Design and an efficient synthesis of new thiorotenone derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.03.036

A series of novel 4-aryl-thiopyrano[3,4-b]pyran-5-one derivatives were synthesized through an efficient one-pot three-component reaction under solvent-free conditions. This work provides a new series of derivatives of thiorotenone with potential biological activity for biomedical screening.

Full text of DOI:10.1016/j.bmcl.2010.03.036

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2884–2887
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and an efficient synthesis of new thiorotenone derivatives
*
Changsheng Yao, Cuihua Wang, Bei Jiang, Xiaodong Feng, Chenxia Yu, Tuanjie Li, Shujiang Tu
School of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou Normal University, Xuzhou, Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 4-aryl-thiopyrano[3,4-b]pyran-5-one derivatives were synthesized through an efficient
one-pot three-component reaction under solvent-free conditions. This work provides a new series of
derivatives of thiorotenone with potential biological activity for biomedical screening.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 October 2009
Revised 3 February 2010
Accepted 6 March 2010
Available online 11 March 2010
Keywords:
Thiopyrano[3,4-b]pyran
Multicomponent reaction
Biomedical screening
Solvent-free synthesis
OMe
Pyran and fused pyran derivatives show diverse pharmacologi-
cal properties such as spasmolytic, diuretic, anticoagulant, antican-
cer, and antianaphylactic activities,1 antihyperglycemic activity,2
antiproliferative activity.3 For example, rotenone (I) and deguelin
(II) and related compounds (rotenoids) are the active ingredients
of botanical insecticides used for at least 160 years to control crop
pests.4,5 The results of bioassay test show that rotenoids are known
not only as toxicants but also as candidate anticancer agents.6–9 In
past decades, much effort has been devoted to the study on the syn-
thesis and bioactivity of rotenoids.10–12 However, only a few studies
on the synthesis and bioactivity of thiorotenoids based on core
structure III have been documented in the literature, for example,
the multi-step synthesis from thiochromanone,13,14 the cyclization
of (2-hydroxyphenyl)(2H-thiochromen-2-yl)methanone obtained
via Wadsworth-Emmons reaction and Mukaiyama directed aldol
cyclization from 2-((2,2-diethoxyethyl)thio)benzaldehyde and
diethyl (methoxy(2-methoxyphenyl)methyl)phosphonate,15–17
and the tandem reactions of dihydro-2H-thiopyran-3(4H)-one and
4-(2-hydroxyphenyl)but-3-en-2-one.18 Given the biological impor-
tance of the rotenoids, it is valuable to modify this important scaf-
fold further. So the fused phenyl rings were removed to give
thiopyrano[3,4-b]pyran scaffold and aryl substituents and a car-
bonyl group were introduced at position 4 and 5, respectively
(IV). These variations may contribute to the bioactivity differences
and provide new compound library with potential biological activ-
ity for biomedical screening.
OMe
O
MeO
MeO
O
O
I
O
O
H
H
H
H
O
O
O
II
O
Ar
O
S
S
O
IV
III
The known synthesis methods of thiorotenoids suffered from
many drawbacks, including long reaction time, complex steps, drastic
reaction conditions, low yields, generating limited diversity and the
use of catalyst and organic solvent. Recently, the progress in the field
of solvent-free reactions is gaining significance because of their high
efficiency, operational simplicity and environmentally benign pro-
cesses. Many organic reactions and complex transformations have
been reported to proceed under solvent-free conditions.19–25 Besides,
the diversity generating potential of multicomponent reactions
(MCRs) has been recognized and their utility in preparing libraries
to screen for functional molecules is well appreciated.26 In continuing
ourworkonthedesignandefficient synthesisofpotentialbiologically
active heterocyclic compounds,27 herein we report a simple work-up,
three-component and catalyst-free synthesis of a range of novel
thiopyrano[3,4-b]pyran derivatives: 2-amino-4,5,6,8-tetrahydro-4-
aryl-5-oxothiopyrano[3,4-b]pyran-3-carbonitrile and ethyl 2-ami-
* Corresponding author. Tel.: +86 516 83403165; fax: +86 516 83500365.
E-mail address: laotu2001@263.net (S. Tu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.036

C. Yao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2884–2887
2885
ArCHO
no-4-aryl-4,5,6,8-tetrahydro-5-oxothiopyrano[3,4-b]pyran-3-carbox-
O
O
O
Ar
O
1
ylate (Scheme 1) and 4-arly-3,4-dihydrothiopyrano[3,4-b]pyran-
2,5(6H,8H)-dione (Scheme 2) under solvent-free conditions. These
novel thiopyrano[3,4-b]pyran derivatives may prove to be of biolog-
ical interest.
O
O
+
solvent-free
S
S
O
O
O
2
5
6
The effect of solvent on the reaction was initially examined by
reacting 4-bromophenyl aldehyde (1 mmol), 2H-thiopyran-
3,5(4H,6H)-dione (1 mmol) and malononitrile (1 mmol) without
catalyst. It was found that if the synthesis was performed in the or-
ganic solvent it gave the expected product, 4b, in moderate to high
yield (47–80%) (Table 1). However, solvent-free reaction exhibited
higher yield (85%) than its liquid-phase counterparts. So we carried
out the solventless reaction to synthesize the desired products.
To screen for the practical temperature for the solvent-free syn-
thesis, the previous reaction was run in 1 mmol scale of substrate
at different temperature (Table 2). As shown in Table 2, the reac-
tion at 85 °C proceeded in highest yield among the seven reaction
temperatures tested. So 85 °C was chosen for this reaction.
Based on the optimized reaction conditions, a series of 2-amino-
4,5,6,8-tetrahydro-4-aryl-5-oxothiopyrano[3,4-b]pyran-3-carboni-
trile were synthesized. As shown in Table 3, the reaction under sol-
vent-free and catalyst-free conditions gave the corresponding
products in moderate to good yields.
The effect of electron and nature of substituents on the aromatic
ring did not show strongly obvious difference in terms of yields. This
protocol can be applied not only to aromatic aldehydes either with
electron-withdrawing groups (such as a nitro group, halogen) or
electron-donating groups(suchasa methoxygroup)butalsohetero-
aromatic aldehydes with moderate to excellent yields under the
sameconditions, whichhighlighted thewide scopeof this condensa-
tion. In order to check the versatility of the procedure, malononitrile
were replaced with other active methylene compoundssuch as ethyl
cyanoacetate and meldrum’s acid. To our delight, under the above
optimized conditions, a series of ethyl 2-amino-4-aryl-4,5,6,8-tetra-
hydro-5-oxothiopyrano[3,4-b]pyran-3-carboxylate and 4-arly-3,4-
dihydrothiopyrano[3,4-b]pyran-2,5(6H,8H)-dione were also
synthesized, respectively, in moderate to good yields (Tables 3 and
4).
Scheme 2.
Table 1
Solvent effect on the synthesis of 4b
Entry
Solvent
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
CH3CN
CHCl3
EtOH
HOAc
H2O
Reflux
Reflux
Reflux
85
85
85
3
5
2.5
4
3
68
55
80
65
47
85
Solvent-free
2
Table 2
Temperature optimization for the synthesis of 4b
Entry
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
25
45
65
75
85
8.5
6.0
4.5
4.0
2.0
2.0
2.0
Trace
45
68
80
85
95
82
76
105
Table 3
Synthesis of product 4 under solvent-free condition at 85 °Ca
Entry
Product
Ar
R
Time (h)
Yieldb(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
C6H5
CN
1
2
2.5
1
1.3
1.6
1.1
0.9
5
2
3
4
3.5
2.9
4
83
85
83
86
84
87
81
82
80
85
80
81
82
82
84
80
4-BrC6H4
2-FC6H4
CN
CN
3-FC6H4
4-FC6H4
CN
CN
All the products were characterized by IR, 1H NMR and HRMS
data.28 The structure of 4i was also established by X-ray crystallo-
graphic analysis (Fig. 1).29
Although thedetailedmechanism of the above reactionremains to
befullyclarified, theformationof2-amino-4,5,6,8-tetrahydro-4-aryl-
5-oxothiopyrano[3,4-b]pyran-3-carbonitrile or ethyl 2-amino-4-
aryl-4,5,6,8-tetrahydro-5-oxothiopyrano[3,4-b]pyran-3-carboxylate
4 and 4-arly-3,4-dihydrothiopyrano[3,4-b]pyran-2,5(6H,8H)-dione 6
could be explained by the reaction sequence presented in Scheme 3
and 4.
3-NO2C6H4
2-ClC6H4
3-ClC6H4
4-OCH3C6H4
2-SC4H3
CN
CN
CN
CN
CN
3-BrC6H4
3-NO2C6H4
4-BrC6H4
3-FC6H4
4-NO2C6H4
3-ClC6H4
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
3
To test the proposed mechanism, we carried out the synthesis of
4b and 6c in two steps, first of which was to get the pure 2-(4-bro-
mobenzylidene)malononitrile 7b and 11c, and then reacted with 2
under similar conditions (Schemes 5 and 6). The target compound
of 4b and 6c were obtained with yield similar to the one-pot ver-
sion. The fact supported the proposed mechanism.
a
General procedure: 1 mmol
1 and 1 mmol 3 were triturated together for
30 min. Then 1 mmol 2 was added and mixed thoroughly. The mixture were kept at
85 °C until completion (monitored by TLC).
b
Isolated yield.
In conclusion, we have provided an effective three-component
route using inexpensive starting materials for the synthesis of a
Table 4
Synthesis of product 6 under solvent-free condition at 85 °Ca
Entry
Product
Ar
Time (h)
Yieldb (%)
17
18
19
20
21
6a
6b
6c
6d
6e
2-ClC6H4
1
3
2.5
3.5
4
85
83
80
82
85
ArCHO
O
O
Ar
O
3,4-(OCH2O)C6H3
4-CH3OC6H4
4-CH3C6H4
1
R
CN
+
solvent-free
S
S
3,4,5-(CH3O)3C6H2
R
O
NH2
a
4
2
3
General procedure: 1 mmol
1 and 1 mmol 5 were triturated together for
30 min. Then 1 mmol 2 was added and mixed thoroughly. The mixture were kept at
85 °C until completion (monitored by TLC).
R = CN, CO2CH2CH3
b
Isolated yield.
Scheme 1.

2886
C. Yao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2884–2887
Figure 1. Crystal structure of 4i.
O
OCH3
O
O
O
O
Ar
O
R
O
O
R
CN
S
R
-H2O
O
+
O
H3CO
HC
+
ArCHO
Ar
S
CN
S
O
CN
1
3
2
7
8
S
O
6c
O
O
Ar
Ar
2
O
Ar
11c
O
R
R
R
S
C
N
Scheme 6.
S
S
OH
O
NH
O
NH2
9
10
Scheme 3.
4
series of thiopyrano[3,4-b]pyran derivatives under solvent-free
and catalyst-free conditions. The experimental simplicity, higher
yields, short reaction time, eco-friendly and the simple work-up
procedure, makes the procedure attractive to synthesize a variety
of these derivatives. The series of novel thiopyrano[3,4-b]pyran
derivatives may prove to be of biological interest and provide
new classes of compounds with potential biological activity for
biomedical screening.
O
O
O
O
O
O
S
O
Ar
C
H
O
+
ArCHO
O
O
Acknowledgments
2
1
11
5
O
Ar
O
Ar
O
Ar
O
O
O
O
We are grateful for financial support by Natural Science Foun-
dation of China (Nos. 20672090 and 200810102050), the Major Ba-
sic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (09KJA430003), Natural Sci-
ence Foundation of Xuzhou City(XM09B016), Graduate Foundation
of Xuzhou Normal University (09YLB030) and Qing Lan Project
(08QLT001).
O
O
O
S
S
S
O
O
O O
O
O
OH
13
OH
12
14
O
Ar
O
+
CO2
+
CH3COCH3
S
O
6
Supplementary data
Scheme 4.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.036.
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synthesized compounds are available in the Supplementary data.
29. The single-crystal growth was carried out in ethanol at room temperature. X-
ray crystallographic analysis was performed using
a Rigaku Saturn
diffractometer. Crystal data for 4i: C16H14N2O3S, colorless, crystal dimension
0.283 Â 0.058 Â 0.052 mm, monoclinic, space group C2/c, a = 31.5225(13),
b = 8.7710(3), c = 23.3362(9) Å, b = 107.586(2)°, V = 6150.5(4) Å3, Mr = 314.35,
Z = 16, Dc = 1.358 g/cm3, k = 0.71073 Å, ) = 0.224 mmÀ1, F(0 0 0) = 2624,
l(Moka
S = 0.991, R1 = 0.0560, wR2 = 0.1072. CCDC 751279 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.