Transition-Metal-Free Esterification of Amides via Selective N C Cleavage under Mild Conditions. Supporting Information

Transcription

1 Transition-Metal-Free Esterification of Amides via Selective N C Cleavage under Mild Conditions Guangchen Li, Peng Lei,, and Michal Szostak*, Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States Department of Applied Chemistry, College of Science, China Agricultural University, Beijing , China michal.szostak@rutgers.edu Supporting Information Table of Contents 1 Tables SI-1 and SI-2 Referred to from the Main Manuscript 2 List of Known Compounds/General Methods 4 Experimental Procedures and Characterization Data 5 General Procedures 5 Characterization Data of Starting Materials 7 Characterization Data of Esterification Products 10 Mechanistic Studies 26 References 27 1 H and 13 C NMR Spectra 28 Corresponding Author: Department of Chemistry, Rutgers University 73 Warren Street, Newark, NJ 07102, United States michal.szostak@rutgers.edu SI-1

2 Table SI-1 Referred to from the Main Manuscript Table SI-1. Summary of State-of-the-art Methods for Esterification of Amides Using Metal- Catalysis and Transition-Metal-Free Conditions. a e Conditions Aromatic Alcohol Aliphatic Alcohol Aliphatic Amide [Ni]/SIPr, 80 C a + [Ni]/terpy, 100 C b + + [Co]/bipy, 60 C c + + [F ], 100 C d + + transition-metal-free, 23 C e a Ref. 15a. b Ref. 15b. c Ref. 17. d Ref. 18. e This study. SI-2

3 Table SI-2 Referred to from the Main Manuscript Table SI-2. Summary of Key Optimization Studies in the Transition-Metal-Free Esterification of Amides by Selective N C Cleavage under Mild Conditions. a Entry Base Solvent 2 (equiv) Base (equiv) Yield b (%) 1 K2CO3 THF K2CO3 dioxane K2CO3 toluene KF toluene <5 5 K3PO4 THF >95 6 KF THF <5 7 KOH THF Na2CO3 THF <5 9 Cs2CO3 THF K3PO4 THF Cs2CO3 THF K3PO4 DMF K3PO4 CH3CN K3PO4 acetone K3PO4 CH2Cl K3PO4 THF K3PO4 THF > THF <2 a Conditions: amide (1.0 equiv), ROH ( equiv), base ( equiv), solvent (1.0 M), 23 C, 15 h. All reactions carried out using standard Schlenk techniques. b Determined by 1 H NMR and/or GC-MS. SI-3

4 List of Known Compounds/General Methods All starting materials reported in the manuscript have been previously described in literature or prepared by the method reported previously unless stated otherwise. Amides were prepared by standard methods. 1-7 All products reported in the manuscript have been previously described in literature. All experiments were performed using standard Schlenk techniques under argon or nitrogen atmosphere unless stated otherwise. All solvents were purchased at the highest commercial grade and used as received or after purification by passing through activated alumina columns or distillation from sodium/benzophenone under nitrogen. All other chemicals were purchased at the highest commercial grade and used as received. Reaction glassware was ovendried at 140 C for at least 24 h or flame-dried prior to use, allowed to cool under vacuum and purged with argon or nitrogen (three cycles). All products were identified using 1 H NMR analysis and comparison with authentic samples. GC and/or GC/MS analysis was used for volatile products. All yields refer to yields determined by 1 H NMR and/or GC or GC/MS using an internal standard (optimization) and isolated yields (preparative runs) unless stated otherwise. 1 H NMR and 13 C NMR spectra were recorded in CDCl3 on Bruker spectrometers at 500 ( 1 H NMR) and 125 MHz ( 13 C NMR). All shifts are reported in parts per million (ppm) relative to residual CHCl3 peak (7.27 and 77.2 ppm, 1 H NMR and 13 C NMR, respectively). All coupling constants (J) are reported in hertz (Hz). Abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; brs, broad singlet. GC-MS chromatography was performed using Agilent HP6890 GC System and Agilent 5973A inert XL EI/CI MSD using helium as the carrier gas at a flow rate of 1 ml/min and an initial oven temperature of 50 C. The injector temperature was 280 C. The detector temperature was 280 C. For runs with the initial oven temperature of 50 C, temperature was increased with a 10 C/min ramp after 50 C hold for 3 min to a final temperature of 280 C, then hold at 280 C for 10 min (splitless mode of injection, total run time of min). All flash chromatography was performed using silica gel, 60 Å, 300 mesh. TLC analysis was carried out on glassplates coated with silica gel 60 F254, 0.2 mm thickness. The plates were visualized using a 254 nm ultraviolet lamp or aqueous potassium permanganate solutions. 1 H NMR and 13 C NMR data are given for all compounds in the Supporting Experimental for characterization purposes. 1 H NMR, 13 C NMR and HRMS data are reported for all new compounds. SI-4

5 Experimental Procedures and Characterization Data Amides 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o were prepared by procedures reported in the literature a, 1 1b, 1 1c, 1 1d, 1 1e, 1 1f, 1 1g, 1 1h, 2 1i, 3 1j, 2 1k, 4 1l, 5 1m, 4 1n, 6 1o 7 are known compounds. Spectroscopic data matched those reported in the literature. All products reported in the manuscript have been previously well described in literature. General Procedure for Esterification. An oven-dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv), alcohol (typically, 1.2 equiv) and K3PO4 (typically, 3.0 equiv), and placed under a positive pressure of nitrogen. THF (typically, 1.0 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for an indicated time. After the indicated time, the reaction mixture was diluted with CH2Cl2 (5 ml) and filtered. The organic layer was washed with water (1 x 5 ml), brine (1 x 5 ml), dried, and concentrated. A sample was analyzed by 1 H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. Unless stated otherwise, the crude product was purified by flash chromatography (EtOAc/hexanes) to give analytically pure product. Representative Procedure for Metal-Free Esterification. 1.0 mmol Scale. Amide 1a. An oven-dried vial equipped with a stir bar was charged with tert-butyl benzoyl(phenyl)carbamate (0.297 g, 1.0 mmol, 1.0 equiv), phenol (0.113 g, 1.2 mmol, 1.2 equiv), and K3PO4 (0.637 g, 3.0 mmol, 3.0 equiv), and placed under a positive pressure of nitrogen. THF (1.0 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for 15 h. After the indicated time, the reaction mixture was diluted with CH2Cl2 (20 ml) and filtered. The organic layer was washed with water (1 x 20 ml), brine (1 x 20 ml), dried, and concentrated. Purification by chromatography on silica gel (EtOAc/hexanes) afforded the title product. White solid. Yield 90%. Characterization data are included in the section below. Representative Procedure for Metal-Free Esterification. 1.0 mmol Scale. Amide 5a. An oven-dried vial equipped with a stir bar was charged with N-methyl-N-tosylbenzamide (0.289 g, 1.0 mmol, 1.0 equiv), phenol (0.113 g, 1.2 mmol, 1.2 equiv), and K3PO4 (0.637 g, 3.0 mmol, 3.0 SI-5

6 equiv), and placed under a positive pressure of nitrogen. THF (1.0 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for 15 h. After the indicated time, the reaction mixture was diluted with CH2Cl2 (20 ml) and filtered. The organic layer was washed with water (1 x 20 ml), brine (1 x 20 ml), dried, and concentrated. Purification by chromatography on silica gel (EtOAc/hexanes) afforded the title product. White solid. Yield 95%. Characterization data are included in the section below. SI-6

7 Characterization Data for Starting Materials tert-butyl benzoyl(phenyl)carbamate (1a). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), (m, 4 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.30 (d, J = 7.4 Hz, 2 H), 1.26 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , 83.50, tert-butyl (4-methylbenzoyl)(phenyl)carbamate (1b). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.9 Hz, 2 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.35 (t, J = 7.2 Hz, 1 H), (m, 4 H), 2.44 (s, 3 H), 1.29 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , 83.27, 27.56, tert-butyl (4-methoxybenzoyl)(phenyl)carbamate (1c). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2 H), 7.43 (t, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 6.95 (d, J = 7.7 Hz, 2 H), 3.88 (s, 3 H), 1.32 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , 83.10, 55.49, tert-butyl phenyl(4-(trifluoromethyl)benzoyl)carbamate (1d). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.29 (d, J = 7.2 Hz, 2 H), 1.27 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , (J F = 65.0 Hz), , , , (J F = 7.5 Hz), (J F = Hz), 84.12, F NMR (471 MHz, CDCl3) δ tert-butyl phenyl((4-(methoxycarbonyl)benzoyl)carbamate (1e). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.1 Hz, 2 H), 7.78 (d, J = 8.1 Hz, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.38 (t, J = 7.3 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 3.97 (s, 3 H), 1.26 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ SI-7

8 171.83, , , , , , , , , , , 84.01, 52.42, tert-butyl phenyl(3,4-difluorobenzoyl)carbamate (1f). White solid. 1 H NMR (500 MHz, CDCl3) δ (t, J = 7.3 Hz, 1 H), 7.52 (brs, 1 H), 7.45 (t, J = 7.4 Hz, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.25 (d, J = 7.9 Hz, 3 H), 1.33 (s, 9 H). 13 C NMR (125 MHz CDCl3) δ , (J F = Hz), , (J F = Hz), , (J F = 5.0 Hz), , , , (J F = 15.0 Hz, J F = 7.5 Hz), (J F = 18.8 Hz), (J F = 17.5 Hz), 83.98, F NMR (471 MHz, CDCl3) δ , tert-butyl (furan-2-carbonyl)(phenyl)carbamate (1g). White solid. 1 H NMR (500 MHz, CDCl3) δ (m, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.28 (d, J = 7.2 Hz, 2 H), 7.04 (d, J = 3.5 Hz, 1 H), 6.53 (dd, J = 3.5, 1.7 Hz, 1 H), 1.42 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , 83.34, tert-butyl (1-decanoyl)(phenyl)carbamate (1h). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.41 (t, J = 7.2 Hz, 2 H), 7.34 (t, J = 7.3 Hz, 1 H), 7.09 (d, J = 7.7 Hz, 2 H), 2.92 (t, J = 7.4 Hz, 2 H), 1.70 (p, J = 7.3, 6.8 Hz, 2 H), 1.40 (s, 9 H), 1.29 (s, 12 H), 0.90 (t, J = 6.4 Hz, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , 82.93, 38.03, 31.90, 29.48, 29.30, 29.23, 27.84, 25.01, 22.69, tert-butyl (cyclohexanecarbonyl)(phenyl)carbamate (1i). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.08 (d, J = 7.1 Hz, 2 H), 3.38 (tt, J = 11.4, 3.3 Hz, 1 H), 1.99 (d, J = 11.9 Hz, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), 1.43 (d, J = 7.9 Hz, 9 H), (m, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , 82.94, 44.57, 29.65, 27.86, 25.88, SI-8

9 tert-butyl phenyl(pivaloyl)carbamate (1j). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.38 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 1.48 (s, 9H), 1.28 (s, 9H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , 82.43, 44.04, 28.36, N-Methyl-N-tosylbenzamide (1k). Colorless oil. 1 H NMR (500 MHz, CDCl3) 7.85 (d, J = 7.4 Hz, 2 H), 7.57 (d, J = 7.3 Hz, 2 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.35 (d, J = 7.6 Hz, 2 H), 3.30 (s, 3 H), δ 2.47 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , 35.61, N-Phenyl-N-tosylbenzamide (1l).White solid. 1 H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 4 H), 7.19 (t, J = 7.1 Hz, 4 H), 2.48 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , , , , Benzoylpiperidine-2,6-dione (1m). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 2 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 2 H), 2.80 (t, J = 6.6 Hz, 4 H), 2.17 (q, J = 6.5 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , 32.41, tert-butyl benzoyl(benzyl)carbamate (1n). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.0 Hz, 2 H), 7.47 (dd, J = 10.9, 7.4 Hz, 3 H), 7.41 (d, J = 7.7 Hz, 2 H), 7.37 (s, 2 H), 7.30 (s, 1 H), 5.02 (s, 2 H), 1.15 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , 83.18, 48.88, N,N-Boc2-Benzamide (1o). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.7 Hz, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.3 Hz, 2 H), 1.39 (s, 18 H). 13 C NMR (125 MHz, CDCl3) δ , , , , 84.27, SI-9

10 Characterization Data for Esterification Products Phenyl benzoate (3a, Scheme 1) According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (1.0 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 90% yield (178.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Methoxyphenyl benzoate (3b, Scheme 1) According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), 4-methoxyphenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 83% yield (18.9 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz, 2 H), 7.66 (t, J = 7.0 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.17 (d, J = 8.5 Hz, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 3.86 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , (Trifluoromethyl)phenyl benzoate (3c, Scheme 1) SI-10

11 According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), 4-(trifluoromethyl)phenol (3.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 85% yield (22.6 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.70 (t, J = 7.0 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 2 H), 7.39 (d, J = 8.2 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , (q, J F = 33.0 Hz), (q, J F = 3.6 Hz), (q, J F = Hz), F NMR (471 MHz, CDCl3) δ ,6-Dimethylphenyl benzoate (3d, Scheme 1) According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), 2,6-dimethylphenol (2.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 92% yield (20.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 2 H), 7.69 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 7.14 (s, 3 H), 2.23 (s, 6 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Bromophenyl benzoate (3e, Scheme 1) SI-11

12 According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), 4-bromophenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 90% yield (24.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.8 Hz, 2 H), 7.68 (t, J = 7.4 Hz, 1 H), (m, 4 H), 7.15 (d, J = 8.6 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Formylphenyl benzoate (3f, Scheme 1) According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), 3-hydroxybenzaldehyde (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 94% yield (21.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ (s, 1 H), 8.24 (d, J = 7.7 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.79 (s, 1 H), 7.69 (t, J = 7.3 Hz, 1 H), 7.64 (t, J = 7.7 Hz, 1 H), (m, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , , Phenyl 4-methylbenzoate (3g, Scheme 1) According to the general procedure, the reaction of tert-butyl (4- methylbenzoyl)(phenyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 85% yield (18.0 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.34 (d, J = 7.9 Hz, 2 SI-12

13 H), 7.29 (d, J = 6.6 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 2.48 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Phenyl 4-methoxybenzoate (3h, Scheme 1) According to the general procedure, the reaction of tert-butyl (4- methoxybenzoyl)(phenyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 92% yield (21.0 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.24 (d, J = 7.3 Hz, 2 H), 7.02 (d, J = 8.4 Hz, 2 H), 3.92 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Phenyl 4-(trifluoromethyl)benzoate (3i, Scheme 1) According to the general procedure, the reaction of tert-butyl phenyl(4- (trifluoromethyl)benzoyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 76% yield (20.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 8.1 Hz, 2 H), 7.81 (d, J = 8.1 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , (q, J F = 32.5 Hz), , , , , (q, J F = 3.7 Hz), (q, J F = Hz), (s). 19 F NMR (471 MHz, CDCl3) δ Methyl phenyl terephthalate (3j, Scheme 1) SI-13

14 According to the general procedure, the reaction of methyl 4-((tertbutoxycarbonyl)(phenyl)carbamoyl)benzoate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 65% yield (16.6 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 7.9 Hz, 2 H), 8.20 (d, J = 7.9 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.26 (d, J = 8.1 Hz, 2 H), 4.00 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , Phenyl 3,4-difluorobenzoate (3k, Scheme 1) According to the general procedure, the reaction of tert-butyl (3,4- difluorobenzoyl)(phenyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 71% yield (16.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ (m, 2 H), 7.47 (t, J = 7.7 Hz, 2 H), (m, 2 H), 7.23 (d, J = 7.8 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , (dd, J F = 257.3, 12.7 Hz), (dd, J F = 250.5, 13.0 Hz), , , (dd, J F = 7.6, 3.7 Hz), (dd, J F = 5.5, 3.6 Hz), , , (d, J F = 18.8 Hz), (d, J F = 17.9 Hz). 19 F NMR (471 MHz, CDCl3) δ (m), (m). Phenyl furan-2-carboxylate (3l, Scheme 1) SI-14

15 According to the general procedure, the reaction of tert-butyl (furan-2- carbonyl)(phenyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 78% yield (14.7 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 7.70 (s, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.41 (d, J = 3.3 Hz, 1 H), (m, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), (m, 1 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Phenyl decanoate (3m, Scheme 1) According to the general procedure, the reaction of tert-butyl decanoyl(phenyl)carbamate (0.10 mmol), phenol (2.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 88% yield (21.8 mg). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.41 (t, J = 7.0 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 7.11 (d, J = 7.8 Hz, 2 H), 2.59 (t, J = 7.5 Hz, 2 H), (m, 2 H), (m, 2 H), (m, 10 H), (m, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , 34.45, 31.89, 29.45, 29.28, 29.14, 24.99, 22.70, Phenyl cyclohexanecarboxylate (3n, Scheme 1) According to the general procedure, the reaction of tert-butyl (cyclohexanecarbonyl)(phenyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 84% yield (17.1 mg). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.41 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 2 H), 2.60 (t, J = 11.2 Hz, 1 H), 2.11 (d, J = 12.8 Hz, 2 H), 1.86 (d, J = 12.8 Hz, 2 H), 1.74 SI-15

16 (d, J = 11.5 Hz, 1 H), 1.64 (dd, J = 23.8, 12.1 Hz, 2 H), 1.38 (td, J = 24.1, 11.8 Hz, 3 H). 13 C NMR (125 MHz, CDCl3) δ 174.6, , , , , 43.24, 28.99, 25.76, Phenyl pivalate (3o, Scheme 1) According to the general procedure, the reaction of tert-butyl phenyl(pivaloyl)carbamate (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 82% yield (14.6 mg). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 7.8 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 2 H), 1.40 (s, 9 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , 39.08, Benzyl benzoate (3p, Scheme 1) According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.10 mmol), phenylmethanol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 94% yield (19.9 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Phenyl benzoate (3a, Scheme 2) SI-16

17 According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), phenylmethanol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 95% yield (188.7 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Methoxyphenyl benzoate (3b, Scheme 2) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 4- methoxyphenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 85% yield (19.4 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz, 2 H), 7.66 (t, J = 7.0 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.17 (d, J = 8.5 Hz, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 3.86 (s, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , (Trifluoromethyl)phenyl benzoate (3c, Scheme 2) SI-17

18 According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 4- (trifluoromethyl)phenol (3.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 71% yield (18.9 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.70 (t, J = 7.0 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 2 H), 7.39 (d, J = 8.2 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , (q, J F = 33.0 Hz), (q, J F = 3.6 Hz), (q, J F = Hz), F NMR (471 MHz, CDCl3) δ ,6-Dimethylphenyl benzoate (3d, Scheme 2) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 2,6-dimethylphenol (2.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 94% yield (21.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 2 H), 7.69 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 7.14 (s, 3 H), 2.23 (s, 6 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Bromophenyl benzoate (3e, Scheme 2) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 4- bromophenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 91% yield (25.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.8 Hz, 2 H), SI-18

19 7.68 (t, J = 7.4 Hz, 1 H), (m, 4 H), 7.15 (d, J = 8.6 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Formylphenyl benzoate (3f, Scheme 2) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 3- hydroxybenzaldehyde (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 92% yield (20.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ (s, 1 H), 8.24 (d, J = 7.7 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.79 (s, 1 H), 7.69 (t, J = 7.3 Hz, 1 H), 7.64 (t, J = 7.7 Hz, 1 H), (m, 3 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , , Benzyl benzoate (3p, Scheme 2) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), phenylmethanol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 93% yield (19.7 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 2 H), 7.59 (t, J = 7.4 Hz, 1 H), (m, 7 H), 5.40 (s, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Phenyl benzoate (3a, Table 1) SI-19

20 According to the general procedure, the reaction of N-phenyl-N-tosylbenzamide (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 97% yield (19.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Phenyl benzoate (3a, Table 1) According to the general procedure, the reaction of 1-benzoylpiperidine-2,6-dione (0.10 mmol), phenol (2.0 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 95% yield (18.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Benzyl benzoate (3p, Table 1) According to the general procedure, the reaction of tert-butyl benzoyl(benzyl)carbamate (0.10 mmol), phenylmethanol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature SI-20

21 for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 80% yield (17.0 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 2 H), 7.59 (t, J = 7.4 Hz, 1 H), (m, 7 H), 5.40 (s, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , Phenyl benzoate (3a, Table 1) According to the general procedure, the reaction of N,N-Boc2-benzamide (0.10 mmol), phenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 92% yield (18.2 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.3 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H). 13 C NMR (125 MHz, CDCl3)δ , , , , , , , , Nitrophenyl benzoate (3q, Table 1) According to the general procedure, the reaction of N,N-Boc2-benzamide (0.10 mmol), 4- nitrophenol (3.0 equiv) and K3PO4 (3.0 equiv) in THF (0.50 M) at 110 C for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 72% yield (17.5 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 8.9 Hz, 2 H), 8.23 (d, J = 7.9 Hz, 2 H), 7.71 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 7.45 (d, J = 8.9 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , Benzyl benzoate (3p, Table 1) SI-21

22 According to the general procedure, the reaction of N,N-Boc2-benzamide (0.10 mmol), phenylmethanol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 90% yield (19.1 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 2 H), 7.59 (t, J = 7.4 Hz, 1 H), (m, 7H), 5.40 (s, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , SI-22

23 Amide to Thioester Conversion S-Phenyl benzothioate (3r, Scheme 3) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), benzenethiol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 80% yield (17.1 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), (m, 7 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , SI-23

24 Late-Stage Diversification 4-Allyl-2-methoxyphenyl benzoate (3s, Scheme 4) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), 4- allyl-2-methoxyphenol (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 86% yield (23.0 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.9 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.7 Hz, 2 H), 7.10 (d, J = 7.9 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 2 H), 3.83 (s, 3 H), 3.44 (d, J = 6.7 Hz, 2 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , , , , 55.91, (8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6Hcyclopenta[a]phenanthren-3-yl benzoate (3t, Scheme 4) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), (8R,9S,13S)-3-hydroxy-13-methyl-7,8,9,11,12,13,15,16-octahydro-6H-cyclopenta[a]phenanthren -17(14H)-one (1.2 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 93% yield (34.8 mg). White solid. 1 H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.7 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.02 (dd, J = 8.5, 2.1 Hz, 1 H), 6.98 (s, 1 H), (m, 2 H), 2.54 (dd, J = 19.0, 8.7 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 3 H), (m, 6 H), 0.95 (s, 3 H). 13 C SI-24

25 NMR (125 MHz, CDCl3) δ , , , , , , , , , , , 50.47, 47.98, 44.21, 38.05, 35.89, 31.59, 29.46, 26.39, 25.81, 21.62, (R)-2,5,7,8-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl benzoate (3u, Scheme 4) According to the general procedure, the reaction of N-methyl-N-tosylbenzamide (0.10 mmol), (R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-ol (1.5 equiv) and K3PO4 (3.0 equiv) in THF (1.0 M) at room temperature for 15 h, afforded after the standard work-up as described above and chromatography the title compound in 93% yield (49.7 mg). Colorless oil. 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 7.5 Hz, 2 H), 7.66 (d, J = 7.4 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 2 H), 2.65 (t, J = 6.7 Hz, 2 H), 2.15 (s, 3 H), 2.09 (s, 3 H), 2.05 (s, 3 H), (m, 2 H), (m, 3 H), (m, 3 H), (m, 10 H), (m, 6 H), (m, 12 H). 13 C NMR (125 MHz, CDCl3) δ , , , , , , , , , , , 75.10, 39.40, 37.59, 37.57, 37.48, 37.44, 37.42, 37.32, 32.82, 32.81, 32.74, 31.26, 31.08, 28.01, 24.83, 24.48, 24.23, 23.73, 22.75, 22.65, 21.07, 20.66, 19.78, 19.71, 19.69, 19.66, 19.63, 13.08, 12.23, SI-25

26 Mechanistic Studies Selectivity Studies: Amides. According to the general procedure, an oven-dried vial equipped with a stir bar was charged with two amide substrates (each 0.20 mmol, 2.0 equiv), phenol (0.10 mmol, 1.0 equiv), and K3PO4 (3.0 equiv). THF (1.0 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature. After the indicated time, the reaction mixture was diluted with CH2Cl2 (5 ml) and filtered. The organic layer was washed with water (1 x 5 ml), brine (1 x 5 ml), dried, and concentrated. A sample was analyzed by 1 H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. The observed selectivity is consistent with the relative electrophilicity of the amide bond. Selectivity Studies: Alcohols. According to the general procedure, an oven-dried vial equipped with a stir bar was charged with an amide substrate (0.10 mmol, 1.0 equiv), two alcohol substrates (each 0.20 mmol, 2.0 equiv), and K3PO4 (3.0 equiv). THF (1.0 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature. After the indicated time, the reaction mixture was diluted with CH2Cl2 (5 ml) and filtered. The organic layer was washed with water (1 x 5 ml), brine (1 x 5 ml), dried, and concentrated. A sample was analyzed by 1 H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. The observed selectivity is consistent with nucleophilic addition to the amide bond. SI-26

27 References 1. Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2017, 19, Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. Org. Lett. 2017, 19, Wu, H.; Guo, W.; Daniel, S.; Li, Y.; Liu, C.; Zeng, Z. Chem. Eur. J. 2018, 24, Liu, C.; Szostak, M. Angew. Chem. Int. Ed. 2017, 56, Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2016, 18, Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39, Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. J. Am. Chem. Soc. 2018, 140, 727. SI-27

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