Metal-Free C(sp 3 )-H Allylation via Aryl Carboxyl Radicals Enabled by Donor-Acceptor Complex Yang Li 1+, Jing Zhang 1+, Defang Li 1,2, and Yiyun Chen 1,2 * Supplementary Information I. General Procedures... 2 II. Optical Absorption and NMR Spectra Studies... 3 III. Detailed Reaction Optimizations... 12 IV. Mechanistic Investigations... 13 V. Substrate Preparations and Characterizations... 17 Synthesis of N-acyloxyl Derivatives... 17 Synthesis of N-acyloxyphthalimide Substrates... 22 Synthesis of Allyl and Vinyl Sulfones... 39 VI. Product Characterizations... 41 VII. Large-Scale Reaction... 64 VIII. References... 65 1
I. General Procedures Unless otherwise noted, all reactions of substrates preparation were conducted in flame-dried glassware under a nitrogen atmosphere using anhydrous solvent passed through an activated alumina column (Innovative Technology). Commercially available reagents were used without further purification. Hantzsch ester (HE) was recrystallized from ethanol. Thin layer chromatography (TLC) was performed using Jiangyou TLC silica gel plates HSG F 254 and visualized using UV light, and potassium permanganate. Flash chromatography was performed on Lisure science EZ purification system using the Santai technologies silica gel cartridge. Preparative thin layer chromatography separations were carried out on 0.25 or 0.50 mm E. Merck silica gel plates (60F-254). Photochemical reactions were carried with 8 W blue LED obtained from DELIXI. 1 H and 13 C NMR spectra were recorded in CDCl 3, unless otherwise noted, on a Bruker AV-400 MHz or an Agilent 500 MHz spectrometer. Chemical shifts in 1 H NMR spectra were reported in parts per million (ppm) on the δ scale from an internal standard of residual CDCl 3 (7.26 ppm). Data for 1 H NMR were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant in Herts (Hz) and integration. Data for 13 C NMR spectra were reported in terms of chemical shift in ppm from the central peak of CDCl 3 (77.16 ppm). IR spectra were recorded on a Thermo Scientific Nicolet 380 FT-IR spectrometer. MS experiments were performed on a Bruker maxis 4G instrument for HRMS-ESI, an Agilent 5973N instrument for EI-MS, and a Waters Micromass GCT Premier instrument for HRMS-EI. Optical absorption spectra were recorded on a Thermo Nanodrop 2000c UV/Vis spectrometer. GC-MS experiments were performed on an Agilent Technologies 7890A (GC system) and 5975C instrument (MS detector). 2
II. Optical Absorption and NMR Spectra Studies Charge-transfer bands in optical absorption spectra Optical absorption spectra between Hantzsch ester 5 (0.05 M) and N-acyloxyl derivatives 1-4 (0.05 M) in 0.5 ml DCM were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. Figure S1. The charge-transfer bands between Hantzsch ester 5 and N-acyloxyl derivatives 1-4. 3
Optical absorption spectra between Hantzsch ester 5 (0.05 M) and N-acyloxyl derivatives 7-10 (0.05 M) in 0.5 ml DMF were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. Figure S2. The charge-transfer bands between Hantzsch ester 5 and N-acyloxyl derivatives 7-10. Optical absorption spectra of Hantzsch ester 5 (0.05 M) and N-acyloxyl derivatives 1-4/7-10 (0.05 M) in 0.5 ml DMF were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer, a new absorption band was observed upon mixing Hantzsch ester 5 and N-acyloxyl derivatives 1-3/7-9. 4
Stoichiometry of the EDA Complex in Solution The Job s plot was constructed to evaluate the stoichiometry of the EDA complex [1] between Hantzsch ester 5 and tetrachloro-substituted N-acyloxyphthalimide 2. We measured the absorption of DCM solutions at 460 nm with different donor/acceptor ratios with constant concentration (0.05 M) of the two components. All the absorption spectra were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. The absorbance values were plotted against the molar fraction (%) of Hantzsch ester 5. The maximal absorbance at 50% molar fraction of 5 indicated the 1:1 stoichiometry of the EDA complex in solution. Figure S3. Job s plots of the EDA complexes between Hantzsch ester 5 and tetrachloro-substituted N-acyloxyphthalimide 2. 5
The Job s plot was constructed to evaluate the stoichiometry of the EDA complex between Hantzsch ester 5 and N-acyloxyphthalimide 7. We measured the absorption of DMF solutions at 450 nm with different donor/acceptor ratios with constant concentration (0.05 M) of the two components. All the absorption spectra were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. The absorbance values were plotted against the molar fraction (%) of Hantzsch ester 5. The maximal absorbance at 50% molar fraction of 5 indicated the 1:1 stoichiometry of the EDA complex in solution. Figure S4. Job s plots of the EDA complexes between Hantzsch ester 5 and N-acyloxyphthalimide 7. 6
The Job s plot was constructed to evaluate the stoichiometry of the EDA complex between Hantzsch ester 5 and tetrachloro-substituted N-acyloxyphthalimide 8. We measured the absorption of DMF solutions at 470 nm with different donor/acceptor ratios with constant concentration (0.05 M) of the two components. All the absorption spectra were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. The absorbance values were plotted against the molar fraction (%) of Hantzsch ester 5. The maximal absorbance at 50% molar fraction of 5 indicated the 1:1 stoichiometry of the EDA complex in solution. Figure S5. Job s plots of the EDA complexes between Hantzsch ester 5 and tetrachloro-substituted N-acyloxyphthalimide 8. 7
Determination of the Association Constant (K EDA ) The association constant of the EDA complex formed between tetrachloro-substituted N-acyloxyphthalimide 2 and Hantzsch ester 5 was determined spectrophotometrically in DCM, employing the Benesi-Hildebrand methodology [2]. We measured the absorption of solutions with constant concentration of tetrachloro-substituted N-acyloxyphthalimide 2 (0.03 M) at 450 nm, and added an excess of Hantzsch ester 5 to increase the donor/acceptor ratios. All the absorption spectra were recorded in 1 cm path quartz cuvettes using a Thermo Nanodrop 2000c UV/Vis spectrometer. According to the methodology, a straight line was obtained when the reciprocal of the absorbance (A) was plotted against the reciprocal of the concentration of the partner in excess. Data obtained were displayed in Table S1. The association constants (K EDA ) were calculated by dividing the intercept by the slope: 3.7 M -1 for the tetrachloro-substituted N-acyloxyphthalimide 2 / Hantzsch ester 5 complex. Table S1: Data obtained by optical absorption spectra for EDA in DMF, with [2] = 0.03 M [HE] (M) 1/[HE] (M -1 ) Abs EDA 1/( Abs EDA -A 0 ) 0.03 33.3 0.029 34.5 0.04 25 0.039 25.6 0.05 20 0.045 22.2 0.06 16.7 0.052 19.2 0.07 14.3 0.061 16.4 Figure S6. Hildebrand-Benesi plots for the EDA complexes generated in DCM upon association of the tetrachloro-substituted N-acyloxyphthalimide 2 and Hantzsch ester 5. 8
NMR Titration Experiments Solutions containing equal molar concentrations of the donor (HE 5, 0.05 M in CDCl 3 ) and the acceptor (N-acyloxyphthalimide 1, 0.05 M in CDCl 3 ) were prepared and mixed to cover acceptor/donor ratio from 0%, 10%, 20% to 100% donor (from 1 to 11 in Figure S7). Figure S7. 1 H NMR titration between Hantzsch ester 5 and N-acyloxyphthalimide 1. 9
Solutions containing equal molar concentrations of the donor (HE 5, 0.05 M in CDCl 3 ) and the acceptor (N-acyloxyphthalimide 7, 0.05 M in CDCl 3 ) were prepared and mixed to cover acceptor/donor ratio from 0%, 10%, 20% to 100% donor (from 1 to 11 in Figure S7). Figure S8. 1 H NMR titration between Hantzsch ester 5 and N-acyloxyphthalimide 7. 10
Visible-light-induced reaction between 1 and 5 A solution of N-acyloxyphthalimides 1 (28.1 mg, 0.1 mmol) and Hantzsch ester 5 (38.0 mg, 0.15 mmol) was placed in a 5 ml clear-colored glass vial. After the addition of 1.0 ml DCM (bubbled with nitrogen gas for 30 minutes to remove oxygen), the vial was sealed and exposed to 8W blue LED at room temperature with stirring for 24 hours. 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol were then added to the reaction mixture with stirring for 2 hours at room temperature. When the reaction was completed, it was concentrated in vacuo, and subjected to flash chromatography to only afford product 6 as a colorless oil (7.6 mg, 51% yield) after flash chromatography (100% hexanes): TLC R f = 0.52 (EtOAc/hexanes = 1/8); 1 H NMR (500 MHz, CDCl 3 ) 7.93 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 2.41 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 167.3, 143.7, 129.7, 129.2, 127.6, 52.1, 21.8. 11
III. Detailed Reaction Optimizations Table S2. Detailed Reaction Optimizations 12
IV. Mechanistic Investigations The Emission Spectra of Light Sources Photochemical reactions in different band-pass wavelengthes were carried with smart xenon lamp light source CEL-HXF300E/HXUV300E obtained from CEAULIGHT. The emission spectra of light sources were in Figure S9 and S10. Figure S9. The emission spectrum of band-pass 450 nm. Figure S10. The emission spectrum of band-pass 475 nm. 13
Radical-Clock Experiments A solution of N-acyloxyphthalimides 44 (33.3 mg, 0.1 mmol) and Hantzsch ester 5 (HE, 38.0 mg, 0.15 mmol) was placed in a 5 ml clear-colored glass vial. After the addition of 1.0 ml DMF (bubbled with nitrogen gas for 30 minutes to remove oxygen), the vial was sealed and exposed to 8W blue LED at room temperature with stirring for 15 hours. When the reaction was completed, it was diluted with 40 ml EtOAc and organic layers were washed with H 2 O (10 ml x 3) and brine (10 ml x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, concentrated in vacuo, and subjected to flash chromatography to afford target product 45 as a colorless oil (7.7 mg, 41% yield, E/Z > 20:1) after flash chromatography (94%:6% hexanes : acetone): TLC R f = 0.31 (EtOAc/hexanes = 1/8); 1 H NMR (500 MHz, CDCl 3 ) 7.90 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.5, 1.1 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 (dd, J = 7.7, 0.9 Hz, 1H), 6.11 (dtd, J = 15.3, 6.3, 0.9 Hz, 1H), 5.81 (d, J = 8.1 Hz, 1H), 5.43 (ddt, J = 15.3, 8.1, 1.7 Hz, 1H), 2.18 2.12 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2970, 1761, 1466, 1285, 1109, 1061, 960, 913, 744, 690 cm 1 ; HRMS-EI (m/z) [M + ]: calcd. for C 12 H 12 O 2 188.0837, found 188.0834.. 14
Carboxylic Acid is not the Reaction Intermediate A solution of aryl carboxylic acid 46 (15.0 mg, 0.1 mmol), allyl sulfone 11 (76.2 mg, 0.3 mmol) and Hantzsch ester 5 (38.0 mg, 0.15 mmol) was placed in a 5 ml clear-colored glass vial. After the addition of 1.0 ml DMF (bubbled with nitrogen gas for 30 minutes to remove oxygen), the vial was sealed and exposed to 8W blue LED at room temperature with stirring for 15 hours. When the reaction was completed, it was diluted with 40 ml EtOAc and organic layers were washed with H 2 O (10 ml x 3) and brine (10 ml x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, concentrated in vacuo, and subjected to NMR detection to observe no conversion, which suggested the carboxylic acid was not the reaction intermediate. 15
Crossover Experiments A solution of N-acyloxyphthalimides 13a (30.9 mg, 0.1 mmol), aryl carboxylic acid 46 (15.0 mg, 0.1 mmol), allyl sulfone 11 (76.2 mg, 0.3 mmol) and Hantzsch ester 5 (38.0 mg, 0.15 mmol) was placed in a 5 ml clear-colored glass vial. After the addition of 1.0 ml DMF (bubbled with nitrogen gas for 30 minutes to remove oxygen), the vial was sealed and exposed to 8W blue LED at room temperature with stirring for 15 hours. 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol were then added to the reaction mixture with stirring for 2 hours at room temperature. When the reaction was completed, it was diluted with 40 ml EtOAc and organic layers were washed with H 2 O (10 ml x 3) and brine (10 ml x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, concentrated in vacuo, and subjected to flash chromatography to only afford product 13 as a yellow oil (20.3 mg, 70% yield), which suggested the intermolecular hydrogen abstraction reaction was unlikely. 16
V. Substrate Preparations and Characterizations Synthesis of N-acyloxyl Derivatives Synthesis of N-acyloxyl Precursors To a solution of substituted anhydride (1.0 eq, 35.0 mmol) and hydroxylamine hydrochloride (2.0 eq, 70.0 mmol) in pyridine (28 ml) was heated at 80 o C for 4 h and then cooled to room temperature. The mixture was added 130 ml water and acidified to ph 2 with concentrated HCl. The precipitate was filtrated and washed by water. The filter was dried in vacuo and purified by recrystallization with EtOH. Synthesis of N-acyloxyl Derivatives General Method To a solution of substituted aryl carboxylic acids (1.0 eq, 5.0 mmol) and N-hydroxyphthalimide derivatives (1.0 eq, 5.0 mmol) in dry DCM (150 ml) was added dicyclohexylcarbodiimide (1.0 eq, 5.0 mmol) at 0 o C and then the mixture was stirred overnight at room temperature. The resulting mixture was filtrated over Celite and the filtrate was concentrated in vacuo, and subjected to flash chromatography to afford the N-alkoxyphthalimides. The product can also be purified by recrystallization with EtOH. 17
1,3-dioxoisoindolin-2-yl 4-methylbenzoate (1). Following the general method, the reaction of 4-methylbenzoic acid (0.68 g, 5.0 mmol) afforded N-acyloxyl derivatives 1 as a white solid (1.08 g, 77% yield): TLC R f = 0.49 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.09 (d, J = 8.4 Hz, 2H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 2.47 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.9, 162.3, 146.2, 134.9, 130.8, 129.7, 129.2, 124.1, 122.6, 22.1; IR (KBr, thin film): 3096, 1770, 1748, 1606, 1357, 1238, 1181, 1015, 997, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 16 H 12 NO 4 282.0761, found 282.0759. 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl 4-methylbenzoate (2). Following the general method, the reaction of 4-methylbenzoic acid (0.68 g, 5.0 mmol) afforded N-acyloxyl derivatives 2 as a light yellow solid (1.28 g, 61% yield): TLC R f = 0.66 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.07 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 2.47 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.5, 157.9, 146.6, 141.1, 130.9, 130.6, 129.8, 125.0, 122.0, 22.1; IR (KBr, thin film): 2997, 1770, 1743, 1606, 1380, 1237, 1178, 1046, 978, 741 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 16 H 8 NCl 4 O 4 417.9202, found 417.9201. 1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl 4-methylbenzoate (3). Following the general method, the reaction of 4-methylbenzoic acid (0.68 g, 5.0 mmol) afforded 18
N-acyloxyl derivatives 3 as a yellow solid (1.12 g, 68% yield): TLC R f = 0.51 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.43 (s, 2H), 8.12 8.08 (m, 4H), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.8, 161.8, 146.1, 135.6, 130.8, 130.6, 129.8, 129.7, 125.9, 124.6, 122.6, 22.1; IR (KBr, thin film): 2977, 2941, 1763, 1731, 1607, 1342, 1130, 1010, 917, 763 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 14 NO 4 332.0917, found 332.0915. 2,5-dioxopyrrolidin-1-yl 4-methylbenzoate (4). Following the general method, the reaction of 4-methylbenzoic acid (0.68 g, 5.0 mmol) afforded N-acyloxyl derivatives 4 as a white solid (0.80 g, 69% yield): TLC R f = 0.17 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.03 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 2.90 (s, 4H), 2.45 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 169.4, 161.9, 146.1, 130.6, 129.6, 122.3, 25.7, 21.9; IR (KBr, thin film): 2990, 2946, 1763, 1729, 1608, 1367, 1195, 1069, 995, 689 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 12 H 12 NO 4 234.0761, found 234.0759. 1,3-dioxoisoindolin-2-yl 2-ethylbenzoate (7). Following the general method, the reaction of 2-ethylbenzoic acid (0.75 g, 5.0 mmol) afforded N-acyloxyphthalimides 7 as a white solid (1.14 g, 77% yield): TLC R f = 0.44 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.16 (d, J = 7.8 Hz, 1H), 7.95 7.91 (m, 2H), 7.83 7.80 (m, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.38 7.34 (m, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 19
; IR (KBr, thin film): 2958, 2926, 1774, 1742, 1466, 1219, 1184, 1080, 990, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 17 H 14 NO 4 296.0917, found 296.0916. 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl 2-ethylbenzoate (8). Following the general method, the reaction of 2-ethylbenzoic acid (0.75 g, 5.0 mmol) afforded N-acyloxyl derivatives 8 as a light yellow solid (1.57 g, 73% yield): TLC R f = 0.69 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.13 8.11 (m, 1H), 7.59 (td, J = 7.6, 1.4 Hz, 1H), 7.39 7.34 (m, 2H), 3.00 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.8, 158.0, 148.1, 141.1, 134.4, 131.4, 130.7, 130.6, 126.3, 125.0, 123.7, 27.6, 15.7; IR (KBr, thin film): 2935, 2878, 1779, 1749, 1366, 1219, 1040, 967, 913, 746 cm 1 ; HRMS-ESI (m/z) [M+NH + 4 ]: calcd. for C 17 H 13 N 2 Cl 4 O 4 448.9624, found 448.9621. 1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl 2-ethylbenzoate (9). Following the general method, the reaction of 2-ethylbenzoic acid (0.75 g, 5.0 mmol) afforded N-acyloxyl derivatives 9 as a light yellow solid (1.23 g, 71% yield): TLC R f = 0.54 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.43 (s, 2H), 8.20 (dd, J = 7.8, 1.5 Hz, 1H), 8.10 (dd, J = 6.1, 3.3 Hz, 2H), 7.75 (dd, J = 6.1, 3.3 Hz, 2H), 7.58 (td, J = 7.6, 1.5 Hz, 1H), 7.39 7.34 (m, 2H), 3.03 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.1, 161.9, 148.0, 135.6, 134.1, 131.5, 130.6, 130.6, 129.8, 126.2, 125.9, 124.7, 124.3, 27.7, 15.7; IR (KBr, thin film): 2974, 2874, 1770, 1737, 1515, 1342, 1148, 1004, 960, 761 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. 20
for C 21 H 16 NO 4 346.1074, found 346.1072. 2,5-dioxopyrrolidin-1-yl 2-ethylbenzoate (10). Following the general method, the reaction of 2-ethylbenzoic acid (0.75 g, 5.0 mmol) afforded N-acyloxyl derivatives 10 as a light yellow solid (1.13 g, 92% yield): TLC R f = 0.20 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.08 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.36 7.30 (m, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.91 (s, 4H), 1.25 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 169.5, 162.3, 148.0, 134.2, 131.4, 130.6, 126.2, 124.1, 27.6, 25.9, 15.7; IR (KBr, thin film): 2970, 2952, 1759, 1736, 1489, 1371, 1249, 1211, 977, 764 cm 1 ; HRMS-ESI (m/z) [M+NH + 4 ]: calcd. for C 13 H 17 N 2 O 4 265.1183, found 265.1181. 21
Synthesis of N-acyloxyphthalimide Substrates Synthesis of N-acyloxyphthalimide substrates General method To a solution of substituted aryl carboxylic acids 3-5 (1.0 eq, 5.0 mmol) and N-hydroxyphthalimide (1.0 eq, 5.0 mmol) in dry DCM (150 ml) was added dicyclohexylcarbodiimide (1.0 eq, 5.0 mmol) at 0 o C and then the mixture was stirred overnight at room temperature. The resulting mixture was filtrated over Celite and the filtrate was concentrated in vacuo, and subjected to flash chromatography to afford the N-alkoxyphthalimides. The product can also be purified by recrystallization with EtOH. 1,3-dioxoisoindolin-2-yl 2-ethyl-4-methylbenzoate (13a). Following the general method, the reaction of 2-ethyl-4-methylbenzoic acid (0.37 g, 2.3 mmol) afforded N-acyloxyphthalimides 13a as a white solid (0.46 g, 66% yield): TLC R f = 0.51 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.09 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.17 7.14 (m, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.1, 162.5, 148.3, 145.2, 134.8, 131.7, 131.5, 129.2, 127.0, 124.1, 121.1, 27.7, 21.9, 15.7; IR (KBr, thin film): 2954, 2925, 2843, 1774, 1737, 1607, 1376, 1187, 739, 693 cm 1 ; HRMS-ESI (m/z) [M+Na + ]: calcd. for C 18 H 15 NnaO 4 332.0893, found 332.0892. 22
1,3-dioxoisoindolin-2-yl 2-ethyl-4-fluorobenzoate (14a). Following the general method, the reaction of 2-ethyl-4-fluorobenzoic acid (0.37 g, 2.2 mmol) afforded N-acyloxyphthalimides 14a as a white solid (0.38 g, 56% yield): TLC R f = 0.44 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.23 (dd, J = 8.7, 5.8 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.09 7.02 (m, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl 3 ) δ -104.3 (m); IR (KBr, thin film): 2970, 2873, 1779, 1746, 1607, 1362, 1233, 988, 879, 698 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 17 H 13 NFO 4 314.0823, found 314.0823. 1,3-dioxoisoindolin-2-yl 4-chloro-2-ethylbenzoate (15a). Following the general method, the reaction of 4-chloro-2-ethylbenzoic acid (0.71 g, 3.8 mmol) afforded N-acyloxyphthalimides 15a as a white solid (0.66 g, 52% yield): TLC R f = 0.48 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.11 (d, J = 8.4 Hz, 1H), 7.94 7.92 (m, 2H), 7.83 7.81 (m, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 3.00 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.5, 162.3, 150.0, 140.6, 134.9, 132.9, 130.7, 129.1, 126.6, 124.2, 122.6, 27.6, 15.4; IR (KBr, thin film): 2961, 2926, 1774, 1743, 1593, 1222, 1016, 992, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 17 H 13 NclO 4 330.0528, found 330.0527. 23
1,3-dioxoisoindolin-2-yl 2-propylbenzoate (16a). Following the general method, the reaction of 2-propylbenzoic acid (1.11 g, 6.7 mmol) afforded N-acyloxyphthalimides 16a as a white solid (1.43 g, 69% yield): TLC R f = 0.44 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.16 (dd, J = 8.0, 1.4 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.56 (td, J = 7.6, 1.4 Hz, 1H), 7.37 7.33 (m, 2H), 2.97 2.93 (m, 2H), 1.71 1.62 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.3, 162.3, 146.5, 134.9, 133.9, 131.5, 131.4, 129.2, 126.2, 124.4, 124.1, 36.5, 24.8, 14.2; IR (KBr, thin film): 2961, 2929, 1774, 1769, 1371, 1231, 1186, 992, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 18 H 16 NO 4 310.1074, found 310.1072. 1,3-dioxoisoindolin-2-yl 2-phenethylbenzoate (17a). Following the general method, the reaction of 2-phenethylbenzoic acid (1.13 g, 5.0 mmol) afforded N-acyloxyphthalimides 17a as a white solid (1.10 g, 59% yield): TLC R f = 0.38 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.22 (dd, J = 7.9, 1.4 Hz, 1H), 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.54 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.5, 1.4 Hz, 1H), 7.29 7.15 (m, 6H), 3.29 3.25 (m, 2H), 2.95 2.91 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) 163.2, 162.3, 145.6, 141.7, 134.9, 134.1, 131.7, 131.7, 129.2, 128.7, 128.4, 126.0, 126.0, 124.3, 124.2, 37.8, 36.8; IR (KBr, thin film): 3058, 3027, 1773, 1743, 1601, 1494, 1370, 1226, 994, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 23 H 18 NO 4 372.1230, found 372.1229. 24
1,3-dioxoisoindolin-2-yl 2-((benzyloxy)methyl)benzoate (18a). Following the general method, the reaction of 2-((benzyloxy)methyl)benzoic acid (1.48 g, 6.1 mmol) afforded N-acyloxyphthalimides 18a as a light yellow solid (1.53 g, 64% yield): TLC R f = 0.35 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.26 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 4.97 (s, 2H), 4.66 (s, 2H); 13 C NMR (125 MHz, CDCl 3 ) 162.7, 162.2, 143.0, 138.2, 134.9, 134.6, 131.4, 129.1, 128.5, 128.1, 127.8, 127.8, 127.4, 124.1, 122.8, 73.2, 69.9; IR (KBr, thin film): 2955, 2925, 1770, 1743, 1467, 1362, 1227, 1186, 992, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 23 H 18 NO 5 388.1179, found 388.1175. 1,3-dioxoisoindolin-2-yl 2-((p-tolyloxy)methyl)benzoate (19a). Following the general method, the reaction of 2-((p-tolyloxy)methyl)benzoic acid (0.53 g, 2.2 mmol) afforded N-acyloxyphthalimides 19a as a light yellow solid (0.25 g, 30% yield): TLC R f = 0.39 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.32 (d, J = 9.0 Hz, 1H), 7.94 (dd, J = 5.5, 3.1 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (t, J = 7.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.46 (s, 2H), 2.27 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.7, 162.2, 156.4, 141.9, 135.0, 134.8, 131.6, 130.5, 130.1, 129.1, 127.9, 127.7, 124.2, 122.5, 114.9, 67.7, 20.6; IR (KBr, thin film): 2952, 2925, 1770, 1743, 1510, 1228, 1186, 993, 818, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 23 H 18 NO 5 388.1179, 25
found 388.1179. 1,3-dioxoisoindolin-2-yl 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzoate (20a). Following the general method, the reaction of 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzoic acid (2.73 g, 7.0 mmol) afforded N-acyloxyphthalimides 20a as a light yellow solid (3.26 g, 87% yield): TLC R f = 0.34 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.27 (dd, J = 8.0, 1.3 Hz, 1H), 8.14 (dd, J = 8.0, 1.3 Hz, 1H), 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.79 7.74 (m, 4H), 7.68 7.66 (m, 4H), 7.43 (td, J = 7.7, 1.2 Hz, 1H), 7.41 7.33 (m, 6H), 5.20 (s, 2H), 1.13 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) 162.1, 146.1, 135.6, 134.9, 134.8, 133.4, 131.4, 129.9, 129.1, 127.9, 126.9, 124.0, 121.4, 63.8, 27.1, 19.6; IR (KBr, thin film): 3070, 2934, 2857, 1768, 1745, 1428, 1362, 1113, 996, 697 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 32 H 30 NSiO 5 536.1888, found 536.1884. 1,3-dioxoisoindolin-2-yl 5,6,7,8-tetrahydronaphthalene-1-carboxylate (21a). Following the general method, the reaction of 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (0.95 g, 5.4 mmol) afforded N-acyloxyphthalimides 21a as a light yellow solid (1.42 g, 82% yield): TLC R f = 0.47 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.00 (d, J = 7.5 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 3.10 3.07 (m, 2H), 2.86 2.82 (m, 2H), 1.82 1.79 (m, 4H); 13 C NMR (125 MHz, CDCl 3 ) 163.5, 162.4, 140.6, 139.1, 135.3, 134.8, 129.2, 129.0, 125.4, 124.8, 124.1, 30.3, 27.8, 23.0, 22.4; IR (KBr, thin film): 2926, 2863, 1781, 26
1744, 1457, 1244, 1076, 967, 826, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 16 NO 4 322.1074, found 322.1072. 1,3-dioxoisoindolin-2-yl 2-isopropylbenzoate (22a). Following the general method, the reaction of 2-isopropylbenzoic acid (0.57 g, 3.5 mmol) afforded N-acyloxyphthalimides 22a as a light yellow solid (0.78 g, 72% yield): TLC R f = 0.51 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.08 (d, J = 7.8 Hz, 1H), 7.95 7.91 (m, 2H), 7.84 7.81 (m, 2H), 7.60 (t, J = 7.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 3.73 (hept, J = 6.8 Hz, 1H), 1.30 (d, J = 6.8 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2964, 2928, 2871, 1775, 1742, 1467, 1365, 1016, 991, 696 cm 1 ; HRMS-ESI (m/z) [M+NH + 4 ]: calcd. for C 18 H 19 N 2 O 4 327.1339, found 327.1337. 27
1,3-dioxoisoindolin-2-yl 2-methyl-6-(2-methylprop-1-en-1-yl)benzoate (23). Following the general method, the reaction of 2-methyl-6-(2-methylprop-1-en-1-yl)benzoic acid (1.00 g, 5.2 mmol) afforded N-acyloxyphthalimides 23 as a white solid (0.46 g, 26% yield): TLC R f = 0.47 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.6, 2.9 Hz, 2H), 6.53 (s, 1H), 2.55 (s, 3H), 1.99 (s, 3H), 1.77 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2958, 2924, 1782, 1743, 1466, 1352, 1216, 1183, 989, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 4 336.1230, found 336.1229. 1,3-dioxoisoindolin-2-yl 4-methyl-2-(2-methylprop-1-en-1-yl)benzoate (25a). Following the general method, the reaction of 4-methyl-2-(2-methylprop-1-en-1-yl)benzoic acid (0.51 g, 2.7 mmol) afforded N-acyloxyphthalimides 25a as a white solid (0.60 g, 66% yield): TLC R f = 0.49 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.12 (d, J = 8.0 Hz, 1H), 7.93 7.89 (m, 2H), 7.81 7.79 (m, 2H), 7.18 7.15 (m, 2H), 6.59 (s, 1H), 2.43 (s, 3H), 1.89 (s, 3H), 1.74 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.8, 162.4, 144.5, 142.2, 136.4, 134.8, 132.3, 131.5, 129.3, 127.3, 124.0, 123.9, 121.1, 26.4, 21.9, 19.5; IR (KBr, thin film): 2959, 2925, 1772, 1742, 1489, 1374, 1228, 1128, 1016, 992, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 4 336.1230, found 336.1228. 28
1,3-dioxoisoindolin-2-yl 4-fluoro-2-(2-methylprop-1-en-1-yl)benzoate (26a). Following the general method, the reaction of 4-fluoro-2-(2-methylprop-1-en-1-yl)benzoic acid (0.81 g, 4.2 mmol) afforded N-acyloxyphthalimides 26a as a light yellow solid (0.98 g, 69% yield): TLC R f = 0.49 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.26 8.23 (m, 1H), 7.93 7.90 (m, 2H), 7.83 7.80 (m, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.60 (s, 1H), 1.90 (s, 3H), 1.77 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl 3 ) δ -103.8 (m); IR (KBr, thin film): 2970, 2913, 1777, 1744, 1603, 1576, 1240, 996, 878, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 15 NFO 4 340.0980, found 340.0978. 1,3-dioxoisoindolin-2-yl 4-chloro-2-(2-methylprop-1-en-1-yl)benzoate (27a). Following the general method, the reaction of 4-chloro-2-(2-methylprop-1-en-1-yl)benzoic acid (0.87 g, 4.1 mmol) afforded N-acyloxyphthalimides 27a as a white solid (1.00 g, 68% yield): TLC R f = 0.51 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.14 (d, J = 9.1 Hz, 1H), 7.91 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.36 7.34 (m, 2H), 6.56 (s, 1H), 1.90 (s, 3H), 1.77 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.3, 162.2, 143.7, 140.0, 138.3, 134.9, 132.6, 131.6, 129.1, 126.7, 124.1, 122.7, 122.5, 26.4, 19.6; IR (KBr, thin film): 2973, 2912, 1776, 1744, 1588, 1229, 997, 879, 784, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 15 NClO 4 356.0684, found 356.0683. 29
1,3-dioxoisoindolin-2-yl 5-methoxy-2-(2-methylprop-1-en-1-yl)benzoate (28a). Following the general method, the reaction of 4-methoxy-2-(2-methylprop-1-en-1-yl)benzoic acid (0.56 g, 2.7 mmol) afforded N-acyloxyphthalimides 28a as a white solid (0.38 g, 40% yield): TLC R f = 0.37 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.23 (d, J = 8.8 Hz, 1H), 7.92 7.90 (m, 2H), 7.80 7.78 (m, 2H), 6.88 6.82 (m, 2H), 6.61 (s, 1H), 3.89 (s, 3H), 1.89 (s, 3H), 1.76 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.6, 162.5, 162.2, 144.9, 136.6, 134.8, 133.8, 129.3, 124.2, 124.0, 117.1, 115.9, 111.9, 55.6, 26.4, 19.6; IR (KBr, thin film): 2961, 2926, 1770, 1743, 1602, 1374, 1186, 991, 876, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 5 352.1179, found 352.1177. 1,3-dioxoisoindolin-2-yl 2-(2-methylprop-1-en-1-yl)-4-(trifluoromethyl)benzoate (29a). Following the general method, the reaction of 2-(2-methylprop-1-en-1-yl)-4-(trifluoromethyl)benzoic acid (0.27 g, 1.1 mmol) afforded N-acyloxyphthalimides 29a as a white solid (0.27 g, 65% yield): TLC R f = 0.45 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.26 (d, J = 8.5 Hz, 1H), 7.94 7.92 (m, 2H), 7.83 7.81 (m, 2H), 7.62 (d, J = 7.2 Hz, 2H), 6.62 (s, 1H), 1.94 (s, 3H), 1.77 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl 3 ) δ -63.4 (s); IR (KBr, thin film): 2943, 2810, 1783, 1747, 1330, 1226, 1174, 1079, 996, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 15 NF 3 O 4 390.0948, found 390.0945. 30
1,3-dioxoisoindolin-2-yl 2-(2-methylprop-1-en-1-yl)benzoate (30a). Following the general method, the reaction of 2-(2-methylprop-1-en-1-yl)benzoic acid (1.99 g, 11.4 mmol) afforded N-acyloxyphthalimides 30a as a white solid (2.79 g, 76% yield): TLC R f = 0.46 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.20 (d, J = 8.0 Hz, 1H), 7.94 7.90 (m, 2H), 7.82 7.78 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.6 Hz, 2H), 6.62 (s, 1H), 1.91 (s, 3H), 1.75 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2961, 2911, 1771, 1742, 1480, 1373, 1227, 1185, 992, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 16 NO 4 322.1074, found 322.1072. 1,3-dioxoisoindolin-2-yl 5-methoxy-2-(2-methylprop-1-en-1-yl)benzoate (31a). Following the general method, the reaction of 5-methoxy-2-(2-methylprop-1-en-1-yl)benzoic acid (0.34 g, 1.6 mmol) afforded N-acyloxyphthalimides 31a as a white solid (0.34 g, 59% yield): TLC R f = 0.36 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.67 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.14 (dd, J = 8.6, 2.8 Hz, 1H), 6.54 (s, 1H), 3.88 (s, 3H), 1.88 (s, 3H), 1.73 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.9, 162.3, 157.7, 136.0, 134.9, 134.8, 132.8, 129.2, 124.8, 124.0, 123.2, 120.3, 115.2, 55.7, 26.3, 19.5; IR (KBr, thin film): 2958, 2925, 1774, 1742, 1494, 1374, 1131, 1185, 996, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 5 352.1179, found 352.1177. 31
1,3-dioxoisoindolin-2-yl 5-fluoro-2-(2-methylprop-1-en-1-yl)benzoate (32a). Following the general method, the reaction of 5-fluoro-2-(2-methylprop-1-en-1-yl)benzoic acid (0.73 g, 3.8 mmol) afforded N-acyloxyphthalimides 32a as a white solid (0.95 g, 74% yield): TLC R f = 0.44 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.90 7.87 (m, 1H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.33 7.30 (m, 2H), 6.54 (s, 1H), 1.90 (d, J = 1.5 Hz, 3H), 1.73 (d, J = 1.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl 3 ) δ -120.0 (m); IR (KBr, thin film): 2977, 1777, 1744, 1489, 1362, 1170, 1004, 969, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 15 NO 4 F 340.0980, found 340.0977. 1,3-dioxoisoindolin-2-yl 3-methyl-2-(2-methylprop-1-en-1-yl)benzoate (33a). Following the general method, the reaction of 3-methyl-2-(2-methylprop-1-en-1-yl)benzoic acid (0.43 g, 2.3 mmol) afforded N-acyloxyphthalimides 33a as a white solid (0.24 g, 32% yield): TLC R f = 0.50 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 7.93 7.89 (m, 3H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 6.27 (s, 1H), 2.27 (s, 3H), 1.91 (s, 3H), 1.50 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 32
; IR (KBr, thin film): 2958, 2925, 1778, 1743, 1466, 1185, 1015, 990, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 4 336.1230, found 336.1228. 1,3-dioxoisoindolin-2-yl 2-(2-methylprop-1-en-1-yl)-4-(trifluoromethyl)benzoate (34a). Following the general method, the reaction of 3-fluoro-2-(2-methylprop-1-en-1-yl)benzoic acid (0.79 g, 4.1 mmol) afforded N-acyloxyphthalimides 34a as a light yellow solid (0.87 g, 63% yield): TLC R f = 0.38 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 7.96 (dd, J = 7.4, 1.7 Hz, 1H), 7.92 (dd, J = 5.5, 3.1Hz, 2H), 7.81 (dd, J = 5.5, 3.1Hz, 2H), 7.40 7.33 (m, 2H), 6.24 (s, 1H), 1.93 (s, 3H), 1.62 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl 3 ) δ -111.7 (m); IR (KBr, thin film): 2976, 2937, 1782, 1744, 1457, 1362, 1257, 1186, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 19 H 15 NFO 4 340.0980, found 340.0978. 1,3-dioxoisoindolin-2-yl 2-(2-methylprop-1-en-1-yl)nicotinate (35a). Following the general method, the reaction of 2-(2-methylprop-1-en-1-yl)nicotinic acid (0.90 g, 5.1 mmol) afforded N-acyloxyphthalimides 35a as a white solid (0.43 g, 26% yield): TLC R f = 0.26 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.82 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 (dd, J = 5.5, 3.1 Hz, 2H), 7.83 (dd, J = 33
5.5, 3.1 Hz, 2H), 7.29 7.26 (m, 1H), 6.82 (s, 1H), 2.04 (s, 3H), 1.98 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.7, 162.1, 158.8, 153.2, 144.7, 138.9, 135.0, 129.1, 124.4, 122.4, 120.5, 120.4, 27.5, 20.2; IR (KBr, thin film): 2958, 2926, 1774, 1742, 1554, 1356, 1195, 1016, 990, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 18 H 15 N 2 O 4 323.1026, found 323.1025. 1,3-dioxoisoindolin-2-yl 2-(2-ethylbut-1-en-1-yl)benzoate (36a). Following the general method, the reaction of 2-(2-ethylbut-1-en-1-yl)benzoic acid (0.88 g, 4.3 mmol) afforded N-acyloxyphthalimides 36a as a light yellow solid (0.10 g, 7% yield): TLC R f = 0.53 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.18 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.39 7.32 (m, 2H), 6.56 (s, 1H), 2.21 (q, J = 7.4 Hz, 2H), 2.12 (q, J = 7.5 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.0, 162.3, 147.1, 142.3, 134.8, 133.5, 131.4, 131.3, 129.3, 126.5, 124.4, 124.1, 122.1, 28.8, 24.1, 13.1, 12.7; IR (KBr, thin film): 2963, 2927, 1773, 1744, 1466, 1186, 1016, 992, 877, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 21 H 20 NO 4 350.1387, found 350.1384. 1,3-dioxoisoindolin-2-yl (E)-2-(2-phenylprop-1-en-1-yl)benzoate (37a). Following the general method, the reaction of (E)-2-(2-phenylprop-1-en-1-yl)benzoic acid (0.77 g, 3.2 mmol) afforded N-acyloxyphthalimides 37a as a white solid (0.92 g, 74% yield, E/Z > 20:1): TLC R f = 0.34 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 34
8.29 (dd, J = 8.0, 1.4 Hz, 1H), 7.91 (dd, J = 5.5, 3.1 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 7.66 (td, J = 7.6, 1.4 Hz, 1H), 7.57 7.55 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.44 7.42 (m, 1H), 7.35 7.31 (m, 2H), 7.27 7.25 (m, 1H), 7.23 (s, 1H), 2.15 (d, J = 1.4 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 162.7, 162.3, 143.1, 141.9, 137.9, 134.8, 133.7, 131.6, 131.6, 129.2, 128.4, 127.5, 127.0, 126.2, 126.1, 124.3, 124.1, 17.4; IR (KBr, thin film): 3029, 1774, 1742, 1495, 1371, 1227, 1186, 1017, 993, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 24 H 18 NO 4 384.1230, found 384.1227. 1,3-dioxoisoindolin-2-yl 2-(cyclopentylidenemethyl)benzoate (38a). Following the general method, the reaction of 2-(cyclopentylidenemethyl)benzoic acid (0.46 g, 2.3 mmol) afforded N-acyloxyphthalimides 38a as a white solid (0.38 g, 48% yield): TLC R f = 0.42 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.16 (dd, J = 8.0, 1.4 Hz, 1H), 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.59 7.56 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 6.88 6.84 (m, 1H), 2.50 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 1.75 1.65 (m, 4H); 13 C NMR (125 MHz, CDCl 3 ) 163.3, 162.3, 150.0, 142.0, 134.8, 133.4, 131.2, 130.0, 129.2, 126.0, 124.1, 123.5, 118.8, 35.2, 31.1, 27.0, 25.6; IR (KBr, thin film): 2953, 1771, 1743, 1468, 1373, 1226, 1186, 1016, 991, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 21 H 18 NO 4 348.1230, found 348.1228. 1,3-dioxoisoindolin-2-yl 2-(3-methylbut-2-en-2-yl)benzoate (39a). Following the general method, the reaction of 2-(3-methylbut-2-en-2-yl)benzoic acid (0.36 g, 1.9 35
mmol) afforded N-acyloxyphthalimides 39a as a white solid (0.15 g, 23% yield): TLC R f = 0.50 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) 8.10 (d, J = 9.1 Hz, 1H), 7.91 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 1.96 (s, 3H), 1.80 (s, 3H), 1.47 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) 163.3, 162.2, 148.4, 134.8, 133.8, 130.9, 130.6, 129.3, 128.4, 128.2, 126.5, 124.9, 124.0, 21.9, 20.7, 20.2; IR (KBr, thin film): 2955, 2925, 1772, 1743, 1604, 1373, 1226, 1016, 992, 695 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 18 NO 4 336.1230, found 336.1228. 1,3-dioxoisoindolin-2-yl 2-(prop-1-en-1-yl)benzoate (40a). Following the general method, the reaction of 2-(prop-1-en-1-yl)benzoic acid (1.71 g, 10.5 mmol) afforded N-acyloxyphthalimides 40a as a white solid (2.30 g, 71% yield, E/Z = 12 : 1): TLC R f = 0.31 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.23 (d, J = 8.8 Hz, 0.08H), 8.13 (d, J = 8.8 Hz, 1.04H), 7.92 (dt, J = 5.5, 3.3 Hz, 2H), 7.80 (dt, J = 5.5, 3.3 Hz, 2H), 7.62 7.55 (m, 2H), 7.42 7.33 (m, 1H), 7.13 (d, J = 15.6 Hz, 1H), 6.84 (dd, J = 11.6, 2.1 Hz, 0.08H), 6.24 (dqd, J = 15.6, 6.7, 0.8 Hz, 1.09H), 5.89 (dq, J = 11.6, 7.1 Hz, 0.09H), 1.91 (dt, J = 6.7, 1.4 Hz, 3.40H), 1.77 (dt, J = 7.0, 1.2 Hz, 0.29H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 3064, 1771, 1743, 1567, 1370, 1225, 1186, 1016, 993, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 18 H 14 NO 4 308.0917, found 308.0915. 36
1,3-dioxoisoindolin-2-yl (E)-2-styrylbenzoate (41a). Following the general method, the reaction of (E)-2-styrylbenzoic acid (1.85 g, 8.3 mmol) afforded N-acyloxyphthalimides 41a as a light yellow solid (2.33 g, 76% yield, E/Z > 20 : 1): TLC R f = 0.31 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 7.95 7.91 (m, 3H), 7.83 7.81 (m, 3H), 7.67 7.63 (m, 1H), 7.56 (dd, J = 8.2, 1.2 Hz, 2H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.34 (dd, J = 8.2, 6.9 Hz, 2H), 7.28 7.24 (m, 1H), 7.10 (d, J = 16.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 3029, 2812, 1742, 1495, 1362, 1228, 1186, 993, 877, 695 cm 1 ; HRMS-ESI (m/z) [M+NH + 4 ]: calcd. for C 23 H 19 N 2 O 4 387.1339, found 387.1337. 1,3-dioxoisoindolin-2-yl 2-(2-cyclopropylvinyl)benzoate (44). Following the general method, the reaction of 2-(2-cyclopropylvinyl)benzoic acid (1.07 g, 5.7 mmol) afforded N-acyloxyphthalimides 44 as a light yellow solid (1.23 g, 65% yield, E/Z = 1:1.5): TLC R f = 0.41 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) 8.25 (dd, J = 7.9, 1.3 Hz, 0.6H), 8.13 (dd, J = 7.9, 1.3 Hz, 0.4H), 7.93 (ddd, J = 6.6, 5.5, 3.1 Hz, 2H), 7.81 (ddd, J = 5.5, 4.5, 3.1 Hz, 2H), 7.70 (d, J = 7.3 Hz, 0.6H), 7.62 (td, J = 7.6, 1.4 Hz, 0.6H), 7.60 7.56 (m, 0.4H), 7.55 7.52 (m, 0H), 7.40 (td, J = 7.7, 1.3 Hz, 0.6H), 7.32 (ddd, J = 8.5, 7.0, 1.6 Hz, 0.4H), 7.22 (d, J = 15.6 Hz, 0.4H), 6.77 (d, J = 11.5 Hz, 0.6H), 5.75 (dd, J = 15.6, 9.0 Hz, 0.4H), 5.14 (dd, J = 11.5, 10.2 Hz, 1H), 37
1.71 1.59 (m, 1H), 0.85 0.78 (m, 2H), 0.56 0.47 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 3064, 2952, 2925, 1771, 1742, 1467, 1186, 1016, 992, 696 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 20 H 16 NO 4 334.1074, found 334.1071. 38
Synthesis of Allyl and Vinyl Sulfones Synthesis of allyl sulfones Ethyl-2-(hydroxymethyl)acrylate (B1) To a solution of paraformaldehyde (1.99 g, 66.6 mmol) and ethylacrylate (5.4 ml, 50 mmol) in 40 ml dioxane-water (1:1, v/v) was added DABCO (7.48 g, 66.7 mmol) and the reaction progress was monitored by TLC. Upon completion, the reaction mixture was partitioned with EtOAc (200 ml) and water (100 ml). The organic layer was separated and washed with brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (50% EtOAc/hexanes) to afford S21 as a colorless oil (3.22 g, 49% yield): TLC R f = 0.49 (EtOAc/hexanes = 1/4); 1 H NMR (500 MHz, CDCl 3 ) δ 6.25 (s, 1H ), 5.82 (s, 1H), 4.31 (d, J = 6.5 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 2.41 (t, J = 6.5 Hz, 1H), 1.31 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 166.3, 139.5, 125.6, 62.5, 60.9, 14.1. Ethyl-2-(bromomethyl)acrylate (B2). To a solution of B1 (3.01 g, 23.0 mmol) was added phosphorus (III) bromide (0.76 ml, 8.0 mmol) in dry ether (20 ml) at -10 o C. The temperature was allowed to rise to 20 o C and stirring was continued for 3 h. Water (10 ml) was then added and the mixture was extracted with petroleum ether (3 x 50 ml). The organic phase was washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% hexanes/etoac) to give B2 as a colorless oil (3.99 g, 89% yield): TLC R f = 0.55 (EtOAc/hexanes = 1/10); 1 H NMR (400 MHz, CDCl 3 ) δ 6.33 (s, 1H ), 5.95 (s, 1H) 4.27 (q, J = 7.2 Hz, 2H), 4.19 (s, 39
2H), 1.33 (t, J =7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 137.6, 128.9, 61.3, 29.4, 14.1. Ethyl-2-((phenylsulfonyl)methyl)acrylate (11). To a solution of B2 (1.99 g, 10.4 mmol) in dry methanol (25 ml) was added sodium phenylsulfinate (2.50 g, 15.2 mmol). After 2.5 h of reflux, the mixture was concentrated under reduced pressure, the obtained residue was dissolved in EtOAc and the mixture was washed with water, brine, dried with Na 2 SO 4, filtered and the filtrate was evaporated and purified by chromatography (50% EtOAc/hexanes ) to give 11 as a viscous oil (1.94 g, 74% yield): TLC R f = 0.50 (EtOAc/hexanes = 1/4); 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 6.51 (s, 1H), 5.92(s, 1H), 4.17(s, 2H), 4.01(q, J = 7.2 Hz, 2H), 1.17(t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.7, 138.4, 133.9, 133.3, 129.1, 129.0, 128.8, 61.5, 57.5, 14.0. 40
VI. Product Characterizations C(sp 3 )-H Allylation Product Characterizations Standard Procedure: A solution of N-acyloxyphthalimides (0.1 mmol, 1.0 equiv.), allyl sulfone 11 (0.3 mmol, 3.0 equiv.), and Hantzsch ester 5 (HE, 38.0 mg, 0.15 mmol, 1.5 equiv.) was placed in a 5 ml clear-colored glass vial. After the addition of 1.0 ml DMF (bubbled with nitrogen gas for 30 minutes to remove oxygen), the vial was sealed and exposed to 8W blue LED at room temperature with stirring for 15 hours. 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol were then added to the reaction mixture with stirring for 2 hours at room temperature. When the reaction was completed, it was diluted with 40 ml EtOAc and organic layers were washed with H 2 O (10 ml x 3) and brine (10 ml x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, concentrated in vacuo, and subjected to flash chromatography to afford the C(sp 3 )-H allylation adduct. *The heating effect from LED irradiation conditions above is minimal. With 15 hours irradiation, the increase of temperature is less than 5 o C. 41
Methyl 2-(4-(ethoxycarbonyl)pent-4-en-2-yl)benzoate (12). Following the standard procedure, the reaction of N-acyloxyphthalimides 7 (29.5 mg, 0.1 mmol), Hantzsch ester 5 (38.0 mg, 0.15 mmol) and allyl sulfone 11 (76.2 mg, 0.3 mmol) in 1 ml DMF for 15 h. 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol were then added with stirring 2h to afford target product 12 as a colorless oil (19.2 mg, 70% yield) after flash chromatography (97%:3% hexanes : EtOAc): TLC R f = 0.41 (EtOAc/hexanes = 1/8); 1 H NMR (400 MHz, CDCl 3 ) 7.70 (dd, J = 7.8, 1.4 Hz, 1H), 7.45 (td, J = 7.6, 1.4 Hz, 1H), 7.38 (dd, J = 8.0, 1.4 Hz, 1H), 7.22 (td, J = 7.6, 1.4 Hz, 1H), 6.08 (d, J = 1.5 Hz, 1H), 5.36 (d, J = 1.5 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.87 (s, 4H), 2.63 2.59 (m, 2H), 1.30 1.26 (m, 6H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2980, 1720, 1629, 1434, 1290, 1252, 1195, 1153, 913, 744 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 16 H 21 O 4 277.1434, found 277.1433. Methyl 2-(4-(ethoxycarbonyl)pent-4-en-2-yl)benzoate (13). Following the standard procedure, the reaction of N-acyloxyphthalimides 13a (30.9 mg, 0.1 mmol), Hantzsch ester 5 (38.0 mg, 0.15 mmol) and allyl sulfone 11 (76.2 mg, 0.3 mmol) in 1 ml DMF for 15 h and then was added 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol with stirring 2h to afford target product 13 as a colorless oil (18.5 mg, 64% yield) after flash chromatography (97%:3% hexanes : EtOAc): TLC R f = 0.34 (EtOAc/hexanes = 1/8); 1 H NMR (500 MHz, CDCl 3 ) 7.66 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 5.39 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 42
3.96 (q, J = 7.1 Hz, 1H), 3.86 (s, 3H), 2.61 (dd, J = 7.0, 2.6 Hz, 2H), 2.37 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2980, 1718, 1612, 1434, 1277, 1250, 1154, 1084, 913, 744 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 17 H 23 O 4 291.1591, found 291.1589. Methyl 2-(4-(ethoxycarbonyl)pent-4-en-2-yl)-4-fluorobenzoate (14). Following the standard procedure, the reaction of N-acyloxyphthalimides 14a (30.9 mg, 0.1 mmol), Hantzsch ester 5 (38.0 mg, 0.15 mmol) and allyl sulfone 11 (76.2 mg, 0.3 mmol) in 1 ml DMF for 15 h and then was added 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol with stirring 2h to afford target product 14 as a colorless oil (17.1 mg, 58% yield) after flash chromatography (97%:3% hexanes : EtOAc): TLC R f = 0.41 (EtOAc/hexanes = 1/8); 1 H NMR (500 MHz, CDCl 3 ) 7.79 (dd, J = 8.8, 6.1 Hz, 1H), 7.06 (dd, J = 10.6, 2.6 Hz, 1H), 6.90 (ddd, J = 8.8, 7.7, 2.6 Hz, 1H), 6.09 (s, 1H), 5.37 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.04 (qd, J = 7.0, 1.7 Hz, 1H), 3.86 (s, 3H), 2.64 2.53 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; 19 F NMR (376 MHz, CDCl3) δ -108.3 (m); IR (KBr, thin film): 2955, 1719, 1682, 1558, 1434, 1285, 1249, 1173, 933, 780 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 16 H 20 O 4 F 295.1340, found 295.1338. 43
Methyl 4-chloro-2-(4-(ethoxycarbonyl)pent-4-en-2-yl)benzoate (15). Following the standard procedure, the reaction of N-acyloxyphthalimides 15a (33.0 mg, 0.1 mmol), Hantzsch ester 5 (38.0 mg, 0.15 mmol) and allyl sulfone 11 (76.2 mg, 0.3 mmol) in 1 ml DMF for 15 h and then was added 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol with stirring 2h to afford target product 15 as a colorless oil (19.1 mg, 61% yield) after flash chromatography (97%:3% hexanes : EtOAc): TLC R f = 0.32 (EtOAc/hexanes = 1/8); 1 H NMR (500 MHz, CDCl 3 ) 7.68 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J = 10.4 Hz, 1H), 6.10 (s, 1H), 5.38 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.96 (q, J = 7.0 Hz, 1H), 3.87 (s, 3H), 2.64 2.53 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) ; IR (KBr, thin film): 2981, 1720, 1592, 1563, 1434, 1286, 1153, 1107, 913, 744 cm 1 ; HRMS-ESI (m/z) [M+H + ]: calcd. for C 16 H 20 O 4 Cl 311.1045, found 311.1043. Methyl 2-(5-(ethoxycarbonyl)hex-5-en-3-yl)benzoate (16). Following the standard procedure, the reaction of N-acyloxyphthalimides 16a (30.9 mg, 0.1 mmol), Hantzsch ester 5 (38.0 mg, 0.15 mmol) and allyl sulfone 11 (76.2 mg, 0.3 mmol) in 1 ml DMF for 15 h and then was added 0.2 ml TMSCHN 2 (2.0 M in hexanes) and 0.5 ml methanol with stirring 2h to afford target product 16 as a colorless oil (17.9 mg, 62% yield) after flash chromatography (97%:3% hexanes : EtOAc): TLC R f = 0.45 (EtOAc/hexanes = 1/8); 1 H NMR (400 MHz, CDCl 3 ) 7.68 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 6.00 (s, 1H), 5.25 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.77 3.70 (m, 1H), 2.76 (dd, J = 14.1, 5.2 Hz, 1H), 2.49 (dd, J = 14.1, 8.8 Hz, 1H), 1.74 (dt, J = 13.6, 6.8 Hz, 1H), 1.63 (dt, J = 14.7, 7.7 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) 44