A Facile and Green Synthesis of Sulforaphane

1152
Chinese Chemical Letters Vol. 17, No. 9, pp 1152-1154, 2006
http://www.imm.ac.cn/journal/ccl.html
A Facile and Green Synthesis of Sulforaphane
Tong Jian DING, Ling ZHOU, Xiao Ping CAO∗
Sate Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000
Abstract: The compound sulforaphane (SFN, 1) has been synthesized via a facile and green
synthetic strategy based on the modification of previous methods. Because of its high
bioactivities and rare content in nature, the present work is of great important significance.
Keywords: SFN, Cruciferae, facile and green synthesis.
Sulforaphane (1, SFN), 4-methylsulfinylbutyl isothiocyanate, was considered as the most
potent inducer of phase II enzymes proteins [glutathione transferases (GSTs) and
NAD(P)H: quinone reductase (QR)] selectively, and strong inhibitor of phase I enzymes
(cytochromes P-450) 1,2 . In this way, the rate of detoxification in phase II was increased
and the activation of carcinogens during phase I was relatively reduced, so SFN plays an
important role in cancer prevention. Naturally, it was produced by hydrolyzation of
glucoraphanin (GRA, 2) and then rearrangement (Figure 1) 1,3 . Plants, belonging to the
family of Cruciferae, were found to be rich in GRA, particularly those of the genus
Brassica, so individuals who consumed large amounts of Cruciferous fruits and
vegetables had a lower risk of developing cancer 2 .
Based on epidemiological studies on the biological activities of SFN, there was a
great interest in this particular isothiocyanate (ITC). Because the content of GRA in
plant only represented 1-2% of dry weight, so large amounts of pure compounds needed
for clinical investigation constituted a major limit 1 . Although it had been synthesized
by many methods so far, however, those procedures produced a series of environmental
impacts, safety concerns and complicated operation. For example, in the procedure of
Desai and Conti, high toxic chemicals potassium cyanide (KCN) and thiophosgene were
used to introduce isothiocyanate group (SCN) 2,4 . Thiophosgene was also used by
Vermeulen to introduce the SCN group for the synthesis of SFN 5 . And Whitesell
carried out the reaction of alcohol with thiophosgene followed by dimethylzinc
[(CH3)2Zn] to prepare chlorosulfite ester, then underwent Grignard reaction to generate
SFN 6a . The process, which has less hazard to environments and health, should be
pursued. In this paper, a facile synthetic strategy for SFN had been provided based on
the modification of previous methods.
∗ E-mail: caoxplzu@163.com

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