Supporting information Highly Chemoselective Esterification Reactions and Boc/THP/TBDMS Discriminating Deprotections Under Samarium(III) Catalysis Pushparathinam Gopinath, Surapaneni Nilaya and Kannoth Manheri Muraleedharan * Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036 INDIA Table of Contents Pages 1. Experimental procedures, spectral- and analytical data 2-7 2. 1 H and 13 C NMR spectra of compound 1b 8 3. 1 H and 13 C NMR spectra of compound 2b 9 4. 1 H and 13 C NMR spectra of compound 3b 10 5. 1 H and 13 C NMR spectra of compound 4b 11 6. 1 H and 13 C NMR spectra of compound 5b 12 7. 1 H and 13 C NMR spectra of compound 6b 13 8. 1 H and 13 C NMR spectra of compound 7b 14 9. 1 H and 13 C NMR spectra of compound 8b 15 10. 1 H and 13 C NMR spectra of compound 9b 16 11. 1 H and 13 C NMR spectra of compound 10b 17 12. 1 H and 13 C NMR spectra of compound 11b 18 13. 1 H and 13 C NMR spectra of compound 12b 19 14. 1 H and 13 C NMR spectra of compound 13b 20 15. 1 H and 13 C NMR spectra of compound 15a 21 16. 1 H and 13 C NMR spectra of compound 15b 22 17. 1 H and 13 C NMR spectra of compound 15c 23 18. 1 H and 13 C NMR spectra of compound 15d 24 19. 1 H and 13 C NMR spectra of compound 15e 25 20. 1 H and 13 C NMR spectra of compound 15f 26 21. 1 H and 13 C NMR spectra of compound 15g 27 22. 1 H and 13 C NMR spectra of compound 15h 28 23. 1 H and 13 C NMR spectra of compound 16b 29 24. 1 H and 13 C NMR spectra of compound 18b 30 25. 1 H and 13 C NMR spectra of compound 19b 31 26. 1 H and 13 C NMR spectra of compound 20b 32 1
General experimental information: All reactions were carried out under nitrogen atmosphere and commercially available alcohols (methyl-, ethyl-,butyl-, isoamyl-, allyl-,benzyl-, isopropyl-,cyclohexyland tert-butyl alcohols) and SmCl 3 from Sigma Aldrich were used in esterification reactions. Thinlayer chromatography (TLC) was performed on 0.25 mm silica gel plates (60 F254 grade) from Merck, and were analyzed using either a 254 nm UV light or Ceric ammonium molybdate staining method. The chromatographic separation was carried out on 100-200 mesh silica gel. Melting points were obtained on electro-thermal apparatus and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded on Bruker Avance 400 MHz instrument, and the chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane, with J values in Hertz. The splitting patterns in 1 H NMR spectra are reported as follows: s = singlet; d = doublet; t = triplet; q = quartet; dd = doublet of doublet; bs = broad singlet; quin = quintet; hept = heptet, dt = doublet of triplet; m = multiplet. 13 C NMR data are reported with the solvent peak (CDCl 3 = 77.0) as the internal standard. High-resolution mass spectra (HRMS) were recorded on a Waters Q-Tof micro TM spectrometer with lock spray source. Infrared spectra were recorded using a Nicolet 6700 FT-IR spectrophotometer. General procedure for esterification: A sealed reaction tube containing mixture of the carboxylic acid and SmCl 3 (0.1-10 mol %) in appropriate alcohol (2 ml) was placed on a pre-heated oil bath (kept at 80-90 o C). After ensuring completion of the reaction by TLC analysis, the excess alcohol was evaporated off and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to get the corresponding esters. 5-(3-Hydroxy-benzo[b]thiophen-2-yl)-3, 3-dimethyl-5-oxo-pentanoic acid ethyl ester (1b) 5-(3-hydroxybenzo[b]thiophen-2-yl)-3,3-dimethyl-5-oxopentanoic acid (150 mg, 0.514 mmol) was esterified using SmCl 3 (3 mol%, 4 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 72 h to get the ethyl ester 1b (154 mg, 94% yield). Analytical data for 1b: 1 H NMR (CDCl 3 ) δ 12.5 (bs, 1H), 7.98 (d, 1H, J = 8.0 Hz), 7.73 (d, 1H, J = 8.4 Hz), 7.53 (t, 1H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.2 Hz), 4.13 (q, 2H, J = 7.2 Hz), 2.87 (s, 2H), 2.53 (s, 2H), 1.25 (t, 3H, J = 7.2 Hz), 1.21 (s, 6H); 13 C NMR (CDCl 3 ) δ 198.6, 171.9, 162.1, 139.0, 130.5, 129.8, 124.7, 123.8, 123.2, 112.5, 60.1, 50.4, 45.5, 33.8, 28.1(2C), 14.3; IR (neat) cm -1 : 2961, 2929, 1725, 1604, 1524, 1275, 1035, 766; HRMS (ESI) exact mass calcd. for C 17 H 21 4 S [M+H] + 321.1161, found [M+H] + 321.1160. 5-(3-Hydroxy-benzo[b]thiophen-2-yl)-5-oxo-3-phenyl-pentanoic acid ethyl ester (2b) 5-(3-Hydroxy-benzo[b]thiophen-2-yl)-5-oxo-3-phenyl-pentanoic acid (100 mg, 0.294 mmol) was esterified using SmCl 3 (3 mol%, 2.3 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 72 h to get desired ester 2b: (105 mg, 97% yield) as a pale yellow solid. Analytical data for 2b: mp 94-95 C; 1 H NMR (CDCl 3 ) δ 12.21 (bs, 1H), 7.95 (d, 1H, J = 8 Hz), 7.71 (d, 1H, J = 8 Hz), 7.52 (dd, 1H, J = 7.6, 8 Hz), 7.39 (dd, 1H, J = 7.2, 8 Hz), 7.29-7.28 (m, 4H), 7.23-7.18 (m, 1H), 4.04 (q, 2H, J = 7.2 Hz), 3.92 (qn, 1H, J = 7.4 Hz), 3.14 (m, 2H), 2.84-2.77 (m. 1H), 2.74-2.68 (m, 1H), 1.14 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 197.1, 171.5, 162.0, 142.7, 139.1, 130.4, 129.9, 128.6 (2C), 127.3 (2C), 127.0, 124.7, 123.8, 123.3, 111.4, 60.5, 46.8, 40.8, 37.8, 14.1; IR (neat) cm -1 : 2977, 1728, 1601, 1522, 1371, 1030, 732; HRMS (ESI) exact mass calcd. for C 21 H 21 4 S [M+H] + 369.1161, found [M+H] + 369.1160. 2-(2-ethoxy-2-oxoethyl)-5-nitrobenzoic acid (3b) A sealed reaction tube containing a mixture of Nitro homophthalic (250 mg, 1.111 mmol) and SmCl 3 (1 mol%, 3 mg) in Ethyl alcohol (2 ml) was heated in an oil bath at 80 o C for 48 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 3b (260 mg, 93% yield) as a white crystalline solid. Analytical data for 3b: mp 110 C; 1 H NMR (CDCl 3 ) δ 8.97 (d, 1H, J = 2.4 Hz), 8.39 (dd, 1H, J = 8.4, 2.4 Hz), 7.51 (d, 1H, J = 8.4 Hz), 4.23-4.18 (m, 4H), 1.28 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 170.2, 170.04, 147.16, 143.7, 133.7, 130.04, 127.4, 126.8, 61.4, 40.6, 14.1; IR (neat) cm -1 ; 3083, 2985, 1731, 1698, 1614, 1524, 1416; HRMS (ESI) exact mass calcd. for C 11 H 11 N 6 Na [M+Na] + 276.0484, found [M+ Na] + 276.0481. 2
2-Methylene-succinic acid 4-ethyl ester (4b) and 2-methylene-succinic acid diethyl ester (4c) Itaconic acid (250 mg, 1.922 mmol), was esterified using SmCl 3 (1 mol %, 5 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 17 h to get 4b (288 mg, 96% yield) as a white crystalline solid along with its diester 4c (16 mg, 4% yield) as a gummy liquid. Analytical data for 4b: mp 42-43 C; 1 H NMR (CDCl 3 ) δ 6.46 (s, 1H), 5.83 (s, 1H), 4.17 (q, 2H, J = 7.1 Hz), 3.34 (s, 2H), 1.26 (t, 3H, J = 7.1 Hz); 13 C NMR (CDCl 3 ) δ 171.3, 170.6, 133.3, 130.6, 61.0, 37.4, 14.1; IR (neat) cm -1 : 2987, 1730, 1725, 1636, 1433, 1269, 1197, 753; HRMS (ESI) exact mass calcd. for C 7 H 11 4 [M+H] + 159.0657, found [M+H] + 159.0658. Analytical data for 5c: 1 H NMR (CDCl 3 ) δ 6.32 (s, 1H), 5.69 (s, 1H) 4.22 (q, 2H, J = 7.2 Hz), 4.14 (q, 2H, J = 7.2 Hz), 3.33 (s, 2H), 1.29 (t, 3H, J = 7.2 Hz), 1.26 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 170.7, 166.1, 134.1, 128.0, 60.9, 60.8, 37.7, 14.0 (2C); IR (neat) cm -1 : 2981, 1724, 1636, 1310, 1187, 1146, 1030; HRMS (ESI) exact mass calcd. for C 9 H 15 4 [M+H] +, 187.0970 found [M+H] + 187.0974. Camphoric acid ethyl ester (5b) Camphoric acid (100 mg, 0.5 mmol), was esterified using SmCl 3 (5 mol%, 6.5 mg), in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 96 h to get the mono ester 5b (95 mg, 83% yield), as a gummy oil. Analytical data for 5b: 1 H NMR (CDCl 3 ) δ 4.1-4.0 (m, 2H), 2.73 (dd, 1H J = 9.2, 9.2 Hz), 2.46 (ddd, 1H, J = 12.4, 12.4, 7.6 Hz), 2.18-2.09 (m, 1H), 1.8-1.7 (m, 1H), 1.45 (ddd, 1H, J = 13.6, 9.6, 4.0 Hz), 1.22-1.18 (m, 9H), 0.8 (s, 3H); 13 C NMR (CDCl 3 ) δ 182.3, 173.9, 60.3, 56.1, 52.7, 46.7, 32.2, 22.7, 22.4, 21.5, 21.2, 14.3; IR (neat) cm -1 : 2974, 1726, 1698, 1461, 1378, 1274, 1175, 752; HRMS (ESI) exact mass calcd. for C 12 H 21 4 [M+H] + 229.1440, found [M+H] + 229.1432. Boc-AlaEt (6b) Boc- alanine (250 mg, 1.32 mmol) was esterified using SmCl 3 (10 mol%, 34 mg) in ethanol (2 ml), according to the general procedure discussed above for 144 h at 40 o C to get 6b (150 mg, 52% isolated yield) as a gummy liquid. After column chromatography, 60 mg of the starting Boc-Ala-H was also recovered. Analytical data for 6b: 1 H NMR (CDCl 3 ) δ 5.1(bs, 1H), 4.3 (bs, 1H), 4.2 (q, 2H, J = 7.12 Hz), 1.44 (s, 9H), 1.38 (d, 3H, J = 7.16 Hz), 1.26 (t, 3H, J = 7.12 Hz); 13 C NMR (CDCl 3 ) δ 173.4, 155.2, 79.8, 61.3, 49.3, 28.3 (3C), 18.7, 14.2,; IR (neat) cm -1 : 3365, 2985, 1706, 1514, 1448, 1360, 1264, 1162, 1059, 760; HRMS (ESI) exact mass calcd. for C 10 H 20 N 4 [M+H] + 218.1392, found [M+H] + 218.1396. BocAlaAlaMe (7b) BocAlaAlaH (250 mg, 0.96 mmol) was esterified using SmCl 3 (10 mol%, 25 mg) in methanol (4 ml) according to the general procedure discussed above for 144 h at 50 o C to get 7b (142 mg, 54% isolated yield) as a white crystalline solid. After column chromatography, 50 mg of the starting material was also recovered. Analytical data for 7b: 1 H NMR (CDCl 3 ) δ 6.78 (brs, 1H), 5.15 (brd, 1H), 4.6-4.51 (m, 1H), 4.2 (brs, 1H), 3.75 (s, 3H), 1.45 (s, 9H), 1.41 (d, 3H, J = 7.2 Hz), 1.36 (d, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 173.2, 172.3, 155.45, 80.1, 52.4, 50.0, 48.0, 28.3(3C), 18.2 (2C); HRMS (ESI) exact mass calcd. for C 12 H 23 N 2 5, [M+H] + 275.1607 found [M+H] + 275.1605. 2-Benzyloxycarbonylamino-pentanedioic acid diethyl ester (8b) N-Cbz protected glutamic acid (250 mg, 0.89 mmol) was esterified using SmCl 3 (1 mol%, 3 mg) in ethanol (3 ml) according to the general procedure discussed above at 80 o C for 48 h to get 8b (272 mg, 91% yield) as a gummy liquid; Analytical data for 8b: R f (25% EtAc /hexanes) 0.48; 1 H NMR (CDCl 3 ) δ 7.35-7.29 (m, 5H), 5.43 (d, 1H, J = 7.2 Hz), 5.1 (s, 2H), 4.39 (m, 1H), 4.20 (q, 2H, J = 5.8 Hz), 4.12 (q, 2H, J = 7.2 Hz), 2.47-2.34 (m, 2H), 2.24-2.17 (m, 1H), 2.04-1.95 (m, 1H), 1.29-1.21 (m, 6H); 13 C NMR (CDCl 3 ) δ 172.7, 171.8, 155.9, 136.2, 128.5 (2C), 128.2 (2C), 128.1, 67.0, 61.6, 60.7, 53.4, 30.2, 27.7, 14.1 (2C); IR (neat) cm -1 : 3350, 3057, 2979, 1728, 1514, 1265, 1206, 1052, 746; ESI (m/z) 338 [M+H] +. Mandelic acid ethyl ester (9b) Mandelic acid (250 mg. 1.643 mmol) was esterified using SmCl 3 (1 mol %, 4.2 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 16 h to get the desired ester 9b (283 mg, 96% yield) as colorless liquid. Analytical data for 9b: 1 H NMR (CDCl 3 ) δ 7.38-7.26 (m, 5H), 5.15 (d, 1H, J = 5.2 Hz ), 4.25-4.12 (m, 2H), 3.57 (d, 1H, J = 5.6 Hz), 1.22 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 173.6, 138.4, 128.5 (2C), 128.4, 126.5 (2C), 72.8, 62.2, 14.0; IR (neat) cm -1 : 3454, 2980, 3
2927, 1731, 1264, 1183, 1069, 738; HRMS (ESI) exact mass calcd. for C 10 H 12 3 Na [M+Na] + 203.0684, found [M+Na] + 203.0681. Diethyl tartarate (10b) Tartaric acid (250 mg. 1.66 mmol) was esterified using SmCl 3 (0.1 mol%, 0.4 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 46 h to get the desired diethyl ester 10b (329 mg, 96% yield) as colourless oil. Analytical data for 10b: 1 H NMR (CDCl 3 ) δ 4.55 (s, 2H), 4.33 (q, 4H, J = 7.16 Hz), 3.3-3.1 (bs, 2H,), 1.33 (t, 6H, J = 7.16 Hz); 13 C NMR (CDCl 3 ) δ 171.5 (2C), 72 (2C), 62.4 (2C), 14.1 (2C); IR (neat) cm -1 : 3476, 2981, 1735, 1298, 1234, 1085, 1017; HRMS (ESI) exact mass calcd. for C 8 H 15 6 (M+H) + 207.0869, found (M+H) + 207.0863. 2-Hydroxy-succinic acid diethyl ester (11b) Malic acid (140 mg, 1.044 mmol), was esterified using SmCl 3 (0.5 mol%, 1.5 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 48 h to get the desired diethyl ester 11b (186 mg, 94% yield). Analytical data for 11b: 1 H NMR (CDCl 3 ) δ 4.49 (dd, 1H, J = 5.2, 5.2 Hz), 4.27 (m, 2H), 4.18 (m, 2H), 3.3 (bs, 1H, H), 2.89-2.75 (two dd merged, 2H), 1.34-1.24 (two triplets merged, 6H); 13 C NMR (CDCl 3 ) δ 173.3, 170.5, 67.2, 61.9, 60.9, 38.7, 14.0 (2C); IR (neat) cm -1 3451, 2984, 1729, 1376, 1169, 1101, 1024; HRMS (ESI) exact mass calcd. for C 8 H 14 5 Na [M+Na] + 213.0739, found [M+Na] + 213.0739. 2-Hydroxy-succinic acid 4-ethyl ester (11c) Malic acid (110 mg, 0.82 mmol), was esterified using SmCl 3 (1 mol%, 2 mg) in ethanol (2 ml) as discussed above and the reaction time was limited to 3 h to get the desired mono ester 11c (71 mg, 46% yield) along with diester 11b (40 mg, 30% yield) as colorless oils. Analytical data for 11c: 1 H NMR (CDCl 3 ) δ 6.37 (bs, 1H), 4.51 (dd, 1H, J = 4.4, 4.4 Hz), 4.27 (m, 2H), 2.95-2.80 (two dd merged, 2H), 1.28 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 175.24, 173.23, 67.1, 62.2, 38.4, 14.1; IR (neat) cm -1 : 2923, 2856, 1726, 1268, 753. 3, 4, 5-Trihydroxy-benzoic acid methyl ester (12b) 3, 4, 5-Trihydroxy-benzoic acid (300 mg, 1.764 mmol), was esterified using SmCl 3 (10 mol%, 45 mg) in methanol (4 ml) according to the general procedure discussed above at 80 o C for 130 h to get the desired ester 12b (260 mg, 74% yield), as yellow solid; Analytical data for 12b: 1 H NMR (CDCl 3 +CD 3 D) δ 7.11 (s, 2H), 4.1 (bs, 3H), 3.8 (s, 3H); 13 C NMR (CDCl 3 +CD 3 D) δ 167.8, 144.4 (2C), 137.7, 120.3, 109.0 (2C), 51.6. HRMS (ESI) exact mass calcd. for C 8 H 9 5 [M+H] + 185.0450, found [M+H] + 185.0452. Cinnamic acid ethyl ester (13b) Cinnamic acid (100 mg, 0.675 mmol), was esterified using SmCl 3 (10 mol%, 17 mg) in ethanol (2 ml) according to the general procedure discussed above at 80 o C for 96 h to get 13b (113 mg, 96% yield), Analytical data for 13b: 1 H NMR (CDCl 3 ) δ 7.69 (d, 1H, J = 16 Hz), 7.53-7.51(m, 2H), 7.38-7.36 (m, 3H), 6.44 (d, 1H, J = 16.4 Hz), 4.27 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 167, 144.6, 134.6, 130.2, 128.9 (2C), 128.0 (2C), 118.3, 60.5, 14.3; IR (neat) cm -1 : 2989, 1708, 1636, 1451, 1312, 1266, 1034, 981; HRMS (ESI) exact mass calcd. for C 11 H 13 2 (M+H) + 177.0916, found (M+H) + 177.0916. 2-(2-methoxy-2-oxoethyl)benzoic acid (15a) A sealed reaction tube containing a mixture of homophthalic acid (250 mg, 1.388 mmol) and SmCl 3 (1 mol%, 4 mg) in methanol (3 ml) was heated in an oil bath at 80 o C for 8 h. Methanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15a (260 mg, 97% yield) as a white crystalline solid. Analytical data for 15a: mp 96-98 C; 1 H NMR (CDCl 3 ) δ 8.15 (d, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.41 (t, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 7.6 Hz), 4.07 (s, 2H), 3.71 (s, 3H); 13 C NMR (CDCl 3 ) δ 172.5, 172, 136.8, 133.3, 132.4, 131.9, 128.5, 127.6, 52.0, 40.6; IR (neat) cm -1 ; 2951, 2510, 1702, 1578, 1403, 1272, 1005; HRMS (ESI) exact mass calcd. for C 10 H 11 4 [M+H] + 195.0657, found [M+H] + 195.0655. 2-Ethoxycarbonylmethyl-benzoic acid (15b) 4
A sealed reaction tube containing a mixture of homophthalic acid (250 mg. 1.388 mmol) and SmCl 3 (1 mol%, 4 mg) in ethanol (2 ml) was heated in an oil bath at 80 o C for 10 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15b (286 mg, 99% yield) as a white crystalline solid. Analytical data for 15b: mp 106 C; 1 H NMR (CDCl 3 ) δ 8.13 (d, 1H, J = 7.6 Hz), 7.53 (dt, 1H, J = 7.2, 1.2 Hz), 7.39 (dt, 1H, J = 7.6, 0.8 Hz), 7.28 (d, 1H, J = 7.6 Hz), 4.17 (q, 2H, J = 7.2 Hz), 4.05 (s, 2H), 1.26 (t, 3H, J = 7.2 Hz); 13 C NMR (CDCl 3 ) δ 172.5, 171.5, 136.9, 133.2, 132.4, 131.9, 128.7, 127.5, 60.8, 40.8, 14.1; IR (neat) cm -1 ; 2979, 2648, 2522, 1728, 1674, 1406, 1274, 1172, 925; HRMS (ESI) exact mass calcd. for C 11 H 13 4 [M+H] + 209.0814, found [M+H] + 209.0813. 2-(2-butoxy-2-oxoethyl)benzoic acid (15c) A sealed reaction tube containing a mixture of homophthalic acid (250 mg. 1.388 mmol) and SmCl 3 (5 mol%, 18 mg) in isobutanol (3 ml) was heated in an oil bath at 90 o C for 40 h. Isobutanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15c (295 mg, 90% yield) as a white crystalline solid. Analytical data for 15c: mp 80-82 C; 1 H NMR (CDCl 3 ) δ 8.27 (d, 1H, J = 7.2 Hz), 7.53 (dt, 1H, J = 7.8, 1.2 Hz), 7.4 (dt, 1H, J = 7.6, 0.8 Hz), 7.29 (d, 1H, J = 7.6 Hz), 4.11 (t, 2H, J = 6.8 Hz), 4.06 (s, 2H), 1.6 (qt, 2H, J = 7.6 Hz),1.36 (sextet, 2H, J = 7.2 Hz), 0.91 (t, 3H, J = 7.6 Hz); 13 C NMR (CDCl 3 ) δ 172.5, 171.6, 137.0, 133.2, 132.4, 131.9, 128.6, 127.5, 64.5, 40.8, 30.6, 19.1, 13.6; IR (neat) cm -1 ; 3073, 2969, 2933, 2874, 1728, 1686, 1576, 1407, 1302; HRMS (ESI) exact mass calcd. for C 13 H 17 4 [M+H] + 237.1127, found [M+H] + 237.1126. 2-(2-(isopentyloxy)-2-oxoethyl)benzoic acid (15d) A sealed reaction tube containing a mixture of homophthalic acid (250 mg, 1.388 mmol) and SmCl 3 (5 mol%, 18 mg) in isoamyl alcohol (3 ml) was heated in an oil bath at 90 o C for 48 h. Isoamyl alcohol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15d (311 mg, 90% yield) as a white crystalline solid. Analytical data for 15d: mp 82-84 C; 1 H NMR (CDCl 3 ) δ 8.14 (d, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.2, Hz), 7.40 (t, 1H, J = 7.6, Hz), 7.28 (d, 1H, J = 7.6 Hz), 4.14 (t, 2H, J = 7 Hz), 4.06 (s, 2H), 1.66 (hept, 1H, J = 6.4 Hz), 1.52 (q, 2H, J = 6.6 Hz), 0.89 (d, 6H, J = 6.4 Hz); 13 C NMR (CDCl 3 ) δ 172.43, 171.6, 137.0, 133.2, 132.4, 131.9, 128.6, 127.5, 63.5, 40.8, 37.2, 25.0, 22.4(2C); IR (neat) cm -1 ; 3074,2960, 2870, 2654, 1734, 1687, 1410, 1349, 1300; HRMS (ESI) exact mass calcd. for C 14 H 19 4 [M+H] + 251.1283, found [M+H] + 251.1279. 2-(2-(allyloxy)-2-oxoethyl)benzoic acid (15e) A sealed reaction tube containing a mixture of homophthalic acid (250 mg, 1.388 mmol) and SmCl 3 (5 mol%, 18 mg) in allyl alcohol (3 ml) was heated in an oil bath at 90 o C for 48 h. Allyl alcohol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15e (250 mg, 82% yield) as a white crystalline solid. Analytical data for 15e: mp 98-100 C; 1 H NMR (CDCl 3 ) δ 8.15 (d, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 7.6 Hz), 5.98-5.86 (m, 1H), 5.29 (bdt, 1H), 5.21 (bd, 1H), (m, 2H), 4.62 (b dd), 4.09 (s, 2H) ; 13 C NMR (CDCl 3 ) δ 172.5, 171.1, 136.7, 133.3, 132.4, 132.1, 131.9, 128.6, 127.6, 118.3, 65.5, 40.7; IR (neat) cm -1 ; 3433, 2934, 1727, 1686, 1577, 1417, 1263; HRMS (ESI) exact mass calcd. for C 12 H 12 4 Na [M+Na] + 243.0633, found [M+Na] + 243.0640. 2-(2-(benzyloxy)-2-oxoethyl)benzoic acid (15f) A sealed reaction tube containing a mixture of homophthalic (250 mg, 1.388 mmol) and SmCl 3 (5 mol%, 18 mg) in benzyl alcohol (2 ml) was heated in an oil bath at 110 o C for 48 h. Added 4 ml of Sat. NaHC 3 in to the reaction mixture. Extracted with ethyl acetate. Solvent was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15f (250 mg, 67% yield) as a white crystalline solid. Analytical data for 15f: mp 104-106 C; 1 H NMR (CDCl 3 ) δ 8.15 (d, 1H, J = 7.6 Hz), 7.55 (t, 1H, J = 7.2 Hz), 7.41 (t, 1H, J = 7.6 Hz), 7.33 (d, 4H, J = 3.6 Hz), 7.29 (d, 2H, J = 7.6 Hz), 5.15 (s, 2H), 4.11 (s, 2H); 13 C NMR (CDCl 3 ) δ 172.49, 171.36, 136.78, 135.87, 133.35, 132.48, 131.95, 128.47 (2C), 128.22 (2C), 5
128.11(2C), 127.61, 66.58, 40.77; IR (neat) cm -1 ; 2946, 1737, 1680, 1574, 1456, 1410; HRMS (ESI) exact mass calcd. for C 16 H 15 4 [M+H] + 271.0970, found [M+H] + 271.0972. 2-(2-(cyclohexyloxy)-2-oxoethyl)benzoic acid (15g) A sealed reaction tube containing a mixture of homophthalic (100 mg, 0.56 mmol) and SmCl 3 (5 mol%, 7.1 mg) in cyclohexanol (0.3 ml) and toulene 3ml was heated in an oil bath at 110 o C for 48 h. Then the residue was chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15g (120 mg, 83% yield) as a white crystalline solid. Analytical data for 15g: mp 112-114 C; 1 H NMR (CDCl 3 ) δ 8.13 (d, 1H, J = 7.2 Hz), 7.53 (dt, 1H, J = 7.2, 0.8 Hz), 7.39 (dt, 1H, J = 7.6, 1.2 Hz), 7.28 (d, 1H, J = 6.4 Hz), 4.81 (d, 1H, J = 8.6 Hz), 4.03 (s, 2H), 1.89-1.79 (m, 2H), 1.72-1.63 (m, 2H), 1.54-1.4 (m, 3H), 1.37-1.2 (m, 3H); 13 C NMR (CDCl 3 ) δ 172.6, 170.9, 137.1, 133.2, 132.34, 131.8, 128.64, 127.4, 73.01, 41.15, 31.44 (2C), 25.35, 23.61 (2C); IR (neat) cm -1 ; 2935, 1730, 1687, 1576, 1415, 1299; HRMS (ESI) exact mass calcd. for C 15 H 19 4 [M+H] + 263.1283, found [M+H] + 263.1291. 2-(2-isopropoxy-2-oxoethyl)benzoic acid (15h) A sealed reaction tube containing a mixture of homophthalic acid (100 mg, 0.55 mmol) and SmCl 3 (5 mol%, 7.1 mg) in IPA (3 ml) was heated in an oil bath at 90 o C for 32 h. IPA was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoester 15h (123 mg, 99% yield) as a white crystalline solid. Analytical data for 15h: mp 98-100 C; 1 H NMR (CDCl 3 ) δ 8.13 (d, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 8 Hz), 7.4 (t, 1H, J = 7.6 Hz), 7.28 (d, 1H, J = 7.6 Hz), 5.04 (heptet, 1H, J = 4.8 Hz), 4.01 (s, 2H), 1.2 (dd, 6H, J = 6.4, 1.9 Hz); 13 C NMR (CDCl 3 ) δ 172.5, 171.04, 137.1, 133.2, 132.4, 131.9, 128.7, 127.5, 68.2, 41.1, 21.7 (2C); IR (neat) cm -1 ; 3068, 2986, 1731, 1680, 1581, 1417, 1308; HRMS (ESI) exact mass calcd. for C 12 H 15 4 [M+H] + 223.0970, found [M+H] + 223.0967. N-Boc-ethanolamine (16b) A sealed reaction tube containing a mixture of tert-butyl 2-(tert-butyldimethylsilyloxy)ethylcarbamate (100 mg, 0.363 mmol) and SmCl 3 (1 mol%, 1 mg) in ethyl alcohol (2 ml) was heated in an oil bath at 80 o C for 16 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford Boc-ethanolamine 16b (58 mg, 99% yield) as a liquid. Analytical data for 16b: 1 H NMR (CDCl 3 ) δ 5.13 (bs, 1H) 3.65 (t, 2H, J = 5.04 Hz), 3.25 (bd, 2H), 3.2-3.1 (bs, 1H), 1.42 (s, 9H); 13 C NMR (CDCl 3 ) δ 156.8, 79.61, 62.3, 43.0, 28.39 (3C); HRMS (ESI) exact mass calcd. for C 17 H 16 N 3 (M+H) + 162.1130, found (M+H) + 162.1135. 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (18b) A sealed reaction tube containing a mixture of tert-butyl 2-(tetrahydro-2H-pyran-2- yloxy)ethylcarbamate (100 mg, 0.38 mmol) and SmCl 3 (1 mol%, 1 mg) in ethyl alcohol (2 ml) was heated in an oil bath at 40 o C for 40 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the 18b (52 mg, 85% yield) as a liquid. Analytical data for 18b: 1 H NMR (CDCl 3 ) δ 4.57 (dd, 1H, J = 2.8, 5.2 Hz), 3.96-3.90 (m, 1H), 3.8-3.68 (m, 4H), 3.57-3.51 (m, 1H), 2.85 (t, 1H, J = 6.8 Hz), 1.87-1.75 (m, 2H), 1.63-1.5 (m, 4H); 13 C NMR (CDCl 3 ) δ 100.3, 70.9, 63.4, 62.3, 30.9, 25.3, 20.1; HRMS (ESI) exact mass calcd. for C 7 H 15 3 (M+H) + 147.1021 found (M+H) + 147.1017. 2,3-dihydroxypropyl acetate (19b ) A sealed reaction tube containing a mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl acetate (100 mg, 1.149 mmol) and SmCl 3 (1 mol%, 1.5 mg) in Ethyl alcohol (2 ml) was heated in an oil bath at 80 o C for 7 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetatehexane solvent system in a gradient mode to afford the mono acetate 19b (68 mg, 88% yield) as a gummy liquid. Analytical data for 19b : 1 H NMR (CDCl 3 ) δ 4.2-4.1 (m, 2H ),3.93 (pentet, 1H, J = 4.8 Hz), 3.69 (dd, 1H, J = 3.6, 11.6 Hz), 3.59 (dd, 1H, J = 6, 11.6 Hz) 3.19-3.09 (bs, 1H), 2.8-2.7 (bs, 1H); 13 C NMR (CDCl 3 ) δ 171.56, 70.12, 65.29, 63.3, 20.83; HRMS (ESI) exact mass calcd. for C 5 H 11 4 [M+H] + 135.0657, found [M+ H] + 135.0662. 1-(3-hydroxyphenyl)ethyl acetate (20b ) 6
A sealed reaction tube containing a mixture of 3-(1-acetoxyethyl)phenyl acetate (150 mg, 0.67 mmol) and SmCl 3 (1 mol%, 2 mg) in Ethyl alcohol (2 ml) was heated in an oil bath at 80 o C for 24 h. Ethanol was then evaporated and the residue chromatographed on silica gel using ethyl acetate-hexane solvent system in a gradient mode to afford the monoacetate 20b (91 mg, 76% yield) as a liquid. Analytical data for 20b: 1 H NMR (CDCl 3 ) δ 7.19 (t, 1H, J = 8 Hz), 6.89 (d, 1H, J = 7.6 Hz), 6.82 (s, 1H), 6.75 (dd, 1H, J = 8.4, 2.4 Hz), 6.41-6.34 (bs, 1H), 5.81 (q, 1H, J = 6.4 Hz), 2.079 (s, 3H), 1.51(d, 3H, J = 6.4 Hz); 13 C NMR (CDCl 3 ) δ 171.16, 155.98, 143.17, 129.73, 117.94, 114.92, 113.17, 72.51, 22.07, 21.35; HRMS (ESI) exact mass calcd. for C 10 H 12 3 Na [M+Na] + 203.0684, found [M+ Na] + 203.0685. Solvent screening for effective deprotection SmCl 3 H H 80 o C I H II H a after 44 h; b after 3 h To a solution of glycerol acetonide (I) in 2 ml of appropriate solvent, Solvent Toluene DMF DCE ACN % Yield NR NR NR 25 a was added SmCl 3 (10 mol%), and the mixture was heated in a sealed tube for 2 d. The solvent was removed under reduced pressure and the residue chromatographed on silica gel using ethyl acetate hexane THF <10% EtH Quantitative b a after 44 h; b after 3 h mixture as the solvent system to get glycerol (II). Results from experiments using ethanol, toluene, DMF, DCE, CH 3 CN and THF are presented in the table attached. ur literature search revealed that SmCl 3 in combination with acetyl chloride/tmscl can deprotect acetal and ketal functionalities. 1,2 To the best of our knowledge, the ability of SmCl 3 to selectively deprotect one acid labile protecting group in presence of another is not yet explored. 1. Wu, S.-H.; Ding, Z.-B. Synth. Commun. 1994, 24, 2173. 2. Ukaji, Y.; Koumoto, N.; Fujisawa, T. Chem. Lett. 1989, 1623. 7
1 H and 13 C NMR Spectra of some of the selected esters H S 1b 13 C NMR, 100 MHz, CDCl 3 8
H S 2b 1 H NMR, 400 MHz, CDCl 3 H S 2b 13 C NMR, 100 MHz, CDCl 3 9
C 2 H 2 N 3b 1 H NMR, 400 MHz, CDCl 3 C 2 H 2 N 3b 13 C NMR, 100 MHz, CDCl 3 10
H 2 C 4b 1 H NMR, 400 MHz, CDCl 3 H 2 C 4b 13 C NMR, 100 MHz, CDCl 3 11
H 2 C H 5b 1 H NMR, 400 MHz, CDCl 3 H 2 C H 5b 13 C NMR, 100 MHz, CDCl 3 12
H BCHN 6b 1 H NMR, 400 MHz, CDCl 3 H BCHN 6b 13 C NMR, 100 MHz, CDCl 3 13
14
Et 2 C H CbzHN ( ) 2 8b 1 H NMR, 400 MHz, CDCl 3 Et 2 C CbzHN H ( ) 2 8b 13 C NMR, 100 MHz, CDCl 3 15
H 9b 1 H NMR, 400 MHz, CDCl 3 H 9b 13 C NMR, 100 MHz, CDCl 3 16
17
Et 2 C H 11b 1 H NMR, 400 MHz, CDCl 3 Et 2 C H 11b 13 C NMR, 100 MHz, CDCl 3 18
H C 2 Me H H 12b 1 H NMR, 400 MHz, CDCl 3 H C 2 Me H H 12b 13 C NMR, 100 MHz, CDCl 3 19
20
CH CH 3 15a 1 H NMR, 400 MHz, CDCl 3 CH CH 3 15a 13 C NMR, 100 MHz, CDCl 3 21
CH Et 15b 13 C NMR, 100 MHz, CDCl 3 22
CH 15c 1 H NMR, 400 MHz, CDCl 3 CH 15c 13 C NMR, 100 MHz, CDCl 3 23
CH 15d 1 H NMR, 400 MHz, CDCl 3 CH 15d 13 C NMR, 100 MHz, CDCl 3 24
CH 15e 1 H NMR, 400 MHz, CDCl 3 CH 15e 13 C NMR, 100 MHz, CDCl 3 25
CH Bn 15f 1 H NMR, 400 MHz, CDCl 3 CH Bn 15f 13 C NMR, 100 MHz, CDCl 3 26
CH 15g 1 H NMR, 400 MHz, CDCl 3 CH 15g 13 C NMR, 100 MHz, CDCl 3 27
CH 15h 1 H NMR, 400 MHz, CDCl 3 CH 15h 13 C NMR, 100 MHz, CDCl 3 28
BocHN H 16b 1 H NMR, 400 MHz, CDCl 3 BocHN H 16b 13 C NMR, 100 MHz, CDCl 3 29
H THP 18b 1 H NMR, 400 MHz, CDCl 3 H THP 18b 13 C NMR, 100 MHz, CDCl 3 30
H H Ac 19b 1 H NMR, 400 MHz, CDCl 3 H H Ac 19b 13 C NMR, 100 MHz, CDCl 3 31
Ac H 20b 1 H NMR, 400 MHz, CDCl 3 Ac H 20b 13 C NMR, 100 MHz, CDCl 3 32