Indian Journal of Chemistry Vol. 55B, August 2016, pp. 1035-1038
Note Synthesis of trans-resveratrol using modified Julia olefination route Suvarna Shenvi, Shivaprakash Shivanna & G Chandrasekara Reddy* Vittal Mallya Scientific Research Foundation, 94/3 & 94/5, 23rd Cross, 29th Main, BTM 2nd Stage, Bangalore 560 076, India E-mail:
[email protected] Received 21 December 2015; accepted (revised) 21 April 2016 Bioactive hydroxystilbinoid−trans-resveratrol [(E)-3,5,4ʹtrihydroxy stilbene, 1] has been synthesized by modified Julia olefination method. The reaction between corresponding carbanion of benzothiazol-2-yl sulfone derivative and p-anisaldehyde dimethyl acetal with sodium hydride as a base, affords mainly cis-3,5,4ʹtrimethoxystilbene 10b with minor quantity of trans-isomer. Both the isomers have been separated in pure form and confirmed by their NMR spectral data. Demethylation of cis-3,5,4ʹtrimethoxystilbene either with AlCl3/pyridine or AlCl3/triethylamine results in the formation of trans-resveratrol. Keywords: Julia olefination, stilbenes, benzothiazol-2-yl sulfone, p-anisaldehyde, trans-resveratrol, Veratrum album
Stilbenes (diphenylethylenes) are naturally occurring compounds present in a number of plant families displaying wide range of biological activities1. Stilbenes having 3,5-dihydroxy substituents with additional hydroxy or methoxy groups having transgeometry are quite common which act as phytoalexins and protect plants from fungal attack2,3. Resveratrol is a natural stilbenoid, produced by several plants belonging to Veratrum album a variety of grandiflorum4. In general, resveratrol can exist in two geometrical forms where the cis-form can undergo isomerisation to more stable trans-form when exposed to ultraviolet irradiation5. Hydroxy stilbenes have been synthesized by many synthetic methods like Perkin reaction6, Wittig reaction7, Wittig-Horner reaction8,9, Heck reaction10, Grignard reaction11, and Claisen condensation12. However, many of these methods are limited to small scale preparation with low yields. In view of this, we explored a new synthetic route for the preparation of trans-resveratrol (1). The classical Julia reaction relies on multi-step sequence comprised of nucleophilic attack of α-metallated aromatic sulfones on aldehydes affording β-hydroxy sulfones, followed by reductive
elimination. In modified Julia olifination method, heterocyclic sulfones were reacted with aldehyde in presence of metallated bases to give correspnding alkoxides13 which undergo Smiles rearrangement with removal of sulphur dioxide and hydroxy benzothiazole moiety as byproducts14-18. In the present study, relatively cheaper starting material 3,5-dihydroxybenzoic acid 2 has been used as depicted in Scheme I. Compound 2 when treated with DMS/K2CO3 in acetone at reflux temperature gave methyl 3,5dimethoxybenzoate 3 which when reduced with LAH resulted in formation of (3,5-dimethoxyphenyl) methanol 4. Further, bromination of this with aq. HBr in toluene using TBAB as a catalyst afforded corresponding benzyl bromide 5 with over all yields of about 84%. The compound 5, thus obtained was mixed with 2-mercaptobenzothiazole 6 using K2CO3 as a base in acetone and the resulting sulfide 7 then oxidized with sodium tungstate and 30% H2O2 to give benzothiazole sulfonyl compound 8. The reaction of compound 8 with p-anisaldehyde in presence of bases like NaH in THF, t-BuOK in MDC, DBU in MDC, and NaHMDS in THF were tried but did not yield the desired product. But when protected aldehyde, i.e. p-anisaldehyde dimethyl acetal 9 was employed and reacted with 8 in presence of NaH in THF, at around 65°C for 6-7 h, we obtained 3,5,4ʹtrimethoxystilbene with E (10a) and Z (10b) isomers in a ratio of 30:70. They were separated by silica gel column chromatography and obtained as pure cis and trans compounds. Structures were confirmed by NMR, GCMS and IR spectra. Demethyaltion of a mixture containing 10a and 10b was tried in AlCl3/Pyridine and AlCl3/TEA, and the final product obtained was exclusively trans-resveratrol 1 with 90% yield. Experimental Section All chemicals and solvents used were of LR grade from Sigma-Aldrich and Merck. Melting points were determined on Acro melting point apparatus using a calibrated thermometer and are uncorrected. 3' 4'
2' 2
HO
1
5'
1'
3
6'
4
6
1
5
OH
OH
INDIAN J. CHEM., SEC B, AUGUST 2016
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Br COOH
OH
COOMe DMS
HO
OH K2 CO3 / Acetone
MeO
2
THF
OMe
5
HBr (48%)
LAH
Toluene / PTC
MeO
3
MeO
OMe
OMe 4 S
K2 CO 3
SH Acetone
N 6 O O S
OCH3
N MeO S
MeO
H3CO
Na 2 WO 4 .2H 2 O
+
OCH3
H2 O2
9
N S S
MeO
8
OMe
7
NaH / THF
OH
OMe
OMe
OMe HO
MeO
+ OMe
MeO TEA / AlCl 3
10a
1 OH
10b trans -Resveratrol
Scheme I — Synthesis of resveratrol
Thin-layer chromatography (TLC) was performed on silica gel pre-coated on aluminium sheet (silica gel 60 F254.Merck). Chromatographic separation of mixtures was performed in open glass columns packed with silica gel (100-200 mesh). NMR spectra were recorded on a Bruker spectrometers 200 and 400 MHz and Jeol 400 MHz using TMS as an internal standard (chemical shifts in δ, ppm). The mass spectra were recorded on GCMS-QP2010S (direct probe) instrument. IR spectra were recorded on Jasco FTIR 4100 spectrometer. Synthesis of methyl 3,5-dimethoxybenzoate, 3 from 2 To a solution of 3,5-dihydroxybenzoic acid 2 (50.0 g, 0.32 mol) and acetone (200 mL), K2CO3 (100.0 g, 0.72 mol) was added and the mixture stirred at RT for 15-20 min. Then DMS (128 g, 3.0 mol) was added drop-wise over a period of 1 h. The temperature was slowly raised to 50-55°C and maintained for 5-6 h. The completion of reaction was monitored by TLC (Hexane: EtOAc, 8: 2). Acetone was distilled off under reduced pressure, water (500 mL) was added and the reaction mass extracted with EtOAc (2 × 200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to get compound 3 (62.0 g, 98%). Off-white solid (C10H12O4). m.p.42-44°C (lit.19 m.p.42°C). GC-MS: m/z (%) [M] +.196 (20), 182 (8),
168 (75), 151 (68), 139 (75), 125 (20), 109 (18), 109 (12), 91 (8). Synthesis of (3,5-dimethoxyphenyl) methanol, 4 from 3 A solution of compound 3 (62.0 g, 0.31 mol) in THF (150 mL) was added drop-wise to a suspension of LAH (10.8 g, 0.28 mol) in THF (50 mL) at 25°C. After stirring at RT for 30-40 min, the reaction mass was refluxed for 4-5 h. The reaction mass was then cooled to ambient temperature and water (100 mL) was added slowly with stirring. Dilute H2SO4 (10% solution, 100 mL) was added and the reaction mass extracted with EtOAc (2 × 100 mL), the organic layer washed with water (2 × 50 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to get crude reaction mass, which was purified further over silica gel column to afford pure compound 4 (50.2 g, 95%). White solid (C9H12O3). m.p.46-48°C (lit.19 m.p.48°C). GC-MS: m/z (%) [M] +. 168 (85), 151 (65), 139 (75), 125 (30), 109 (28), 109 (22), 91 (15). Synthesis of 1-(bromomethyl)-3,5-dimethoxybenzene, 5 from 4 To a solution of compound 4 (35 g, 0.20 mol) in toluene (100 mL), was added catalytic amount of TBAB (2.0 g, 6.5 mmol) and aqueous 48% aq. HBr
NOTE
(33 mL, 0.30 mol) at 25°C. The resulting solution was stirred at RT for 10-12 h. The completion of reaction was monitored by TLC (Mobile phase; Hexane: EtOAc, 8: 2), the toluene layer separated and concentrated under vacuum. The residue obtained was purified further over silica gel column using 10% EtOAc in hexane, to obtain compound 5 (42 g, 88%).White solid (C9H11BrO2,). m.p.70-72°C. GCMS: m/z (%) [M] +.232 (8), 210 (25), 168 (100), 151 (65), 139 (75), 125 (30), 109 (28), 109 (22), 91 (15). Synthesis of 2-[(3,5-dimethoxybenzyl)sulfanyl]-1,3benzothiazole, 7 from 5 To a solution of 1,3-benzothiazole-2-thiol 6 (10.0 g, 0.06 mol) in acetone (100 mL) was added K2CO3 (10 g, 0.07 mol). The mixture was stirred at RT for 30 min. Thereafter, compound 5 (14.0 g, 0.06 mol) was added and the reaction mass stirred at 50-55°C for 5-6 h. The acetone was removed under reduced pressure and water (150 mL) was added. The reaction mass was extracted with EtOAc (2 × 100 mL), the EtOAc extract dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude material. Further purification over silica gel column yielded compound 7 (17.5 g, 92%). Pale yellow viscous liquid (C16H15NO2S2). 1H NMR (200 MHz, CDCl3): δ 3.74 (s, 6 H), 4.52 (s, 2 H), 6.61 (brs, 3H), 7.25 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H); GC-MS: m/z (%) [M] +.317 (58), 301 (15), 284 (100), 270 (5), 254 (8), 242 (5), 227 (6), 182 (5), 166 (10), 151 (18), 134 (8), 121 (8), 108 (15), 91 (25), 77 (15). Synthesis of 2-[(3,5-dimethoxybenzyl) sulfonyl]1,3-benzothiazole, 8 from 7 To a solution of compound 7 (15 g, 0.048 mol) and methanol (150 mL), sodium tungstate dihydrate (7.5 g, 0.023 mol) was added at 0-5°C under stirring. Then 30% H2O2 (15 mL) was added drop-wise for about 30 min and the temperature was slowly raised to 2530°C. The reaction was then maintained at RT for 1012 h. The completion of reaction was monitored by TLC (Hexane:EtOAc, 7:3). Methanol was distilled off and water (200 mL) was added. The aqueous layer was extracted with EtOAc (2 × 100 mL), washed with water (2 × 5 mL), dried over anhydrous sodium sulphate and the EtOAc extract concentrated under reduced pressure. Then methanol (50 mL) was added to the concentrate, and stirred for 10 min at RT and filtered. Product was air dried to get pure sulfone 8 (14.4 g, 87%). White solid (C16H15NO4S2).
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m.p.152-55°C. 1H NMR (200 MHz, CDCl3): δ 3.59 (s, 6 H), 4.67 (s, 2 H), 6.36 (br, 3 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H); GC-MS: m/z (%) [M] +. 349 (65), 334 (5), 317 (20), 301 (5), 284 (100), 270 (7), 254 (5), 242 (7), 227 (5), 182 (5), 166 (15), 151 (8), 134 (5), 121 (6), 108 (5), 91 (35), 77 (25). Synthesis of (E/Z)-3,5,4ʹ-trimethoxy stilbene (10a and 10b), from 8 A solution of compound 8 (10.0 g, 0.014 mol) in THF (50 mL) was added to NaH (2.0 g 0.04 mol) in THF (50 mL) at 0-5°C under nitrogen atmosphere and maintained at the same temperature for 30 min under stirring. Then p-anisaldehyde dimethyl acetal 9 (6.16 g, 0.017 mol) in THF (10 mL) was added under stirring. The resulting mass was stirred at RT for 30 min and then the temperature raised to 65°C and maintained for 6-7 h. The completion of the reaction was monitored by TLC (Hexane:EtOAc, 8:2). The reaction was slowly quenched by pouring the reaction mass into ice and acidified with dilute HCl till the pH was ~6 and aqueous layer extracted with EtOAc (2 × 100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (6.8 g, 88%) was subjected to column chromatography and eluted with Hexane:EtOAc (8.5:1.5) to obtain products 10a and 10b in pure form. (E)-3,5,4ʹ-Trimethoxy stilbene, 10a Pale yellow solid (C17H18O3). m.p.56-58°C. 1 H NMR (400 MHz, CDCl3): δ 3.82 (s, 9H, 3×-OMe), 6.37 (t, 1H, J = 2.4 Hz, H-4), 6.65 (d, 2H, J = 2.4 Hz, H-2, 6), 6.88 (d, 1H, J = 16.4 Hz, CH=CH), 6.90 (d, 2H, J = 8.4 Hz, H-3,5), 7.05 (d, 1H, J = 16.4 Hz, CH=CH), 7.45 (d, 2H, J = 8.4 Hz, H-2, 6); 13C NMR (100 MHz, CDCl3): δ 55.26, 55.29, 55.34, 99.55, 104.26, 114.26, 126.5, 127.7, 128.6, 129.86, 139.6, 159.33, 160.90; GC-MS: m/z (%) [M] +. 270 (100), 255 (15), 239 (5), 224 (15), 212 (10), 195 (8), 165 (5), 153 (6), 139 (5), 128 (5), 115 (12), 107 (5), 105 (7), 91 (12), 77 (8), 69 (5), 63 (6), 43 (100). (Z)-3,5,4ʹ-Trimethoxy stilbene, 10b Pale yellow liquid (C17H18O3). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 9H, 3×-OMe), 6.32 (t, 1H, J = 2.4 Hz, H-4), 6.43 (d, 2H, J = 2.4 Hz, H-2, 6), 6.45 (d, 1H, J = 11.6 Hz, CH=CH), 6.53 (d, 1H, J = 12.0 Hz, CH=CH), 6.77 (d, 2H, J = 8.4 Hz, H-3,5), 7.22 (d, 2H, J = 8.4 Hz, H-2,6); 13C NMR (100 MHz, CDCl3): δ 55.15 (3×OCH3), 99.84, 107.01, 113.72, 128.61,
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INDIAN J. CHEM., SEC B, AUGUST 2016
129.48, 130.23, 139.6, 158.67, 160.50; GC-MS: m/z (%) [M] +. 270 (100), 255 (10), 239 (7), 224 (12), 212 (12), 195 (10), 165 (5), 153 (6), 139 (4), 128 (5), 115(15), 107 (5), 105 (7), 91( 12), 77 (8), 69 (5), 63 (6), 43 (100). Synthesis of (E)-3,5,4ʹ-trihydroxy stilbene from (10a and 10b) To a solution of TEA (26.2 g, 0.05 mol) in chlorobenzene (12.5 g, 0.022 mol) was added anhydrous AlCl3 (8.3 g, 0.013 mol) under nitrogen atmosphere at 05°C in small portions over 30 min. The reaction mixture was then maintained at ambient temperature for 30 min under stirring. The temperature was slowly raised to 60°C and maintained at the same temperature for another 1 h. Then a mixture of compound 10a and 10b (5g, 0.0037 mol) in chlorobenzene (12.5g, 0.022 mol) was added over a period of 30 min at 60-70°C. The completion of the reaction was monitored by TLC (Chloroform:MeOH 9:1). The reaction mixture was cooled to RT and quenched into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was then washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude thus obtained was then subjected to column purification over silica gel (70-230 mesh) and eluted with chloroform and methanol (9:1) to get pure compound 1, yield (3.85 g, 90%). Pale yellow solid, (C14H12O3). m.p.254-256°C (lit.8 m.p.253-255°C). IR (KBr): 3290, 1588, 1512, 1326, 1154, 965, 832 cm−1; 1 H NMR (400 MHz, DMSO-d6): δ 6.11 (t, 1H, J = 1.6 Hz, H-4), 6.38 (d, 2H, J = 1.6 Hz, H-2, 6), 6.73 (d, 1H, J = 8.0 Hz, H-3ʹ, 5ʹ), 6.83 (d, 2H, J = 16.0 Hz, CH=CH), 6.95 (d, 1H, J = 16.8 Hz, CH=CH), 7.38 (d, 2H, J = 8.4 Hz, H-2ʹ, 6ʹ), 9.19 (s, 2H, OH), 9.55 (s, 1H, OH); GCMS: m/z (%) [M] +.228 (90), 211 (15), 199 (7), 193 (15), 181 (17), 173 (10), 165 (5), 153 (6), 139 (5), 128 (5),
115 (12), 107 (5), 105 (7), 91 (12), 77 (8), 69 (5), 63 (6), 43 (100). Acknowledgement The authors express their sincere thanks to Dr. Anil Kush, CEO of Vittal Mallya Scientific Research Foundation, for his keen interest and encouragement. References 1 Shakibaei M, Harikumar K B & Aggarwal B B, Mol Nutr Food Res, 53 (2009) 115. 2 Chang X, Heene E, Qiao F & Nick P, PLoS ONE, 6 (2011) e26405. 3 Sobolev V S, Neff S A & Gloer J B, J Agric Food Chem, 57 (2009) 62. 4 Gambini J, Ingles M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, Mas-Bargues C, Abdelaziz K M, GomezCabrera M C, Vina J & Borras C, Oxid Med Cell Longev, 2015 (2015) 837042. 5 Trela B C & Waterhouse A L, J Agric Food Chem, 44 (1996) 1253. 6 Sinha A K, Kumar V, Sharma A, Sharma A & Kumar R, Tetrahedron, 63 (2007) 11070. 7 Alonso F, Riente P & Yus M, Tetrahedron Lett, 50 (2009) 3070. 8 Shen Z L, Zhuo G L & Jiang X Z, Indian J Chem, 41B (2002) 239. 9 Han S Y, Lee H S, Choi D H, Hwang J W, Yang D M & Jun J G, Synth Commun, 39 (2009) 1425. 10 Jeffery T & Ferber B, Tetrahedron Lett, 44 (2003) 193. 11 Jephcote V J & Shen H, US Pat 20120022284 A1 (2012). 12 Wiffen J W & Mccague R, EP 1884508 A1 (2008). 13 Julia M & Paris J M, Tetrahedron Lett, 14 (1973) 4833. 14 Plesniak K, Zarecki A & Wicha J, Top Curr Chem, 275 (2007) 163. 15 Guiso M, Marra C & Farina A, Tetrahedron Lett, 43 (2002) 597. 16 Andrus M B, Liu J, Meredith E L & Nartey E, Tetrahedron Lett, 44 (2003) 4819. 17 Alonso D A & Varea N M, Tetrahedron Lett, 45 (2004) 573. 18 Alonso D A, Fuensanta M, Najera C & Varea M, J Org Chem, 70 (2005) 6404. 19 Ridley D D, Ritchie E & Taylor W C, Aust J Chem, 21 (1968) 2979.
