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Synlett 2023; 34(04): 379-387
DOI: 10.1055/a-1984-9105
letter

Application of Halogen-Bonding Catalysis for Markovnikov-Type Hydrothiolation of Alkenes

Xue Zhang
,
Nuoyu Liang
,
Ruining Li
,
Zhankui Sun  ∗
We thank Shanghai Jiao Tong University for financial support.
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Abstract

Carbon–sulfur bond-formation reactions are applied widely in organic synthesis and chemical biology. Hydrothiolation of alkenes provides a direct way to build carbon–sulfur bonds. Most known methods proceed via radical processes and result in anti-Markovnikov-type products. Herein, we demonstrate that I2 catalyzes the hydrothiolation of alkenes and provides Markovnikov-type products in good to excellent yields. Titration studies revealed that thiol was activated by I2 through halogen bonding. This metal-free reaction has advantages such as green and mild conditions, high functionality tolerance, broad substrate scope, and atom economy. Its application was further demonstrated in peptide syntheses.

Key words

thiols - halogen bonding - hydrothiolation - Markovnikov reaction - alkenes - addition

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1984-9105.
  • Supporting Information


Publikationsverlauf

Eingereicht: 01. November 2022

Angenommen nach Revision: 23. November 2022

Accepted Manuscript online:
23. November 2022

Artikel online veröffentlicht:
03. Januar 2023

© 2022. Thieme. All rights reserved

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  • 7 General Procedure: To a 25 mL single-necked bottle were added thiol compound (2.00 mmol, 2.0 equiv), styrene derivative (1.00 mmol, 1.0 equiv), iodine (0.20 mmol, 0.2 equiv), and EtOAc (6 mL). The mixture was stirred at room temperature for 7 hours. The mixture was concentrated and the residue was purified by column chromatography on silica with PE/EtOAc mixture as the eluent. Ethyl 2-((2-Phenylpropan-2-yl)thio)acetate (3a) The product was obtained as colorless oil (224 mg, 94% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.56–7.50 (m, 2 H), 7.32 (t, J = 7.7 Hz, 2 H), 7.21 (t, J = 7.3 Hz, 1 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.97 (s, 2 H), 1.73 (s, 6 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 145.5, 128.3, 126.8, 126.7, 61.3, 48.5, 32.59, 30.1, 14.1. HRMS (ESI): m/z calcd for C13H18NaO2S [M + Na]+: 261.0920; found: 261.0921. IR (film): 2966, 2929, 1736, 1447, 1366, 1264, 1130, 1074, 1030, 699 cm–1. Ethyl 2-((2-(Naphthalen-1-yl)propan-2-yl)thio)acetate (3b) The product was obtained as colorless oil (245 mg, 85% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 9.13 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.57–7.46 (m, 3 H), 7.41 (t, J = 7.7 Hz, 1 H), 3.80 (q, J = 7.1 Hz, 2 H), 2.92 (s, 2 H), 1.98 (s, 6 H), 1.06 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 139.4, 135.0, 131.1, 129.2, 129.1, 127.3, 125.3, 124.8, 124.5, 61.0, 48.8, 32.8, 31.6, 13.8. HRMS (ESI): m/z calcd for C17H20NaO2S [M + Na]+: 311.1076; found: 311.1082. IR (film): 2966, 2361, 1735, 1509, 1388, 1263, 1119, 1073, 1031, 802, 778 cm–1. Ethyl 2-((2-(Naphthalen-2-yl)propan-2-yl)thio)acetate (3c) The product was obtained as colorless oil (242 mg, 84% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.83 (dt, J = 12.2, 4.2 Hz, 5 H), 7.52–7.45 (m, 2 H), 3.94 (q, J = 7.1 Hz, 2 H), 2.96 (s, 2 H), 1.85 (s, 6 H), 1.12 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.6, 142.8, 132.9, 132.3, 128.2, 128.2, 127.4, 126.2, 126.1, 125.7, 124.7, 61.2, 48.8, 32.7, 29.9, 14.0. HRMS (ESI): m/z calcd for C17H20NaO2S [M + Na]+: 311.1076; found: 311.1079. IR (film): 2977, 2931, 2361, 1735, 1274, 1124, 1030, 817, 749, 477 cm–1. Ethyl 2-((2-(Anthracen-2-yl)propan-2-yl)thio)acetate (3d) The product was obtained as colorless oil (315 mg, 93% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 9.78 (s, 1 H), 8.45 (s, 1 H), 8.18–8.11 (m, 1 H), 8.02–7.93 (m, 2 H), 7.50 (dd, J = 8.0, 3.9 Hz, 3 H), 7.40 (t, J = 7.8 Hz, 1 H), 3.77 (q, J = 7.1 Hz, 2 H), 2.95 (s, 2 H), 2.07 (s, 6 H), 1.01 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.6, 139.2, 133.3, 131.0, 130.8, 129.7, 129.4, 128.9, 127.5, 127.4, 126.9, 125.9, 125.5, 125.2, 124.1, 61.1, 49.3, 33.0, 31.7, 13.9. HRMS (ESI): m/z calcd for C21H22NaO2S [M + Na]+: 361.1233; found: 361.1262. IR (film): 2976, 2928, 2361, 1734, 1265, 1121, 1031, 880, 735, 473 cm–1. Ethyl 2-((2-(4-Methoxyphenyl)propan-2-yl)thio)acetate (3e) The product was obtained as colorless oil (254 mg, 95% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 3.76 (s, 3 H), 2.94 (s, 2 H), 1.68 (s, 6 H), 1.18 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 158.2, 137.4, 127.8, 113.4, 61.1, 55.2, 48.1, 32.5, 30.1, 14.0. HRMS (ESI): m/z calcd for C14H20KO3S [M + K]+: 307.0765; found: 307.0712. IR (film): 2967, 2935, 1735, 1610, 1512, 1254, 1184, 1130, 1033, 832 cm–1. Ethyl 2-((2-(p-Tolyl)propan-2-yl)thio)acetate (3f) The product was obtained as colorless oil (246 mg, 97% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 8.2 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 4.03 (q, J = 7.1 Hz, 2 H), 2.96 (s, 2 H), 2.32 (s, 3 H), 1.71 (s, 6 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.6, 142.4, 136.2, 128.8, 126.5, 61.1, 48.3, 32.5, 30.0, 20.9, 14.0. HRMS (ESI): m/z calcd for C14H20NaO2S [M + Na]+: 275.1076; found: 275.1079. IR (film): 2966, 2924, 1735, 1512, 1365, 1264, 1129, 1094, 1032, 818 cm–1. Ethyl 2-((2-(4-Fluorophenyl)propan-2-yl)thio)acetate (3g) The product was obtained as colorless oil (230 mg, 90% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.46 (dd, J = 8.6, 5.5 Hz, 2 H), 6.96 (t, J = 8.7 Hz, 2 H), 4.00 (q, J = 7.1 Hz, 2 H), 2.93 (s, 2 H), 1.67 (s, 6 H), 1.17 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 161.5 (d, J = 246 Hz), 141.3 (d, J = 3.0 Hz), 128.4 (d, J = 8.1 Hz), 114.8 (d, J = 21.2 Hz), 61.2, 48.0, 32.5, 30.2, 14.0. 19F NMR (376 MHz, CDCl3): δ = –116.11. HRMS (ESI): m/z calcd for C13H17FNaO2S [M + Na]+: 279.0825; found: 279.0817. IR (film): 2965, 2361, 2344, 1735, 1509, 1262, 1092, 1031, 836, 800 cm–1. Ethyl 2-((2-(4-Chlorophenyl)propan-2-yl)thio)acetate (3h) The product was obtained as colorless oil (240 mg, 88% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 7.06 (d, J = 8.6 Hz, 2 H), 3.81 (q, J = 7.1 Hz, 2 H), 2.75 (s, 2 H), 1.49 (s, 6 H), 0.99 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 144.2, 132.5, 128.2, 128.2, 61.3, 48.0, 32.4, 30.0, 14.0. HRMS (ESI): m/z calcd for C13H17ClNaO2S [M + Na]+: 295.0530; found: 295.0530. IR (film): 2979, 2361, 1735, 1491, 1266, 1131, 1097, 1031, 1013, 829 cm–1. Ethyl 2-((2-(4-Bromophenyl)propan-2-yl)thio)acetate (3i) The product was obtained as colorless oil (298 mg, 94% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.47–7.33 (m, 4 H), 3.99 (q, J = 7.1 Hz, 2 H), 2.93 (s, 2 H), 1.66 (s, 6 H), 1.17 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.3, 144.7, 131.2, 128.5, 120.7, 61.3, 48.1, 32.5, 29.9, 14.0. HRMS (ESI): m/z calcd for C13H17BrKO2S [M + K]+: 354.9764; found: 354.9767. IR (film): 2979, 2931, 1735, 1489, 1396, 1269, 1130, 1094, 1008, 825 cm–1. Ethyl 2-((1,1-Diphenylethyl)thio)acetate (3j) The product was obtained as colorless oil (215 mg, 72% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.45–7.40 (m, 4 H), 7.34–7.28 (m, 4 H), 7.27–7.22 (m, 2 H), 4.05 (q, J = 7.1 Hz, 2 H), 3.06 (s, 2 H), 2.10 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 145.4, 128.3, 128.1, 127.0, 61.5, 57.1, 33.3, 30.6, 14.2. HRMS (ESI): m/z calcd for C18H20NaO2S [M + Na]+: 323.1076; found: 323.1079. IR (film): 2979, 1735, 1492, 1444, 1264, 1134, 1029, 762, 742, 699 cm–1. Ethyl 2-((2-(4-Ethylphenyl)butan-2-yl)thio)acetate (3k) The product was obtained as colorless oil (239 mg, 85% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 7.7 Hz, 2 H), 7.14 (d, J = 7.9 Hz, 2 H), 4.01 (q, J = 7.1 Hz, 2 H), 2.94 (s, 2 H), 2.62 (q, J = 7.6 Hz, 2 H), 2.06 (dq, J = 14.5, 7.4 Hz, 1 H), 1.96–1.83 (m, 1 H), 1.69 (s, 3 H), 1.22 (t, J = 4.0 Hz, 3 H), 1.19 (t, J = 3.0 Hz, 3 H), 0.82 (t, J = 7.4 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 142.5, 141.1, 127.6, 127.2, 61.1, 52.6, 35.2, 32.0, 28.3, 25.3, 15.4, 14.1, 9.1. HRMS (ESI): m/z calcd for C16H24NaO2S [M + Na]+: 303.1389; found: 303.1390. IR (film): 2967, 2935, 2361, 2344, 1736, 1263, 1131, 1092, 1032, 801 cm–1. Ethyl 2-((2-Phenylpentan-2-yl)thio)acetate (3l) The product was obtained as colorless oil (244 mg, 92% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 7.6 Hz, 2 H), 7.28 (t, J = 7.7 Hz, 2 H), 7.16 (t, J = 7.3 Hz, 1 H), 3.98 (qd, J = 7.1, 1.9 Hz, 2 H), 2.91 (s, 2 H), 2.02–1.93 (m, 1 H), 1.88–1.77 (m, 1 H), 1.71 (s, 3 H), 1.40–1.28 (m, 1 H), 1.16 (t, J = 7.1 Hz, 3 H), 1.11–1.00 (m, 1 H), 0.83 (t, J = 7.3 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.5, 144.2, 128.0, 127.1, 126.5, 61.0, 52.2, 45.0, 31.8, 25.7, 17.9, 14.3, 14.0. HRMS (ESI): m/z calcd for C15H22NaO2S [M + Na]+: 289.1233; found: 289.1244. IR (film): 2961, 2935, 2361, 2344, 1735, 1446, 1265, 1133, 1030, 699 cm–1. Ethyl 2-((1-(4-Methoxyphenyl)ethyl)thio)acetate (3m) The product was obtained as colorless oil (180 mg, 71% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 4.15–4.08 (m, 3 H), 3.77 (s, 3 H), 3.00 (d, J = 14.9 Hz, 1 H), 2.88 (d, J = 14.9 Hz, 1 H), 1.53 (d, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.6, 158.8, 134.7, 128.6, 113.8, 61.2, 55.2, 43.6, 33.0, 22.0, 14.2. HRMS (ESI): m/z calcd for C13H18NaO3S [M + Na]+: 277.0869; found: 277.0811. IR (film): 2965, 2930, 2836, 1734, 1611, 1512, 1464, 1249, 1032, 833 cm–1. Ethyl 2-((1-(Naphthalen-2-yl)ethyl)thio)acetate (3n) The product was obtained as colorless oil (218 mg, 80% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.88–7.80 (m, 3 H), 7.75 (d, J = 1.3 Hz, 1 H), 7.57 (dd, J = 8.5, 1.8 Hz, 1 H), 7.53–7.45 (m, 2 H), 4.36 (q, J = 7.1 Hz, 1 H), 4.18–4.05 (m, 2 H), 3.05 (d, J = 15.0 Hz, 1 H), 2.92 (d, J = 15.0 Hz, 1 H), 1.69 (d, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.6, 140.0, 133.2, 132.9, 128.7, 127.8, 127.7, 126.5, 126.3, 126.0, 125.2, 61.3, 44.5, 33.0, 21.9, 14.2. HRMS (ESI): m/z calcd for C16H18KO2S [M + K]+: 313.0659; found: 313.0676. IR (film): 2968, 2928, 1735, 1264, 1125, 1030, 818, 800, 749, 478 cm–1. Ethyl 2-((1-([1,1′-Biphenyl]-4-yl)ethyl)thio)acetate (3o) The product was obtained as colorless oil (245 mg, 82% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.66 - 7.57 (m, 4 H), 7.46 (t, J = 7.8 Hz, 4 H), 7.37 (t, J = 7.3 Hz, 1 H), 4.26 (q, J = 7.0 Hz, 1 H), 4.18 (qd, J = 7.1, 3.0 Hz, 2 H), 3.11 (d, J = 14.9 Hz, 1 H), 3.00 (d, J = 14.9 Hz, 1 H), 1.66 (d, J = 7.1 Hz, 3 H), 1.30 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 141.9, 140.6, 140.2, 128.7, 127.9, 127.3, 127.2, 126.9, 61.2, 43.9, 33.0, 21.9, 14.1. HRMS (ESI): m/z calcd for C18H20NaO2S [M + Na]+: 323.1076; found: 323.1073. IR (film): 2967, 1735, 1486, 1263, 1130, 1030, 798, 767, 734, 698 cm–1. Diethyl 2,2′-((1,4-Phenylenebis(propane-2,2-diyl))bis(sulfanediyl))diacetate (3p) The product was obtained as colorless oil (179 mg, 90% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.46 (s, 4 H), 4.05 (q, J = 7.1 Hz, 4 H), 2.98 (s, 4 H), 1.71 (s, 12 H), 1.21 (t, J = 7.1 Hz, 6 H). 13C NMR (101 MHz, CDCl3): δ = 170.5, 143.9, 126.4, 61.2, 48.1, 32.5, 29.9, 14.0. HRMS (ESI): m/z calcd for C20H30NaO4S2 [M + Na]+: 421.1478; found: 421.1475. IR (film): 2964, 2361, 2344, 1735, 1458, 126, 1097, 1028, 800, 669 cm–1. Ethyl 2-((2-Phenylpropan-2-yl)thio)acetate (4a) The product was obtained as colorless oil (224 mg, 94% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.56–7.50 (m, 2 H), 7.32 (t, J = 7.7 Hz, 2 H), 7.21 (t, J = 7.3 Hz, 1 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.97 (s, 2 H), 1.73 (s, 6 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 145.5, 128.3, 126.8, 126.7, 61.3, 48.5, 32.59, 30.1, 14.1. HRMS (ESI): m/z calcd for C13H18NaO2S [M + Na]+: 261.0920; found: 261.0921. IR (film): 2966, 2929, 1736, 1447, 1366, 1264, 1130, 1074, 1030, 699 cm–1. Ethyl 2-((2-Phenylpropan-2-yl)thio)propanoate (4b) The product was obtained as colorless oil (224 mg, 89% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.56–7.51 (m, 2 H), 7.34–7.28 (m, 2 H), 7.23–7.18 (m, 1 H), 4.02–3.89 (m, 2 H), 3.00 (q, J = 7.3 Hz, 1 H), 1.74 (s, 3 H), 1.71 (s, 3 H), 1.23–1.15 (m, 6 H). 13C NMR (101 MHz, CDCl3): δ = 174.2, 145.8, 128.1, 126.7, 126.0, 60.9, 49.4, 40.6, 30.5, 30.2, 18.9, 14.0. HRMS (ESI): m/z calcd for C14H20NaO2S [M + Na]+: 275.1076; found: 275.1070. IR (film): 2967, 2930, 1733, 1447, 1259, 1132, 1098, 1029, 802, 699 cm–1. Methyl 3-((2-Phenylpropan-2-yl)thio)propanoate (4c) The product was obtained as colorless oil (217 mg, 91% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.55–7.51 (m, 2 H), 7.32 (t, J = 7.8 Hz, 2 H), 7.23–7.18 (m, 1 H), 3.62 (s, 3 H), 2.49 (t, J = 7.5 Hz, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 1.71 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 172.4, 146.4, 128.2, 126.6, 126.5, 51.7, 47.9, 34.2, 30.2, 24.5. HRMS (ESI): m/z calcd for C13H18NaO2S [M + Na]+: 261.0920; found: 261.0925. IR (film): 2965, 1741, 1437, 1364, 1244, 1133, 1099, 1029, 769, 699 cm–1. 3-((2-Phenylpropan-2-yl)thio)propanoic Acid (4d) The product was obtained as colorless oil (198 mg, 89% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.55–7.52 (m, 2 H), 7.35–7.30 (m, 2 H), 7.24–7.20 (m, 1 H), 2.50–2.45 (m, 2 H), 2.36–2.31 (m, 2 H), 1.72 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 178.3, 146.3, 128.3, 126.8, 126.6, 48.1, 34.3, 30.3, 24.2. HRMS (ESI): m/z calcd for C12H16NaO2S [M + Na]+: 247.0763; found: 247.0766. IR (film): 2966, 1711, 1419, 1446, 1261, 1132, 1098, 1029, 768, 698 cm–1. 3-((2-Phenylpropan-2-yl)thio)propan-1-ol (4e) The product was obtained as colorless oil (197 mg, 74% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.56 - 7.51 (m, 2 H), 7.32 (t, J = 7.7 Hz, 2 H), 7.21 (t, J = 7.3 Hz, 1 H), 3.55 (t, J = 6.1 Hz, 2 H), 2.32 (t, J = 7.1 Hz, 2 H), 1.72 (s, 6 H), 1.64–1.57 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 146.7, 128.2, 126.6, 126.6, 61.8, 47.7, 31.8, 30.3, 26.1. HRMS (ESI): m/z calcd for C12H18NaOS [M + Na]+: 233.0971; found: 233.0971. IR (film): 3384, 2964, 2927, 2870, 1494, 1446, 1133, 1030, 768, 698 cm–1. Cyclohexyl(2-phenylpropan-2-yl)sulfane (4f) The product was obtained as colorless oil (218 mg, 93% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 8.3, 1.0 Hz, 2 H), 7.31 (t, J = 7.7 Hz, 2 H), 7.20 (t, J = 7.3 Hz, 1 H), 2.35–2.27 (m, 1 H), 1.72 (s, 6 H), 1.66–1.55 (m, 4 H), 1.44 (s, 1 H), 1.29–1.12 (m, 5 H). 13C NMR (101 MHz, CDCl3): δ = 147.4, 128.0, 126.6, 126.4, 48.3, 42.6, 35.4, 31.1, 26.2, 25.7. HRMS (ESI): m/z calcd for C15H22NaS [M + Na]+: 257.1334; found: 257.1361. IR (film): 2968, 1588, 1489, 1222, 1155, 1129, 1088, 823, 769, 697 cm–1. Benzyl(2-phenylpropan-2-yl)sulfane (4g) The product was obtained as colorless oil (210 mg, 87% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.64–7.60 (m, 2 H), 7.38 (t, J = 7.8 Hz, 2 H), 7.29–7.23 (m, 3 H), 7.20 (d, J = 6.9 Hz, 1 H), 7.18–7.14 (m, 2 H), 3.43 (s, 2 H), 1.75 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 146.4, 138.3, 129.0, 128.5, 128.3, 126.8, 126.7, 126.7, 48.7, 34.7, 30.4. GC-MS (EI): m/z calcd for C16H18S 242.1; found: 242.1. IR (film): 2964, 2924, 1494, 1453, 1261, 1132, 1098, 1029, 803, 697. (4-(tert-Butyl)benzyl)(2-phenylpropan-2-yl)sulfane (4h) The product was obtained as colorless oil (250 mg, 84% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.5 Hz, 2 H), 7.40 (t, J = 7.7 Hz, 2 H), 7.33–7.28 (m, 3 H), 7.13 (d, J = 8.1 Hz, 2 H), 3.45 (s, 2 H), 1.80 (s, 6 H), 1.34 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 149.7, 146.5, 135.1, 128.7, 128.2, 126.7, 126.6, 125.4, 48.6, 34.5, 34.1, 31.5, 30.4. HRMS (ESI): m/z calcd for C20H26NaS [M + Na]+: 321.1647; found: 321.1636. IR (film): 2963, 2867, 1494, 1447, 1364, 1133, 1098, 1029, 768, 698 cm–1. (4-Methoxybenzyl)(2-phenylpropan-2-yl)sulfane (4i) The product was obtained as colorless oil (242 mg, 89% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.61–7.55 (m, 2 H), 7.36 (t, J = 7.7 Hz, 2 H), 7.23 (d, J = 7.3 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 H), 3.76 (s, 3 H), 3.36 (s, 2 H), 1.72 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 158.6, 146.5, 130.2, 130.1, 128.3, 126.7, 126.6, 113.9, 55.4, 48.6, 34.0, 30.4. HRMS (ESI): m/z calcd for C17H20KOS [M + K]+: 311.0866; found: 311.0890. IR (film): 3508, 2962, 2926, 1610, 1511, 1249, 1097, 1032, 804, 698 cm–1. (4-Fluorobenzyl)(2-phenylpropan-2-yl)sulfane (4j) The product was obtained as colorless oil (219 mg, 84% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.68–7.60 (m, 2 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.12 (dd, J = 8.3, 5.6 Hz, 2 H), 6.95 (t, J = 8.6 Hz, 2 H), 3.43 (s, 2 H), 1.78 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 161.8 (d, J = 246 Hz), 146.2, 134.0 (d, J = 4.0 Hz), 130.5 (d, J = 8.1 Hz), 128.2, 126.7, 115.2 (d, J = 21.2 Hz), 48.6, 33.8, 30.3. 19F NMR (376 MHz, CDCl3): δ = –115.90. HRMS (ESI): m/z calcd for C16H18FS [M + H]+: 261.1108; found: 261.1103. IR (film): 2964, 2360, 2344, 1508, 1261, 1223, 1098, 1030, 803, 698 cm–1. (4-Chlorobenzyl)(2-phenylpropan-2-yl)sulfane (4k) The product was obtained as colorless oil (237 mg, 86% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.60–7.56 (m, 2 H), 7.36 (t, J = 7.7 Hz, 2 H), 7.26 (t, J = 7.3 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.3 Hz, 2 H), 3.37 (s, 2 H), 1.73 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 146.2, 136.9, 132.5, 130.3, 128.5, 128.3, 126.7, 126.7, 48.8, 34.0, 30.3. HRMS (ESI): m/z calcd for C16H17ClKS [M + K]+: 315.0371; found: 315.0393. IR (film): 2965, 2925, 1490, 1446, 1132, 1094, 1015, 807, 768, 698 cm–1. (2-Phenylpropan-2-yl)(4-(trifluoromethyl)benzyl)sulfane (4l) The product was obtained as colorless oil (272 mg, 88% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.59–7.55 (m, 2 H), 7.48 (d, J = 8.1 Hz, 2 H), 7.36 (t, J = 7.7 Hz, 2 H), 7.28 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 3.45 (s, 2 H), 1.74 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 146.1, 142.7 (d, J = 2.0 Hz), 129.0 (q, J = 97.0 Hz), 129.3, 128.3, 126.8, 126.7, 124.3 (d, J = 274 Hz), 125.3 (q, J = 12.1 Hz), 48.9, 34.3, 30.3. 19F NMR (376 MHz, CDCl3): δ = –62.50. HRMS (ESI): m/z calcd for C17H18F3S [M + H]+: 311.1076; found: 311.1077. IR (film): 2967, 1618, 1492, 1324, 1164, 1124, 1067, 1019, 847, 698 cm–1. (4-Fluorophenyl)(2-phenylpropan-2-yl)sulfane (4m) The product was obtained as colorless oil (236 mg, 96% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 10:1). 1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 2 H), 7.29 (d, J = 6.8 Hz, 1 H), 7.21–7.14 (m, 2 H), 6.93 (t, J = 8.4 Hz, 2 H), 1.77 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 163.3 (d, J = 249 Hz), 146.2, 138.6 (d, J = 8.1 Hz), 128.0, 126.7, 126.6, 115.4 (d, J = 22.2 Hz), 51.1, 29.6. HRMS (ESI): m/z calcd for C15H16FS [M + H]+: 247.0951; found: 247.0951. IR (film): 2968, 2924, 1588, 1489, 1222, 1155, 1088, 832, 767, 697 cm–1. S-(2-Phenylpropan-2-yl) Ethanethioate (4n) The product was obtained as colorless oil (140 mg, 72% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 7.5 Hz, 2 H), 7.34 (t, J = 7.7 Hz, 2 H), 7.27–7.21 (m, 1 H), 2.19 (s, 3 H), 1.87 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 195.4, 145.8, 128.2, 126.9, 126.3, 52.5, 31.1, 28.9. HRMS (ESI): m/z calcd for C11H14NaOS [M + Na]+: 217.0658; found: 217.0620. IR (film): 2965, 2926, 2360, 2343, 1735, 1263, 1129, 1029, 766, 698 cm–1. S-(2-Phenylpropan-2-yl) Benzothioate (4o) The product was obtained as colorless oil (184 mg, 72% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.5 Hz, 2 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.38 (dt, J = 12.3, 7.9 Hz, 4 H), 7.26 (t, J = 7.3 Hz, 1 H), 2.00 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 191.3, 146.1, 137.9, 133.1, 128.5, 128.2, 127.1, 126.9, 126.3, 52.6, 29.3. HRMS (ESI): m/z calcd for C16H16NaOS [M + Na]+: 279.0814; found: 279.0829. IR (film): 2968, 2352, 1660, 1580, 1447, 1204, 1175, 1132, 907, 690 cm–1. Ethane-1,2-diyl Bis(2-((2-phenylpropan-2-yl)thio)acetate) (4p) The product was obtained as colorless oil (189 mg, 85% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.55–7.50 (m, 4 H), 7.32 (t, J = 7.7 Hz, 4 H), 7.21 (t, J = 7.3 Hz, 2 H), 4.07 (s, 4 H), 2.99 (s, 4 H), 1.72 (s, 12 H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 145.4, 128.3, 126.9, 126.7, 62.7, 48.6, 32.3, 30.1. HRMS (ESI): m/z calcd for C24H30NaO4S2 [M + Na]+: 469.1478; found: 469.1481. IR (film): 2966, 2360, 1735, 1447, 1261, 1126, 1099, 1030, 769, 699 cm–1. Methyl N-((Benzyloxy)carbonyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (4q) The product was obtained as colorless oil (280 mg, 73% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 20:1). 1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 7.7 Hz, 2 H), 7.42–7.27 (m, 7 H), 7.21 (t, J = 7.3 Hz, 1 H), 5.55 (d, J = 8.0 Hz, 1 H), 5.10 (s, 2 H), 4.45 (dt, J = 7.8, 5.2 Hz, 1 H), 3.66 (s, 3 H), 2.75–2.58 (m, 2 H), 1.70 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 170.9, 155.5, 145.7, 136.1, 128.3, 128.1, 128.0, 128.0, 126.6, 126.3, 66.8, 53.2, 52.3, 47.9, 31.7, 30.0. HRMS (ESI): m/z calcd for C21H25NNaO4S [M + Na]+: 10.1397; found: 410.1336. IR (film): 3345, 3033, 2965, 1726, 1507, 1438, 1212, 1057, 770, 699 cm–1. Methyl N-(((Benzyloxy)carbonyl)-l-alanyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5a) The product was obtained as yellow oil (133 mg, 58% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.7 Hz, 2 H), 7.40–7.27 (m, 7 H), 7.19 (t, J = 7.3 Hz, 1 H), 6.48 (d, J = 6.1 Hz, 1 H), 5.43 (d, J = 6.7 Hz, 1 H), 5.13 (s, 2 H), 4.59 (dt, J = 7.5, 5.1 Hz, 1 H), 4.27–4.15 (m, 1 H), 3.66 (s, 3 H), 2.71–2.66 (m, 2 H), 1.67 (s, 6 H), 1.34 (d, J = 7.0 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 172.0, 170.7, 155.8, 146.0, 136.4, 128.6, 128.3, 128.3, 128.1, 126.9, 126.5, 67.1, 52.7, 51.7, 50.4, 48.2, 31.4, 30.2, 30.0, 19.0. HRMS (ESI): m/z calcd for C24H30N2NaO5S [M + Na]+: 481.1768; found: 481.1768. IR (film): 3309, 2954, 1719, 1671, 1523, 1454, 1256, 1070, 745, 699 cm–1. Methyl N-(((Benzyloxy)carbonyl)-l-methionyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5b) The product was obtained as yellow oil (160 mg, 62% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.8 Hz, 2 H), 7.33 (m, 7 H), 7.19 (t, J = 7.3 Hz, 1 H), 6.69 (d, J = 7.3 Hz, 1 H), 5.66 (d, J = 8.0 Hz, 1 H), 5.13 (s, 2 H), 4.58 (dd, J = 12.4, 5.2 Hz, 1 H), 4.36 (dd, J = 13.5, 6.6 Hz, 1 H), 3.66 (s, 3 H), 2.67 (ddd, J = 17.5, 12.9, 5.1 Hz, 2 H), 2.58 (t, J = 7.1 Hz, 2 H), 2.12 (s, 3 H), 1.96 (dd, J = 15.0, 7.9 Hz, 2 H), 1.67 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 170.5, 155.8, 145.8, 136.3, 128.6, 128.3, 128.2, 128.1, 127., 126.5, 67.1, 53.5, 52.6, 51.6, 48.2, 32.1, 31.3, 30.2, 30.0, 29.8, 15.2. HRMS (ESI): m/z calcd for C26H34N2NaO5S2 [M + Na]+: 541.1801; found: 541.1801. IR (film): 3308, 2963, 1745, 1668, 1522, 1438, 1214, 1178, 1049, 699. Methyl N-(((Benzyloxy)carbonyl)-l-seryl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5c) The product was obtained as yellow oil (143 mg, 48% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.35 (d, J = 11.3 Hz, 8 H), 7.28 - 7.20 (m, 2 H), 5.73 (s, 1 H), 5.09 (s, 2 H), 4.90 (s, 1 H), 4.36 (s, 1 H), 3.75 (s, 3 H), 3.57 (s, 1 H), 3.29 (t, J = 8.1 Hz, 1 H), 3.19 (d, J = 4.6 Hz, 2 H), 1.56 (d, J = 6.0 Hz, 6 H). 13C NMR (101 MHz, CDCl3): δ = 170.5, 170.3, 156.2, 145.1, 136.3, 128.7, 128.5, 128.3, 128.2, 127.3, 125.8, 67.2, 62.7, 54.7, 52.9, 52.0, 40.7, 29.8, 28.2. HRMS (ESI): m/z calcd for C24H30N2NaO6S [M + Na]+: 497.1717; found: 497.1716. IR (film): 2923, 2852, 2360, 1735, 1654, 1508, 1211, 1083, 970, 697 cm–1. Methyl N-(((Benzyloxy)carbonyl)-l-threonyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5d) The product was obtained as yellow oil (134 mg, 55% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.6 Hz, 2 H), 7.34 (m, 7 H), 7.21 (t, J = 7.2 Hz, 1 H), 6.94 (d, J = 7.4 Hz, 1 H), 5.74 (d, J = 7.7 Hz, 1 H), 5.15 (s, 2 H), 4.57 (dd, J = 12.9, 5.6 Hz, 1 H), 4.30 (s, 1 H), 4.17 (d, J = 7.5 Hz, 1 H), 3.67 (s, 3 H), 3.09 (s, 1 H), 2.73–2.62 (m, 2 H), 1.67 (s, 6 H), 1.17 (d, J = 6.4 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.7, 170.3, 156.6, 145.7, 136.1, 128.5, 128.2, 128.2, 128.0, 126.8, 126.4, 67.3, 67.2, 58.7, 52.6, 51.7, 48.1, 31.2, 30.1, 30.0, 17.8. HRMS (ESI): m/z calcd for C25H33N2O6S [M + H]+: 489.2054; found: 489.2054. IR (film): 2962, 2924, 2361, 2344, 1735, 1522, 1458, 1260, 1021, 799 cm–1. Methyl N-(((Benzyloxy)carbonyl)-l-phenylalanyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5e) The product was obtained as yellow oil (151 mg, 56% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.7 Hz, 2 H), 7.39–7.23 (m, 10 H), 7.20 (d, J = 6.9 Hz, 3 H), 6.41 (d, J = 7.0 Hz, 1 H), 5.46 (d, J = 7.7 Hz, 1 H), 5.10 (s, 2 H), 4.57 (dd, J = 12.3, 5.1 Hz, 1 H), 4.45 (d, J = 7.0 Hz, 1 H), 3.65 (s, 3 H), 3.05 (d, J = 6.3 Hz, 2 H), 2.68–2.56 (m, 2 H), 1.65 (s, 3 H), 1.63 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.5, 170.4, 155.8, 145.9, 136.3, 129.5, 128.7, 128.6, 128.3, 128.2, 128.1, 127.0, 126.9, 126.5, 67.0, 55.9, 52.6, 51.7, 48.1, 38.8, 31.4, 30.2, 30.0. HRMS (ESI): m/z calcd for C30H34N2NaO5S [M + Na]+: 557.2081; found: 557.2081. IR (film): 3309, 2955, 1744, 1665, 1522, 1497, 1438, 1213, 1029, 698 cm–1. Methyl N-(((Benzyloxy)carbonyl)-l-tyrosyl)-S-(2-phenylpropan-2-yl)-l-cysteinate (5f) The product was obtained as yellow oil (144 mg, 52% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.8 Hz, 2 H), 7.39–7.25 (m, 7 H), 7.18 (t, J = 7.1 Hz, 1 H), 7.00 (d, J = 7.5 Hz, 2 H), 6.68 (d, J = 8.0 Hz, 2 H), 6.45 (s, 1 H), 6.34 (d, J = 7.0 Hz, 1 H), 5.43 (d, J = 7.4 Hz, 1 H), 5.10 (s, 2 H), 4.54 (dd, J = 12.3, 5.1 Hz, 1 H), 4.35 (d, J = 6.3 Hz, 1 H), 3.64 (s, 3 H), 2.95 (d, J = 6.2 Hz, 2 H), 2.62 (qd, J = 12.9, 5.1 Hz, 2 H), 1.65 (s, 3 H), 1.63 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.9, 170.5, 156.0, 155.3, 145.9, 136.2, 130.6, 128.7, 128.4, 128.3, 128.1, 127.6, 127.0, 126.5, 115.8, 67.3, 56.2, 52.7, 51.8, 48.2, 38.1, 31.4, 30.2, 30.0. HRMS (ESI): m/z calcd for C30H34N2NaO6S [M + Na]+: 573.2030; found: 573.2022. IR (film): 3324, 2962, 1665, 1516, 1439, 1365, 1218, 1174, 1028, 699 cm–1. Methyl N-(N2,N6-Bis((benzyloxy)carbonyl)-l-lysyl)-S-(2-phe-nylpropan-2-yl)-l-cysteinate (5g) The product was obtained as yellow oil (173 mg, 53% yield) after purification by flash column chromatography on silica gel (PE/EtOAc = 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.7 Hz, 2 H), 7.41–7.24 (m, 12 H), 7.20 (t, J = 7.1 Hz, 1 H), 6.51 (d, J = 7.2 Hz, 1 H), 5.61 (d, J = 7.6 Hz, 1 H), 5.14 (s, 1 H), 5.11 (s, 2 H), 5.06 (s, 2 H), 4.58 (dd, J = 11.9, 5.0 Hz, 1 H), 4.17 (d, J = 6.0 Hz, 1 H), 3.60 (s, 3 H), 3.17 (d, J = 4.9 Hz, 2 H), 2.67 (d, J = 4.7 Hz, 2 H), 1.79 (s, 1 H), 1.66 (s, 6 H), 1.55 (s, 1 H), 1.47 (dd, J = 16.7, 9.9 Hz, 2 H), 1.34 (s, 2 H). 13C NMR (101 MHz, CDCl3): δ = 171.4, 170.8, 156.6, 156.1, 145.9, 136.7, 136.4, 128.6, 128.5, 128.3, 128.2, 128.2, 128.1, 128.1, 126.9, 126.5, 67.1, 66.7, 54.5, 52.6, 51.7, 48.2, 40.4, 32.4, 31.3, 30.2, 30.0, 29.4, 22.0. HRMS (ESI): m/z calcd for C35H43N3NaO7S [M + H]+: 672.2714; found: 672.2719. IR (film): 3325, 2952, 1718, 1519, 1455, 1240, 1132, 1028, 740, 698 cm–1.