Supporting Information Aromatic Cation Activation: Nucleophilic Substitution of Alcohols and Carboxylic Acids

Transcription

1 Supporting Information Aromatic Cation Activation: Nucleophilic Substitution of Alcohols and Carboxylic Acids Thanh V. Nguyen* and Alp Bekensir Department of Chemistry, Curtin University, Perth, WA 6102, Australia S1

2 Table of Contents General Methods... S3 Synthesis and characterization data of 1,1-dichlorocycloheptatriene (1)... S4 General procedure for chlorination of alcohol... S4 General procedure for bromination of alcohol... S5 General procedure for acyl substitution of carboxylic acid... S5 General procedure for catalytic chlorination and bromination of alcohol... S6 Optimization of chlorination reaction with benzyl alcohol... S6 Characterization data of products... S7 Monitoring progress of the reaction with 1-phenyl ethanol by 1 H NMR... S14 Reaction with (R)-(-)-Mandelic acid:... S16 NMR spectra... S18 S2

3 General Methods Reactions, unless otherwise stated, were conducted under a positive pressure of dry nitrogen in oven-dried glassware. Tetrahydrofuran (THF), benzene, toluene and diethyl ether were dried over sodium wire and distilled from sodium benzophenone ketyl. Dichloromethane was dried by distillation from calcium hydride. Magnesium sulfate was dried at 140 C for 12 h prior to use. Commercially available reagents were used as purchased unless otherwise noted. Analytical thin layer chromatography was performed using silica gel plates precoated with silica gel 60 F 254 (0.2 mm). Flash chromatography employed mesh silica gel. Solvents used for chromatography are quoted as volume/volume ratios. 1 H NMR spectra were recorded at 298 K unless otherwise stated using Bruker Avance III 400 MHz spectrometers. Data is expressed in parts per million (ppm) downfield shift from tetramethylsilane with residual solvent as an internal reference (δ 7.26 ppm for chloroform) and is reported as position (δ in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J in Hz) and integration (number of protons). 13 C NMR spectra were recorded at 298 K unless otherwise stated using Bruker Avance III 100 MHz spectrometers with complete proton decoupling. Data is expressed in parts per million (ppm) downfield shift relative to the internal reference ( 77.2 ppm for the central peak of deuterated chloroform) and is reported as position (δ in ppm). Mass spectra were recorded on a VG Autospec or Bruker Apex 3 FTICR MS instruments at the Research School of Chemistry, Australian National University. S3

4 Synthesis and characterization data of 1,1-dichlorocycloheptatriene (1) To a solution of tropone (1.06 g, 10.0 mmol) in dry dichloromethane (10 ml) was added oxalyl chloride (1.27 g, 10.0 mmol) dropwise and the reaction mixture was stirred at rt until gas emission ceased (5 min). This solution can be used as is (in situ generation) for alkyl/acyl nucleophilic substitution reaction, or can be concentrated under reduced pressure to yield a dark yellow solid. The solid was recrystallized from hexanes/dichloromethane to afford the title compound as a light yellow solid (1.42 g, 88% yield). 1 H NMR (400 MHz, CDCl 3 ) 6.53 (d, J = 8.0 Hz, 2H), 6.20 (tt, J = 8.0 Hz, 4.0 Hz, 2H), 6.04 (dt, J = 8.0 Hz, 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) 159.3, 134.7, 120.4, EI-MS m/z: ([( 37 ClC 7 H 6 )] +, 33%), ([( 35 ClC 7 H 6 )] +, 100%). HRMS (EI) m/z: (Calc. for [( 37 ClC 7 H 6 )] + = ), (Calc. for [( 35 ClC 7 H 6 )] + = ). 1,1-dichlorocycloheptatriene (1) decomposed under IR and elemental analyses conditions. General procedure for chlorination of alcohol (Table 1) To a solution of tropone (106 mg, 1.0 mmol) in dry dichloromethane (3 ml) was added oxalyl chloride (127 mg, 1.0 mmol) dropwise and the reaction mixture was stirred at rt until gas emission ceased (5 min). A solution of alcohol (1 mmol, 1.0 equiv) in dry dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred at rt (or 75 C) for the indicated time. When the reaction was complete (monitored by TLC or 1 H NMR), the reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO 2, hexanes dichloromethane:hexanes 1:9) to obtain the chloride product. Tropone was recovered by subsequent elution of the column with EtOAc:hexanes 1:1. S4

5 General procedure for bromination of alcohol (Table 1) To a solution of tropone (106 mg, 1.0 mmol) in dry dichloromethane (3 ml) was added oxalyl chloride (127 mg, 1.0 mmol) dropwise and the reaction mixture was stirred at rt until gas emission ceased (5 min). A solution of bromide salt (LiBr or n Bu 4 NBr depending on which alcohol, 2.5 mmol, 2.5 equiv in 3 ml of dry dichloromethane) was added dropwise. The reaction mixture was stirred at rt for 10 minutes before a solution of alcohol (1 mmol, 1.0 equiv) in dry dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred at rt for the indicated time. When the reaction was complete (monitored by TLC or 1 H NMR), the reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO 2, hexanes dichloromethane:hexanes 1:9) to obtain the bromide product. General procedure for acyl substitution of carboxylic acid (Table 2) To a solution of tropone (106 mg, 1.0 mmol) in dry dichloromethane (3 ml) was added oxalyl chloride (127 mg, 1.0 mmol) dropwise and the reaction mixture was stirred at rt until gas emission ceased (5 min). A solution of carboxylic acid (1.0 mmol, 1.0 equiv) and triethylamine (223 mg, 2.2 mmol, 2.2 equiv) in dichloromethane (2 ml) was added in one portion. After stirring at rt for the indicated time, benzylamine (161 mg, 1.5 mmol, 1.5 equiv) or the alcohol (1 ml) was added to the reaction mixture in one portion. After stirring for an additional 60 minutes, the reaction mixture was diluted with dichloromethane (20 ml) and washed successively with sat. aq. NaHCO 3 and brine. The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO 2, dichloromethane:hexanes 2:8 dichloromethane or EtOAc:hexanes 1:9 5:5) to yield the desired amide or ester product and recover tropone. S5

6 General procedure for catalytic chlorination and bromination of alcohol (Table 3) A solution of oxalyl chloride (1.1 mmol) in dichloromethane (5 ml) was added via syringe pump over the indicated time to a stirring solution of the alcohol substrate (1.0 mmol) and tropone (indicated mol%) in dichloromethane (5 ml) at rt (75 C in chloroform for entry 4). After the addition is completed, the reaction mixture was stirred at that temperature for another 1 h. When the reaction was complete (monitored by TLC or 1 H NMR), the reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO 2, hexanes dichloromethane:hexanes 1:9) to obtain the chloride or bromide product. Optimization of chlorination reaction with benzyl alcohol Entry Solvent Equiv of 1 Additive Time Yield 1 CH 3 CN min 69% 2 DMSO min 43% 3 DMF min messy 4 THF min 54% 5 Acetone min 24% 6 Toluene min 57% 7 DCE min 84% 8 CH 3 Cl min 90% 9 CH 3 Cl min 89% 10 CH 2 Cl min 92% 11 CH 2 Cl min 91% 12 CH 2 Cl min 91% 13 CH 2 Cl 2 - HCl 1.5 equiv 360 min 10% 14 CH 2 Cl 2 - (COCl) equiv 360 min 8%* * The crude product contained mainly a mixture of mono- and dibenzyl oxalate esters. S6

7 Characterization data of products (Chloromethyl)benzene 1 (Table 1, entry 1): Prepared according to the general procedure from benzyl alcohol at rt to yield a colorless oil (115 mg, 0.91 mmol, 91% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 4.60 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 137.7, 128.9, 128.8, 128.6, 46.5 ppm. 4-Methoxybenzyl chloride 2 (Table 1, entry 2): Prepared according to the general procedure from 4-methoxybenzyl alcohol at rt to yield a pale yellow oil (146 mg, 0.93 mmol, 93% yield). 1 H NMR (400 MHz, CDCl 3 ) 7.33 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 3.82 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 159.8, 120.2, 129.8, 114.3, 55.4, 46.5 ppm. 4-Nitrobenzyl chloride 3 (Table 1, entry 3): Prepared according to the general procedure from 4-nitrobenzyl alcohol at rt to yield an off-white solid (154 mg, 0.90 mmol, 90% yield). 1 H NMR (400 MHz, CDCl 3 ) 8.22 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 4.65 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 147.9, 144.5, 129.5, 124.1, 44.7 ppm. 2,4-Dimethylbenzyl chloride 4 (Table 1, entry 4): Prepared according to the general procedure from 2,4-dimethylbenzyl alcohol at rt to yield a pale yellow oil (133 mg, 0.86 mmol, 86% yield). 1 Altamura, M.; Perrotta, E. J. Org. Chem. 1993, 58, Newman, S. G.; Bryan, C. S.; Perez D.; Lautens, M. Synthesis 2011, Ding, R.; He, Y.; Wang, X.; Xu, J.; Chen, Y.; Feng, M.; Qi, C. Molecules 2011, 16, Hu, Y. L.; Ge, Q.; He, Y.; Lu, M. Chem. Cat. Chem. 2010, 2, 392. S7

8 1 H NMR (400 MHz, CDCl 3 ) 7.23 (d, J = 8.0 Hz, 1H), (m, 2H), 4.63 (s, 2H) 2.43 (s, 3H), 2.36 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 139.0, 137.2, 131.7, 130.0, 128.5, 127.1, 45.0, 21.3, 18.8 ppm. 4-Vinylbenzyl chloride 5 (Table 1, entry 5): Prepared according to the general procedure from 4-vinylbenzyl alcohol at rt to yield a pale yellow oil (128 mg, 0.84 mmol, 84% yield). The starting material and product are prone to polymerization. 1 H NMR (400 MHz, CDCl 3 ) 7.42 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.74 (dd, J = 16.0 Hz, 12.0 Hz, 1H), 5.79 (d, J = 16.0 Hz, 1H), 5.30 (d, J = 12.0 Hz, 1H), 4.59 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 137.9, 137.1, 136.4, 130.0, 126.7, 114.7, 46.2 ppm. Cinnamyl chloride 6 (Table 1, entry 6): Prepared according to the general procedure from cinnamyl alcohol at rt to yield a colorless oil (137 mg, 0.90 mmol, 90% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 6.67 (d, J = 16.0 Hz, 1H), 6.33 (dt, J = 8.0 Hz, 4.0 Hz, 1H), 4.27 (dd, J = 8.0 Hz, 4.0 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 136.1, 134.3, 128.8, 128.4, 126.9, 125.1, 45.6 ppm. 1,3-bis(Chloromethyl)benzene 7 (Table 1, entry 7): Prepared according to the general procedure from 1,3-bis(hydroxymethyl)benzene at rt to yield an off-white solid (133 mg, 0.76 mmol, 76% yield). 1 H NMR (400 MHz, CDCl 3 ) 7.43 (s, 1H), (m, 3H), 4.60 (s, 4H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 138.2, 129.3, 128.8, 128.7, 46.0 ppm. 1,6-Dichlorohexane 8 (Table 1, entry 8): Prepared according to the general procedure from 1,6-hexanediol at 75 C to yield a colorless oil (98 mg, 0.63 mmol, 63% yield). Due to high 5 Montheard, J. P.; Camps, M. C. R. Acad. Sci., Serie C: Sciences Chimiques 1980, 291, Goren, Z.; Heeg, M. J.; Mobashery, S. J. Org. Chem , 56, Tan, Y.-C.; Gan, X.-M.; Stanchfield, J. L.; Duesler, E. N.; Paine, R. T. Inorg. Chem. 2001, 40, S8

9 volatility of the product, after column chromatography the solvent was evaporated at 158 mmhg. 1 H NMR (400 MHz, CDCl 3 ) 3.53 (t, J = 8.0 Hz, 4H), 1.78 (m, 4H), 1.46 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 45.0, 32.6, 26.3 ppm. 1-Chloroheptane 9 (Table 1, entry 9): Prepared according to the general procedure from 1- heptanol at 75 C to yield a colorless oil (98 mg, 0.81 mmol, 81% yield). Due to high volatility of the product, after column chromatography the solvent was evaporated at 158 mmhg. 1 H NMR (400 MHz, CDCl 3 ) 3.53 (t, J = 6.0 Hz, 2H), 1.77 (m, 2H), (m, 8H), 0.89 (t, J = 6.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 45.3, 32.9, 31.9, 28.8, 27.1, 22.8, 14.2 ppm. 5-Chloropentyne 10 (Table 1, entry 10): Prepared according to the general procedure from 5- hydroxypentyne at 75 C to yield a colorless oil (86 mg, 0.84 mmol, 84% yield). Due to high volatility of the product, after column chromatography the solvent was evaporated at 158 mmhg. 1 H NMR (400 MHz, CDCl 3 ) 3.65 (t, J = 8.0 Hz, 2H), 2.38 (td, J = 8.0 Hz, 4.0 Hz, 2H), (m, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 82.7, 69.4, 43.6, 31.3, 16.0 ppm. (2-Chloroethyl)benzene 11 (Table 1, entry 11): Prepared according to the general procedure from 1-phenylethanol at 75 C to yield a pale yellow oil (124 mg, 0.88 mmol, 88% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 3.72 (t, J = 8.0 Hz, 2H), 3.08 (t, J = 8.0 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 138.2, 129.0, 128.7, 127.0, 45.1, 39.3 ppm. 8 Barry, C. N.; Evans, S. A. Jr. J. Org. Chem. 1983, 48, Leadbeater, N. E.; Torenius, H. M.; Tye, H. Tetrahedron 2003, 59, Scott, L. T.; Cooney, M. J.; Otte, C.; Puls, C.; Haumann, T.; Boese, R.; Carroll, P. J.; Smith, A. B. III; de Meijere, A. J. Am. Chem. Soc. 1994, 116, Drabowicz, J.; Luczak, J.; Mikolajczyk, M. J. Org. Chem. 1998, 63, S9

10 (1-Chloroethyl)benzene 12 (Table 1, entry 12): Prepared according to the general procedure from methylbenzyl alcohol at rt to yield a pale yellow oil (125 mg, 0.89 mmol, 89% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 5.11 (q, J = 8.0 Hz, 2H), 1.86 (d, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 143.0, 128.8, 128.4, 126.7, 58.9, 26.7 ppm. Chlorocyclohexane 13 (Table 1, entry 13): Prepared according to the general procedure from cyclohexanol at 75 C to yield a pale yellow oil (101 mg, 0.85 mmol, 85% yield). Due to high volatility of the product, after column chromatography the solvent was evaporated at 158 mmhg. 1 H NMR (400 MHz, CDCl 3 ) 3.98 (m, 1H), 2.03 (m, 2H), (m, 8H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 60.4, 36.8, 25.2 (two coincident resonances) ppm. 2-Chlorooctane 14 (Table 1, entry 14): Prepared according to the general procedure from 2- octanol at 75 C. Due to high volatility of the product, after column chromatography the solvent was evaporated at 158 mmhg to yield a colorless oil (116 mg, 0.78 mmol, 78% yield). 1 H NMR (400 MHz, CDCl 3 ) 4.01 (m, 1H), (m, 2H), 1.59 (d, J = 8.0 Hz, 3 H), (m, 8 H), (m, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 59.1, 40.6, 31.9, 29.0, 26.8, 25.5, 22.7, 14.2 ppm. 12 Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, Mondal, D.; Li, S. Y.; Bellucci, L.; Laino, T.; Tafi, A.; Guccione, S.; Lepore, S. D. J. Org. Chem. 2013, 78, Haughton, L; Williams, J.M.J. Synthesis. 2001, 943. S10

11 (Bromomethyl)benzene 15 (Table 1, entry 18): Prepared according to the general procedure for bromination of alcohol, with LiBr as bromide source, from benzyl alcohol at rt to yield a colorless oil (125 mg, 0.73 mmol, 73% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 4.52 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 137.9, 129.2, 128.9, 128.6, 33.7 ppm. 4-Nitrobenzyl bromide 3 (Table 1, entry 19): Prepared according to the general procedure for bromination of alcohol, with LiBr as bromide source, from 4-nitrobenzyl alcohol at rt to yield an off-white solid (151 mg, 0.70 mmol, 70% yield). 1 H NMR (400 MHz, CDCl 3 ) 8.19 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 4.51 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 147.8, 144.9, 130.1, 124.2, 31.1 ppm. (2-Bromoethyl)benzene 15 (Table 1, entry 20): Prepared according to the general procedure for bromination of alcohol, with n Bu 4 NBr as bromide source, from 1-phenylethanol at rt to yield a pale yellow oil (150 mg, 0.81 mmol, 81% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 3.59 (t, J = 8.0 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 139.1, (two coincident resonances), 127.1, 39.6, 33.1 ppm. 1-Bromoheptane 9 (Table 1, entry 21): Prepared according to the general procedure for bromination of alcohol, with n Bu 4 NBr as bromide source, from 1-heptanol at rt to yield a colorless oil (130 mg, 0.79 mmol, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) 3.40 (t, J = 6.0 Hz, 2H), 1.85 (m, 2H), (m, 8H), 0.89 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 34.2, 33.0, 31.8, 28.6, 28.3, 22.8, 14.2 ppm. 15 Denton, R.M.; An, J.; Adeniran, B.; Blake, A.; Lewis, W.; Poulton, A. J. Org. Chem. 2011, 76, S11

12 Ethyl benzoate 16 (Table 2, entry 1): Prepared according to the general procedure from benzoic acid to yield a colorless oil (89 mg, 0.59 mmol, 59% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 2H), (m, 1H), (m, 2H), 4.38 (q, J = 8.0 Hz, 2H), 1.39 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 166.7, 132.9, 130.7, 129.6, 128.4, 61.0, 14.4 ppm. Ethyl 4-methoxybenzoate 16 (Table 2, entry 3): Prepared according to the general procedure from 4-methoxybenzoic acid to yield a colorless oil (117 mg, 0.65 mmol, 65% yield). 1 H NMR (400 MHz, CDCl 3 ) 7.99 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.33 (q, J = 8.0 Hz, 2H), 3.83 (s, 3H), 1.36 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 166.5, 163.4, 131.6, 123.1, 113.7, 60.7, 55.5, 14.5 ppm. N-Benzylbenzamide 17 (Table 2, entry 4): Prepared according to the general procedure from benzoic acid to yield a white solid (129 mg, 0.61 mmol, 61% yield). 1 H NMR (400 MHz, CDCl 3 ) 7.79 (m, 2H), (m, 8H), 6.61 (bs, 1H), 4.63 (d, J = 4.0 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 167.5, 138.4, 134.6, 131.7, 128.9, 128.7, 128.0, 127.7, 127.1, 44.3 ppm. N-Benzyl 4-methoxybenzamide 18 (Table 2, entry 6): Prepared according to the general procedure from 4-methoxybenzoic acid to yield a white solid (150 mg, 0.62 mmol, 62% yield). 16 Jagadeesh, R. V.; Junge, H.; Pohl, M.-M.; Radnik, J.; Brueckner, A.; Beller, M. J. Am. Chem. Soc. 2013, 135, Pineda, A.; Gomez, L.; Balu, A. M.; Sebastian, V.; Ojeda, M.; Arruebo, M.; Romero, A. A.; Santamaria, J.; Luque, R. Green Chem. 2013, 15, Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M. Dang, T. T. Johannes, C. W.; Chen, A. Tetrahedron Lett. 2013, 54, S12

13 1 H NMR (400 MHz, CDCl 3 ) 7.72 (d, J = 8.0 Hz, 2H), (m, 5H), 6.82 (d, J = 8.0 Hz, 2H), 6.70 (t, J = 6.0 Hz, 1H), 4.53 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 167.1, 162.3, 138.6, 129.0, 128.8, 127.9, 127.5, 126.8, 113.8, 55.5, 44.1 ppm. Benzyl acetate 19 (Table 2, entry 7): Prepared according to the general procedure from acetic acid to yield a colorless oil (134 mg, 0.89 mmol, 89% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 5.12 (s, 2H), 2.10 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 171.1, 136.1, (two coincident resonances), 128.4, 66.5, 21.1 ppm. Benzyl butyrate 20 (Table 2, entry 8): Prepared according to the general procedure from n- butyric acid to yield a colorless oil (153 mg, 0.86 mmol, 86% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 5.12 (s, 2H), 2.34 (td, J = 8.0 Hz, 4.0 Hz, 2H), (m, 2H), 0.98 (dt, J = 8.0 Hz, 4.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 173.5, 136.3, 128.6, 128.4, 128.3, 66.1, 36.3, 18.5, 13.7 ppm. Ethyl phenylacetate 21 (Table 2, entry 9): Prepared according to the general procedure from phenylacetic acid to yield a colorless oil (145 mg, 0.88 mmol, 88% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 4.17 (q, J = 8.0 Hz, 2H), 3.63 (s, 2H), 1.27 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 170.3, 138.4, 128.7, 127.8, 127.4, 126.8, 43.7, 23.1 ppm. N-Benzylacetamide 22 (Table 2, entry 10): Prepared according to the general procedure from acetic acid to yield a white solid (127 mg, 0.85 mmol, 85% yield). 19 Chiarotto, I.; Feroci, M.; Sotgiu, G.; Inesi, A. Eur. J. Org. Chem. 2013, Hu, B.; Li, Y.; Li, Z.; Meng, X. Org. Biomol. Chem. 2013, 11, Ke, J.; He, C.; Liu, H.; Xu, H.; Lei, A. Chem. Commun. 2013, 49, Rao, S. N.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2013, 15, S13

14 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 6.52 (bs, 1H), 4.36 (d, J = 4.0 Hz, 2H), 1.96 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 171.1, 136.1, (two coincident resonances), 128.4, 66.5, 21.1 ppm. N-Benzylbutyramide 23 (Table 2, entry 11): Prepared according to the general procedure from butyric acid to yield a white solid (140 mg, 0.79 mmol, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 6.59 (bs, 1H), 4.38 (d, J = 8.0 Hz, 2H), (m, 2H), (m, 2H), 0.94 (t, J = 8H, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 173.2, 138.6, 128.6, 127.6, 127.3, 43.4, 38.5, 19.2, 13.8 ppm. N-Benzyl phenylacetamide 24 (Table 2, entry 12): Prepared according to the general procedure from phenylacetic acid to yield a white solid (189 mg, 0.84 mmol, 84% yield). 1 H NMR (400 MHz, CDCl 3 ) (m, 10H), 4.50 (d, J = 8.0 Hz, 2H), 4.29 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 160.0, 137.0, 132.8, 130.0, 129.0, 128.8, (two coincident resonances), 127.4, 43.7, 43.4 ppm. Monitoring progress of the reaction with 1-phenyl ethanol by 1 H NMR Two identical reaction mixtures were set up according to the general procedure for chlorination of alcohol with 1-phenylethanol (24.4 mg, 0.2 mmol) and 1,1-dichlorocycloheptatriene (32.2 mg, 0.2 mmol) in CDCl 3 (1.2 ml) inside two NMR tubes. The first reaction was followed by 1 H NMR over the course of the reaction at rt as a reference point and the second one was monitored at 75 C. Both of them showed clear evidence for the formation of S2 intermediate and the reaction at 75 C rapidly progressed towards the final product S3. See below for overlaid NMR spectra. 23 Davulcu, S.; Allen, C. L.; Milne, K.; Williams, J. M. J. Chem. Cat. Chem. 2013, 5, Gernigon, N.; Zheng, H.; Hall, D. G. Tetrahedron Lett. 2013, 54, S14

15 Figure S1. Monitoring the reaction at rt ( 1 H NMR, CDCl 3 ). The reaction was slow at rt, showing only traces of product S3 after 120 minutes. Figure S2. Monitoring the reaction at 75 C ( 1 H NMR, CDCl 3 ). The reaction was completed after 30 minutes. S15

16 Reaction with (R)-(-)-Mandelic acid: Reaction (A): To a stirring solution of 1 (1.61 g, 10 mmol, 1.0 equiv) in dry dichloromethane (20 ml) was added a solution of (R)-(-)-mandelic acid (1.52 g, 10 mmol, 1.0 equiv) and triethylamine (6.06 g, 60 mmol, 6.0 equiv) in dry dichloromethane (15 ml) dropwise. After stirring for 60 minutes, ethanol (2 ml) was added to the reaction mixture in one portion. After stirring for an additional 120 minutes, the reaction mixture was diluted with dichloromethane (20 ml) and washed successively with aq. HCl 1 M, sat. aq. NaHCO 3 and brine solutions. The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO 2, EtOAc:hexanes 1:9 5:5) to yield (R)-ethyl mandelate (9, 1.18g, 66%), (S)-2-chloro-2-phenylacetic acid ethyl ester (11, 99.3 mg, 5%) and tropone (828 mg, 78% based on the calculated amount of consumed material). Reaction (B): To a stirring solution of 1 (4.83 g, 30 mmol, 3.0 equiv) in dry dichloromethane (80 ml) was added a solution of (R)-(-)-mandelic acid (1.52 g, 10 mmol, 1.0 equiv) and triethylamine (6.06 g, 60 mmol, 6.0 equiv) in dry dichloromethane (20 ml) dropwise. After stirring for 60 minutes, ethanol (2 ml) was added to the reaction mixture in one portion. After stirring for an additional 120 minutes, the reaction mixture was washed successively with aq. HCl 1 M, sat. aq. NaHCO 3 and brine solutions. The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO 2, EtOAc:hexanes 1:9 5:5) to yield (S)-2-chloro-2-phenylacetic acid ethyl ester (11, 1.52 g, 77%) and tropone (1.40 g, 66% based on the calculated amount of consumed material). S16

17 (R)-Ethyl mandelate 25 (9 from reaction A) 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 5.16 (s, 1H), (m, 2H), 3.47 (bs, 1H) 1.23 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 173.9, 138.6, 128.7, 128.6, 126.7, 73.1, 62.4, 14.2 ppm. (S)-2-Chloro-2-phenylacetic acid ethyl ester 26 (11 from reaction B) 1 H NMR (400 MHz, CDCl 3 ) (m, 5H), 5.34 (d, J = 4.0 Hz, 1H), (m, 2H), 1.26 (t, J = 8.0 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) 168.5, 136.1, 129.4, 129.0, 128.1, 62.7, 59.3, 14.1 ppm. [α] 26 D = +82 (2% in absolute ethanol, literature value 27 = ). ee = 94%. 25 Gopinath, P.; Nilaya, S.; Muraleedharan, K. M. Org. Lett. 2011, 13, Haughton, L.; Williams, J. M. J. Synthesis 2001, DePuy, C. H.; Breitbeil, F. W.; DeBruin, K. R. J. Am. Chem. Soc. 1966, 88, S17

18 NMR spectra Compound 1 (Scheme 1) S18

19 S19

20 S20

21 S21

22 S22

23 S23

24 S24

25 S25

26 S26

27 S27

28 S28

29 S29

30 S30

31 S31

32 S32

33 Compound 9 Compound 11 S33