Controllable and efficient oxidation of thioether by 2-iodoxybenzoic acid (IBX) in water: Semisynthesis of sophocarpine

Article abstract of DOI:10.1016/j.tetlet.2013.12.060

A metal-free, environment friendly, easy-to-operate, and efficient method for the semisynthesis of sophocarpine from matrine has been developed in an overall yield of 91%. The route features a controllable and efficient oxidation of thioether to sulfoxide by 2-iodoxybenzoic acid (IBX) in water.

Full text of DOI:10.1016/j.tetlet.2013.12.060

Tetrahedron Letters 55 (2014) 950–953
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Tetrahedron Letters
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Controllable and efficient oxidation of thioether by 2-iodoxybenzoic
acid (IBX) in water: semisynthesis of sophocarpine
⇑
Chaojie Li, Yuxiu Liu, Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal-free, environment friendly, easy-to-operate, and efficient method for the semisynthesis of soph-
ocarpine from matrine has been developed in an overall yield of 91%. The route features a controllable
and efficient oxidation of thioether to sulfoxide by 2-iodoxybenzoic acid (IBX) in water.
Ó 2014 Published by Elsevier Ltd.
Received 27 August 2013
Revised 31 October 2013
Accepted 17 December 2013
Available online 21 December 2013
Keywords:
Matrine
Sophocarpine
2-Iodoxybenzoic acid (IBX)
Semisynthesis
Sulfoxide
Introduction
O
H
O
H
O
H
H
H
H
H
H
H
N
H
N
H
N
H
Matrine-type alkaloids widely exist in the sophora flavescens,
sophora alopecuroides, and sophora subprostrara and attract consid-
erable attentions1–4 because of their broad biological activities,
such as analgesic, anti-arrhythmic, antiviral, anti-inflammatory,
anti-tumor, diuresis, detumescence, immunosuppression, antibac-
terial, and insecticidal.5–13 Matrine, oxymatrine, and sophocar-
pine14 (Fig. 1) are the representative natural matrine-type
alkaloids.
N
N
N
O
Sophocarpine
Matrine
Oxymatrine
Figure 1. Structure of matrine, oxymatrine, and sophocarpine.
Matrine has a high content in total alkaloid of sophora species
(for example, the content of matrine in total alkaloid of sophora
alopercuroides L. is 32%15) and can be easily purified. In China, ma-
trine suppository is clinically used to treat colpitis and chronic cer-
vicitis while matrine injection is used to cure hepatitis. It is also
reported to have moderate anti-tumor activities.16 Oxymatrine
also exists in the total alkaloid of sophora alopercuroides L., and it
probably derives from matrine, because matrine can be easily oxi-
dized to oxymatrine.17 In contrast, sophocarpine only accounts for
6% of total alkaloid of sophora alopercuroides L.15 The low abun-
dance and the difficulty in purification limited its further
application.
O
Ph
Ph
S
H
S
H
O
H
O
H
O
H
O
H
H
H
H
H
N
H
N
H
N
H
N
H
H
H
N
N
N
N
Sophocarpine
Matrine
2
1
Scheme 1. Retrosynthetic analysis of sophocarpine.
great significance to develop a practical method to synthesize
sophocarpine from easily available matrine.
Matrine and sophocarpine belong to lactam and
rated lactam, respectively. Commonly used transformation meth-
ods from amide to ,b-unsaturated amide including: (1)
preparation of -phenylselenide, followed by elimination of the
Structure modification of matrine-type alkaloids and evaluating
their biological activities have become the focus of the scientists
from all over the world.1–4 Sophocarpine is convenient for deriva-
tization because of its conjugated double bond, therefore, it is of
a,b-unsatu-
a
a
corresponding oxyselenide, in which highly toxic and expensive
selenium reagents such as PhSeCl18, PhSeBr,19 or PhSeSePh20 are
inevitable; (2) elimination of phenylsulfinyl from a-phenylsulfinyl
⇑
Corresponding author.
E-mail address: wang98h@263.net (Q. Wang).
0040-4039/$ - see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.12.060

C. Li et al. / Tetrahedron Letters 55 (2014) 950–953
951
up till now no exact transformation has been accomplished, which
suggests that the transformation may not be as easy as we think.
In this Letter, we would like to first report a metal-free, environ-
ment friendly, and efficient method for the semisynthesis of soph-
ocarpine via the intermediate 14-phenylsulfinylmatrine 1, with
controllable and efficient oxidation of thioether to sulfoxide by
2-iodoxybenzoic acid (IBX) in water as the key step (Scheme 1).
O
Ph
S
H
O
H
O
H
O
S
O
S
H
H
N
H
N
H
Base
NH2
OCH3
+
H
N
1
N
4
3
Matrine
Scheme 2. Reaction of matrine and methyl phenylsulfinate.
Results and discussion
Table 1
At the beginning, we attempted to oxidize matrine to sophocar-
pine by IBX directly as some ketones could be oxidized to a,b-unsat-
Preparation of 14-thiophenylmatrine 2
Ph
urated ketones.27 Unfortunately, we recovered all the matrine after
refluxing with IBX in acidic aqueous solution for more than 20 h.
Next, we attempted the direct sulfinylation through condensa-
tion reaction of matrine and methyl phenylsulfinate 321 (Scheme 2).
However, several kinds of bases or solvents such as NaH/THF, NaH/
PhCH3, LDA/THF, and LiHMDS/THF were used, but little or no de-
sired product was obtained. Byproduct 4 was separated as the
main product when LiHMDS was used as the base, which was also
mentioned in the reported literature.28
O
S
H
H
N
H
+
O
H
Base
S
N
H
S
H
H
N
H
N
5
martine
2
Entry
Base
Ratio matrine:base
Temperature
Isolated yield
1
2
3
NaH
t-BuOK
LDA
1:3
1:3
1:2.2
0–25 °C or reflux
0–25 °C or reflux
À78–25 °C
0a
Then, we envisioned preparing 14-thiophenylmatrine (2) by
deprotonation of matrine followed by reacting with diphenyl disul-
fide (5). NaH and t-BuOK showed no effect (Table 1, entry 1,2). LDA
was proved to be efficient deprotonating reagent, and 2 was ob-
tained in excellent isolated yield (96%, Table 1, entry 3). The prod-
uct was identified by 1H NMR, 13C NMR, and TLC to be a pair of
diasteroisomers. Subsequent experiments showed that the two
isomers have similar reactivities, so they are unnecessary to be
separated with each other.
With 2 in hand, we then focused our attention to the oxidation
of 2 to sulfoxide 1. Several kinds of commonly used oxidant were
tried, such as N-bromosuccinimide22, NaIO423, oxone24, and m-
chloroperoxybenzoic acid25, but no acceptable result was obtained
because the thiophenyl of 2 was found to be over-oxidized to sul-
fone and the tertiary amine was also apt to be oxidized to N-oxide
0a
96%b
a
Reaction conditions: Matrine (0.5 mmol) and NaH/t-BuOK (4.5 mmol) were
refluxed in THF (50 mL) for 60 min, then 5 (1.8 mmol) was added slowly, and the
reaction mixture was refluxed for another 4 h. TLC showed this reaction did not
work.
b
Reaction conditions Ref. 31.
amide, which is directly prepared from amide and methyl
phenylsulfinate21 or by oxidation of
a
-phenylsulfide amide22–25
;
(3) dehydrogenation to the corresponding a,b-unsaturated lactams
in one-pot manner at À78 °C just by treating their lithium enolates
with N-tert-butylbenzenesulfinimidoyl chloride26, but the reagent
needs to be prepared in advance. All of the above methods seem
to be able to be applied to the semisynthesis of sophocarpine, but
Table 2
Oxidization and desulfuration of 14-thiophenylmatrine 2a
Ph
O
Ph
S
H
S
H
O
H
O
H
O
H
N
N
H
N
H
1.0 equiv. K2CO3
[O]
H
PhCH3 reflux
H
H
H
H
N
N
N
2
sophocarpine
1
Entry
Oxidant
Ratio 2:oxidant
Solvent and additives
Temperature
Time (h)
Yieldb
0
1
2
3
4
5
6
7
8
9
NBS
NaIO4
Oxone
m-CPBA
IBX
IBX
IBX
IBX
IBX
1:1.1
1:2
1:1.2
1:1.2
1:2
1:2
1:2
1:3
1:3
CH3OH:CH2Cl2 = 1:1
CH3OH:H2O = 1:1
CH3OH
25 °C
25 °C
25 °C
25 °C
Reflux
Reflux
Reflux
Reflux
70 °Ce
70 °Ce
70 °Ce
6
6
6
6
3
3
3
2
4
3
3
c
—
c
—
c
CH2Cl2
—
CHCl3:H2O = 1:1 TBABd
DMSO
0
0
H2O TsOH(1.5 equiv)
H2O TsOH(1.5 equiv)
H2O TsOH(1.5 equiv)
H2O HCl(1.5 equiv)
H2O HCl(1.5 equiv)
45
66
83
95
94
10
IBX
IBX
1:3
1:3
11f
a
b
c
d
e
f
Oxidation reaction conditions: 2 (2.0–3.0 mmol), solvent (40 mL).
Isolated yield of sophocarpine.
TLC shows that several byproducts are generated at the first step, and compound 1 is difficult to be purified.
Catalytic amount.
Internal temperature.
2 (11.0 mmol), solvent (240 mL).

952
C. Li et al. / Tetrahedron Letters 55 (2014) 950–953
(Table 2, entry 1–4). 2-Iodoxybenzoic acid (IBX) was reported to be
able to oxidize sulfides to sulfoxides either in a mixed solvent of
CHCl3 and water with phase transfer catalyst or in DMSO, whereas
no over-oxidation to sulfones was observed in excessive IBX and in
longer time for its special mechanism.29 But IBX does not dissolve
in most of organic solvents except DMSO, which limited its appli-
cation. Moreover, we also noticed that although primary and sec-
ondary amines can be oxidized by IBX30, no example was found
in the literature that IBX was used to oxidize a compound contain-
ing a tertiary amine group. Thus, we tried IBX to oxidize 2. Unfor-
tunately, the reactions still could not give desired result either in a
mixed solvent of CHCl3 and water with catalytic amounts of tetra-
butylammonium bromide (TBAB) or in DMSO (Table 2, entry 5, 6).
The phenomenon suggested that the solubility was not the only
factor to influence the reaction, the lone pair of tertiary nitrogen
atom should also be considered about. As both IBX and 14-thi-
ophenylmatrine salt can dissolve in water, we hypothesized that
the oxidation step might be conducted in an acidic aqueous solu-
tion. The formation of salt might not only increase the solubility
of 2 in water but also eliminate the influence of the lone pair of
nitrogen atom as well. To our delight, when p-toluenesulfonic acid
was chosen as the additive and 2 equiv. IBX was used with water as
the sole solvent, this reaction did partially occur (Table 2, entry 7).
2 was consumed totally when increasing the amount of IBX to 3
equiv, and after treating with potassium carbonate in refluxed tol-
uene, 66% yield of sophocarpine was isolated (Table 2, entry 8). The
isolated yield of sophocarpine increased to 83% when keeping the
internal temperature of the reaction system at 70 °C for 4 h (Ta-
ble 2, entry 9). The yield was further increased to 95% while we
changed p-toluenesulfonic acid to hydrochloric acid (Table 2, entry
10), which may owe to better solubility of 2. Excellent yield (94%)
of sophocarpine can also be obtained when performed in the opti-
mized condition in larger scale (Table 2, entry 11).
References and notes
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8. Hamida, B. Q.; Philip, R. W.; Mushtaq, A. K. Phytother. Res. 2002, 16, 154–156.
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13. Kamei, J.; Xiao, P.; Ohsawa, M.; Kubo, H.; Higashiyama, K.; Takahashi, H.; Li, J.;
Nagase, H.; Ohmiya, S. Eur. J. Pharmacol. 1997, 337, 223–226.
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16. Wang, L.; You, Y.; Wang, S.; Liu, X.; Liu, B.; Wang, J.; Lin, X.; Chen, M.; Liang, G.;
Yang, H. Bioorg. Med. Chem. Lett. 2012, 22, 4100–4102.
17. Shigeru, O.; Hirotaka, O.; Joju, H.; Isamu, M. Chem. Pharm. Bull. 1980, 28, 546–
551.
18. Zimmerman, H. E.; Mitkin, O. D. J. Org. Chem. 2007, 72, 6091–6096.
19. Micouin, L.; Diez, A.; Castells, J.; López, D.; Rubiralta, M. Tetrahedron Lett. 1995,
36, 1693–1696.
20. Lou, Z.; Li, P.; Pan, Q.; Han, K. Chem. Commun. 2013, 49, 2445–2447.
21. Amat, M.; Rez, M.; Llor, N.; Bosch, J. Org. Lett. 2002, 4, 2787–2790.
22. Ali, M. H.; Hartman, M.; Lamp, K.; Schmitz, C.; Wencewicz, T. Synth. Commun.
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Conclusions
31. To a stirred solution of diisopropylamine (5.0 mL, 45.5 mmol) in THF (70 mL)
under argon at À78 °C was added dropwise n-butylithium (2.4 M in hexane,
16.1 mL). 15 min later, matrine (4.0 g, 16.1 mmol) in THF (20 mL) was added via
syringe over 5 min. The temperature was increased to 25 °C within 10 min, and
after 1 h, diphenyl disulfide (3.59 g, 16.4 mmol) in THF (10 mL) was added via
syringe over 5 min 2 h. Later, TLC analysis (CHCl3/CH3OH/NH3H2O 20:1:1)
showed the complete consumption of matrine. After the reaction was quenched
by the addition of the saturated aqueous sodium carbonate (50 mL), the
reaction mixture was poured into separator funnel and separated. The aqueous
layer was extracted with ethyl acetate (50 mL Â 3). The combined organic layer
was dried over anhydrous sodium sulfate, and then concentrated. The crude
product was purified by column chromatography on silica gel (eluted with
CH2Cl2/petroleum ether 1:1 ? CH2Cl2/ethyl acetate 10:1) to give the compound
2 (5.5 g, 96%) as a yellow liquid. 1H NMR (400 MHz, CDCl3) d 7.56–7.47 (m, 2H),
7.32–7.22 (m, 3H), 4.39 (dd, J = 12.8, 4.4 Hz, 1H), 3.91–3.76 (m, 2H), 3.10 (t,
J = 12.8 Hz, 1H), 2.88–2.74 (m, 2H), 2.27–2.14 (m, 1H), 2.14–2.03 (m, 2H), 2.00–
In conclusion, we have successfully developed a metal-free,
environment friendly, easy-to-operate, and efficient method for
the transformation from matrine to sophocarpine. The semisynthe-
sis involves an a ,
-substitution of matrine with diphenyl disulfide31
an oxidation of 14-thiophenylmatrine to 14-phenylsulfinyl ma-
trine by IBX, and subsequent elimination with the assistance of
potassium carbonate.32 The reaction can be scaled up easily and
the total isolated yield of this semisynthesis is more than 90%, thus
it can provide a large amount sample for further bioassay and
structure derivatization. The utilization of IBX in acidic aqueous
solution for oxidation of thioether to sulfoxide is unwonted and
artful, and we hope that the green procedure could find broad
application in the future.
1.90 (m, 2H), 1.84 (d, J = 13.6 Hz, 1H), 1.80–1.65 (m, 4H), 1.62–1.34 (m, 7H). 13
C
NMR (100 MHz, CDCl3) d 167.3, 134.7, 132.5, 128.8, 127.2, 63.5, 57.14, 57.09,
53.4, 49.6, 42.8, 42.4, 35.3, 27.7, 26.3, 25.0, 21.1, 20.7. HRMS (ESI) calcd for
(C21H28N2OS+H)+ 357.1995, found 357.1998.
Acknowledgments
32. Compound 2 (0.97 g, 2.7 mmol) was added to the solution of concentrated HCl
(0.34 mL, 4.1 mmol) in H2O (50 mL), and the mixture was stirred until the
compound 2 was dissolved. Then, IBX was added in one portion while keeping
internal temperature between 50 °C and 70 °C for 3 h. TLC analysis (CHCl3/
CH3OH/NH3H2O 20:1:1) showed the complete consumption of 2. After cooling
to room temperature the mixture was filtered through a Celite pad. The filtrate
was alkalified with saturated aqueous sodium carbonate (50 mL) and then
extracted with CH2Cl2 (50 mL Â 5). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated to afford the crude product 1, which was
used in the next step without further purification.
We are grateful to the National Key Project for Basic Research
(2010CB126100), the National Natural Science Foundation of China
(21132003, 21121002, 21372131), the National Key Technology Re-
search and Development Program (2011BAE06B05), and Specialized
Research Fund for the Doctoral Program of Higher Education
(20120031110010) for generous financial support for our programs.
Potassium carbonate (0.43 g, 2.7 mmol) was added to a stirred solution of
compound 1 in toluene and the reaction mixture was heated to reflux for 1.5 h.
After cooling to room temperature, the solution was added to saturated
aqueous sodium carbonate (50 mL), and then poured into separator funnel. The
aqueous layer was extracted with ethyl acetate (50 mL Â 3). The combined
organic layer was washed with saturated brine, dried over anhydrous sodium
sulfate, and concentrated. The crude product was purified by column
chromatography on silica gel (eluted with CH2Cl2 ? CH2Cl2/NEt3 500:1) to
give sophocarpine (0.63 g, 95%) as a white solid. mp 51–52 °C (lit.33 52–53 °C).
Supplementary data
Supplementary data (1H NMR and 13C NMR spectrum of 14-
thiophenylmatrine 2 and sophocarpine) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.12.060.

C. Li et al. / Tetrahedron Letters 55 (2014) 950–953
953
1H NMR (300 MHz, CDCl3) d 6.54–6.39 (m, 1H), 5.89 (d, J = 9.9 Hz, 1H), 4.14 (dd,
J = 12.9, 4.8 Hz, 1H), 4.07–3.93 (m, 1H), 3.17 (t, J = 12.9 Hz, 1H), 2.93–2.78 (m,
2H), 2.72–2.55 (m, 1H), 2.27–2.09 (m, 2H), 2.06–1.91 (m, 2H), 1.88–1.39 (m,
10H). 13C NMR (100 MHz, CDCl3) d 165.7, 137.6, 124.4, 63.4, 57.2, 51.4, 41.9,
41.4, 34.5, 27.7, 27.3, 26.5, 21.0, 20.7. The data of synthetic sophocarpine were
in good agreement with reported values.33
33. Zhang, L.; Li, G.; Houghton, P. J.; Jackson, S.; Twentyman, P. R. J. Chin. Mat. Med.
1997, 22, 740–743.