A new and effective approach to the synthesis of sulforaphane

Article abstract of DOI:10.2174/1570178611666151015214407

Background: Sulforaphane [1-isothiocyanato-(4-methylsulfinyl)butane] identified from appears to possess health benefits such as activities against breast, skin and prostate cancer and diabetes. and studies provide evidence that it can provide protection at every stage of cancer progression. Sulforaphane was firstly synthesized by Von Schmidt and P.Karrer in 1948 via phthalimide route but after Zhang and co-worker reported its bioactivity in 1992, the chemical synthesis of sulforaphane by alternate route has attracted several research groups in the past 20 years . Methods: The synthesis started with the preparation of-methylthiolanium tetrafluoroborate by sonication of thiolane (1) with methyl iodide followed by anionic metathesis with NaBF4 in-butanol to give thiolanium tetrafluorborate (2). The ring opening of 2 by SN2 is conducted in 16 hours at 60 oC (as indicated by TLC) to obtain 1-Azido-(4-methylsulfinyl)butane (3). Conversion 3 into Erucin (4) was successfully obtained by Staudinger reaction, followed by oxidation of 4 in transition metal-free condition (H2O2/ glacial acetic acid) to give sulforaphane in racemic form. Results: Sulforaphane was obtained with 41% yield overall via only four steps with high purity without column chromatography. The approach not only opened up a new synthetic pathway to this naturally occurring isothiocyanate and its analogues, but also suggested a possible solution for converting by-products in petroleum refining processes into useful compounds. Conclusion: Sulforaphane was successfully synthesized from thiolane, a waste product in petroleum processing in a simpler and more efficient fashion, eco-friendy approach. All products were obtained in high yield and high purity. In comparison with previously reported strategies, this new approach is believed to be the shortest and the most efficient synthetic route to date.

Full text of DOI:10.2174/1570178611666151015214407

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Letters in Organic Chemistry, 2016, 13, 7-10
7
A New and Effective Approach to the Synthesis of Sulforaphane
Duy-Viet Voa, Van-Dat Truonga,*, Thanh-Dao Tranb, Van-Thanh-Nhan Doc, Ngoc-Tuan-Anh Phama,
and Khac-Minh Thaib,*
aDepartment of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, Ho
b
Chi Minh City, 700000, Viet Nam; Department of Medicinal Chemistry, Faculty of Pharmacy, Uni-
versity of Medicine and Pharmacy, Ho Chi Minh City, 700000, Viet Nam; cUniversity of Natural Sci-
ences, Vietnam National University Ho Chi Minh City, 700000, Viet Nam
Received August 30, 2015: Revised September 29, 2015: Accepted October 15, 2015
Abstract:
Background: Sulforaphane [1-isothiocyanato-(4-methylsulfinyl)butane] identified from ꢀꢁꢂꢃꢃꢄꢅꢂꢅ ꢂ ꢆ
appears to possess health benefits such as activities against breast, skin and prostate cancer and diabe-
tes.ꢆꢇꢈꢆꢉꢄꢊꢁꢋ and ꢄꢈꢆꢉꢄꢉꢋꢆstudies provide evidence that it can provide protection at every stage of cancer
progression. Sulforaphane was firstly synthesized by Von Schmidt and P.Karrer in 1948 via phthalimide route but after
Zhang and co-worker reported its bioactivity in 1992, the chemical synthesis of sulforaphane by alternate route has at-
tracted several research groups in the past 20 years .
Methods: The synthesis started with the preparation of ꢌ-methylthiolanium tetrafluoroborate by sonication of thiolane (1)
with methyl iodide followed by anionic metathesis with NaBF4 in ꢈ-butanol to give thiolanium tetrafluorborate (2). The
ring opening of 2 by SN2 is conducted in 16 hours at 60 oC (as indicated by TLC) to obtain 1-azido-(4-
methylsulfinyl)butane (3). Conversion 3 into Erucin (4) was successfully obtained by Staudinger reaction, followed by
oxidation of 4 in transition metal-free condition (H2O2/ glacial acetic acid) to give sulforaphane in racemic form.
Results: Sulforaphane was obtained with 41% yield overall via only four steps with high purity without column chroma-
tography. The approach not only opened up a new synthetic pathway to this naturally occurring isothiocyanate and its ana-
logues, but also suggested a possible solution for converting by-products in petroleum refining processes into useful com-
pounds.
Conclusion: Sulforaphane was successfully synthesized from thiolane, a waste product in petroleum processing in a sim-
pler and more efficient fashion, eco-friendy approach. All products were obtained in high yield and high purity. In com-
parison with previously reported strategies, this new approach is believed to be the shortest and the most efficient syn-
thetic route to date.
Keywords: Brassicaceae, cancer prevention, isothiocyanate, sulforaphane, thiolane, thiolanium salt.
1. INTRODUCTION
co-worker reported its bioactivity in 1992 [4] the synthesis
of sulforaphane has gained considerable attention from sev-
eral research groups in the past 20 years [9-14]. Because of
its anticancer activity, there were several chemical syntheses
of sulforaphane under racemic form [1, 4, 8, 15-17], radioac-
tive 14C labeled [1, 18] or enantiopure form [19-22], despite
their potential utility, many of these methods have several
limitations such as the use of hazardous chemicals, longer
times via multistep synthesis. Here we introduced a new ap-
proach to the synthesis of racemic sulforaphane by nucleo-
philic ring opening of thiolanium salt by azide anion
(Scheme 1) [23].
Sulforaphane [1-isothiocyanato-(4-methylsulfinyl)butane]
was identified from Brassicaceae appears to possess health
benefits such as activities against breast, skin and prostate
cancer and diabetes. Invitro and invivo studies provide evi-
dence that it can provide protection at every stage of cancer
progression [1, 2]. Cruciferous vegetables have been widely
used in medicines, food supplements, spices and anticancer
foods. Sulforaphane’s content in vegetables is so low (200-500
ꢀg per gram cabbage) that its isolation from nature is quite
challenging. Although only R-sulforaphane is proactive but its
racemic form is still employed in anticancer research [3-7].
Sulforaphane was first synthesized by Schmidt and Kar-
rer in 1948 via phthalimide route [8] but after Zhang and
2. MATERIALS AND METHOD
All chemical agents and solvents were purchased from
Merck and Sigma-Aldrich and employed without further
purification. The structure of intermediate and final products
*Address correspondence to these authors at the School of Pharmacy, Uni-
versity of Medicine and Pharmacy Ho Chi Minh City, 700000, Vietnam;
Tel: +84-909 680 385; Fax: +84-8-38225435;
E-mails: thaikhacminh@uphcm.edu.vn; thaikhacminh@gmail.com (Thai K-M),
dattv@uphcm.edu.vn (Truong V-D).
1
was confirmed by H NMR and 13C NMR spectra measured
on a Bruker 500 spectrometer. GC-MS analyses were per-
1875-6255/16 $58.00+.00
© 2016 Bentham Science Publishers

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Letters in Organic Chemistry, 2016, Vol. 13, No. 1
Vo et al.
1) CH3I, ultrasonic, 30 mins
NaN3, DMF
16 hs, 60 oC
N3
S
2) NaBF4, 30 mins, 80 oC
S
S
-
BF4
3
2
1
1) PPh3 / ether, 3 hs, RT
N
H2O2 30%, RT
2) CS2 , 1 h, RT
N
S
C
S
C
S
S
Glac
ial ac
etic
aci
d 1 h
Sulforaphane
O
4
Scheme 1. Synthesis pathway of sulforaphane.
a
a
b
S
S
X-
+
CH3N3
I
a
S
a: direction attack of X-
b: direction attack of N3
X-: Cl-, Br-, I-
b
-
b
-
N3
Scheme 2. Suggested mechanism for the reaction of thiolanium iodide with NaN3.
formed on an Agilent GC System 7890A, equipped with a
mass selective detector Agilent 5973 and a capillary column
HP-5MS (30 m ꢀ 0.25 mm ꢀ 0.25 ꢀm).
rials remain by nucleophilic ring closuring the product. On
the other hand, azide anion can attack the S-methyl carbon
according to the pathway (b) to form CH3N3 and tetrahy-
drothiophene, this is an irrevesible route. Pathway (a) is re-
versible and pathway (b) is irreversible, therefore the equilib-
rium will shift to pathway (b) leading to CH3N3, and tetrahy-
drothiophene is the main producing obtained. Scheme 2 is
also suggested that this synthesizing procedure can be ap-
plied to synthesize sulforaphane derivatives.
The synthesis started with the preparation of S-
methylthiolanium tetrafluoroborate by sonication of 1 with
methyl iodide followed by anionic metathesis with NaBF4 in
n-butanol gave 2. As previously reported [24], our method is
less time consuming with higher yields.
The key step in this method is the subsequent nucleo-
philic ring opening of 2 by NaN3 to obtain 3. Although pre-
vious experiments [23] used water as solvent but the reaction
took too long (48 hours) in harsh conditions to complete.
Therefore DMF is used instead, aiming at achieving milder
conditions with reasonable yield. The ring opening of 2 by
SN2 is conducted in 16 hours at 60°C (as indicated by TLC)
to obtain 3 whereas direct nucleophilic ring opening of thio-
lanium iodide by NaN3 in the same condition will give a
large amount of 1, CH3N3 (b) and 4-iodobutyl methyl sulfide
(a). It is suggested that, iodide anion as a strong nucleophile
preventing azide from attacking at most reactive site as de-
picted in Scheme 2.
2.1. Attempted Synthesis of 1-azido-(4-methylsulfinyl)
butane from 1-methylthiolanium Iodide
Yield: 61%. b.p. 119°C. Rf = 0.81 (DCM:MeOH = 1:1).
The obtained coumpound has 1H NMR (500 MHz, D2O): ꢀ =
1.94 (m, 2 H); 13C NMR (125 MHz, D2O): ꢀ = 31.79, 31.15;
and MS (ESI, 70 eV): m/z = 88 [C4H8S + 1]. This characteri-
zation data suits with tetrahydrothiophene profile (C4H8S, M
= 88) not 1-azido-(4-methylsulfinyl)butane.
2.2. Synthesis of 1-azido-(4-methylsulfinyl)butane from
S-methylthiolanium Tetrafluorborate
Yield: 69%. b.p. 87°C. P = 10 torr. Rf = 0.50
(DCM:MeOH = 1:5). The synthetic coumpound give 1H
NMR (500 MHz, D2O): ꢀ = 3.32 (t, J = 6.3 Hz, 2 H), 2.57 (t,
J = 6.9 Hz, 2 H), 2.10 (s, 3 H), 1.64-1.71 (m, 4 H); 13C NMR
(125 MHz, D2O): ꢀ = 51.11, 33.79, 27.97, 26.15, 15.60 and
MS (ESI, 70 eV): m/z = 146.075 [C5H11N3S + 1]. This char-
acterization data suits with 4-(methylthio)butyl azide profile
(C5H11N3S, M = 145).
The conversion of the compound 3 into 4 was success-
fully carried out by the Staudinger reaction [17], followed by
the oxidation of 4 under transition metal-free conditions
(H2O2/ glacial acetic acid) to give sulforaphane in the race-
mic form [25].
All reactions used are quite simple and the products were
obtained in high yields with high puritiy, so purification by
column chromatography is not required. Although our ap-
proach still exploits some hazardous chemicals, namely
PPh3, CS2 and thiolane but it can be recovered, reaction time
and the number of steps required were remarkably reduced.
Also, a solution for converting thiolane minor products in
petroleum processing into useful product is provided by this
method.
Comparing with M. H. Benn et al.’s method (Step 2: ring
opening of 2 to 3) [26], our method had higher yield, the
process of purification was simpler without column chroma-
tography. In step 4, m-chloroperoxybenzoic acid/ dichloro-
methane [2] was replaced by H2O2/water.
These methods in step 2 and 4 were used in invidual re-
action but not yet used in overal reaction to synthesize Sul-
foraphane and not yet published before. Our process had 4
steps with high yield, purity product.
As shown in Scheme 2, the nucleophile iodide attacked 2
to opening thiolane ring and 4-iodobutyl methyl sulfide was
formed. This is a reversible route, hence some starting mate-

A New and Effective Approach to the Synthesis of Sulforaphane
Letters in Organic Chemistry, 2016, Vol. 13, No. 1
9
44.59, 33.09, 28.69, 25.69, 15.29. MS (ESI, 70 eV): m/z =
162.041 [C6H11NS2 + 1].
3. RESULTS
3.1. Thiolanium Tetrafluorborate (2)
Sulforaphane: 1H NMR (500 MHz, CDCl3): ꢀ = 3.59 (t,
J = 6.3 Hz, 2 H), 2.73 (m, 2 H), 2.59 (s, 3 H), 1.86-1.97 (m,
4 H). 13C - NMR (125 MHz, CDCl3): ꢀ = 131.20, 53.50,
44.59, 38.69, 25.59, 20.09. MS (ESI, 70 eV): m/z = 178.035
[C6H11NOS2 + 1].
A glass-caped testtubecharged with 0,88 g (0,01 mol)
thiolane 1 and 1,42 g (0,01 mol) methyl iodide in 1:1 ratio
was immersed in an ultrasonic bath and sonicated for 30
minutes at 50°C. After completion, the reaction mixture was
transferred into a flask and added one equivalent sodium
tetrafluoroborate 1,10 g (0,01 mol) and 10 mL n-butanol.
The mixture was stirred for 30 minutes at 80°C and then
cooled to precipitate crude 2. Purification by recrystallization
in ethanol gave pure 1,56 g 2 (yield: 82%).
CONCLUSION
Sulforaphane was successfully synthesized from thiolane,
a waste product in petroleum processing in a simpler and
more efficient fashion, eco-friendlier approach. All products
were obtained in high yield and high purity. In comparison
with previously reported strategies, this new approach is
believed to be the shortest and the most efficient synthetic
route to date.
3.2. 1-azido-(4-methylsulfinyl)butane (3)
1,90 g (0,01 mol) 2 and 1,95 g (0,03 mol) sodium azide
(1:3) in 20 mL DMF were dissolved and the mixture was
vigorously stirred at 60°C for 16 hours in an oil bath. After
completion, the reaction mixture was diluted with water and
extracted with diethyl ether (3 ꢀ 15 mL). The organic phase
was dried over anhydrous Na2SO4 and the solvent was re-
moved under vacuum. The product was purified by distilla-
tion, giving 1,00 g 3 (87°C, P = 10 torr, yield: 69%).
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
3.3. Erucin (4)
This work was supported by the Vietnam’s National
Foundation for Science and Technology Development - NA-
FOSTED (Grant # 104.01.2012.78 to Thanh-Dao Tran).
1,45 g (0,01 mol) compound 3 and 2,62 g (0,01 mol)
triphenylphosphine (1:1) were added to 20 mL diethyl ether
and stirred in a flask equipped with a condenser at room
temperature for 3 hours. After completion, the solvent was
removed, one equivalent of carbon disulfide 0,76 g (0,01
mol) was added and the mixture was stirred for 1 hour. The
reaction mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous Na2SO4 and the sol-
vent was removed under vacuum. The obtained product was
purified by distillation to give 1,27 g 4 (86 - 87°C, P = 10
torr, yield: 79%).
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
web site along with the published article.
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