SUPPLEMENTARY MATERIAL

Transcription

1 SUPPLEMENTARY MATERIAL Valuable Building Block for the Synthesis of Lunularic Acid, Hydrangeic Acid and their Analogues Ramesh Mukkamla a, Asik Hossain a & Indrapal Singh Aidhen a * a Department of Chemistry, Indian Institute of Technology Madras, Chennai , India address: isingh@iitm.ac.in. Corresponding author: Tel ; Fax: Abstract: A new functionalized sulfone based building block has been synthesized that enabled C-C bond formation through Julia olefination. The utility of developed building block was demonstrated by successful synthesis of two natural products Lunularic acid, Hydrangeic acid and initial libraries of their analogues. Keywords: Lunularic acid; Hydrangeic acid; Amorfrutin; Cajaninstilbene acid; Julia olefination; bi-benzyl natural products. 1

2 Table of contents S.No Title Page Numbers 1 General procedure 3 2 Synthesis of 5-((benzo[d]thiazol-2ylthio) methyl)-2, 2-dimethyl- 4H-benzo[d][1,3]dioxin-4-one (13) 3 3 Synthesis of 5-((benzo[d]thiazol-2-ylsulfonyl) methyl)-2,2-3-4 dimethyl-4h-benzo[d][1,3]dioxin-4-one (9) 4 General procedure for olefination of building block 9 with 4 aldehydes (14a-i) 5 Spectral description for 15a-i General procedure for hydrolysis of the olefinated compounds 15ai 9-12 and Spectral description for 8 &18a-h 7 General procedure for hydrogenation of intermediates 15a-i and Spectral description for 16a-h 8 General procedure for hydrolysis of compounds 16a-h and Spectral description for 7&17a-f 9 1 H-NMR and 13 C-NMR spectra

3 Experimental section: General procedure: All the reactions were carried out by oven dried glassware under an inert atmosphere of nitrogen. Tetrahydrofuran was dried and distilled over Na Ph 2 CO, whereas, dichloromethane (CH 2 Cl 2 ) and N, N-dimethylformamide (DMF) were distilled over Calcium hydride. Thinlayer chromatography was performed on pre-coated silica gel F 254 aluminium plates with visualization under short UV light or by staining with Hanessian reagent. Melting points were obtained using a melting point apparatus and are uncorrected. NMR experiments were recorded on BRUKER AV 400 and 500 FT NMR instrument operating at 400 and 500 MHz respectively using tetramethylsilane (TMS) as the internal standard. HRMS were recorded on a MICRO Q TOF mass spectrometer by using ESI technique at 10 ev. Synthesis of 5-((benzo[d]thiazol-2ylthio) methyl)-2, 2-dimethyl-4H-benzo[d][1,3]dioxin- 4-one (13): To a solution of 12 (2.64 g, 9.79 mmol), 2-mercaptobenzothiazole (1.96 g, mmol) in CH 2 Cl 2 (25 ml) at 0 C was added triethylamine (2.74 ml, mmol), then stirring was continued at room temperature and progress of the reaction was monitored by TLC, after complete consumption of starting material the reaction mixture was diluted with water (50 ml) then extracted in to CH 2 Cl 2 (3 x 30 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), and dried over anhydrous sodium sulphate and then filtered. The filtrate was concentrated under vacuum; the resulting crude product was purified by silica gel column chromatography gave the sulphide 13 as white crystalline solid. Yield = 3.15g (91%); mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.89 (d, J = 8.0 Hz, 1H, BTH); 7.71 (d, J = 8.0 Hz, 1H, BTH); (m, 3H, ArH); (m, 1H, ArH); 6.88 (dd, J 1 = 7.6 Hz, J 2 = 2.0 Hz, 1H, ArH); 5.05 (s, 2H, CH 2 ); 1.72 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (CH); (CH); (CH); (CH); (CH); (CH); (CH); (C); (C); 35.6 (CH 2 ); 25.8 (CH 3 ) ppm. HRMS-ESI: Calcd. For C 18 H 16 N O 3 S 2 [M+H]: found Synthesis of 5-((benzo[d]thiazol-2-ylsulfonyl) methyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (9): To a solution of compound 13 in methanol (30 ml) was added sodium 3

4 tungstate dihydrate (Na 2 WO 4 2H 2 O) (1.975 g, 6.01 mmol), 30% hydrogen peroxide (H 2 O 2 ) (9 ml, mmol) and stirred at room temperature for 12 h. After complete consumption of starting material, methanol in reaction mixture was evaporated under reduced pressure and the reaction residue was dissolved in water (50 ml) and extracted into CH 2 Cl 2 (3 x 40 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography provided the building block 9 as white crystalline solid. Yield = g (87%); mp = C. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.21 (d, J = 8.4 Hz, 1H, BTH); 7.96 (d, J = 8.4 Hz, 1H, BTH); 7.62 (m, 1H, BTH); 7.57 (m, 1H, BTH); 7.42 (t, J = 7.6 Hz, 1H, ArH); 7.03 (d, J = 7.6 Hz, 1H, ArH); 7.00 (d, J = 8.4 Hz, 1H, ArH); 5.62 (s, 2H, CH 2 ); 1.68 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (CH); (CH); (C); (C); 57.6 (CH 2 ); 25.5 (CH 3 ) ppm. HRMS-ESI: Calcd. For C 18 H 16 N O 5 S 2 [M+H]: found General procedure for olefination of building block 9 with aldehydes (14a-i): To a solution of building block 9 (0.2 g, 0.51 mmol) in dry DMF (3 ml) at 0 º C, under nitrogen atmosphere was added sodium hydride (0.04 g, mmol). The solution turned reddish orange colour indicating the formation of carbanion. After 5 min of stirring, corresponding aldehydes (14a-i) (0.765 mmol) was added directly. The temperature of the reaction was gradually raised from 0 C to room temperature and stirring continued at room temperature for 4-5 h. The progress of the reaction was monitored by TLC and after complete consumption of starting material; the reaction mixture was quenched with saturated NH 4 Cl (15 ml) solution followed by extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with 10% aqueous solution of NaOH (3 x 15 ml) to remove by-product hydroxybenzothiazole, followed by water (20 ml), brine (20 ml) and dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The obtained crude compounds were subjected to column chromatography using silica gel as stationary phase, and combination of hexane/ethyl acetate as mobile phase gave the protected olefinated products 15a-i as presented below. 4

5 (E)-4-(2-(2, 2-dimethyl-4oxo-4H-benzo[d] [1, 3] dioxin-5-yl) vinyl) phenyl acetate (15a): Yield = 132 mg (76%); R f = 0.4 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.21 (d, J = 16.0 Hz, 1H, CH); 7.57 (d, J = 8.4 Hz, 2H, ArH); 7.48 (t, J = 8.0 Hz, 1H, ArH); 7.39 (d, J = 7.6 Hz, 1H, ArH); (m, 2H, ArH); 7.05 (d, J = 16.4 Hz, 1H, CH); (m, 1H, ArH); 2.30 (s, 3H, COCH 3 ); 1.72 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (CH); (CH); (C); (C); 25.7 (CH 3 ); 21.2 (CH 3 ) ppm. IR (KBr Pellet): 1765, 1721, 1602, 1471, 1364, 1323, 1275, 1187, 1050, and 1016 cm -1. HRMS-ESI: Calcd. For C 20 H 18 O 5 Na [M+Na]: found (E)-5-(2-(benzo[d] [1, 3] dioxol-5-yl) vinyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (15b): Yield = 165 mg (98%); R f = 0.4 (EtOAc-Hexane 2:8); mp = C 1 H NMR (400 MHz, CDCl 3 ) δ: 8.10 (d, J = 16.0 Hz, 1H, CH); 7.46 (t, J = 8.0 Hz, 1H, ArH); 7.37 (d, J = 7.6 Hz, 1H, ArH); 7.14 (s, 1H, ArH); 6.99 (d, J = 16.4 Hz, 1H, CH) ; 6.98 (d, J = 7.6 Hz, 1H, ArH); 6.84 (d, J = 8.0 Hz, 1H, ArH); 6.79 (d, J = 8.0 Hz, 1H, ArH); 5.97 (s, 2H, CH 2 ); 1.72 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C), (C), (C); (CH); (CH); (C); (CH); (CH); (CH); (C); (C); (CH); (CH); (C); (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 3084, 2897, 1727, 1593, 1577, 1493, 1471, 1442, 1381, 1318, 1253, 1226, 1044, 964, 930, and 776 cm -1. HRMS-ESI: Calcd. For C 19 H 17 O 5 [M+H]: found

6 (E)-5-(4-methoxystyryl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (15c): Yield = 88 mg (56%); R f = 0.5 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.15 (d, J = 16.4 Hz, 1H, CH); 7.52 (d, J = 8.8 Hz, 2H, ArH); 7.46 (t, J = 8.0 Hz, 1H, ArH); 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.05 (d, J = 16.4 Hz, 1H, CH); 6.9 (d, J = 8.8 Hz, 2H, ArH); 6.84 (d, J = 7.6 Hz, 1H, ArH); 3.82 (s, 3H, OCH 3 ); 1.72 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (C); (C); 55.4 (CH 3 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 2993, 1727, 1595, 1509, 1467, 1387, 1322, 1248, 1176, 1041, 957, 922, and 821 cm -1. HRMS-ESI: Calcd. For C 19 H 19 O 4 [M+H]: found (E)-5-(4-butoxystyryl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (15d): Yield = 122 mg (68%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.15 (d, J = 16.0 Hz, 1H, CH); 7.49 (d, J = 6.8 Hz, 2H, ArH); 7.46 (t, J = 8.0 Hz, 1H, ArH); 7.40 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H, ArH); 7.05 (d, J = 16.0 Hz, 1H, CH); 6.89 (d, J = 6.8 Hz, 2H, ArH); 6.83 (dd, J 1 = 7.8 Hz, J 2 = 1.6 Hz, 1H, ArH); 3.98 (t, J = 6.4 Hz, 2H, OCH 2 ); (m, 2H, Alkyl CH 2 ); 1.72 (s, 6H, 2 x CH 3 ); (m, 2H, Alkyl CH 2 ); 0.98 (t, J = 7.6 Hz, 3H, Alkyl CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (C); (C); 67.9 (OCH 2 ); 31.4 (CH 2 ); 25.8 (2 x CH 3 ); 19.3 (CH 2 ); 13.9 (CH 3 ) ppm. IR (KBr Pellet): 2959, 2926, 2360, 1723, 1596, 1509, 1467, 1386, 1318, 1249, 1042, 960 cm -1. HRMS-ESI: Calcd. For C 22 H 24 O 4 Na [M+Na]: found (E)-2, 2-dimethyl-5-(4-(octyloxy)styryl)-4H-benzo[d][1,3]dioxin-4-one (15e): 6

7 Yield = 116 mg (55%); R f = 0.7 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.15 (d, J = 16.0 Hz, 1H, CH); (m, 2H, ArH); 7.46 (t, J = 8.0 Hz, 1H, ArH); 7.40 (dd, J 1 = 7. 8 Hz, J 2 = 0.8 Hz, 1H, ArH); 7.05 (d, J = 16.4 Hz, 1H, CH); 6.89 (d, J = 8.8 Hz, 2H, ArH); 6.83 (dd, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H, ArH); 3.97 (t, J = 6.8 Hz, 2H, OCH 2 ); (m, 2H, Alkyl CH 2 ); 1.72 (s, 6H, 2 x CH 3 ); (m, 10H, 5 x CH 2 ); 0.89 (t, J = 7.2 Hz, 3H, Alkyl CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (CH); (C); (C); (CH); (C); (CH); (CH); (CH); (C); (CH); (C); (C); (C); 68.2 (OCH 2 ); 31.9 (CH 2 ); 29.5 (CH 2 ); 29.4 (CH 2 ); 29.3 (CH 2 ); 26.1 (CH 2 ); 25.8 (CH 3 ); 22.8 (CH 2 ); 14.2 (CH 3 ) ppm. IR (KBr Pellet): 2920, 2852, 1724, 1598, 1509, 1472, 1384, 1351, 1321, 1272, 1248, 1204, 1172, 1044, 830, 776 cm -1. HRMS-ESI: Calcd. For C 26 H 32 O 4 Na [M+Na]: found (E)-5-(3, 4-dichlorostyryl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (15f): Yield = 158 mg (89 %); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.22 (d, J = 16.0 Hz, 1H, CH); 7.62 (d, J = 1.6 Hz, 1H, ArH); 7.5 (t, J = 7.8 Hz, 1H, ArH); (m, 3H, ArH); 6.93 (d, J = 16.0 Hz, 1H, CH); 6.91 (d, J = 8.2 Hz, 1H, ArH); 1.73 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (C); (CH); (CH); (CH); (CH); (CH); (CH); (C); (C); 25.8 (CH 3 ) ppm. IR (KBr Pellet): 1724, 1595, 1477, 1384, 1352, 1318, 1273, 1046, 814, 774 cm -1. HRMS-ESI: Calcd. For C 18 H 14 O 3 Na Cl 2 [M+Na]: found (E)-5-(2, 4-difluorostyryl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (15g): 7

8 Yield = 74 mg (91%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.22 (d, J = 16.4 Hz, 1H, CH); 7.7 (m, 1H, ArH); 7.49 (t, J = 8.0 Hz, 1H, ArH); 7.4 (d, J = 7.6 Hz, 1H, ArH); 7.18 (d, J = 16.4 Hz, 1H, CH); (m, 3H, ArH); 1.73 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ:162.9 (dd, 1 J 1C-F = 210 Hz, 2 J 2C-F = 12 Hz, C); (C); (dd, 1 J 1C-F = 170 Hz, 2 J 2C-F = 12 Hz, C); (C); (C); (CH); (m, CH); (C); (m, C); (CH); (CH); (dd, J 1 = 21.5 Hz, J 2 = 4 Hz, CH); (C); (C); (m, CH); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 2361, 2338, 1725, 1592, 1499, 1470, 1385, 1319, 1267, 1234, 1210, 1043, 965, 846, 808, 774 cm -1. HRMS-ESI: Calcd. For C 18 H 14 O 3 K F 2 [M+K]: found (E)-5-(4-(benzyloxy)styryl)-2,2-dimethyl-4-methylene-4H-benzo[d][1,3]dioxin-4-one (15h): Yield = 118 mg (76%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.16 (d, J = 16.4 Hz, 1H, CH); 7.52 (d, J = 8.8 Hz, 2H, ArH); (m, 7H, ArH); 7.05 (d, J = 16.4 Hz, 1H, CH); 6.98 (d, J = 8.8 Hz, 2H, ArH); 6.85 (d, J = 8.0 Hz, 1H, ArH); 5.09 (s, 2H, CH 2 ); 1.73 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (CH); (CH); (CH); (C); (C); 70.1 (CH 2 ); 25.8 (CH 3 ) ppm. IR (KBr Pellet): 1719, 1596, 1509, 1468, 1386, 1352, 1321, 1250, 1043, 998 cm -1. HRMS-ESI: Calcd. For C 25 H 23 O 4 [M+H]: found (E)-2, 2-dimethyl-5-(3, 4, 5-trimethoxystyryl)-4H-benzo[d] [1, 3] dioxin-4one (15i): Yield = 184 mg (99 %); R f = 0.3 in 20% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.15 (d, J = 16.0 Hz, 1H, CH); 7.46 (d, J = 8.0 Hz, 1H, ArH); 7.39 (d, J = 7.6 Hz, 1H, ArH); 7.00 (d, J = 16.4 Hz, 1H, CH); 6.86 (dd, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H, ArH); 8

9 6.79 (s, 2H, ArH); 3.90 (s, 6H, 2 x OCH 3 ); 3.86 (s, 3H, OCH 3 ); 1.72 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); (C); (CH); 61.0 (CH 3 ); 56.2 (CH 3 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 3000, 2929, 2361, 2337, 1724, 1583, 1504, 1472, 1385, 1344, 1321, 1241, 1125, 1045, 775 cm -1. HRMS-ESI: Calcd. For C 21 H 23 O 6 [M+H]: found General procedure for hydrolysis of the olefinated compounds 15a-i: The general hydrolysis procedure was followed on all the substrates; (15a-i) is illustrated with substrate 15b as a representative example. The compound 15b (0.149 mg, 0.46 mmol) dissolved in THF (3 ml) followed by KOH (128.8 mg, 2.3 mmol) solution in 3 ml of water was added. The reaction mixture was refluxed for overnight, cooled to room temperature, acidified to ph 1, and extracted with EtOAc (3 x 10 ml). The combined organic layers were, washed with brine, dried over Na 2 SO 4 and concentrated. The obtained crude compound was purified by column chromatography gave the hydrolysed product (18a). (E)-2-hydroxy-6-(4-hydroxystyryl) benzoic acid (8): Yield = 130 mg (80%); R f = 0.1 in 40% EtOAc-Hexane; mp = C; 1 H NMR (500 MHz, CD 3 OD) δ: 7.60 (d, J = 16.0 Hz, 1H, -CH); (m, 3H); 7.12 (d, J = 7.6 Hz, 1H, ArH); 6.86 (d, J = 16.0 Hz, 1H, -CH); (m, 3H) ppm. 13 C NMR (125 MHz, CD 3 OD) δ: (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH) ppm. IR (KBr Pellet): 3451, 1594, 1483, 1446, 1380, 1352, 1255, 1213, 1039, 932 cm -1. Positive mode ESI-MS (m/z): 257 (M+H)+. (E)-2-(2-(benzo[d] [1, 3] dioxol-5yl) vinyl)-6-hydroxybenzoic acid (18a): Yield = 130 mg (75%); R f = 0.1 in 40% EtOAc-Hexane; mp = C; 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.24 (t, J = 8.0 Hz, 1H, ArH); 7.22 (d, J = 16.0 Hz, 1H, CH); 7.14 (d, J = 8.0 Hz, 1H, ArH); 7.09 (d, J = 1.2 Hz, 1H, ArH); 7.03 (d, J = 16.4 Hz, 1H, CH); 6.98 (dd, J 1 = 8.2 Hz, J 2 = 1.2 Hz, 1H, ArH); 6.92 (d, J = 8.0 Hz, 1H, ArH); 6.79 (d, J = 8.0 Hz, 1H, ArH); 6.04 (s, 2H, CH 2 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (C); 9

10 147.1 (C); (C); (C); (CH); (CH); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH 2 ) ppm. IR (KBr Pellet): 3451, 1594, 1483, 1446, 1380, 1352, 1255, 1213, 1039, 932 cm -1. HRMS-ESI: Calcd. For C 16 H 12 O 5 [M+Na]: found (E)-2-hydroxy-6-(4-methoxystyryl) benzoic acid (18b): Yield = 52 mg (70%); R f = 0.1 in 40% EtOAc-Hexane; 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.44 (d, J = 7.6 Hz, 2H, ArH); (m, 4H, ArH); 6.95 (d, J = 7.6 Hz, 2H, ArH); (m, 1H, ArH); 3.77 (s, 3H, OCH 3 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); 55.1 (CH 3 ) ppm. IR (KBr Pellet): 3446, 2833, 1665, 1592, 1509, 1461, 1375, 1292, 1235, 1174, 1118, 1017, 826, 778 cm -1. HRMS-ESI: Calcd. For C 16 H 14 O 4 K [M+K]: found (E)-2-(4-butoxystyryl)-6-hydroxybenzoic acid (18c): Yield = 104 mg (79%); R f = 0.1 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.70 (d, J = 16.0 Hz, 1H, CH); (m, 3H, ArH); 7.11 (d, J = 7.6 Hz, 1H, ArH); 6.93 (d, J = 8.4 Hz, 1H, ArH); 6.89 (d, J = 8.4 Hz, 2H, ArH); 6.83 (d, J = 16.0 Hz, 1H, CH); 3.98 (t, J = 6.4 Hz, 2H, CH 2 ); (m, 2H, CH 2 ); (m, 2H, CH 2 ); 0.98 (t, J = 7.2 Hz, 3H, CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (C); 67.9 (CH 2 ); 31.4 (CH 2 ); 19.3 (CH 2 ); 13.9 (CH 3 ) ppm. IR (KBr Pellet): 3443, 2957, 2930, 2361, 2336, 1653, 1596, 1510, 1458, 1380, 1352, 1254, 1137, 968, 827 cm -1. HRMS-ESI: Calcd. For C 19 H 21 O 4 [M+H]: found (E)-2 hydroxy-6-(4-(octyloxy)styryl)benzoic acid (18d): 10

11 Yield = 53 mg (73%); R f = 0.1 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.69 (d, J = 16.0 Hz, 1H, CH); (m, 3H, ArH); 7.12 (d, J = 7.6 Hz, 1H, ArH); 6.93 (d, J = 8.4 Hz, 1H, ArH); 6.90 (d, J = 8.4 Hz, 2H, ArH); 6.84 (d, J = 16.0 Hz, 1H, CH); 3.98 (t, J = 6.4 Hz, 2H, OCH 2 ); (m, 2H, CH 2 ); (m, 10H, 5 x CH 2 ); 0.89 (t, J = 4.0 Hz, 3H, CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (C); 68.3 (CH 2 ); 31.9 (CH 2 ); 29.5 (CH 2 ); 29.4 (CH 2 ); 26.1 (CH 2 ); 22.8 (CH 2 ); 14.2 (CH 3 ) ppm. IR (KBr Pellet): 3445, 2960, 2933, 2363, 2326, 1663, 1598, 1510, 1459, 1381, 1353, 1255, 1138, 967, 828 cm -1. HRMS-ESI: Calcd. For C 23 H 28 O 4 K [M+K]: found (E)-2-(3, 4-dichlorostyryl)-6-hydroxybenzoic acid (18e): Yield = 50 mg (53%); R f = 0.1 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, DMSO-d 6 ) δ:7.75 (s, 1H, ArH); 7.62 (d, J = 8 Hz, 1H, ArH); 7.50 (d, J = 8 Hz, 1H, ArH); 7.36 (d, J = 16.4 Hz, 1H, CH); 7.30 (t, J = 7.6 Hz, 1H, ArH); 7.19 (d, J = 7.2 Hz, 1H, ArH); 7.10 (d, J = 16 Hz, 1H, CH); 6.86 (d, J = 7.6 Hz, 1H, ArH) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (C); (C); (C); (C); (CH); (CH); (C); (CH); (CH); (CH); (CH); (CH); (CH) ppm. HRMS-ESI: Calcd. For C 15 H 11 O 3 Cl 2 [M+H]: found (E)-2-(2, 4-difluorostyryl)-6-hydroxybenzoic acid (18f): Yield = 61 mg (83%); R f = 0.1 in 40% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, DMSO-d 6 ) δ:7.68 (d, J = 6.4 Hz, 1H, ArH); (bs, 1H, ArH); (m, 2H); 7.19 (d, J = 7.6 Hz, 1H, ArH); (m, 2H); 6.90 (d, J = 7.2 Hz, 1H, ArH) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ:161.8 (dd, 1 J 1C-F = 182 Hz, 2 J 2C-F = 13 Hz, C); (dd, 1 J 1C-F = 184 Hz, 2 J 2C-F = 13 Hz, C); (C); (CH); (CH); (m, CH); (C); (CH); (C); (C); (CH); (CH); (dd, J 1 = 11

12 21 Hz, J 2 =3 Hz, CH); (t, J = 26 Hz, CH) ppm. HRMS-ESI: Calcd. For C 15 H 10 O 3 F 2 Na [M+Na]: found (E)-2-(4-(benzyloxy)styryl)-6-hydroxybenzoic acid (18g): Yield = 110 mg (88%); R f = 0.1 in 50% EtOAc/Hexane; mp = C; 1 H NMR (500 MHz, CD 3 OD) δ: 7.73 (d, J = 16.0 Hz, 1H, -CH); (m, 4H); 7.34 (t, J = 7.0 Hz, 2H, ); (m, 2H); 7.10 (d, J = 7.5 Hz, 1H, ArH); 6.92 (d, J = 8.5 Hz, 2H, ArH); 6.85 (d, J = 16.0 Hz, 1H, -CH); 6.79 (d, J = 8.0 Hz, 1H, ArH); 5.04 (s, 2H, -OCH 2 Ph) ppm. 13 C NMR (125 MHz, CD 3 OD) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (CH); (CH); (CH); (CH); (CH); 71.0 (CH 2 ) ppm. IR (KBr Pellet): 3452, 1651, 1589, 1505, 1455, 1418, 1343, 1250, 1128, 1028, 997, 960, 830, 773 cm -1. Positive mode ESI-MS (m/z): 347 (M+H) +. (E)-2-hydroxy-6-(3, 4, 5-trimethoxystyryl) benzoic acid (18h): Yield = 95 mg (72%); R f = 0.1 in 40% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.31 (d, J = 16.0 Hz, 1H, CH); 7.25 (t, J = 8.0 Hz, 1H, ArH); 7.15 (d, J = 7.6 Hz, 1H, ArH); 7.03 (d, J = 16.4 Hz, 1H, CH); (m, 3H, ArH); 3.81 (s, 6H, 2 x OCH 3 ); 3.67 (s, 3H, OCH 3 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (C); (C); (C); (C); (CH); (CH); (CH); (C); (CH); (CH); (CH); 60.0 (CH 3 ); 55.8 (CH 3 ) ppm. IR (KBr Pellet): 3452, 1651, 1589, 1505, 1455, 1418, 1343, 1250, 1128, 1028, 997, 960, 830, 773 cm -1. HRMS-ESI: Calcd. For C 18 H 19 O 6 [M+H]: found General procedure for hydrogenation of intermediates 15a-i: The general hydrogenation procedure was followed on all the substrates; 15a-h is illustrated with substrate 15b as a representative example. To a solution of 15b (81 mg, 0.25 mmol) in MeOH (2 ml), 10% Pd/C (26.6 mg, mmol) was added. Then de-gassed the reaction mixture with H 2, and then stirred the reaction mixture at room temperature under hydrogen 12

13 atmosphere (balloon) for overnight. After complete hydrogenation, the catalyst was filtered through celite pad; obtained filtrate was evaporated under reduced pressure to get reduced compound 16b. 4-(2-(2, 2-dimethyl-4-oxo-4H-benzo[d] [1, 3] dioxin-5yl) ethyl) phenyl acetate (16a): Yield = 47 mg (99%); R f = 0.4 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.38 (t, J = 8.0 Hz, 1H, ArH); (m, 2H, ArH); 6.98 (d, J = 8.4Hz, 2H, ArH); 6.86 (d, J = 7.6 Hz, 1H, ArH); (m, 1H, ArH); (m, 2H, CH 2 ); (m, 2H, CH 2 ); 2.28 (s, 3H, CH 3 ); 1.69 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (C); (CH); (CH); (CH); (CH); (CH); (C); (C); 36.9 (CH 2 ); 36.8 (CH 2 ); 25.7 (CH 3 ); 21.2 (CH 3 ) ppm. IR (KBr Pellet): 1762, 1725, 1598, 1381, 1351, 1317, 1272, 1216, 1193, 1050, 1013, 915 cm -1. HRMS-ESI: Calcd. For C 20 H 20 O 5 Na [M+Na] found (E)- (2-benzo[d] [1, 3] dioxol-5yl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16b): Yield = 53 mg (66%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.38 (t, J = 8.0 Hz, 1H, ArH); (m, 3H, ArH); (m, 2H, ArH); 5.90 (s, 2H, CH 2 ); 3.33 (t, J = 8.0 Hz, 2H, CH 2 ); 2.81 (t, J = 8.0 Hz, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (C); (C); (CH); (CH); (CH); (CH); (C); (CH); (CH); (C); (CH 2 ); 37.3 (CH 2 ); 37.1 (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 2922, 2817, 1726, 1608, 1588, 1499, 1481, 1444, 1382, 1353, 1309, 1240, 1045, 925, 855, 806, 771 cm -1. HRMS-ESI: Calcd. For C 19 H 19 O 5 [M+H] found

14 5-(4-methoxyphenethyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16c): Yield = 71 mg (90%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.37 (t, J = 8.0 Hz, 1H, ArH); 7.15 (d, J = 8.4 Hz, 2H, ArH); (m, 4H, ArH); 3.78 (s, 3H, OCH 3 ); 3.59 (t, J = 7.6 Hz, 2H, CH 2 ); 2.84 (t, J = 8.0 Hz, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); (C); 55.3 (OCH 3 ); 36.9 (CH 2 ); 36.7 (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 2949, 2831, 1724, 1604, 1584, 1511, 1479, 1380, 1353, 1322, 1258, 1057, 923, 828 cm -1. HRMS- ESI: Calcd. For C 19 H 21 O 4 [M+H]: found (4-butoxyphenethyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16d): Yield = 74 mg (82%); R f = 0.5 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.37 (t, J = 7.6 Hz, 1H, ArH); 7.13 (d, J = 8.4 Hz, 2H, ArH); 6.84 (d, J = 7.6 Hz, 1H, ArH); (m, 3H, ArH); 3.39 (t, J = 6.4 Hz, 2H, OCH 2 ); 3.35 (t, J = 7.6 Hz, 2H, CH 2 ); 2.83 (t, J = 8.4 Hz, 2H, CH 2 ); (m, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ); (m, 2H, CH 2 ); 0.97 (t, J = 7.6 Hz, 3H, CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); (C); 67.8 (OCH 2 ); 37.0 (CH 2 ); 36.7 (CH 2 ); 31.5 (CH 2 ); 25.8 (CH 3 ); 19.4 (CH 2 ); 14.0 (CH 3 ) ppm. IR (KBr Pellet): 2936, 2869, 1725, 1600, 1510, 1475, 1385, 1351, 1315, 1264, 1239, 1048, 824 cm -1. HRMS-ESI: Calcd. For C 22 H 26 O 4 Na [M+Na]: found , 2-dimethyl-5-(4-(octyloxy) phenethyl)-4h-benzo[d] [1, 3] dioxin-4-one (16e): 14

15 Yield = 80 mg (99%); R f = 0.7 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.37 (t, J = 8.0 Hz, 1H, ArH); (m, 2H, ArH); 6.85 (d, J = 8.0 Hz, 1H, ArH); (m, 3H, ArH); 3.92 (t, J = 6.8 Hz, 2H, OCH 2 ); (m, 2H, CH 2 ); (m, 2H, CH 2 ); (m, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ); (m, 10H, 5 x CH 2 ); (m, 3H, CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); (C); 68.1 (CH 2 ); 37.0 (CH 2 ); 36.7 (CH 2 ); 31.9 (CH 2 ); 29.5 (CH 2 ); 29.4 (CH 2 ); 29.3 (CH 2 ); 26.2 (CH 2 ); 25.7 (CH 3 ); 22.8 (CH 2 ); 14.2 (CH 3 ) ppm. IR (KBr Pellet): 2924, 2853, 1720, 1602, 1582, 1509, 1476, 1388, 1377, 1351, 1321, 1260, 1240, 1056, 818 cm -1. HRMS-ESI: Calcd. For C 26 H 34 O 4 Na [M+Na]: found (3, 4-dichlorophenethyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16f): Yield = 66 mg (83%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.39 (t, J = 8.0 Hz, 1H, ArH); (m, 2H, ArH); 7.09 (dd, J 1 = 8.4 Hz, J 2 = 2.0 Hz, 1H, ArH); 6.84 (d, J = 7.6 Hz, 2H, ArH); 3.32 (t, J = 8.0 Hz, 2H, CH 2 ); 2.84 (t, J = 7.6 Hz, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (C); (CH); (CH); (CH); (C); (C); 36.6 (CH 2 ); 36.5 (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 1725, 1599, 1472, 1387, 1352, 1308, 1131, 1049 cm -1. HRMS- ESI: Calcd. For C 18 H 16 O 3 Na Cl 2 [M+Na] found (2, 4-difluorophenethyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16g): Yield = 73 mg (82%); R f = 0.6 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.35 (t, J = 8.0 Hz, 1H, ArH); (m, 1H, ArH); (m, 4H, ArH); 3.34 (t, J = 7.2 Hz, 2H, CH 2 ); 2.91 (t, J = 8.0 Hz, 2H, CH 2 ); 1.70 (s, 6H, 2 x CH 3 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ:161.5 (dd, 1 J 1C-F = 240 Hz, 2 J 2C-F = 12 Hz, C); (dd, 1 J 1C-F = 245 Hz, 2 J 2C-F = 12 Hz, C); (C); (C); (CH); (m, CH);

16 (CH); (C); (C); (C); (CH); (C); (dd, J 1 = 20.5 Hz, J 2 = 3 Hz, CH); (C); (t, J = 26 Hz, CH); 35.3 (CH 2 ); 29.6 (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 1725, 1603, 1587, 1503, 1479, 1383, 1353, 1321, 1273, 1204, 1132, 1060, 961, 808 cm -1. HRMS-ESI: Calcd. For C 18 H 16 O 3 F 2 Na [M+Na] found (4-hydroxyphenethyl)-2, 2-dimethyl-4H-benzo[d] [1, 3] dioxin-4-one (16h): Yield = 59 mg (98%); R f = 0.3 in 30% EtOAc/Hexane; mp = C; 1 H NMR (500 MHz, CDCl 3 ) δ: 7.39 (t, J = 8.0 Hz, 1H, ArH); 7.09 (d, J = 8.5 Hz, 2H, ArH); 6.88 (d, J = 7.5 Hz, 1H, ArH); 6.82 (d, J = 8.0 Hz, 1H, ArH); 6.77 (d, J = 8.5 Hz, 2H, ArH); 5.7 (s, 1H, OH); 3.35 (t, J = 8.0 Hz, 2H, CH 2 ); 2.82 (t, J = 7.5 Hz, 2H, CH 2 ); 1.69 (s, 6H, 2 x CH 3 ) ppm.. 13 C NMR (125 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (C); (CH); (C); (CH); (CH); (CH); (C); (C); 37.0 (CH 2 ); 36.8 (CH 2 ); 25.7 (CH 3 ) ppm. IR (KBr Pellet): 3330, 2361, 2338, 1710, 1602, 1517, 1478, 1448, 1384, 1478, 1448, 1384, 1350, 1316, 1264, 1051, 828 cm -1. HRMS-ESI: Calcd. For C 18 H 19 O 4 [M+H] found General procedure for hydrolysis of compounds 16a-h The general hydrolysis procedure was followed on all the substrates; (16a-h) is illustrated with substrate 16a as a representative example. The compound 16a (46 mg, 0.14 mmol) in THF (2 ml) was added KOH (39.2 mg, 0.70 mmol) solution in H 2 O (2 ml). Then the reaction mixture was refluxed for overnight, cooled to room temperature, neutralized with 5% HCl, and extracted with EtOAc (3 x 10 ml). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated. The crude compound was purified by column chromatography provided the titled compound (17a). 2-hydroxy-6-(4-hydroxyphenethyl) benzoic acid (7): Yield = 40 mg (83%); R f = 0.1 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, DMSO-d 6 ) δ:9.12 (bs, 1H, OH); (m, 1H, ArH); 6.98 (d, J = 7.6 Hz, 2H, ArH); 6.72 (d, J = 7.6 Hz, 1H, ArH); (m, 3H, ArH); (m, 2H, CH 2 ); 16

17 (m, 2H, CH 2 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (C); (C); (C); (CH); (CH); (CH); (CH); (CH); 36.4 (CH 2 ) ppm. IR (KBr Pellet): 3462, 1648, 1596, 1513, 1448, 1354, 1245, 1203, 825, 771 cm -1. Negative mode ESI-MS (m/z): 257 (M-H)-. 2-(2-(benzo[d] [1, 3] dioxol-5-yl) ethyl)-6-hydroxybenzoic acid (17a): Yield = 30 mg (75%); R f = 0.1 in 30% EtOAc/Hexane; 1 H NMR (500 MHz, DMSO-d 6 ) δ: 7.16 (t, J = 7.5 Hz, 1H, ArH); 6.79 (d, J = 8.0 Hz, 1H, ArH); 6.77 (s, 1H, ArH); 6.75 (d, J = 8.0 Hz, 1H, ArH); 6.64 (d, J = 8.0 Hz, 1H, ArH); 5.95 (s, 2H, CH 2 ); 2.86 (bs, 2H, CH 2 ); (bs, 2H, CH 2 ) ppm. 13 C NMR (125 MHz, DMSO-d 6 ) δ: (C); (C); (C); (C); (C); (C); (C); (C); (CH); (CH); (CH); (CH); (CH); (CH 2 ); 36.9 (CH 2 ); 36.5 (CH 2 ) ppm. HRMS-ESI: Calcd. For C 16 H 14 O 5 Na [M+Na] found hydroxy-6-(4-methoxyphenethyl) benzoic acid (17b): Yield = 42 mg (77%); R f = 0.1 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, CDCl 3 ) δ:7.35 (t, J = 8.0 Hz, 1H, ArH); 7.11 (d, J = 8.4 Hz, 2H, ArH); 6.90 (d, J = 8.0 Hz, 1H, ArH); 6.83 (d, J = 8.4Hz, 2H, ArH); 6.74 (d, J =7.6Hz, 1H, ArH); 3.79 (s, 3H, OCH 3 ); (m, 2H, CH 2 ); (m, 2H, CH 2 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); 55.4 (CH 3 ); 38.9 (CH 2 ); 37.5 (CH 2 ) ppm. IR (KBr Pellet): 3449, 2929, 2362, 1659, 1602, 1512, 1467, 1378, 1285, 1242, 1214, 1180, 1117, 1024, 822, 760 cm -1. HRMS-ESI: Calcd. For C 16 H 16 O 4 Na [M+Na] found (4-butoxyphenethyl)-6-hydroxybenzoic acid (17c): 17

18 Yield = 49 mg (87%); R f = 0.1 in 30% EtOAc/Hexane; mp = C; 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 1H, ArH); 7.07 (d, J = 8.0 Hz, 2H, ArH); 6.87 (d, J = 8.0 Hz, 1H, ArH); 6.78 (d, J = 8.0 Hz, 2H, ArH); 6.70 (d, J = 7.5 Hz, 1H, ArH); 3.92 (t, J = 6.5 Hz, 2H, OCH 2 ); 3.24 (t, J = 7.5 Hz, 2H, CH 2 ); 2.83 (t, J = 7.5 Hz, 2H, CH 2 ); (m, 2H, CH 2 ); (m, 2H, CH 2 ); 0.97 (t, J = 7.5 Hz, 3H, CH 3 ) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); 67.8 (CH 2 ); 38.8 (CH 2 ); 37.4 (CH 2 ); 31.5 (CH 2 ); 19.3 (CH 2 ); 14.0 (CH 3 ) ppm. IR (KBr Pellet): 3455, 2957, 2933, 2360, 2337, 1598, 1511, 1460, 1381, 1352, 1300, 1243, 822 cm -1. HRMS-ESI: Calcd. For C 19 H 22 O 4 Na [M+Na] found hydroxy-6-(4-(octyloxy) phenethyl) benzoic acid (17d): Yield = 38 mg (62%); R f = 0.1 in 30% EtOAc/Hexane; mp = C; 1 H NMR (500 MHz, CDCl 3 ) δ: 7.35 (t, J = 8.0 Hz, 1H, ArH); 7.09 (d, J = 8.0 Hz, 2H, ArH); 6.89 (d, J = 8.5 Hz, 1H, ArH); 6.82 (d, J = 8.5 Hz, 2H, ArH); 6.73 (d, J = 7.0 Hz, 1H, ArH); 3.92 (t, J = 6.5 Hz, 2H, OCH 2 ); 3.26 (t, J = 7.5 Hz, 2H, CH 2 ); 2.85 (t, J = 8.5 Hz, 2H, CH 2 ); (m, 2H, CH 2 ); (m, 10H, 5 x CH 2 ); 0.88 (t, J = 6.5 Hz, 3H, CH 3 ) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ: (C); (C); (C); (C); (CH); (C); (CH); (CH); (CH); (CH); (C); 68.2 (CH 2 ); 38.9 (CH 2 ); 37.5 (CH 2 ); 31.9 (CH 2 ); 29.5 (CH 2 ); 29.4 (CH 2 ); 26.2 (CH 2 ); 22.8 (CH 2 ); 14.2 (CH 3 ) ppm. HRMS-ESI: Calcd. For C 23 H 30 O 4 Na [M+Na] found (3, 4-dichlorophenethyl)-6-hydroxybenzoic acid (17e): Yield = 47 mg (88%); R f = 0.1 in 30% EtOAc/Hexane; 1 H NMR (400 MHz, DMSO-d 6 ) δ:7.51 (d, J = 8.0 Hz, 1H, ArH); 7.43 (s, 1H, ArH); (m, 2H, ArH); 6.77 (d, J = 8.0 Hz, 1H, ArH); 6.68 (d, J = 7.2 Hz, 1H, ArH); 2.91 (bs, 2H, CH 2 ); 2.82 (bs, 2H, CH 2 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (C); (C); (CH); (C); 18

19 130.3 (CH); (CH); (CH); (CH); (CH); 35.9 (CH 2 ); 35.5 (CH 2 ) ppm. HRMS-ESI: Calcd. For C 15 H 13 O 3 Cl 2 [M+H] found (2, 4-difluorophenethyl)-6-hydroxybenzoic acid (17f): Yield = 42 mg (79%); R f = 0.1 in 30% EtOAc/Hexane; mp = C; 1 H NMR (400 MHz, DMSO-d 6 ) δ: (bs, 1H, ArH); (m, 2H, ArH); 6.98 (bs, 1H, ArH); 6.75 (d, J = 7.2 Hz, 1H, ArH); 6.62 (d, J = 7.2 Hz, 1H, ArH); 2.95 (bs, 2H, CH 2 ); 2.82 (bs, 2H, CH 2 ) ppm. 13 C NMR (100 MHz, DMSO-d 6 ) δ: (C); (m, C); (C); (C); (CH); (CH); (C); (CH); (CH); (d, J = 21 Hz, CH); (t, J = 26 Hz, CH); 34.5 (CH 2 ); 29.5 (CH 2 ) ppm. HRMS-ESI: Calcd. For C 15 H 12 O 3 F 2 Na [M+Na] found

20 ppm ppm 20

21 ppm ppm 21

22 ppm ppm 22

23 ppm ppm 23

24 ppm ppm 24

25 ppm ppm 25

26 ppm ppm 26

27 ppm ppm 27

28 ppm ppm 28

29 ppm ppm 29

30 ppm ppm 30

31 ppm ppm ppm 31

32 ppm ppm 32

33 ppm ppm 33

34 ppm ppm 34

35 ppm ppm 35

36 ppm ppm 36

37 ppm ppm 37

38 ppm ppm 38

39 ppm ppm 39

40 ppm ppm 40

41 ppm ppm 41

42 ppm ppm 42

43 ppm ppm 43

44 ppm ppm 44

45 ppm ppm 45

46 ppm ppm 46

47 ppm ppm 47

48 ppm ppm 48

49 ppm ppm 49

50 ppm ppm 50

51 ppm ppm 51

52 ppm ppm 52