A Facile and Green Synthesis of Sulforaphane

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HO HO HO HO Tong Jian DING et al. 1153 Figure 1 SFN enzymatically hydrolysed from GRA O OH -O3SO 2 myrosinase rearrangement 1 N S O S S C N Scheme 1 Synthesis of SFN OH a Br OH b N3 3 4 5 N3 OTs d N3 S e S C N S f 1 6 7 8 Reagents: a. HBr (40%), benzene, 53% yield; b. NaN3, DMF, 61% yield; c. TsCl, Py, CH2Cl2, 95% yield; d. MeSNa, DMF; e. PPh3, ether, then CS2; f. oxone, CH2Cl2, 80% yield (from 6 to 1). As shown in Scheme 1, a mixture of 1,4-butanediol 3 and aqueous hydrobromic acid (HBr, 40%) in benzene was refluxed for 20 hs, removing the water at the same time, to afford monobromoalkanol 4 as an oil in 53% yield purified by Kugelrohr distillation 7 . Then alcohol 4 was reacted with sodium azide (NaN3) at 70°C for 24 hs in dry N,N-dimethylformamide (DMF) to afford 4-azido-1-butanol 5 as an oil in 61% yield 8 . Treatment of 5 with p-toluenesulfonyl chloride (TsCl) in the presence of pyridine in dichloromethane (CH2Cl2) gave the protected alcohol 6 as an oil in 95% yield. Then a solution of compound 6 in DMF was added into the mixture of NaSMe in dry DMF under argon atmosphere at 0°C, the SN2 type reaction proceeded to give 4-azidobutyl methyl sulfide 7 6a , which was easy to loss in the process of distillation of solvent in vaccum, fortunately, the existence of a little solvent did not affect the next step reaction. 7 was reacted with triphenylphosphine (PPh3) in ether for 3 hs. After removing the solvent, carbon disulfide (CS2) was added to the reaction system, the resulting mixture was refluxed for another 1 h to afford the compound 8 6a . The crude 8 was subjected to oxone oxidation to give SFN 1 as a yellow oil purified by silica gel chromatography in 80% yield based on the compound 6 (last three steps from 6 to 1). The structures of the compounds were confirmed by the spectra (NMR and MS) 9 . The spectral data of 1 H and 13 C NMR coincided with that of reported SFN 10 . Our synthetic strategy avoided the use of KCN 2,4 and thiophosgene 2,4,5 . Because the isothiocyanate group was introduced by NaN3, PPh3/CS2 on the basis of references 6 , the yield was excellent. Moreover the complicated operation was avoided such as strictly anhydrous and low temperature to introduce the methylsulfinyl group 6a . All of the reactions involved in our route were very easy to control as to the synthesis of the racemic SFN. All of the reagents used were not expensive. In summary, SFN had been synthesized via a facile method based on the general modification of previous routes. The advantages of the past strategies had been applied and disadvantages discarded. The synthetic transformation utilized readily available OH c O S
1154 A Facile and Green Synthesis of Sulforaphane starting materials and the yield was satisfactory for every step. The overall yield was 25% based on 1,4-butanediol 3. Compared to the reported overall yields (4.4% based on [ 14 C] KCN 2 and 20% based on phthalimide potassium salt 5 ). We were confident that the present work could be applied to synthesize more compounds of this type, so as to study the structure-activity relationship. The interesting results impelled our further work including detailed biological studies to be progressed. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 20472025 and No. 20021001). References and Notes 1. J. Barillari, D. Canistro, R. Iori, et al., J. Agric. Food Chem., 2005, 53, 2475. 2. C. A. D’Souza, S. Amin, D. Desai, J. Label. Compd. Radiopharm., 2003, 46, 851. 3. B. Warton, J. N. Matthiessen, M. A. Shackleton, J. Agric. Food Chem., 2001, 49, 5244. 4. A. Kjær, J. Conti, Acta Chem. Scand., 1954, 8, 295. 5. M. Vermeulen, B. Zwanenburg, G. J. F. Chitenden, et al., Eur. J. Med. Chem., 2003, 38, 729. 6. (a) J. K. Whitesell, M. S. Wong, J. Org. Chem., 1994, 59, 597. (b) H. Staudinger, J. Meyer, Helv. Chim. Acta, 1919, 2, 635. (c) P. Molina, M. Alajarin, A. Arques, Synthesis, 1982, 596. 7. S. K. Kang, W. S. Kim, B. H. Moon, Synthesis, 1985, 1161. 8. V. Gracias, K. E. Frank, J. Aubé, et al., Tetrahedron, 1997, 53, 16241. 9. Selected data for the compounds: Compound 6: 1 H NMR (CCl 4, 300MHz, δ ppm): 7.72 (d, 2H, J=6.6 Hz, ArH), 7.30 (d, 2H, J=6.6 Hz, ArH), 4.01 (t, 2H, J=5.4 Hz, N 3-CH 2-), 3.27 (t, 2H, J=6 Hz, -CH 2-OTs), 2.52 (s, 3H, CH3-C 6H 4-), 1.74-1.60 (m, 4H, -CH 2-CH 2-); 13 C NMR (CCl 4, 75MHz, δ ppm): 147.6, 137.0, 133.1, 131.3, 72.5, 53.9, 29.5, 28.5, 25.0; FAB-MS: m/z 270([M+H] + ). Compound 1: 1 H NMR (CCl 4, 300MHz, δ ppm): 3.64 (t, 2H, J=6.2 Hz, -CH 2-NCS), 2.76-2.66 (m, 2H, -CH2-SO-), 2.55 (s, 3H, CH 3-SO-), 1.92-1.89 (m, 4H, -CH 2-CH 2-); 13 C NMR (CCl 4, 75MHz, δ ppm): 131.7, 53.1, 44.9, 38.5, 29.5, 20.5; EI-MS: m/z 177(M + ), 119([M-SCN] + ), 114([M-MeSO] + ). 10. Y. Zhang, P. Talalay, C. G. Cho, et al., Proc. Natl. Acad. Sci., 1992, 89, 2399. Received 24 March, 2006
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A Facile and Green Synthesis of Sulforaphane

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