) in THF (100 mL) was added KH (30 wt% in mineral oil, 821 mg, 6.14 mmol) in one portion. After 5 min, benzyl bromide (0.73 mL, 6.14 mmol) was added via syringe. This reaction mixture was stirred for 4 h, then quenched with water (30 mL). The mixture was concentrated to remove

THF, and the remainder was extracted with EtOAc. The organic phase was dried over Na2SO4. Concentration and flash chromatography (9% EtOAc in petroleum ether) afforded benzyl ether 10 (884 mg, 54% yield) as a pale yellow oil: IR (film) 3015, 2910, 1725, 1487, 1315, 1217, 1096 cm-

1; 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.36-7.28 (m, 5H), 5.90-5.77 (m, 1H), 5.15-5.05 (m, 2H), 4.91 (dd, J = 7.0, 5.4 Hz, 1H), 4.58 (ABq, Δν = 23.9 Hz, J = 11.6 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.74-2.63 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 174.8, 161.5, 147.1, 137.4, 133.0, 128.6, 128.1, 128.0 (2C), 118.5, 78.8, 72.3, 61.6, 41.4, 14.5; HRMS (ESI) calcd for C17H20NO3S ([M+H]+) m/z 318.1164, found 318.1154.

(S)-3-(3-(Benzyloxy)-3-(4-((ethoxycarbonyl)methyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16a).

To a solution of alkene 10 (463 mg, 1.46 mmol) in THF (100 mL) and water (100 mL) were added osmium tetroxide (2.5 wt% in tert-butanol, 0.14 mL, 0.014 mmol). After 20 min, sodium periodate (1.25 g, 5.84 mmol) was added. After 16 h, reaction was quenched with saturated aqueous sodium thiosulfate solution (200 mL) and extracted with EtOAc. The

organic phase was dried over Na2SO4, and concentrated, then filtered through a short column of silica gel, eluting with EtOAc. Concentration furnished the crude aldehyde, which was dissolved in CH2Cl2 (45 mL) along with (S)-3-amino-4-phenylmethyl-2-oxazolidinone (15; 281 mg, 1.46 mmol). After 46 h, concentration and gradient flash chromatography (6% EtOAc in CH2Cl2 to EtOAc) afforded hydrazone 16a (493 mg, 68% yield, inseparable 1:1 mixture of diastereomers) as a colorless oil: IR (film) 3118, 3085, 3063, 3028, 2921, 2245, 1753, 1213, 1094 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.21-8.19 (m, 1H), 8.06-7.96 (m, 1H), 7.39-7.02 (m, 10H), 5.20-5.15 (m, 1H), 4.66 (ABq, Δν = 21.9 Hz, J = 11.6 Hz, 2H), 4.43-4.35 (m, 2H), 4.33-4.04 (m, 3H), 3.23-2.98 (m, 3H), 2.78-2.69 (m, 1H), 1.41-1.35 (m, 3H), (diastereomer peaks were unresolved); 13C{1H}

OH

S

N CO2Et

12

OBn

S

N CO2Et

10

NNO

Bn

O

OBnN

SCO2Et

16a

S3

NMR (75 MHz, CDCl3) δ 173.8 and 173.7, 161.4, 154.1, 150.2 and 150.0, 147.52 and 147.49, 137.1 and 137.0, 135.3 and 135.2, 129.4 and 129.3, 129.1 and 129.0, 128.70 and 128.68, 128.29 and 128.27, 128.25, 128.19, 127.4, 76.8 and 76.7, 72.5 and 72.4, 65.84 and 65.80, 61.7, 57.5 and 57.4, 40.6 and 40.4, 37.0 and 36.8, 14.5 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C26H27N3O5SNa ([M+Na]+) m/z 516.1569, found 516.1566.

1-(4-(Hydroxymethyl)thiazol-2-yl)but-3-en-1-ol (S1). A solution of homoallylic alcohol 12 (2.26 g, 9.94 mmol) in THF (50 mL) was cooled to –78 °C, and lithium aluminum hydride (2.0 M in THF, 15.9 mL, 31.79 mmol) was added slowly via syringe. After 5 min, the reaction was removed from the coolant bath. After 10 min, the reaction was quenched by slow addition of water (50 mL). The quenched mixture was filtered, extracted with EtOAc, and dried over

Na2SO4. Concentration and gradient flash chromatography (67% EtOAc in petroleum ether to EtOAc) afforded diol S1 (1.008 g, 55% yield) as a colorless oil: IR (film) 3311, 3017, 1216, 1057 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.13 (s, 1H), 5.90-5.74 (m, 1H), 5.25-5.13 (m, 2H), 4.98 (dd, J = 7.7, 4.7 Hz, 1H), 4.70 (s, 2H), 3.50 (br s, 2H), 2.79-2.52 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 175.4, 156.0, 133.1, 119.5, 115.1, 70.9, 60.7, 42.5; HRMS (ESI) calcd for C8H12NO2S ([M+H]+) m/z 186.0589, found 186.0594.

2-(1-(Benzyloxy)but-3-enyl)-4-((benzyloxy)methyl)thiazole (14). To a solution of diol S1 (726 mg, 3.19 mmol, prepared using the procedure reported above without chromatographic purification) in THF (50 mL) was added KH (30 wt% in mineral oil, 0.94 g, 7.02 mmol). After 5 min, benzyl bromide (0.84 mL, 7.02 mmol) was added. After 3 h, the reaction was quenched with water (10 mL) and

extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. Concentration and gradient flash chromatography (17% EtOAc in petroleum ether) afforded bis-benzyl ether 14 (1.04 g, 89% over 2 steps) as a colorless oil: IR (film) 3065, 3031, 2858, 1641, 1497, 1475, 1364, 1320, 1100 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.47-7.25 (m, 11H), 5.98-5.82 (m, 1H), 5.22-5.06 (m, 2H), 4.85 (dd, J = 6.5, 6.2 Hz, 1H), 4.73-4.66 (m, 5H), 4.56 (d, J = 11.6 Hz, 1H), 2.78-2.67 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.6, 153.7, 138.0, 137.6, 133.4, 128.5, 128.5, 128.0 (2C), 127.9, 127.8, 118.1, 116.4, 78.9, 72.8, 71.9, 68.1, 41.5; HRMS (ESI) calcd for C22H24NO2S ([M+H]+) m/z 366.1528, found 366.1530.

(S)-3-(3-(benzyloxy)-3-(4-((benzyloxy)methyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16c).

To a solution of benzyl ether 14 (843 mg, 2.31 mmol) in THF (115.5 mL) and water (115.5 mL) were added osmium tetroxide (2.5 wt% in tert-butanol, 0.23 mL, 0.023 mmol). After 30 min, sodium periodate (1.97 g, 9.24 mmol) was added. After 6 h, the reaction was quenched with saturated aqueous sodium thiosulfate solution (250 mL) and extracted

with EtOAc. The organic phase was dried over Na2SO4, and concentrated, then filtered through a short column of silica gel, eluting with EtOAc. Concentration furnished the crude aldehyde, which was dissolved in CH2Cl2 (172 mL) along with (S)-3-amino-4-phenylmethyl-2-oxazolidinone (15; 688 mg, 3.58 mmol). After 12 h, concentration and gradient flash chromatography (33% EtOAc

OH

S

N CH2OH

S1

OBn

S

N CH2OBn

14

NNO

Bn

O

OBnN

SCH2OBn

16c

S4

in petroleum ether to 40% EtOAc in petroleum ether) afforded hydrazone 16c (507 mg, 40% yield, inseparable 1:1 mixture of diastereomers) as a colorless wax: IR (film) 3009, 2919, 2861, 1763, 1497, 1477, 1454, 1407, 1215, 1092 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.00-7.92 (m, 1H), 7.45-7.25 (m, 14H), 7.13-7.00 (m, 2H), 5.12-5.05 (m, 1H), 4.77-4.54 (m, 6H), 4.36-4.24 (m, 1H), 4.20 (dd, J = 8.6, 7.9 Hz, 1H), 4.08 (dd, J = 8.6, 4.6 Hz, 1H), 3.21-2.96 (m, 3H), 2.79-2.62 (m, 1H), (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 172.5 and 172.4, 154.2 and 154.1, 150.1 and 149.9, 138.0, 137.29, 137.26, 135.2, 129.4, 129.0, 128.62, 128.59, 128.56, 128.1, 128.0 (2C), 127.9, 127.4, 116.7, 73.0, 72.1 and 72.0, 68.1, 65.8, 56.99 and 56.96, 40.4 and 40.3, 36.6 and 36.5 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C31H32N3O4S ([M+H]+) m/z 542.2114, found 542.2115.

(2-(1-(benzyloxy)but-3-enyl)thiazol-4-yl)methanol) (13). A solution of ester 10 (1.56 g, 4.91 mmol) in THF (98 mL) was cooled to –78 °C, and lithium aluminum hydride (2.0 M in THF, 4.91 mL, 9.82 mmol) was added slowly via syringe. After 1 h, the reaction was warmed to room temperature, quenched by slow addition of water (50 mL), and extracted with EtOAc. The organic phase was dried over

Na2SO4 and concentrated. Flash chromatography (67% EtOAc in petroleum ether) afforded alcohol 13 (1.26 g, 93% yield) as a pale yellow oil: IR (film) 3339, 3078, 3031, 2978, 2869, 1642, 1454, 1324, 1075 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 5H), 7.20 (s, 1H), 5.93-5.74 (m, 1H), 5.19-5.02 (m, 2H), 4.83-4.74 (m, 3H), 4.58 (ABq, Δν = 36.5 Hz, J = 11.6 Hz, 2H), 3.36 (br s, 1H), 2.80-2.57 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 174.2, 156.2, 137.6, 133.2, 128.5, 128.0 (2C), 118.2, 115.3, 78.7, 72.0, 60.8, 41.4; HRMS (ESI) calcd for C15H18NO2S ([M+H]+) m/z 276.1058, found 276.1053.

(S)-3-(3-(benzyloxy)-3-(4-((hydroxyl)methyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16b).

To a solution of alkene 13 (86 mg, 0.31 mmol) in THF (21 mL) and water (21 mL) were added osmium tetroxide (2.5 wt% in tert-butanol, 0.12 mL, 0.012 mmol). After 5 min, sodium periodate (265 mg, 1.24 mmol) was added. After 5.5 h, the reaction was quenched with saturated aqueous sodium thiosulfate solution (50 mL) and extracted with EtOAc. The

organic phase was dried over Na2SO4, and concentrated, then filtered through a short column of silica gel, eluting with EtOAc. Concentration furnished the crude aldehyde, which was dissolved in CH2Cl2 (31 mL) along with (S)-3-amino-4-phenylmethyl-2-oxazolidinone (15; 119 mg, 0.62 mmol). After 12.5 h, concentration and gradient flash chromatography (83% EtOAc in petroleum ether to EtOAc to 5% methanol in EtOAc) afforded 16b (106 mg, 75% yield, inseparable 1:1 mixture of diastereomers) as a colorless wax: IR (film) 3404, 3013, 1763, 1405, 1217, 1092 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.91-7.84 (m, 1H), 7.38-7.19 (m, 9H), 7.09-7.04 (m, 2H), 5.08-5.02 (m, 1H), 4.75-4.52 (m, 4H), 4.33-4.23 (m, 1H), 4.20-4.15 (m, 1H), 4.10-4.03 (m, 1H), 3.73 (br s, 1H), 3.15-2.93 (m, 3H), 2.77-2.63 (m, 1H), (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 172.5, 156.8, 154.0, 149.6 and 149.4, 137.0, 134.9, 129.2, 128.8, 128.43 and 128.42, 127.9 (2C), 127.2, 115.4, 76.5 and 76.4, 71.9 and 71.8, 65.6, 60.6, 56.4, 40.04 and 39.97, 36.1 and 36.0 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C24H25N3O4SNa ([M+Na]+) m/z 474.1463, found 474.1451.

OBn

S

N CH2OH

13

NNO

Bn

O

OBnN

SCH2OH

16b

S5

(S)-3-(3-(benzyloxy)-3-(4-((acetyl)methyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16d).

To a solution of alcohol 16b (106 mg, 0.235 mmol) and DMAP (43 mg, 0.352 mmol) in CH2Cl2 (4.7 mL) was added acetic anhydride (33 µL, 0.352 mmol) via syringe. After 22 h, concentration and gradient flash chromatography (50% EtOAc in petroleum ether to 67% EtOAc in petroleum ether) afforded acetate 16d (117 mg, 100% yield, inseparable 1:1

mixture of diastereomers) as a colorless oil: IR (film) 3018, 1745, 1404, 1218, 1094, 1029 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.02-7.95 (m, 1H), 7.44-7.19 (m, 9H), 7.16-7.03 (m, 2H), 5.18 (s, 2H), 5.12-5.03 (m, 1H), 4.66 (ABq, Δν = 31.4 Hz, J = 11.6 Hz, 2H), 4.37-4.19 (m, 2H), 4.14-4.08 (m, 1H), 3.20-3.03 (m, 3H), 2.79-2.65 (m, 1H), 2.10 (s, 3H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 172.9 and 172.8, 170.7, 154.0, 151.3, 150.0 and 149.8, 137.09 and 137.06, 135.1, 129.3, 128.9, 128.5, 128.0 (2C), 127.3, 118.3, 76.5, 72.1 and 72.0, 65.6, 61.6, 57.01 and 56.95, 40.2 and 40.1, 36.52 and 36.46, 20.9 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C26H27N3O5SNa ([M+Na]+) m/z 516.1569, found 516.1573.

(S)-3-(3-(Benzyloxy)-3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16g).

To a solution of alcohol 16b (137 mg, 0.303 mmol) and imidazole (52 mg, 0.76 mmol) in DMF (2 mL) was added TBDPSCl (86 µL, 0.33 mmol) via syringe. After 12 h, the mixture was partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and concentrated. Flash chromatography (33% EtOAc in

petroleum ether) afforded silyl ether 16g (189 mg, 92% yield, inseparable 1:1 mixture of diastereomers) as a colorless oil: IR (film) 3018, 2932, 2860, 1768, 1216, 1112 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.95-7.89 (m, 1H), 7.72-7.64 (m, 4H), 7.47-7.23 (m, 15H), 7.09-7.00 (m, 2H), 5.03-4.98 (m, 1H), 4.85 (s, 2H), 4.62 (ABq, Δν = 37.7 Hz, J = 11.4 Hz, 2H), 4.33-4.16 (m, 2H), 4.12-4.04 (m, 1H), 3.18-2.91 (m, 3H), 2.74-2.59 (m, 1H); 1.11 (s, 9H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 172.0 and 171.9, 157.2, 154.2, 150.3 and 150.0, 137.4, 135.7 (2C), 135.2, 133.3, 129.9, 129.4, 129.0, 128.6, 128.2, 128.1, 127.9 (2C), 127.4, 114.6, 77.4, 72.0 and 71.9, 65.8, 63.2, 57.03 and 56.97, 40.2, 36.55 and 36.48, 27.0, 19.4 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C40H43N3O4SSiNa ([M+Na]+) m/z 712.2641, found 712.2643.

(S)-3-(3-(Benzyloxy)-3-(4-((tert-butyldimethylsilyloxymethyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16f).

To a solution of alcohol 16b (44 mg, 0.098 mmol) and pyridine (0.04 mL, 0.49 mmol) in CH2Cl2 (1 mL) was added TBSCl (22 mg, 0.15 mmol). After 19 h, concentration and flash chromatography (50% EtOAc in petroleum ether) afforded silyl ether 16f (36 mg, 65% yield, inseparable 1:1 mixture of diastereomers) as a pale yellow oil: IR (film)

3009, 2956, 2927, 2858, 1771, 1403, 1217, 1097 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.98-7.91 (m, 1H), 7.40-7.18 (m, 9H), 7.14-7.04 (m, 2H), 5.07-5.01 (m, 1H), 4.85-4.79 (m, 2H), 4.73-4.53 (m, 2H), 4.36-4.18 (m, 2H), 4.14-4.07 (m, 1H), 3.21-2.94 (m, 3H), 2.78-2.65 (m, 1H), 0.94 (s, 9H),

NNO

Bn

O

OBnN

SCH2OAc

16d

NNO

Bn

O

OBnN

SCH2OTBDPS

16g

NNO

Bn

O

OBnN

SCH2OTBS

16f

S6

0.10 (s, 6H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 172.04 and 171.96, 157.6, 154.1, 150.3 and 150.0, 137.3, 135.2, 129.4, 129.1, 128.63 and 128.61, 128.2, 128.1, 127.4, 114.4, 76.6, 72.0 and 71.9, 65.8, 62.4, 57.1 and 57.0, 40.3, 36.6 and 36.5, 26.0, 18.5, -5.2; HRMS (ESI) calcd for C30H39N3O4SSiNa ([M+Na]+) m/z 588.2328, found 588.2330.

(S)-3-(3-(Benzyloxy)-3-(4-((pivaloylmethyl)thiazol-2-yl)propylideneamino)-4-benzyloxazolidin-2-one (16e).

To a solution of alcohol 16b (220 mg, 0.487 mmol) and pyridine (0.20 mL, 2.4 mmol) in CH2Cl2 (4.9 mL) was added pivaloyl chloride (0.09 mL, 0.7 mmol) via syringe. After 16 h, concentration and flash chromatography (50% EtOAc in petroleum ether) afforded pivaloate 16e (209 mg, 80% yield, inseparable 1:1 mixture of diastereomers) as a colorless oil:

IR (film) 3019, 2980, 2939, 1742, 1208, 1144, 1047 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.02-7.95 (m, 1H), 7.38-7.23 (m, 9H), 7.14-7.04 (m, 2H), 5.22-5.19 (m, 2H), 5.09-5.04 (m, 1H), 4.74-4.56 (m, 2H), 4.37-4.18 (m, 2H), 4.14-4.08 (m, 1H), 3.20-3.08 (m, 1H), 3.08-3.03 (m, 2H), 2.80-2.65 (m, 1H), 1.23 (s, 9H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 178.1, 172.53 and 172.48, 154.1, 152.0, 150.0 and 149.8, 137.2, 135.1, 129.4, 129.0, 128.6, 128.1 (2C), 127.4, 117.21 and 117.17, 76.6 and 76.5, 72.1 and 72.0, 65.7, 61.9, 57.0, 40.24 and 40.16, 38.9, 36.5 and 36.4, 27.2 (some diastereomer peaks were unresolved); HRMS (ESI) calcd for C29H34N3O5S ([M+H]+) m/z 536.2219, found 536.2208.

General Procedure A: Mn-mediated radical addition; without InCl3 To a Schlenk flask charged with N-acylhydrazone (8a, 8b, 16a–16g, 1 equiv) and CH2Cl2 (0.029 M) were added isopropyl iodide (10 equiv) via syringe followed by dimanganese decacarbonyl (1 equiv). The Schlenk flask was sealed and irradiated (300 nm, Rayonet photoreactor) for 6 h. Concentration and flash chromatography or gradient flash chromatography furnished the N-acylhydrazine products 9a, 9b, 17c–17e.

General Procedure B: Mn-mediated radical addition; lower concentration, with InCl3 (3.5 equiv) A Schlenk flask charged with N-acylhydrazone (8a, 8b, 16a–16g, 1 equiv), indium chloride (3.5 equiv), and CH2Cl2 (0.017 M) was stirred for 30 min. Isopropyl iodide (3 equiv) was added via syringe, followed by dimanganese decacarbonyl (1 equiv). The Schlenk flask was sealed and irradiated (300 nm, Rayonet photoreactor) for 6 h. Concentration and flash chromatography or gradient flash chromatography furnished the N-acylhydrazine products 9a, 9b, 17c–17e.

(S)-3-(1-(Benzyloxy)-1-(4-((benzyloxy)methyl)thiazol-2-yl)-4-methylpentan-3-ylamino)-4-benzyloxazolidin-2-one (17c).

From N-acylhydrazone 16c (118 mg, 0.218 mmol, 1:1 mixture of diastereomers) via General Procedure B was obtained amine 17c (80.3 mg, 63%, 1:1 mixture of diastereomers) as a colorless oil: IR (film) 3270, 3018, 2962, 2870, 1752, 1497, 1454, 1395, 1373, 1216, 1092 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.50-7.18 (m, 14H), 7.11-7.00 (m, 2H), 5.11-5.03 (m, 1H), 4.74-4.52 (m, 6H), 4.35-4.28 (m,

1H), 4.08-3.74 (m, 3H), 3.30-2.97 (m, 2H), 2.54-2.42 (m, 1H), 2.12-1.77 (m, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 174.2, 158.6, 154.2, 138.0, 137.6, 135.8, 129.3, 128.9, 128.59, 128.57, 128.03, 127.97

NH

NOBn

N

SCH2OBn

17c

O

Bn

O

NNO

Bn

O

OBnN

SCH2OPiv

16e

S7

(2C), 127.9, 127.1, 116.1, 77.8, 73.0, 72.5, 68.2, 65.6, 60.0, 57.8, 36.4, 36.0, 28.8, 19.1, 16.0 (diastereomer peaks were unresolved); HRMS (ESI) calcd for C34H40N3O4S ([M+H]+) m/z 586.2740, found 586.2740.

(S)-3-(1-(Benzyloxy)-1-(4-((acetoxy)methyl)thiazol-2-yl)-4-methylpentan-3-ylamino)-4-benzyloxazolidin-2-one (17d).

From N-acylhydrazone 16d (993 mg, 2.02 mmol, 1:1 mixture of diastereomers) via General Procedure A was obtained amine 17d (464 mg, 43% yield, 1:1 mixture of diastereomers) as a colorless oil: IR (film) 3280, 3019, 2960, 1745, 1498, 1455, 1374, 1217, 1094, 1029 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.20 (m, 9H), 7.12-7.01 (m, 2H), 5.20 (s, 2H),

5.08 (dd, J = 7.9, 3.8 Hz, 1H), 4.65 (ABq, Δν = 35.1 Hz, J = 11.4 Hz, 2H), 4.31 (d, J = 5.4 Hz), 4.18-3.77 (m, 3H), 3.22 (dd, J = 13.5, 3.3 Hz, 1H), 3.16-3.06 (m, 1H), 2.50 (dd, J = 13.5, 10.0 Hz, 1H), 2.11 (s, 3H), 2.08-1.79 (m, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 174.8, 170.8, 158.6, 151.4, 137.5, 135.8, 129.2, 129.0, 128.6, 128.1, 128.0, 127.2, 118.0, 77.8, 72.6, 65.7, 61.8, 60.0, 58.0, 36.5, 35.9, 28.8, 21.1, 19.1, 16.0 (diastereomer peaks were unresolved); HRMS (ESI) calcd for C29H35N3O5SNa ([M+Na]+) m/z 560.2195, found 560.2198.

(S)-3-(1-(Benzyloxy)-1-(4-((pivaloxy)methyl)thiazol-2-yl)-4-methylpentan-3-ylamino)-4-benzyloxazolidin-2-one (17e).

From N-acylhydrazone 16e (104 mg, 0.194 mmol, 1:1 mixture of diastereomers) via General Procedure B was obtained amine 17e (53 mg, 47% yield, 1:1 mixture of diastereomers) as a colorless oil: IR (film) 3290, 2963, 2872, 1755, 1604, 1497, 1398, 1368, 1281, 1216, 1160, 1095 cm-

1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.22 (m, 9H), 7.12-7.05 (m, 2H), 5.22 (s, 2H), 5.08 (dd, J = 7.7, 3.9 Hz, 1H),

4.64 (ABq, Δν = 36.2 Hz, J = 11.4 Hz, 2H), 4.35 (br s, 1H), 4.05 (dd, apparent t, J = 8.2 Hz, 1H), 3.95 (dd, J = 8.8, 4.5 Hz, 1H), 3.91-3.80 (m, 1H), 3.21 (dd, J = 13.4, 3.4 Hz, 1H), 3.17-3.08 (m, 1H), 2.49 (dd, J = 13.4, 9.9 Hz, 1H), 2.14-1.78 (m, 3H), 1.24 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H) (diastereomer peaks were unresolved); 13C{1H} NMR (75 MHz, CDCl3) δ 178.1, 174.2, 158.5, 151.8, 137.3, 135.7, 129.1, 128.8, 128.5, 128.0, 127.9, 127.0, 116.7, 77.6, 72.4, 65.5, 61.9, 59.8, 57.8, 38.8, 36.4, 35.8, 28.7, 27.2, 18.9, 15.9 (diastereomer peaks were unresolved); HRMS (ESI) calcd for C32H42N3O5S ([M+H]+) m/z 580.2845, found 580.2840.

(S)-3-(4-Methyl-1-phenylpentan-3-ylamino)-4-benzyloxazolidin-2-one (9a). From hydrocinnamaldehyde N-acylhydrazone 8a (25 mg, 0.081 mmol) via General Procedure B

was obtained amine 9a (18 mg, 63%, >95:5 diastereomer ratio) as colorless oil: IR (film) 2961, 2872, 1750 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.44-7.11 (m, 10H), 4.19-3.98 (m, 2H), 3.98-3.84 (m, 1H), 3.65 (br s, 1H), 3.35 (dd, J = 13.4, 3.1 Hz, 1H), 2.98-2.85 (m, 1H), 2.78 (t, J = 7.9 Hz, 2H), 2.59 (dd, J = 13.2, 10.1 Hz, 1H), 2.05-1.59 (m, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.9, 142.4, 136.1, 129.2, 129.0, 128.6, 128.5, 127.2, 126.0, 65.9, 64.2, 59.7, 37.0, 32.5, 30.5,

28.7, 18.8, 17.6; HRMS (ESI) calcd for C22H29N2O2 ([M+H]+) m/z 353.2229, found 353.2239.

NH

NOBn

N

SCH2OAc

17d

O

Bn

O

NH

NOBn

N

SCH2OPiv

17e

O

Bn

O

HN N

O

Bn

O

Ph9a

S8

S9

`

S10

S11

S12

S13

S14

S15

S16

S17

S18

S19

S20

S21

S22

S23

S24

S25

S26

S27

S28

S29

S30

S31

S32

S33

S34

S35

S36

S37

S38

S39