6. EXPERIMENTAL PART
6.2. Part B
6.2.6. Synthesis of malonates 171a-d, 188, 195
166
Rf 0.30 (hexane/EA 5:1);
IR 𝜈̃[cm-1]: 3063 (w), 3031 (w), 2926 (w), 2866 (w), 1719 (w), 1584 (s), 1510 (m), 1452 (m), 1375 (w), 1345 (w), 1288 (w), 1260 (s), 1236 (m), 1220 (m), 1139 (vs), 1080 (w), 1053 (m), 1027 (s), 957 (m), 845 (w), 822 (w), 798 (w), 733 (s), 694 (s), 681 (m), 630 (w);
1H NMR (401 MHz, CDCl3): δ 7.52-7.28 (m, 15H, Ph), 7.08 (d, J = 2.0 Hz, 1H, H-10), 7.02 (d, J = 16.2 Hz, 1H, H-7/8), 6.98 (dd, J = 8.3, 1.9 Hz, 1H, H-14), 6.90 (d, J = 16.2 Hz, 1H, H-7/8), 6.86 (d, J
= 8.2 Hz, 1H, H-13), 6.77 (d, J = 2.2 Hz, 2H, H-2,6), 6.56 (t, J = 2.2 Hz, 1H, H-4), 5.19 (s, 2H, C12- OCH2Ph), 5.08 (s, 4H, C3,5-OCH2Ph), 3.96 (s, 3H, OCH3);
13C{1H} NMR (101 MHz, CDCl3): δ 160.3 (s, C-3, C-5), 149.9 (s, C-11), 148.3 (s, C-12), 139.7 (s, C-1/9), 137.1 (s, C12-OBnipso), 137.0 (s, C3,5-OBnipso), 130.8 (s, C-1/9), 129.2 (d), 128.7 (d, 4×C, C3,5-OBn), 128.7 (d, 2×C), 128.1 (d, 2×C), 128.0 (d), 127.7 (d, 4×C, C3,5-OBn), 127.4 (d, 2×C), 127.0 (d), 120.0 (d, C-14), 114.1 (d, C-13), 109.6 (d, C-10), 105.7 (d, C-2,6), 101.4 (d, C-4), 71.1 (t, C12-OCH2Ph), 70.2 (t, C3-OCH2Ph, C5-OCH2Ph), 56.1 (q, OCH3);
MS (APCI+) m/z, (%): 529 (100, [M + H]+), 438 (29, [M + H − Bn]+);
HRMS (APCI+) m/z: [M + H]+ calcd. for C36H33O4 529.2373; found: 529.2372.
167
1H (401 MHz, CDCl3): δ 7.68 (s, 1H, H-7), 7.01 (dd, J = 8.2, 2.0 Hz, 1H, H-6), 6.98 (d, J = 2.0 Hz, 1H, H-2), 6.91 (d, J = 8.2 Hz, 1H, H-5), 5.94 (s, 1H, OH), 3.88 (s, 3H, C3-OMe), 3.86 (s, 3H, COOCH3), 3.83 (s, 3H, COOCH3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.9 (s, COOMe), 165.0 (s, COOMe), 148.5 (s, C-4), 146.7 (s, C-3), 143.1 (d, C-7), 125.2 (s, C-1), 125.0 (d, C-6), 122.8 (s, C-8), 115.0 (d, C-5), 111.4 (d, C-2), 56.0 (q, C3-OCH3), 52.8 (q, COOCH3), 52.7 (q, COOCH3);
MS (ESI+) m/z, (%): 289 (100, [M + Na]+), 235 (20, [M +H – MeOH]+), 167 (7);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C13H14NaO6 289.0683; found: 289.0683;
Anal. calcd. for C13H14O6 (266.25): C, 58.65; H, 5.30. Found: C, 58.51; H, 5.09.
Step 2. Phenol 170a (5.32 g, 20 mmol) was suspended in dry toluene (200 mL) at 0 °C. Under a stream of dry nitrogen, PPh3 (7.87 g, 30 mmol) and 2-(trimethylsilyl)ethanol (3.7 mL, 26 mmol) were added.
The resulting suspension was stirred vigorously and diisopropyl azodicarboxylate (5.1 mL, 26 mmol) was added dropwise leading to gradual dissolution of the suspension producing clear yellow-red solution. After 20 min, the temperature was increased to 23 °C for 30 min. The solvent was removed under vacuum, THF (20 mL), water (4 mL) and acetic acid (4 mL) were added and the mixture was stirred for 30 min. The volatiles were stripped off in vacuum and the crude product was purified by flash chromatography (pure cyclohexane to cyclohexane/EA 9:1) to yield 5.73 g (78%) of 171a as a colourless solid, mp 65-67 °C.
Dimethyl 2-{3-methoxy-4-[2-(trimethylsilyl)ethoxy]benzylidene}malonate (171a)
Rf 0.34 (hexane/EA 5:1);
IR (film) 𝜈̃[cm-1]: 3000 (w), 2951 (w), 2899 (w), 2847 (w), 1724 (m), 1622 (w), 1596 (w), 1513 (m), 1465 (w), 1435 (w), 1423 (w), 1379 (w), 1336 (w), 1247 (s), 1217 (vs), 1192 (m), 1164 (m), 1140 (vs), 1067 (m), 1034 (w), 987 (w), 964 (w), 836 (s), 753 (w);
1H (401 MHz, CDCl3): δ 7.69 (s, 1H, H-7), 7.04 (dd, J = 8.4, 2.1 Hz, 1H, H-6), 6.98 (d, J = 2.1 Hz, 1H, H-2), 6.83 (d, J = 8.4 Hz, 1H, H-5), 4.20-4.12 (m, 2H, OCH2CH2TMS), 3.87 (s, 3H, COOCH3), 3.85 (s, 3H, C3’-OCH3), 3.84 (s, 3H, COOCH3), 1.28-1.16 (m, 2H, OCH2CH2TMS), 0.08 (s, 9H, Si(CH3)3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.9 (s, C-9/10), 165.0 (s, C-9/10), 151.1 (s, C-4), 149.4 (s, C- 3), 143.1 (d, C-7), 125.2 (s, C-1), 124.4 (d, C-6), 122.8 (s, C-8), 112.2 (d, C-2/5), 111.9 (d, C-2/5), 66.6 (t, OCH2CH2TMS), 55.9 (q, OCH3), 52.8 (q, OCH3), 52.7 (q, OCH3), 17.8 (t, OCH2CH2TMS), – 1.3 (q, Si(CH3)3);
MS (ESI+) m/z, (%): 755 (9, [2M + Na]+), 405 (9, [M + K]+), 389 (100, [M + Na]+), 367 (9, [M + H]+), 307 (66, [M + H – MeOH – CO]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C18H26NaO6Si 389.1391; found: 389.1389.
Synthesis of 171b
168
Step 1. A mixture of vanillin (3.04 g, 20 mmol), diethyl malonate (4.3 mL, 28 mmol), piperidine (0.3 mL, 3 mmol) and AcOH (0.12 mL, 2 mmol) in toluene (20 mL) was heated to reflux using a Dean- Stark trap for 4 h. After the azeotropic distillation of water ceased, the solvent was distilled off to reduce the volume to ~1/3. After cooling, PE (10 mL) was added resulting in the formation of a precipitate. The solvent was decanted, and the solids were triturated with fresh PE (10 mL), and finally with a 10:1 mixture of PE and Et2O (25 mL). Filtration and drying under vacuum yielded 5.88 g (99%) of 170b as a light beige solid, mp 106-107 °C. Analytical data were in an agreement with the literature.267 Note: A slight excess of diethyl malonate (1.4 equiv.) is required for complete conversion and gives analytically pure product without further purification. A stoichiometric amount malonate under otherwise identical conditions afforded lower yield (64-72%).
Diethyl 2-(4-hydroxy-3-methoxybenzylidene)malonate (170b)
Rf 0.18 (hexane/EA 3:1);
IR (film) 𝜈̃[cm-1]: 3600-3200 (br.), 2982 (w), 2938 (w), 2904 (w), 2843 (w), 1717 (m), 1624 (w), 1589 (w), 1515 (m), 1464 (w), 1430 (w), 1379 (w), 1290 (m), 1257 (s), 1206 (vs), 1179 (s), 1157 (vs), 1127 (m), 1094 (w), 1063 (m), 1022 (m), 952. (w), 859 (w), 735 (w);
1H NMR (401 MHz, CDCl3): δ 7.64 (s, 1H, H-7), 7.06-6.99 (m, 2H, H-2, H-6), 6.91 (d, J = 8.2 Hz, 1H, H-5), 5.90 (s, 1H, OH), 4.29 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.34 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.88 (s, 3H, OCH3), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.31 (t, J = 7.1 Hz, 3H, OCH2CH3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.4 (s, COOEt), 164.6 (s, COOEt), 148.3 (s, C-4), 146.7 (s, C-3), 142.2 (d, C-7), 125.4 (s, C-1), 124.9 (d, C-6), 123.7 (s, C-8), 114.9 (d, C-5), 111.5 (d, C-2), 61.8 (t, OCH2CH3), 61.6 (t, OCH2CH3), 56.0 (q, OCH3), 14.3 (q, OCH2CH3), 14.1 (q, OCH2CH3);
MS (ESI+) m/z, (%): 611 (27, [2M + Na]+), 317 (100, [M + Na]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C15H18O6Na 317.0996; found: 317.0995.
Step 2. Following the procedure for 171a, phenol 170b (2.94 g, 10 mmol) was alkylated in dry toluene (80 mL) using PPh3 (3.93 g, 15 mmol), 2-(trimethylsilyl)ethanol (1.9 mL, 13 mmol) and diisopropyl azodicarboxylate (2.6 mL, 13 mmol). Yield 3.159 g (80%) of 171b as a soft colourless amorphous solid. A less polar solvent proved critical for obtaining high yield as the reaction in THF gives yields below 50%.180
Diethyl 2-{3-methoxy-4-[2-(trimethylsilyl)ethoxy]benzylidene}malonate (171b)
Rf 0.43 (hexane/EA 5:1);
IR (film) 𝜈̃[cm-1]: 2981 (w), 2953 (w), 2903 (w), 2874 (w), 1719 (s), 1622 (w), 1596 (w), 1513 (m), 1465 (w), 1423 (w), 1379 (w), 1355 (w), 1275 (s), 1246 (s), 1224 (s), 1210 (m), 1190 (m), 1164 (m), 1141 (s), 1095 (m), 1062 (m), 1034 (w), 990 (w), 934 (w), 855 (s), 836 (s), 807 (m), 770 (w), 752 (w);
1H NMR (401 MHz, CDCl3): δ 7.65 (s, 1H, H-7), 7.06 (dd, J = 8.3, 2.2 Hz, 1H, H-6), 7.02 (d, J = 2.1 Hz, 1H, H-2), 6.82 (d, J = 8.3 Hz, 1H, H-5), 4.35 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.29 (q, J = 7.1 Hz,
169 2H, OCH2CH3), 4.18-4.12 (m, 2H, OCH2CH2Si), 3.84 (s, 3H, OMe), 1.33 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.25-1.18 (m, 2H, OCH2CH2Si), 0.08 (s, 9H, SiCH3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.4 (s, COOEt), 164.6 (s, COOEt), 150.9 (s, C-4), 149.3 (s, C-3), 142.2 (d, C-7), 125.4 (s, C-1), 124.4 (d, C-6), 123.6 (s, C-8), 112.14 (d, C-5), 112.07 (d, C-2), 66.5 (t, CH2CH2Si), 61.7 (t, OCH2CH3), 61.6 (t, OCH2CH3), 55.9 (q, OMe), 17.8 (t, OCH2CH2Si), 14.3 (q, OCH2CH3), 14.1 (q, OCH2CH3), −1.3 (q, SiCCH3);
MS (ESI+) m/z, (%): 811 (24, [2M + Na]+), 417 (100, [M + Na]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C20H30NaO6Si 417.1704; found: 417.1702.
Synthesis of 171c
Step 1. A mixture of vanillin (3.04 g, 20 mmol), diisopropyl malonate (5.3 mL, 28 mmol), piperidine (0.30 mL, 3 mmol) and AcOH (0.12 mL, 2 mmol) in toluene (20 mL) was heated to reflux using a Dean-Stark trap for 3 h. After the azeotropic distillation of water ceased, the mixture was cooled, concentrated and dried under high vacuum. The semi-solid mixture was purified by flash chromatography (PE/EA, 11:1 to 3:1) to yield 6.44 g (quant.) of 170c white colourless solid, mp 60- 62 °C.
Diisopropyl 2-(4-hydroxy-3-methoxybenzylidene)malonate (170c)
Rf 0.45 (hexane/EA 3:1);
IR (film) 𝜈̃[cm-1]: 3600-3250 (br.), 2981 (w), 2938 (w), 2878 (w), 2842 (w), 1715 (m), 1624 (w), 1590 (w), 1515 (m), 1465 (w), 1453 (w), 1430 (w), 1374 (w), 1289 (m), 1257 (m), 1211 (s), 1178 (m), 1160 (m), 1129 (m), 1102 (s), 1061 (m), 1031 (w), 923 (w), 908 (w), 833 (w), 818 (w), 765 (w);
1H (401 MHz, CDCl3): δ 7.59 (s, 1H, H-7), 7.06 (dd, J = 8.3, 2.0 Hz, 1H, H-6), 7.03 (d, J = 2.0 Hz, 1H, H-2), 6.90 (d, J = 8.2 Hz, 1H, H-5), 5.90 (s, 1H, OH), 5.24 (sept, J = 6.3 Hz, 1H, OCH(CH3)2), 5.14 (sept, J = 6.2 Hz, 1H, OCH(CH3)2), 3.88 (s, 3H, OCH3), 1.31 (d, J = 6.3 Hz, 6H, OCH(CH3)2), 1.30 (d, J = 6.3 Hz, 6H, OCH(CH3)2);
13C{1H} NMR (101 MHz, CDCl3): δ 167.0 (s, C-9/10), 164.2 (s, C-9/10), 148.2 (s, C-4), 146.6 (s, C- 3), 141.6 (d, C-7), 125.5 (s, C-1/8), 124.9 (d, C-6), 124.5 (s, C-1/8), 114.8 (d, C-5), 111.6 (d, C-2), 69.3 (d, OCH(CH3)2), 69.2 (d, OCH(CH3)2), 56.0 (q, OCH3), 22.0 (q, OCH(CH3)2), 21.8 (q, OCH(CH3)2);
MS (ESI−) m/z, (%): 321 (100, [M − H]−), 306 (16);
HRMS (ESI−) m/z: [M − H]− calcd. for C17H21O6 321.1344; found: 321.1344.
Step 2. Following the procedure for 171a, phenol 170c (5.975 g, 18.5 mmol) was alkylated in dry toluene (125 mL) using PPh3 (7.30 g, 27.8 mmol), 2-(trimethylsilyl)ethanol (3.45 mL, 24.1 mmol) and diisopropyl azodicarboxylate (4.74 mL, 24.1 mmol). Yield 6.59 g (84%) of 171c as a colourless oil that slowly crystallizes on standing, mp 48-50 °C.
170
Diisopropyl 2-{3-methoxy-4-[2-(trimethylsilyl)ethoxy]benzylidene}malonate (171c)
Rf 0.46 (hexane/EA 5:1);
IR (film) 𝜈̃[cm-1]: 2980 (w), 2952 (w), 2897 (w), 2832 (w), 1718 (s), 1623 (w), 1597 (w), 1513 (m), 1466 (w), 1423 (w), 1374 (w), 1333 (w), 1246 (vs), 1228 (vs), 1191 (m), 1165 (m), 1142 (s), 1105 (vs), 1059 (m), 1036 (m), 990 (w), 964 (w), 855 (m), 836 (s), 808 (w), 768 (w), 753 (w);
1H (401 MHz, CDCl3): δ 7.59 (s, 1H, H-7), 7.07 (dd, J = 8.3, 2.1 Hz, 1H, H-6), 7.03 (d, J = 2.1 Hz, 1H, H-2), 6.81 (d, J = 8.3 Hz, 1H, H-5), 5.24 (sept, J = 6.3 Hz, 1H, OCH(CH3)2), 5.13 (sept, J = 6.3 Hz, 1H, OCH(CH3)2), 4.18-4.09 (m, 2H, OCH2CH2TMS), 3.83 (s, 3H, OCH3), 1.31 (d, J = 6.3 Hz, 6H, OCH(CH3)2), 1.29 (d, J = 6.3 Hz, 6H, OCH(CH3)2), 1.23-1.16 (m, 2H, OCH2CH2TMS), 0.07 (s, 9H, Si(CH3)3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.0 (s, C-9/10), 164.2 (s, C-9/10), 150.7 (s, C-4), 149.3 (s, C- 3), 141.5 (d, C-7), 125.5 (s, C-8), 124.4 (s, C-1), 124.3 (d, C-6), 112.2 (d, C-2/5), 112.1 (d, C-2/5), 69.2 (d, OCH(CH3)2), 69.1 (d, OCH(CH3)2), 66.5 (t, OCH2CH2TMS), 55.9 (q, OCH3), 21.9 (q, OCH(CH3)2), 21.7 (q, OCH(CH3)2), 17.8 (t, OCH2CH2TMS), –1.3 (q, Si(CH3)3);
MS (ESI+) m/z, (%): 867 (5, [2M + Na]+), 445 (44, [M + Na]+), 423 (12, [M + H]+), 335 (25, [M – COOi-Pr]+), 293 (100, [M – COOi-Pr – CH3CHCH2]+);
HRMS (ESI+) m/z: [M + H]+ calcd. for C22H35O6Si 423.2197; found: 423.2195, [M + Na]+ calcd. for C22H34O6NaSi 445.2017; found: 445.2013;
Anal. calcd. for C22H34O6Si (422.59): C, 62.53; H, 8.11. Found: C, 62.29; H, 8.06.
Synthesis of 171d
Step 1. A mixture of vanillin (3.04 g, 20 mmol), di-tert-butyl malonate (6.3 mL, 28 mmol), piperidine (0.30 mL, 3 mmol) and acetic acid (0.12 mL, 2 mmol) in toluene (20 mL) was heated to reflux using a Dean-Stark trap for 4 h. After the azeotropic distillation of water ceased, the mixture was cooled and concentrated and dried in high vacuum. The semi-solid mixture was purified by flash chromatography (silica, 11:1 to 5:1 PE/EA) to yield 4.36 g (62%) of 170d as a colourless amorphous solid.
Di-tert-butyl 2-(4-hydroxy-3-methoxybenzylidene)malonate (170d)
Rf 0.60 (hexane/EA 3:1);
171 IR (film) 𝜈̃[cm-1]: 3550-3300 (br.); 2978 (w), 2936 (w), 2847 (w), 1710 (s), 1625 (w), 1591 (w), 1516 (m), 1455 (w), 1431 (w), 1392 (w), 1367 (m), 1240 (s), 1146 (vs), 1128 (m), 1067 (m), 1031 (m), 954 (w), 848 (w), 818 (w), 772 (w), 744 (w);
1H (401 MHz, CDCl3): δ 7.46 (s, 1H, H-7), 7.12-7.03 (m, 2H, H-2, H-6), 6.89 (d, J = 8.7 Hz, 1H, H- 5), 5.88 (s, 1H, OH), 3.88 (s, 3H, OCH3), 1.54 (s, 9H, Ot-Bu), 1.53 (s, 9H, Ot-Bu);
13C{1H} NMR (101 MHz, CDCl3): δ 166.7 (s, C-9/10), 164.0 (s, C-9/10), 147.9 (s, C-4), 146.6 (s, C- 3), 140.2 (d, C-7), 126.7 (s, C-8), 125.9 (s, C-1), 124.7 (d, C-6), 114.7 (d, C-5), 111.7 (d, C-2), 82.2 (s, COOCMe3), 81.9 (s, COOCMe3), 56.1 (q, OCH3), 28.3 (q, t-Bu), 28.1 (q, t-Bu);
MS (ESI–) m/z, (%): 349 (100, [M – H]–), 175 (12);
HRMS (ESI–) m/z: [M – H]– calcd. for C19H25O6 349.1657; found: 349.1657;
Anal. calcd. for C19H26O6 (350.41): C, 65.13; H, 7.48. Found: C, 64.89; H, 7.59.
Step 2. Following the procedure for 171a, from phenol 170d (1.38 g, 3.94 mmol) was alkylated in dry toluene (30 mL) using PPh3 (1.55 g, 5.91 mmol), 2-(trimethylsilyl)ethanol (0.73 mL, 5.12 mmol) and diisopropyl azodicarboxylate (1.00 mL, 5.12 mmol). Yield 1.57 g (88%) of 171d as a colourless oil that forms an amorphous solid after two months at –18 °C.
Di-tert-butyl 2-{3-methoxy-4-[2-(trimethylsilyl)ethoxy]benzylidene}malonate (171d)
Rf 0.40 (hexane/EA 11:1);
IR (film) 𝜈̃[cm-1]: 2977 (w), 2954 (w), 2935 (w), 2903 (w), 2833 (w), 1713 (m), 1624 (w), 1597 (w), 1513 (m), 1466 (w), 1423 (w), 1392 (w), 1367 (w), 1335 (w), 1247 (s), 1237 (s), 1139 (vs), 1064 (m), 1035 (m), 991 (w), 964 (w), 944 (w), 837 (s), 774 (w), 747 (w), 694 (w);
1H (401 MHz, CDCl3): δ 7.47 (s, 1H, H-7), 7.10 (m, 2H, H-2, H-6), 6.81 (d, J = 8.5, Hz, 1H, H-5), 4.19-4.10 (m, 2H, OCH2CH2TMS), 3.84 (s, 3H, OCH3), 1.54 (s, 9H, OC(CH3)3), 1.53 (s, 9H, OC(CH3)3), 1.28-1.15 (m, 2H, OCH2CH2TMS), 0.07 (s, 9H, Si(CH3)3);
13C{1H} NMR (101 MHz, CDCl3): δ 166.7 (s, C-9/10), 164.1 (s, C-9/10), 150.5 (s, C-4), 149.3 (s, C- 3), 140.2 (d, C-7), 126.6 (s, C-8), 125.9 (s, C-1), 124.0 (d, C-6), 112.6 (d, C-2), 112.1 (d, C-5), 82.2 (s, OC(CH3)3), 81.9 (s, OC(CH3)3), 66.4 (t, OCH2CH2TMS), 56.1 (q, OCH3), 28.3 (q, OC(CH3)3), 28.1 (q, OC(CH3)3), 17.8 (t, OCH2CH2TMS), –1.3 (q, Si(CH3)3);
MS (ESI+) m/z, (%): 923 (33, [2M + Na]+), 489 (5, [M + K]+), 473 (30, [M + Na]+), 451 (10, [M + H]+), 395 (13, [M + H – isobutene]+), 339 (42, [M + H – 2×isobutene]+), 321 (17, [M + H – 2×isobutene – H2O]+), 293 (100, [M + H – 2×isobutene – H2O – CO]+);
HRMS (ESI+) m/z: [M + H]+ calcd. for C24H39O6Si 451.2510; found: 451.2509, [M + Na]+ calcd. for C24H38NaO6Si 473.2330; found: 473.2327;
Anal. calcd. for C24H38O6Si (450.65): C, 63.97; H, 8.50. Found: C, 63.67; H, 8.38.
172
Synthesis of malonate 188
Step 1. A mixture of syringaldehyde (3.64 g, 20 mmol), diethyl malonate (4.3 mL, 28 mmol), piperidine (0.30 mL, 3 mmol) and AcOH (0.12 mL, 2 mmol) in toluene (20 mL) was heated to reflux using a Dean-Stark trap for 4 h. After the azeotropic distillation of water ceased, the mixture was cooled and concentrated in vacuum to ~1/2 volume. PE (50 mL) and Et2O (5) were added, the resulting suspension was matured for 1 h and filtered. The solids were washed with PE (200 mL) and dried under vacuum affording 6.19 g (95%) of 194 as a pale-yellow solid, mp 111-112 °C.
Diethyl 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonate (194)
Rf 0.15 (hexane/EA 3:1);
IR (film) 𝜈̃[cm-1]: 3550-3250 (br.), 2979 (w), 2938 (w), 2842 (w), 1723 (s), 1623 (m), 1601 (m), 1514 (s), 1459 (m), 1429 (w), 1396 (w), 1382 (w), 1328 (w), 1217 (vs), 1157 (s), 1112 (s), 1067 (s), 1044 (w), 1023 (w), 989 (w), 830 (w), 623 (w);
1H NMR (401 MHz, CDCl3): δ 7.63 (s, 1H, H-7), 6.77 (s, 2H, H-2, H-6), 6.10-5.50 (b. s, 1H, OH), 4.34 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.29 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.88 (s, 6H, OCH3), 1.33 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.4 (s, COOEt), 164.5 (s, COOEt), 147.1 (s, C-3, C-5), 142.4 (d, C-7), 137.5 (s, C-4), 124.3 (s, C-1/8), 124.2 (s, C-1/8), 106.9 (d, C-2, C-6), 61.8 (t, OCH2CH3), 61.6 (t, OCH2CH3), 56.4 (q, 2×C, OCH3), 14.3 (q, OCH2CH3), 14.2 (q, OCH2CH3);
MS (ESI+) m/z, (%): 671 (43, [2M + Na]+), 363 (23, [M + K]+), 347 (100, [M + Na]+), 325 (36, [M + H]+), 279 (86, [M – EtO]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C16H20O7Na 347.1101; found: 347.1099;
Anal. calcd. for C11H14O2 (324.33): C, 59.25; H, 6.22. Found: C, 59.49; H, 6.27.
Step 2. Following the procedure for 171a, phenol 194 (3.24 g, 10 mmol) was alkylated in dry toluene (45 mL) using PPh3 (3.93 g, 15 mmol), 2-(trimethylsilyl)ethanol (1.9 mL, 13 mmol) and diisopropyl azodicarboxylate (2.6 mL, 13 mmol). Yield 3.57 g (84%) of 188 as a colourless solid, mp 44-45 °C.
Diethyl 2-{3,5-dimethoxy-4-[2-(trimethylsilyl)ethoxy]benzylidene}malonate (188)
Rf 0.45 (hexane/EA, 5:1);
IR (film) 𝜈̃[cm-1]: 2980 (w), 2953 (w), 2901 (w), 2841 (w), 1722 (s), 1626 (w), 1579 (m), 1503 (m), 1454 (w), 1421 (w), 1393 (w), 1377 (w), 1333 (w), 1241 (vs), 1209 (s), 1155 (w), 1124 (vs), 1064 (m), 1041 (w), 1025 (w), 966 (w), 945 (w), 856 (s), 834 (s), 762 (w), 693 (w), 620 (w);
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1H NMR (401 MHz, CDCl3): δ 7.64 (s, 1H, H-7), 6.73 (s, 2H, H-2, H-6), 4.39-4.25 (m, 4H, OCH2CH3), 4.17-4.05 (m, 2H, OCH2CH2TMS), 3.82 (s, 6H, OCH3), 1.37-1.27 (m, 6H, OCH2CH3), 1.19-1.08 (m, 2H, OCH2CH2TMS), 0.02 (s, 9H, Si(CH3)3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.2 (s, COOEt), 164.3 (s, COOEt), 153.7 (s, C-3, C-5), 142.2 (d, C-7), 139.3 (s, C-4), 128.0 (s, C-1), 125.2 (s, C-8), 107.1 (d, C-2, C-6), 71.2 (t, OCH2CH2TMS), 61.8 (t, OCH2CH3), 61.7 (t, OCH2CH3), 56.2 (q, 2×C, OCH3), 18.9 (t, OCH2CH2TMS), 14.3 (q, OCH2CH3), 14.1 (q, OCH2CH3), −1.4 (q, Si(CH3)3);
MS (ESI+) m/z, (%): 871 (4, [2M + Na]+), 463 (7, [M + K]+), 447 (100, [M + Na]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C21H32O7NaSi 447.1810; found: 447.1804;
Anal. Calcd. for C11H14O2 (424.56): C, 59.41; H, 7.60. Found: C, 59.30; H, 7.42.
Synthesis of benzylated malonate 195
A mixture of malonate 194 (6.5 g, 20 mmol), BnBr (4.8 mL, 40 mmol) and calcinated K2CO3 (5.53 g, 40 mmol) in DMF (40 mL) was stirred at r.t. for 2 days. The mixture was partitioned between water (250 mL) and EA (250 mL). The organic layer was dried over Na2SO4, concentrated, and purified by flash chromatography (pure cyclohexane to cyclohexane/EA 4:1) to yield 8.0 g of 195 (96%) as a colourless solid.
Diethyl 2-[4-(benzyloxy)-3,5-dimethoxybenzylidene]malonate (195)
Rf 0.46 (hexane/EA 3:1);
IR (film) 𝜈̃[cm-1]: 3031 (w), 2980 (w), 2936 (w), 2842 (w), 1720 (s), 1625 (w), 1579 (m), 1503 (m), 1454 (m), 1421 (w), 1377 (w), 1333 (w), 1239 (s), 1210 (s), 1155 (m), 1124 (vs), 1064 (m), 988 (w), 837 (w), 734 (m), 697 (m);
1H (401 MHz, CDCl3): δ 7.64 (s, 1H, H-7), 7.48-7.44 (m, 2H, Ph), 7.37-7.27 (m, 3H, Ph), 6.72 (s, 2H, H-2), 5.05 (s, 1H, OCH2Ph), 4.32 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.30 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.81 (s, 6H, C3-OCH3), 1.33 (t, J = 11.7, 7.2 Hz, 3H, OCH2CH3), 1.30 (t, J = 11.7, 7.2 Hz, 3H, OCH2CH3);
13C{1H} NMR (101 MHz, CDCl3): δ 167.1 (s, COOEt), 164.3 (s, COOEt), 153.7 (s, 2×C, C-3), 142.2 (d, C-7), 139.3 (s, C-4), 137.6 (s, Phipso), 128.6 (d, Phmeta), 128.5 (s, C-1), 128.3 (d, Phortho), 128.1 (d, Phpara), 125.5 (s, C-8), 107.1 (d, C-2), 75.2 (t, OCH2Ph), 61.8 (t, OCH2CH3), 61.7 (t, OCH2CH3), 56.2 (q, 2×C, C-3), 14.3 (q, OCH2CH3), 14.1 (q, OCH2CH3);
MS (ESI+) m/z, (%): 851 (7, [M + Na]+), 437 (100, [2M + Na]+); MS (APCI+) m/z, (%): 415 (100, [M + H]+), 369 (70, [M + H – EtOH]+);
HRMS (ESI+) m/z: [M + Na]+ calcd. for C23H26O7Na 439.1571; found: 437.1568; HRMS (APCI+) m/z: [M + H]+ calcd. for C23H27O7 415.1751; found: 415.1750.
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