Synthesis, skeletal rearrangement, and biological activities of spirooxindoles: Exploration of a stepwise C-piancatelli rearrangement

Article abstract of DOI:10.1002/ejoc.201301238

Based on our previous studies, the scope of the transformation of 2-furylcarbinols into spirofurooxindoles, and also the skeletal rearrangements of spiro[furo-oxindoles] and spiro[thieno-oxindoles] were studied. The spiro[furo-oxindoles] thermally rearranged into spiro[pentenone-oxindoles] by a mechanism involving the conrotatory electrocyclization of the 4π-electron system. The free energy of the electrocyclization step was calculated to interpret the stereochemical outcomes. In contrast, the spiro[thieno-oxindoles] were rearranged under acidic conditions into thieno[2,3-c]quinolin-4-ones, involving an interesting dienone-phenol-like mechanism. The transformation of 2-furylcarbinols into spiro[pentenone-oxindoles] seems to be the first stepwise C-Piancatelli rearrangement. The spirooxindole products were biologically evaluated, and some of them showed promising cytotoxic activities against DU145 and LNCaP tumor cell lines. We describe the scope of the transformation of 2-furylcarbinols into spiro[furo-oxindoles], and the skeletal rearrangements of spiro[furo-oxindoles] and spiro[thieno-oxindoles]. The transformation of 2-furylcarbinols into spiro[pentenone-oxindoles] represents the first stepwise C-Piancatelli rearrangement. Some of the spirooxindole products showed promising cytotoxic activities against tumor cell lines. Copyright

Full text of DOI:10.1002/ejoc.201301238

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FULL PAPER
DOI: 10.1002/ejoc.201301238
Synthesis, Skeletal Rearrangement, and Biological Activities of Spirooxindoles:
Exploration of a Stepwise C-Piancatelli Rearrangement
Li Huang,[a] Xiaoyu Zhang,[a] Jing Li,[b] Ke Ding,[c] Xuehui Li,[a] Wenxu Zheng,*[b] and
Biaolin Yin*[a]
Keywords: Heterocycles / Spiro compounds / Rearrangement / Aromatic substitution / Cyclization
Based on our previous studies, the scope of the transforma- comes. In contrast, the spiro[thieno-oxindoles] were re-
tion of 2-furylcarbinols into spirofurooxindoles, and also the
skeletal rearrangements of spiro[furo-oxindoles] and spiro-
[thieno-oxindoles] were studied. The spiro[furo-oxindoles]
thermally rearranged into spiro[pentenone-oxindoles] by a
mechanism involving the conrotatory electrocyclization of
the 4π-electron system. The free energy of the electrocycliza-
tion step was calculated to interpret the stereochemical out-
arranged under acidic conditions into thieno[2,3-c]quinolin-
4-ones, involving an interesting dienone–phenol-like mecha-
nism. The transformation of 2-furylcarbinols into spiro[pent-
enone-oxindoles] seems to be the first stepwise C-Piancatelli
rearrangement. The spirooxindole products were biologically
evaluated, and some of them showed promising cytotoxic ac-
tivities against DU145 and LNCaP tumor cell lines.
ditions for the Piancatelli rearrangement. First, we envi-
sioned that by studying the intramolecular Piancatelli re-
arrangement, we might be able to avoid the requirement of
dilute reaction conditions with excessive water, so opening
up a general route to spiro-heterocyclic compounds. Sec-
ondly, using carbon nucleophiles to trap oxacarbenium spe-
cies B would be interesting for the construction of spiro C-
skeletons (C-Piancatelli rearrangement). Thirdly, replacing
the furan ring of α-furylcarbinols by a thiophene or other
five-membered aromatic ring would lead to numerous new
heterocyclic compounds.
Introduction
In 1976, Piancatelli et al. reported an acid-catalysed re-
arrangement (the so-called Piancatelli rearrangement) of
suitable 2-furylcarbinols into 4-hydroxycyclopentenone de-
rivatives.[1] The mechanism of this rearrangement has not
been fully studied, but it is widely believed to proceed by
a thermal conrotatory electrocyclization of the 4π-electron
system.[2] The key steps include (Scheme 1): (a) protonation
of the hydroxy group of α-furylcarbinols to form intermedi-
ate A; (b) nucleophilic attack at the other α position of the
furan ring to form dienyl enol ether B; (c) ring-opening; and
(d) thermal electrocyclization of the 4π-electron system D
to form cyclopentenones 1. Although the Piancatelli re-
arrangement has been used as a key step in the construction
of a series of natural products and biologically active mo-
lecules such as the prostaglandins,[3] this reaction originally
had limited synthetic applications, because it usually re-
quires a stoichiometric amount of acid, and dilute aqueous
reaction conditions. For the intensive exploitation of furan
derivatives as green, renewable building blocks for organic
synthesis,[4] it would be desirable to find new reaction con-
Scheme 1. Proposed mechanism of the Piancatelli reaction. conr. =
conrotatory.
[a] School of Chemistry and Chemical Engineering, South China
University of Technology,
Guangzhou, Guangdong 510640, China
E-mail: blyin@scut.edu.cn
Heterocyclic spirooxindoles 2 (Figure 1) have attracted
much attention due to their significant biological activi-
ties.[5] A literature search revealed that their biological ac-
tivities are usually associated with the structural features of
their B rings. For example, compound 3, with a pyrrolidine
B-ring, is an inhibitor of the MDM2–p53 interaction.[6]
Compound 4 has an isoxazolidine as its B-ring, and it
shows potent cytotoxic effects against the A431 human epi-
http://www.scut.edu.cn/ce/
[b] College of Science, South China Agricultural University,
Guangzhou, Guangdong 510640, China
E-mail: wzheng@scau.edu.cn
http://www.scau.edu.cn
[c] Guangzhou Institute of Biomedicine and Health, Chinese
Academy of Sciences,
Guangzhou, Guangdong 510530, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301238.
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L. Huang, X. Zhang, J. Li, K. Ding, X. Li, W. Zheng, B. Yin
FULL PAPER
dermoid carcinoma cell line.[7] In contrast, compounds 5 trocyclization mechanism.[11c] Through these studies, a li-
and 6 show significant inhibition of the growth of the brary of new spirooxindoles with diverse B-rings with po-
MCF-7 human breast cancer cell line[8] and A549 lung ade- tent biological activities was established (Scheme 2). In this
nocarcinoma cells,[9] respectively.
paper, we report the results of our studies of the scope of
the stepwise C-Piancatelli rearrangement reaction, the
mechanism of the transformation of 8 into 10, the scope of
the rearrangement of 10a into 11a, theoretical studies to
support the mechanism, the rearrangement of 10b, and the
anti-tumor activities of the spirooxindole products.
Results and Discussion
1.1. The Reaction Scope of the Transformation of 8a into
10a
First, various 2-furylcarbinols 8a with different R groups
were tested to investigate the reaction scope under the opti-
mized conditions previously reported [namely CuSO4·5H2O
(1.5 equiv.) and AcOH (0.1 equiv.) in toluene at 100 °C for
5 h]. The results are listed in Table 1. Similarly to other
Table 1. Scope of the reaction of 8a with different R groups.[a,b]
Figure 1. Biologically active spirooxindoles with various B-rings.
Accordingly, it would be desirable to develop methods
that might lead to structural diversity in the B-ring of spiro- Entry
8
R
10
Yield[c] [%]
oxindoles 2, starting from readily available materials.[10] Re-
1
8a-1
8a-2
8a-3
8a-4
8a-5
8a-6
8a-7
3,4,5-tri-MeO
3,5-di-MeO
3,4-di-MeO
3,5-di-Me
3-MeO
4-MeO
H
10a-1
10a-2
10a-3
10a-4
10a-5
10a-6
10a-7
85
83
66
46
57
n.d.
n.d.
cently, we used the electron-rich N-aromatic ring of 2-furyl-
carbinol 8a as an intramolecular nucleophile to trap the
oxacarbenium in 9a, which resulted in carbocyclization to
give efficient access to spirofurooxindole 10a.[11a] In ad-
dition, we also found that 2-thienylcarbinols 8b were trans-
formed into spirothienooxindoles 10b in a similar fash-
ion,[11b] and also that 10a can undergo a skeletal rearrange-
2
3
4
5
6
7
[a] All reactions were performed on a 0.3 mmol scale. [b] Entries 1–
7 have been presented in ref.[11a] [c] Isolated yield. n.d.: not de-
ment to provide spiropentenoneoxindoles 11a by a 4π-elec- tected.
Scheme 2. Strategy for the synthesis of spirooxindoles.
2
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Synthesis and Properties of Spirooxindoles
Friedel–Crafts reactions, the electron density of the N- of the desired product was observed (Table 3, entry 12). The
phenyl ring apparently influenced the yields. A higher elec- cause of this failure might be the instability of the furan
tron density at the ortho positions of the phenyl ring ring under the acidic conditions and low resonance stabili-
bonded to the amino group generally led to higher yields zation of the furan ring. Similarly, when Ar was a 2-thienyl
(8a-1 Ͼ 8a-2 Ͼ 8a-3 Ͼ 8a-4 Ͼ 8a-7). The failure of the group, compound 10a-25 was formed in a very low yield,
reactions of 8a-6 and 8a-7 may have resulted from the low due to its resonance stabilization being lower than that of
electron density (Table 1, entries 6 and 7).
a phenyl ring (Table 3, entry 13). Negative results were ob-
Next, different Y groups were screened (Table 2). When tained when R1 was a vinyl group or an unstable phenyl-
Y was NMe or NBn, the desired product (i.e., 10a-8 or 10a- ethynyl group (Table 3, entries 14 and 15). Due to their high
9, respectively) was obtained (Table 2, entries 8 and 9). The resonance stabilizations, when both Ar and RЈ were phenyl
fact that 10a-9 was formed in a lower yield than 10a-8 or groups, the desired product (i.e., 10a-38) was obtained in a
10a-1 was possibly due to the steric hindrance of the Bn fairly good yield (Table 3, entry 16).
group being larger than that of Me or Et. Without N-pro-
tection (Y = NH; Table 2, entry 4) a complex reaction mix-
Table 3. Scope of the reaction of 8a with different Ar groups.[a,b]
ture was obtained. If Y was NCbz, NEtCH2, or O, none of
the desired product was isolated, but most of the starting
material (i.e., 8a) was recovered (Table 2, entries 5–7). These
failures implied that a less strongly electron-withdrawing
carbonyl group at the C-5 position of the furan ring would
be beneficial to the stability of the carbocation and thus to
the cyclization of 8a into 10a.
Entry
8
Ar
10
Yield[c] [%]
Table 2. Scope of the reaction of 8a with different Y groups.[a]
1
2
3
4
5
6
7
8
8a-1
Ph
10a-1
85
33
trace
75
76
92
85
87
80
8a-14
8a-15
8a-16
8a-17
8a-18
8a-19
8a-20
8a-21
8a-22
8a-23
8a-24
8a-25
8a-26
8a-27
8a-28
4-MeO–Ph
2,4-di-MeO–Ph
2,6-di-Me–Ph
2-Me–Ph
4-Cl–Ph
2-Cl–Ph
2-F–Ph
10a-14
10a-15
10a-16
10a-17
10a-18
10a-19
10a-20
10a-21
10a-22
10a-23
10a-24
10a-25
10a-26
10a-27
10a-28
9
2-Br–Ph
10
11
12
13
14
15
16[e]
4-NO2–Ph
1-naphthyl
2-furyl
2-thienyl
CH2=CH
phenylthienyl
Ph
85
Entry
8
Y
10
Yield[b] [%]
87[d] (5:1)
n.d.
25
1
2
3
4
5
6
7
8a-1
NEt
10a-1
85
88
50
n.d.
n.d.
n.d.
n.d.
8a-8
NMe
NBn
NH
NCBz
NEtCH2
O
10a-8
n.d.
n.d.
87
8a-9
10a-9
8a-10
8a-11
8a-12
8a-13
10a-10
10a-11
10a-12
10a-13
[a] Unless otherwise noted, RЈ = H. All reactions were performed
on a 0.3 mmol scale. [b] Entries 1, 2, 7, 10, and 11 have been pre-
sented in ref.[11a] [c] Isolated yield. [d] Ratio in parentheses based
[a] All reactions were performed on a 0.3 mmol scale. [b] Isolated
yield. n.d.: not detected.
1
on H NMR spectroscopy. [e] RЈ = Ph. n.d.: not detected.
Finally, various Ar groups were also screened. As shown
in Table 3, the electronic properties and resonance stabiliza-
tion of the Ar groups apparently influenced the cyclization.
Lower yields of the products were obtained when Ar was a
phenyl group with one or more strongly electron-donating
methoxy groups (Table 3, entries 2 and 3). It was inferred
that more strongly electron-donating groups would result in
1.2. Explorations into the Role of the Acid Cocatalyst for
the Transformation of 8 into 10
In principle, the transformation of 8a-1 into 10a-1 can
a more reactive carbenium ion, thus leading to polymeriza- be conceptually viewed as a special intramolecular Friedel–
tion of the furan ring. In contrast, when Ar was substituted Crafts reaction using the oxocarbenium ion as the alkyl-
with a weakly electron-donating methyl group or an elec- ating agent. Usually, harsh reaction conditions, including
tron-withdrawing group, the products (i.e., 10a) were pro- strong-acid catalysts, are required for this reaction.[13] How-
duced in good to excellent yields (Table 3, entries 4–10). ever, a series of strong Lewis acids such as TiCl4, SnCl4,
Interestingly, when Ar was a 1-naphthyl group (Table 3, en- and BF3·Et2O were not suitable for the transformation of
try 11), the products were formed as a mixture of two rota- 8a-1 into 10a-1, as they led to complex reaction mixtures.
mers, possibly due to a lack of free rotation about the Weaker Brønsted or Lewis acids, i.e., CSA (camphorsulf-
naphthyl–CH= linkage.[12] If Ar was an electron-rich 2-furyl onic acid), PTSA (para-toluenesulfonic acid), AcOH,
group, a complex reaction mixture was obtained, and none Yb(OTf)3, AlCl3, and ZnCl2 were also ineffective. To eluci-
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L. Huang, X. Zhang, J. Li, K. Ding, X. Li, W. Zheng, B. Yin
FULL PAPER
date the role of the acid cocatalyst (CuSO4·5H2O/AcOH) ganic copper salt, i.e., Cu(OTs)2. Because the stability of a
and gain further insights into the mechanism, some control thiophene ring is higher than that of a furan ring, 0.5 equiv.
experiments were conducted. As shown in Table 4, when of TsOH was required to guarantee the strongly acidic con-
CuSO4·5H2O (1.5 equiv.) was used as a promoter, 8a-1Ј (de- ditions.
rived from O-acetylation of 8a-1) was hardly transformed
into 10a-1 (Table 4, entry 1), which implied that the role of
AcOH might not be to facilitate formation of the carb-
enium ion by transforming the hydroxy group into an acet-
oxy group, a better leaving group. The reaction did not
take place in the presence of AcOH alone (Table 4, entry 2).
1.3. Skeletal Rearrangement of Spirofurooxindoles 10a into
Spiropentenoneoxindoles 11a
More strongly acidic Cu(OTf)2 led to a low yield of 42%
of the product, and a complex reaction mixture (Table 4,
groups were heated in DCE (1,2-dichloroethane) at 130 °C
entry 3). Lowering the amount of Cu(OTf)2 to 0.5 equiv.
resulted in a yield of 65% of the product, and a less com-
plex reaction mixture (Table 4, entry 4). No reaction oc-
curred with the more weakly acidic Cu(OAc)2 (Table 4, en-
try 5). When CuX2 (X = Cl, Br) were used, halogenation of
First, three spirofurooxindoles 10a with different R
under metal-free conditions. As shown in Table 5, introduc-
tion of a methoxy group at the 3-position of the N-phenyl
group significantly increased the diastereoselectivity of the
reaction (Table 5, entry 1 Ͼ entry 3 Ͻ entry 2). The stereo-
chemistry of the major isomer of the product was deter-
mined based on single-crystal X-ray diffraction analysis
(cis-16a-39, see the Supporting Information, CCDC-
the furan ring of 8a-1 and the α position of the enol ether
segment of 10a-1 were observed (Table 4, entries 6–7). No-
tably, a combination of CuSO4·5H2O with Cu(OAc)2 gave
958433). The substituents on the Ar rings of 10a also influ-
a yield comparable with that obtained using CuSO4·5H2O/
enced the reaction (Table 6). Introduction of an ortho sub-
AcOH (Table 4, entry 8). Therefore, we concluded that
stituent onto the Ar ring greatly improved the diastereo-
firstly, a certain degree of acidity was crucial for this reac-
selectivity (Table 6, entries 4–6). Because of steric hin-
tion. Under more weakly acidic conditions, the transforma-
drance, introduction of two methyl groups at the 2- and 6-
tion did not proceed, while under very strongly acidic con-
positions of the Ar rings resulted in no reaction under these
ditions, the starting material was prone to decomposition.
conditions (Table 6, entry 7). Substrate 10a-28 also failed to
Secondly, an organic copper salt was beneficial to this reac-
undergo the rearrangement, due to the large steric hin-
drance of its Ar and R2 groups (R2 = Ar = Ph, Table 6,
entry 8). Interestingly, the size of the R1 group slightly in-
fluenced the diastereoselectivity (Table 7). A larger R1
group generally led to a higher diastereoselectivity (Me Ͻ
Et Ͻ Bn; 11a-8 Ͻ 11a-1 Ͻ 11a-9).
tion, because a lipophilic counterion was required as a sort
of phase-transfer catalyst. The role of AcOH is to produce
the favourable Cu(OAc)2. For the transformation of 8b to
10b,[11b] CuSO4·5H2O/TsOH was used as the acid cocata-
lyst. This combination would also produce a favourable or-
Table 4. Some control experiments.[a]
Table 5. Synthesis of 11a from 10a.[a,b]
Entry
Acid
Yield[b] [%]
1[c]
2
3
4
5
6
7
8
9
CuSO4·5H2O
AcOH
Cu(OTf)2[e]
Cu(OTf)2
Cu(OAc)2
CuBr2
20
n.r.[d]
56
42
n.r.[d]
trace
trace
Entry
10a
R
11a (Yield [%][c],
cis/trans[d]
)
CuCl2
Cu(OAc)2[f]/CuSO4·5H2O 82
1
2
3
10a-1
10a-2
10a-3
3,4,5-tri-MeO
3,5-di-MeO
4,5-di-MeO
11a-1 (94, 4:1)
11a-2 (91, 5:1)
11a-3 (89, 1.5:1)
CuSO4·5H2O
62
85
10
CuSO4·5H2O/AcOH[f]
[a] All reactions were carried out on a 0.3 mmol scale. Unless other-
wised, the amount of the acid was 1.5 equiv. and 8a-1 was used as
the substrate. [b] Isolated yield. [c] 8a-1Ј was used as the substrate.
[d] n.r.: no reaction. [e] 0.5 equiv. [f] 0.1 equiv.
[a] Unless otherwise noted, the reaction time was 12 h. [b] All reac-
tions were performed on a 0.2 mmol scale. Entries 1–3 have been
presented in ref.[11c] [c] Isolated yield. [d] Ratios are based on 1H
NMR spectroscopy.
4
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Synthesis and Properties of Spirooxindoles
Table 6. Synthesis of 11a from 10a.[a]b]
we treated 8a-1 with CuSO4·5H2O (1.5 equiv.) and AcOH
(0.1 equiv.) in the aprotic solvent DCE at 130 °C for 24 h.
C-Piancatelli rearrangement product 11a-1 was formed in
only 21% isolated yield, accompanied by many other by-
products. Even though the yield was low, the C-Piancatelli
rearrangement had been achieved for the first time. We also
found that 11a-1 was prone to decompose under the acidic
reaction conditions, and this was possibly the reason for the
low yield of 11a-1 from 8a-1. When 8a-1 was treated with
ZnCl2 (1.5 equiv.) in aqueous 1,2-dimethoxyethane, hydrol-
ysis of the amide group was observed, and none of the de-
sired product (i.e., 11a-1) was isolated (Scheme 3).
Entry
10a
Ar
11a
Yield [%][c]
(cis/trans[d]
)
1
2
3
4
5
6
10a-1
Ph
11a-1
94 (4:1)
93 (5.6:1)
86 (1.8:1)
94 (Ͼ 99:1)
92 (Ͼ 99:1)
87 (Ͼ 99:1)
n.r.
10a-18
10a-22
10a-17
10a-19
10a-20
10a-29
10a-28
4-Cl–Ph
4-NO2–Ph
2-Me–Ph
2-Cl–Ph
2-F–Ph
2,6-di-Me–Ph 11a-29
Ph 11a-28
11a-18
11a-22
11a-17
11a-19
11a-20
7
8[e]
n.r.
[a] Unless otherwise noted, the reaction time was 12 h. [b] All reac-
tions were performed on a 0.2 mmol scale. [c] Isolated yield. [d]
1
Ratios are based on H NMR spectroscopy.
Scheme 3. Transformation of 8a-1 into 11a-1.
Table 7. Synthesis of 11a from 10a.[a,b]
Stereochemical models A and B were presented to ratio-
nalize the stereoselectivities observed. We proposed that in-
termediate F of model B, which leads to cis-8, was favoured,
due to the steric hindrance between the aryl and carbonyl
groups being lower than that between the aryl group and
the N-phenyl ring (Scheme 4). To provide additional sup-
port for the stereochemical models, the free energy was cal-
culated for the reaction. Molecular geometries of the inter-
mediates, transition states, and products [10a-30 (Ar = 1-
Np, R = 3,5-di-MeO, R1 = Et)] were optimized at the
Becke3LYP/6-31+G* level of DFT theory.[15–17] The sol-
vation effects of DCE (experimentally used) were simulated
using the integral equation formulation of the polarized
continuum model (PCM).[18] As the DFT functions poorly
describe dispersion effects, dispersion correction for the free
energies was estimated using the DFT-D3 program devel-
oped by Grimme and co-workers.[19] Frequency analysis
was used to confirm whether the energy of the molecule is
a local minimum (with no imaginary frequency) or a transi-
tion state (with one imaginary frequency), and to provide
free energies at 298.15 K. Intrinsic reaction coordinate
(IRC) analysis was applied to confirm that the transition
state could reach the starting material and the product. All
Entry
10a (R1)
11a (Yield [%][c],
cis/trans[d]
)
1
2
3
10a-8 (Me)
10a-1 (Et)
10a-9 (Bn)
11a-8 (92, 2.2:1)
11a-1 (94, 4:1)
11a-9 (85, 5.5:1)
[a] Unless otherwise noted, the reaction time was 12 h. [b] All reac-
tions were performed at a 0.2 mmol scale. [c] Isolated yield. [d] Ra-
1
tios are based on H NMR spectroscopy.
We previously reported that the furandiols exclusively calculations were performed with the Gaussian 09 pro-
underwent dehydration–spiroacetalization to give spiro- gram.[20] As shown in Figure 2, although the free energy of
acetal enol ethers when treated with acid in an aprotic aro- intermediate F is 2.8 kcal/mol greater than that of interme-
matic solvent such as toluene. In contrast, if they were diate E, the cyclization energy barrier for F is 7.92 kcal/mol
treated with an acid in a protic solvent, the furandiols less than that for E, implying that the cyclization of F
underwent O-Piancatelli rearrangement to produce cyclo- should occur much more quickly than that of E. The free
pentenones.[14] To achieve the C-Piancatelli rearrangement, energy of the product cis-11a-30 is 0.72 kcal/mol less than
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Scheme 4. Plausible stereochemical models.
Figure 2. Free-energy profile (in kcal/mol) for the reactions in DCE (left) and the optimized structures of intermediates, transition states,
and products (right).
that of trans-11a-30. Thus, the formation of cis-11a-30 is structure of htis product was assigned based on spectro-
kinetically and thermodynamically favourable.
scopic analysis (IR, 2D NMR, and MS, see the Supporting
Information). 2-Thienyl-carbinol 8b-1 was also converted
into 12b-1 in a comparable 75% yield under the same reac-
tion conditions, and 10b-1 was detected as an intermediate,
according to the TLC during the course of the reaction
1.4. Rearrangement of Spirothienooxindoles 10b into
Thieno[2,3-c]quinolin-4-ones 12b
Encouraged by the accomplishment of the transforma- (Scheme 5). The rearrangement of 10b into 12b might pro-
tion of 10a into 11a, we aimed to achieve the skeletal re- ceed by a dienone–phenol-like mechanism.[21] Specifically,
arrangement of spirothienooxindoles 10b into spirothiones after protonation at the α position of the enol thioether
11b. However, as it is more difficult to cleave the C–S bond functionality, 8b could be converted into carbocation 14
than the C–O bond, when 10b-1 was heated in various polar and then into 16, which could then undergo a 1,2-carbonyl
solvents (e.g., DCE, DMF, DMSO, acetonitrile, or H2O) at migration to release ring-strain and then deprotonation to
130 °C or higher temperatures, no reaction occurred, and form 12b (Scheme 6). 5H-Thieno[3,2-c]quinolin-4-ones have
only the starting material was recovered. Interestingly, when been reported to show excellent anticancer activities.[22]
10b-1 was treated with CuSO4·5H2O (150 mol-%) and They can also be used as building blocks for the construc-
PTSA (50 mol-%) in DCE at 110 °C, it was converted into tion of biologically active fused heterocycles.[23] A small li-
5H-thieno[3,2-c]quinolin-4-one (12b-1) in 78% yield. The brary of 12b with various Ar and R groups was prepared
6
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Synthesis and Properties of Spirooxindoles
Scheme 5. Synthesis of 12b-1.
Scheme 6. Possible mechanism for the formation of 12b from 8b.
from 8b concisely and effectively in moderate to good yields toxic compounds. Four spirofuryloxindoles (10a) were more
(Table 8).
cytotoxic against Du145 and LNCaP cells than against PC3
(Table 9, entries 1–5). Compound 10a-20 (Table 9, entry 4)
was the most active, and had the lowest GI50 (3.18 μm)
against Du145 cells. A comparison of the GI50 values of
Biological Results and Discussion
To explore the antiproliferative activities of these deriva- 10a-20 and 10a-1 implies that the introduction of a 2-F
tives, several compounds were selected to test their effects group into the Ar ring remarkably improves the cytotoxicity
on the human tumor cell lines, such as Du145, LNCaP, and (nearly sevenfold). In contrast, five spirothienooxindoles
PC3 cells. As shown in Table 9, some of the tested spiroox- (10b) were more cytotoxic against LNCaP and PC3 cells
indoles showed fairly good cytotoxic activities against these than against Du145. Notably, compared to 10a-1, 10b-1 was
tumor cell lines. The cytotoxicity GI50 values range from more cytotoxic against LNCaP (2.31 vs. 21.67 μm; 5.98 vs.
600 nM against Du145 cells for the most cytotoxic (com- Ͼ 50 μm), but less cytotoxic against Du145 (21.54 vs.
pound 11a-38) to no significant inhibition for the least cyto- Ͼ 50 μm).
Eur. J. Org. Chem. 0000, 0–0
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L. Huang, X. Zhang, J. Li, K. Ding, X. Li, W. Zheng, B. Yin
FULL PAPER
Table 8. Synthesis of 12b.[a]
As for spiropentenoneoxindoles 11a, some of them
showed promising cytotoxic activities against Du145,
LNCaP, and PC3 cells. Compounds 11a-18, 11a-31, and
11a-38 were cyctotoxic against Du145 cells in the relatively
low micromolar GI50 range (0.82 μm, 0.68 μm, and 0.60 μm,
respectively), and compound 11a-30 showed clear cytotox-
icity against LNCaP cells with a GI50 of 0.71 μm. Substitu-
tion on the aryl ring influenced the cytotoxicity remarkably.
For example, when R = 3,4,5-tri-MeO, compound 11a-18,
bearing one chlorine atom at the para position of the phenyl
ring, was much more cytotoxic against Du145 cells than
was 11a-1, without substitution on the phenyl ring (19.85
vs. 0.82 μm). Those compounds with 2-Me, 2-Cl, and 4-NO2
substituents on the phenyl ring also showed good cytotox-
icity against Du145 cells (1.13, 1.90, and 2.60 μm, respec-
tively). However, compound 11a-20, with a 2-fluoro substit-
uent on its phenyl ring, showed no significant inhibition
of Du145, LNCaP, or PC3 cells. The cytotoxicity of three
spiropentanoneoxindoles 16a, prepared by hydrogenation
of the corresponding compounds 11a, was also evaluated.
Entry
8b (Ar; R)
11b (Yield[b] [%])
1
2
3
4
5
6
7
8
8b-1 (Ph; 3,4,5-tri-MeO)
8b-2 (Ph; 3,5-di-MeO)
12b-1 (78)
12b-2 (72)
12b-3 (58)
12b-18 (86)
12b-31 (77)
12b-32 (78)
12b-23 (74)
12b-33 (75)
12b-34 (70)
12b-35 (68)
12b-36 (53)
8b-3 (Ph; 3,4-di-MeO)
8b-18 (4-Cl-Ph; 3,4,5-tri-MeO)
8b-31 (2-Cl-Ph; 3,5-di-MeO)
8b-32 (2-Cl-Ph; 3,4-di-MeO)
8b-23 (1-Np; 3,4,5-tri-MeO)
8b-33 (4-F-Ph; 3,4,5-tri-MeO)
8b-34 (4-F-Ph;3,5-di-MeO)
8b-35 (4-F-Ph; 3,4-di-MeO)
8b-36 (4-F-Ph; 3,5-di-Me)
9
10
11
[a] All reactions were performed on a 0.3 mmol scale. [b] Isolated
yield. 1-Np = 1-naphthyl.
Table 9. The biological activities of the spirooxindole products.[a]
[a] The standard error of the GI50 was generally less than 10%.
8
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Synthesis and Properties of Spirooxindoles
(100 MHz, CDCl3): δ = 172.8, 158.9, 156.5, 152.8, 140.2, 138.4,
136.0, 130.5, 130.3, 128.1, 128.0, 125.4, 109.4, 100.8, 92.6, 90.4,
61.8, 61.2, 56.5, 26.7 ppm. HRMS (ESI, ion-trap): calcd. for
C22H22NO5 [M + H]+ 380.1498; found 380.1491.
Compared to their unreduced counterparts (i.e., 11a), com-
pounds 16a generally showed lower cytotoxicity against the
three tumor cell lines, and they did not show significant
inhibition of PC3 cells (GI50 Ͼ 50 μm).
5-Benzylidene-4Ј,5Ј,6Ј-trimethoxy-1Ј-benzyl-5H-spiro[furan-2,3Ј-
indolin]-2Ј-one (10a-9): Brown oil (68 mg, 50%): IR (thin film,
neat): ν = 2936, 1730, 1616, 1470, 1340, 1261, 1131, 1037, 813,
˜
Conclusions
1
746 cm–1. H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.6 Hz, 2
H), 7.37–7.31 (m, 5 H), 7.27–7.23 (m, 2 H), 7.10 (t, J = 7.6 Hz, 1
H), 6.67 (d, J = 5.6 Hz, 1 H), 6.16 (s, 1 H), 6.11 (d, J = 5.6 Hz, 1
H), 5.59 (s, 1 H), 4.97 (d, J = 15.6 Hz, 1 H), 4.83 (d, J = 15.6 Hz,
1 H), 3.76 (br., 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9,
158.9, 156.3, 152.8, 139.3, 138.5, 136.1, 135.4, 130.6, 130.2, 128.9,
128.2, 128.1, 127.9, 127.4, 125.5, 109.6, 100.9, 92.6, 91.4, 61.8, 61.1,
56.4, 44.1 ppm. HRMS (ESI, ion-trap): calcd. for C28H26NO5 [M
+ H]+ 456.1811; found 456.1802.
In summary, we have shown that 2-furylcarbinols and 2-
thienylcarbinols, with a side-chain tethered by an electron-
rich phenyl ring, are transformed into spirooxindoles under
acidic conditions. This transformation involved an interest-
ing and dearomatizing Friedel–Crafts reaction. The strategy
could be valuable for designing some new reactions for the
construction of new heterocyclic compounds using five-
membered aromatic rings as the starting materials. The
skeletal rearrangements of the spirooxindole products were
also studied. The rearrangement of spirofurooxindoles into
spiropentenoneoxindoles provides additional evidence for
the thermal conrotatory electrocyclization of the 4π-elec-
tron mechanism. The rearrangement of spirothienooxin-
doles into thieno[2,3-c]quinolin-4-ones proceeded by an
interesting and unprecedented dienone–phenol-like mecha-
nism. Finally, some of the spirooxindole products showed
promising cytotoxic activities against the DU145 and
LNCaP tumor cell lines.
5-(2,6-Dimethylbenzylidene)-1Ј-ethyl-4Ј,5Ј,6Ј-trimethoxy-5H-spiro-
[furan-2,3Ј-indolin]-2Ј-one (10a-16): Brown oil (94 mg, 75%): IR
(thin film, neat): ν = 2936, 1728, 1615, 1469, 1345, 1222, 1134, 933,
˜
1
798, 626 cm–1. H NMR (400 MHz, CDCl3): δ = 7.00–6.98 (m, 3
H), 6.68 (d, J = 5.6 Hz, 1 H), 6.17 (s, 1 H), 6.02 (d, J = 5.6 Hz, 1
H), 5.51 (s, 1 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.69 (q,
J = 7.2 Hz, 2 H), 2.32 (s, 6 H), 1.25 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.8, 158.2, 156.3, 152.7, 139.3,
138.0, 137.2, 133.9, 130.6, 129.2, 127.0, 126.4, 109.5, 97.4, 91.6,
90.1, 61.4, 61.2, 56.5, 35.1, 20.7, 12.8 ppm. HRMS (ESI, ion-trap):
calcd. for C25H28NO5 [M + H]+ 422.1968; found 422.1958.
1Ј-Ethyl-4Ј,5Ј,6Ј-trimethoxy-5-(2-methylbenzylidene)-5H-spiro-
[furan-2,3Ј-indolin]-2Ј-one (10a-17): Brown oil (92 mg, 76%). IR
(thin film, neat): ν = 2936, 1728, 1612, 1473, 1345, 1231, 1133,
˜
Experimental Section
1088, 934, 794, 749 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.98
(d, J = 7.6 Hz, 1 H), 7.11–7.05 (m, 2 H), 6.99 (d, J = 7.6 Hz, 1 H),
6.67 (d, J = 5.6 Hz, 1 H), 6.29 (s, 1 H), 6.05 (d, J = 5.6 Hz, 1 H),
5.67 (s, 1 H), 3.92 (s, 3 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.75 (q, J =
7.2 Hz, 2 H), 2.35 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.4, 159.0, 156.4, 152.9, 139.3,
138.3, 134.8, 134.4, 133.3, 130.7, 130.2, 129.8, 128.3, 125.7, 125.6,
109.7, 97.5, 90.5, 61.7, 61.2, 56.6, 35.2, 20.3, 12.9 ppm. HRMS
(ESI, ion-trap): calcd. for C24H26NO5 [M + H]+ 408.1811; found
408.1803.
General Remarks: All reactions were carried out under a nitrogen
atmosphere. Unless otherwise specified, all reagents and starting
materials were purchased from commercial suppliers and used as
received. Solvents were purified according to standard literature
procedures. IR spectra were recorded by the FTIR method with
samples in the form of thin films or KBr pellets. 1H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded using CDCl3 as a
solvent, and ratios of compounds were determined from the 1H
NMR spectra. Chemical shifts are reported in ppm downfield from
tetramethylsilane. Coupling constants are expressed in Hz; splitting
patterns are designated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and dd (double doublet). Analytical thin-
layer chromatography (TLC) was performed on silica gel plates
using mixtures of petroleum ether and ethyl acetate as the eluent.
Mass spectra were obtained using a high-resolution ESI mass spec-
trometer.
5-(2-Chlorobenzylidene)-1Ј-ethyl-4Ј,5Ј,6Ј-trimethoxy-5H-spiro-
[furan-2,3Ј-indolin]-2Ј-one (10a-19): Brown oil (108 mg, 85%): IR
(thin film, neat): ν = 2935, 1729, 1613, 1472, 1345, 1229, 1090,
˜
1
1154, 940, 812, 752 cm–1. H NMR (400 MHz, CDCl3): δ = 8.11–
8.09 (m, 1 H), 7.30–7.28 (m, 1 H), 7.12–7.08 (m, 1 H), 7.00–6.96
(m, 1 H), 6.96 (d, J = 6.0 Hz, 1 H), 6.29 (s, 1 H), 6.11 (d, J =
6.0 Hz, 1 H), 5.99 (s, 1 H), 3.92 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3
H), 3.75 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.0, 160.4, 156.6, 152.9, 139.3,
133.7, 131.4, 130.6, 129.5, 129.1, 126.5, 126.3, 109.1, 96.0, 92.8,
90.5, 61.6, 61.2, 56.6, 35.3, 12.9 ppm. HRMS (ESI, ion-trap): calcd.
for C23H23ClNO5 [M + H]+ 428.1108; found 428.1101.
General Procedure for the Preparation of 10a from 8a: A mixture
of 8a (0.3 mmol), toluene (5 mL), CuSO4·5H2O (112.5 mg,
0.45 mmol), and acetic acid (1.7 μL) was stirred at 100 °C. After
TLC indicated the disappearance of 8a, the mixture was cooled to
room temperature, and the solid was filtered off. The organic sol-
vent was removed from the filtrate, and the residue was purified by
flash chromatography on silica gel (EtOAc/petroleum ether, 1:2) to
give 10a.
5Ј-(2-Fluorobenzylidene)-2-oxo-spiro[1-ethyl-5,6,7-trimethoxyindole-
3,2Ј-(2Ј,5Ј-dihydrofuran)] (10a-20): Brown oil (107 mg, 87%): IR
(thin film, neat): ν = 2935, 1727, 1611, 1476, 1344, 1206, 1154,
˜
1
5-Benzylidene-4Ј,5Ј,6Ј-trimethoxy-1Ј-methyl-5H-spiro[furan-2,3Ј-
indolin]-2Ј-one (10a-8): Brown oil (100 mg, 88 %): IR (thin film,
1088, 937, 795, 754 cm–1. H NMR (400 MHz, CDCl3): δ = 8.06–
8.02 (m, 1 H), 7.04–6.94 (m, 3 H), 6.66 (d, J = 5.6 Hz, 1 H), 6.29
(s, 1 H), 6.10 (d, J = 5.6 Hz, 1 H), 5.82 (s, 1 H), 3.94 (s, 3 H), 3.80
neat): ν = 2934, 1731, 1613, 1473, 1342, 1274, 1093, 995, 812,
˜
703 cm–1. H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 7.6 Hz, 2 (s, 3 H), 3.76 (q, J = 7.2 Hz, 2 H), 3.76 (s, 3 H), 1.33 (t, J = 7.2 Hz,
1
H), 7.23–7.20 (m, 2 H), 7.08–7.04 (m, 1 H), 6.63 (d, J = 5.6 Hz, 1 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 160.5, 160.2,
H), 6.28 (s, 1 H), 6.04 (d, J = 5.6 Hz, 1 H), 5.56 (s, 1 H), 3.92 (s,
160.1, 158.0, 156.5, 152.9, 139.4, 138.3, 131.1, 130.5, 129.5, 129.5,
3 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.21 (s, 3 H) ppm. 13C NMR 126.6, 126.5, 124.1, 123.9, 123.8, 123.8, 114.7, 114.5, 109.4, 92.8,
Eur. J. Org. Chem. 0000, 0–0
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L. Huang, X. Zhang, J. Li, K. Ding, X. Li, W. Zheng, B. Yin
FULL PAPER
91.6, 91.6, 90.5, 61.8, 61.3, 56.6, 35.3, 12.9 ppm. HRMS (ESI, ion-
trap): calcd. for C23H23FNO5 [M + H]+ 412.1561; found 412.1554.
1Ј-Benzyl-4Ј,5Ј,6Ј-trimethoxy-5-phenylspiro[cyclopent[2]ene-1,3Ј-
indoline]-2Ј,4-dione (11a-9): Brown syrup (77 mg, 85%, cis/trans =
5.5:1): IR (thin film, neat): ν = 1625, 1464, 1134, 624 cm–1. 1H
˜
5Ј-(2-Bromobenzylidene)-2-oxo-spiro[1-ethyl-5,6,7-trimethoxyindole-
3,2Ј-(2Ј,5Ј-dihydrofuran)] (10a-21): Brown oil (113 mg, 80%): IR
NMR (400 MHz, CDCl3; cis isomer): δ = 7.34–7.01 (m, 9 H), 7.02
(d, J = 5.6 Hz, 1 H), 6.39 (d, J = 7.6 Hz, 2 H), 5.90 (s, 1 H), 5.03
(d, J = 16 Hz, 1 H), 4.47 (s, 1 H), 4.16 (d, J = 16 Hz, 1 H), 4.01
(s, 3 H), 3.82 (s, 3 H), 3.68 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3; cis isomer): δ = 205.3, 173.6, 158.3, 155.3, 150.7, 138.9,
137.4, 136.4, 134.7, 133.0, 130.4, 128.6, 128.3, 127.6, 127.3, 126.5,
110.6, 90.7, 63.6, 61.4, 61.2, 59.8, 56.1, 44.2 ppm; 1H NMR
(400 MHz, CDCl3; trans isomer): δ = 7.34–7.01 (m, 11 H), 6.59 (d,
J = 5.6 Hz, 1 H), 5.93 (s, 1 H), 5.12 (d, J = 16 Hz, 1 H), 4.70 (d,
J = 16 Hz, 1 H), 4.39 (s, 1 H), 3.71 (s, 3 H), 3.62 (s, 3 H), 3.56 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3; trans isomer, selected
data): δ = 129.5, 128.8, 127.8, 127.2, 60.7, 60.3, 59.9 ppm. HRMS
(ESI, ion-trap): m/z calcd. for C28H26NO5 [M + H]+ 456.1744;
found 456.1743.
(thin film): ν = 2940, 1729, 1618, 1490, 1326, 1200, 1158, 1098,
˜
1
940, 798, 749 cm–1. H NMR (400 MHz, CDCl3): δ = 8.09 (d, J =
7.6 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.17–7.13 (m, 1 H), 6.90–
6.87 (m, 1 H), 6.69 (d, J = 5.6 Hz, 1 H), 6.28 (s, 1 H), 6.12 (d, J =
5.6 Hz, 1 H), 5.97 (s, 1 H), 3.93 (s, 3 H), 3.80 (s, 3 H), 3.77 (q, J =
7.2 Hz, 2 H), 3.72 (s, 3 H), 1.26 1.33 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.1, 160.4, 156.6, 153.0, 139.4,
138.4, 131.3, 129.7, 127.1, 126.7, 122.9, 109.2, 99.0, 92.8, 90.5, 61.7,
61.2, 56.3, 35.3, 12.9 ppm. HRMS (EI, ion-trap): calcd. for
C
23H23BrNO5 [M + H]+ 412.1561; found 472.0760; found
472.0774.
4Ј,6Ј-Dimethoxy-1Ј-methyl-5-(thiophen-2-ylmethylene)-5H-spiro-
[furan-2,3Ј-indolin]-2Ј-one (10a-25): Brown oil (26 mg, 25%): IR
General Procedure for the Preparation of 12b from 8b: A mixture
of 8b (0.3 mmol), ClCH2CH2Cl (5 mL), CuSO4·5H2O (112.5 mg,
0.45 mmol), and pTsOH (25.8 mg, 0.15 mmol) was stirred at 110 °C
for 12 h. After TLC indicated the disappearance of 8b, the mixture
was cooled to room temperature, and the solid was filtered off. The
organic solvent was removed from the filtrate, and the residue was
purified by flash chromatography on silica gel (EtOAc/petroleum
ether, 1:3) to give 12b.
(thin film, neat): ν = 1628, 1139, 622 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.07–7.05 (m, 2 H), 6.92–6.90 (m, 1 H), 6.57 (d, J =
5.6 Hz, 1 H), 6.13–6.11 (m, 2 H), 6.01 (d, J = 5.6 Hz, 1 H), 5.81
(s, 1 H), 3.84 (s, 3 H), 3.69 (s, 3 H), 3.19 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.9, 163.8, 158.8, 157.9, 146.2, 139.3,
130.7, 129.2, 126.7, 124.6, 123.3, 103.6, 94.1, 93.0, 92.3, 89.1, 55.9,
55.6, 26.8 ppm. HRMS (EI, ion-trap): calcd. for C19H18NO4S [M
+ H]+ 356.0957; found 356.0952.
2-Benzyl-5-ethyl-7,8,9-trimethoxythieno[2,3-c]quinolin-4(5H)-one
(12b-1): White solid (95.7 mg, 78 %), m.p. 131.5–132.5 °C. IR
5-(Diphenylmethylene)-1Ј-ethyl-4Ј,6Ј-dimethoxy-5H-spiro[furan-
2,3Ј-indolin]-2Ј-one (10a-28): Brown oil (114 mg, 87 %): IR (thin
(KBr): ν = 2930, 1644, 1568, 1455, 1288, 1243, 1097, 800.3, 762,
˜
1
film, neat): ν = 2357, 1728, 1620, 1456, 1349, 1206, 624 cm–1. H
700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1 H), 7.33–
7.22 (m, 5 H), 6.67 (s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.21 (s, 2
H), 4.07 (s, 3 H), 3.98 (s, 3 H), 3.89 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4, 154.0, 148.6,
144.2, 140.3, 139.6, 137.2, 133.3, 128.9, 128.7, 128.6, 126.6, 122.7,
107.6, 94.0, 61.2, 60.7, 56.2, 37.5, 36.2, 12.7 ppm. HRMS (EI, ion-
trap): calcd. for C23H24NO4S [M + H]+ 410.1420; found 410.1415.
˜
NMR: δ = 7.44–7.42 (m, 2 H), 7.37–7.32 (m, 5 H), 7.22–7.19 (m,
2 H), 7.12–7.08 (m, 1 H), 6.59 (d, J = 5.6 Hz, 1 H), 6.12 (s, 1 H),
6.10 (s, 1 H), 5.98 (d, J = 5.6 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H),
3.73 (q, J = 7.2 Hz, 2 H), 1.29 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.9, 163.6, 158.8, 157.9, 145.1, 141.2,
139.6, 131.3, 130.8, 129.9, 129.3, 128.1, 127.6, 126.6, 125.8, 113.4,
104.2, 92.5, 91.6, 89.3, 55.8, 55.7, 35.4, 12.9 ppm. HRMS (ESI, ion-
trap): calcd. for C28H26NO4 [M + H]+ 440.1862; found 440.1853.
2-Benzyl-5-ethyl-7,9-dimethoxythieno[2,3-c]quinolin-4(5H)-one
(12b-2): White solid (81.6 mg, 72 %), m.p. 161.5–163.5 °C. IR
(KBr): ν = 2931, 1736, 1644, 1455, 1374, 1318, 1241, 1210, 1157,
˜
General Procedure for the Preparation of 11a from 10a: A mixture
of 10a (0.2 mmol) and DCE (3 mL) in a Schlenk flask was stirred
at 130 °C for 12 h until TLC indicated the disappearance of 10a.
The mixture was then cooled to room temperature. The organic
solvent was removed, and the residue was purified by flash
chromatography on silica gel (EtOAc/petroleum ether, 1:1) to give
11a.
1
1084, 813, 702 cm–1. H NMR (400 MHz, CDCl3): δ = 7.43 (s, 1
H), 7.32–7.22 (m, 5 H), 6.53 (s, 1 H), 6.38 (s, 1 H), 4.39 (q, J =
7.2 Hz, 2 H), 4.20 (s, 2 H), 3.99 (s, 3 H), 3.91 (s, 3 H), 1.37 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.6, 158.7,
156.4, 143.3, 140.9, 139.8, 138.5, 128.5, 128.6, 127.8, 126.6, 122.5,
104.1, 92.2, 92.0, 55.8, 55.5, 37.7, 36.2, 12.7 ppm. HRMS (ESI, ion-
trap): calcd. for C22H22NO3S [M + H]+ 380.1315; found 380.1311.
4Ј,5Ј,6Ј-Trimethoxy-1Ј-methyl-5-phenylspiro[cyclopent[2]ene-1,3Ј-
indoline]-2Ј,4-dione (11a-8): Brown syrup (69 mg, 92%, cis/trans =
2-Benzyl-5-ethyl-7,8-dimethoxythieno[2,3-c]quinolin-4(5H)-one
(12b-3): White solid (65.9 mg, 58 %), m.p. 149.5–151.5 °C. IR
2.2:1): IR (thin film, neat): ν = 2932, 1716, 1614, 1468, 1339, 1252,
˜
(KBr): ν = 2926, 1638, 1572, 1460, 1274, 1168, 1040, 765, 700 cm–1.
˜
1
1123, 697 cm–1. H NMR (400 MHz, CDCl3; cis isomer): δ = 7.28
1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1 H), 7.35–7.24 (m, 5
H), 7.01 (s, 1 H), 6.86 (s, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.21 (s,
2 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.1, 150.7, 145.2, 144.7, 143.0,
139.5, 131.3, 129.1, 128.7, 128.7, 126.9, 123.8, 111.6, 105.5, 98.5,
56.3, 56.2, 37.5, 36.7, 12.9 ppm. HRMS (ESI, ion-trap): calcd. for
C22H22NO3S [M + H]+ 380.1314; found 380.1315.
(d, J = 5.6 Hz, 1 H), 7.16–7.15 (m, 3 H), 6.94–6.92 (m, 2 H), 6.69
(d, J = 5.6 Hz, 1 H), 6.14 (s, 1 H), 4.38 (s, 1 H), 4.01 (s, 3 H), 3.91
(s, 3 H), 3.86 (s, 3 H), 2.82 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3; cis isomer): δ = 205.3, 173.5, 158.4, 155.5, 150.8, 139.9,
136.3, 134.7, 133.1, 129.7, 128.0, 127.4, 115.3, 110.7, 89.6, 63.6,
61.4, 61.2, 59.4, 56.4, 26.5 ppm. 1H NMR (400 MHz, CDCl3; trans
isomer): δ = 7.24 (d, J = 5.6 Hz, 1 H), 7.09–7.08 (m, 3 H), 6.82–
6.81 (m, 2 H), 6.56 (d, J = 5.6 Hz, 1 H), 6.06 (s, 1 H), 4.33 (s, 1
H), 3.78 (s, 3 H), 3.69 (s, 3 H), 3.56 (s, 3 H), 3.22 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3; trans isomer): δ = 206.0, 176.7, 156.7,
155.1, 150.8, 139.4, 137.5, 134.0, 133.1, 129.2, 127.8, 127.1, 115.3,
108.6, 89.5, 62.7, 60.8, 60.0, 59.4, 56.3, 26.8 ppm. HRMS (ESI,
2-(4-Chlorobenzyl)-5-ethyl-7,8,9-trimethoxythieno[2,3-c]quinolin-
4(5H)-one (12b-18): White solid (110 mg, 86%), m.p. 146–148 °C.
IR (KBr): ν = 2932, 1643, 1496, 1457, 1288, 1243, 1138, 1096, 930,
˜
799 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38 (s,1 H), 7.26–7.24
(m, 2 H), 7.20–7.18 (m, 2 H), 6.65 (s, 1 H), 4.38 (q, J = 7.2 Hz, 2
ion-trap): m/z calcd. for C22H22NO5 [M + H]+ 380.1492; found H), 4.14 (s, 2 H), 4.05 (s, 3 H), 3.96 (s, 3 H), 3.87 (s, 3 H), 1.36 (t,
380.1493.
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3,
10
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Pages: 13
Synthesis and Properties of Spirooxindoles
1
154.1, 148.6, 143.4, 140.4, 138.1, 137.1, 133.3, 132.5, 130.0, 128.9,
128.7, 122.8, 107.5, 93.9, 61.2, 60.7, 56.2, 37.5, 35.5, 12.7 ppm.
HRMS (ESI, ion-trap): calcd. for C23H23ClNO4S [M + H]+
444.1030; found 444.1024.
202.5 °C. IR (KBr): ν = 1697, 1654, 1523, 1247, 820, 750 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 7.40 (s, 1 H), 7.26–7.23 (m, 2 H),
7.04–6.99 (m, 3 H), 6.87 (s, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 4.18
(s, 2 H), 4.00 (s, 3 H), 3.93 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 163.3, 160.6, 158.0, 150.8, 145.3,
144.7, 142.7, 135.2, 131.3, 130.2, 130.1, 129.1, 123.9, 115.7, 115.5,
111.5, 105.5, 98.5, 56.3, 56.2, 37.5, 35.8, 12.9 ppm. HRMS (ESI,
ion-trap): calcd. for C22H21FNO3S [M + H]+ 398.1219; found
398.1218.
2-(2-Chlorobenzyl)-5-ethyl-7,9-dimethoxythieno[2,3-c]quinolin-
4(5H)-one (12b-31): White solid (95 mg, 77 %), m.p. 139.5–
141.5 °C. IR (KBr): ν = 2926, 1637, 1510, 1462, 1225, 1040,
˜
764 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.38 (m, 2 H),
7.33–7.31 (m, 1 H), 7.23–7.21 (m, 2 H), 7.02 (s, 1 H), 6.86 (s, 1 H),
4.40 (q, J = 7.2 Hz, 2 H), 4.32 (s, 2 H), 3.99 (s, 3 H), 3.93 (s, 3 H),
1.38 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
158.0, 150.7, 145.2, 144.6, 141.0, 137.1, 133.9, 131.3, 130.8, 129.8,
129.1, 128.5, 127.2, 124.3, 111.5, 105.5, 98.4, 56.2, 56.2, 37.4, 34.1,
12.9 ppm. HRMS (ESI, ion-trap): calcd. for C22H21ClNO3S [M +
H]+ 414.0925; found 414.0921.
5-Ethyl-2-(4-fluorobenzyl)-7,9-dimethylthieno[2,3-c]quinolin-4(5H)-
one (12b-36): White solid (58 mg, 53%), m.p. 190.5–192.5 °C. IR
(KBr): ν = 2888, 1649, 1518, 1397, 820, 763, 735 cm–1. H NMR
1
˜
(400 MHz, CDCl3): δ = 7.53 (s, 1 H), 7.27–7.23 (m, 2 H), 7.16 (s,
1 H), 7.03–6.98 (m, 2 H), 6.96 (s, 1 H), 4.45 (q, J = 7.2 Hz, 2 H),
4.21 (s, 2 H), 2.70 (s, 3 H), 2.47 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 163.3, 160.7, 158.2, 143.7,
143.4, 138.1, 137.2, 135.2, 134.6, 130.2, 130.2, 130.1, 126.2, 123.6,
116.0, 115.6, 115.4, 113.5, 37.7, 35.4, 23.4, 21.9, 12.8 ppm. HRMS
(ESI, ion-trap): calcd. for C22H21FNOS [M + H]+ 366.1324; found
366.1322.
2-(2-Chlorobenzyl)-5-ethyl-7,8-dimethoxythieno[2,3-c]quinolin-
4(5H)-one (12b-32): White solid (96.6 mg, 78%), m.p. 164–166 °C.
IR (KBr): ν = 2926, 1636, 1509, 1460, 1272, 1039, 761 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 7.41–7.39 (m, 2 H), 7.33–7.31 (m, 1
H), 7.24–7.21 (m, 2 H), 7.04 (s, 1 H), 6.86 (s, 1 H), 4.41 (q, J =
7.2 Hz, 2 H), 4.33 (s, 2 H), 4.00 (s, 3 H), 3.94 (s, 3 H), 1.38 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.0, 150.7,
145.2, 144.6, 141.0, 137.1, 133.9, 131.3, 130.8, 129.8, 129.1, 128.5,
127.2, 124.3, 111.5, 105.5, 98.5, 56.3, 56.2, 37.5, 34.1, 12.9 ppm.
HRMS (ESI, ion-trap): calcd. for C22H21ClNO3S [M + H]+
414.0925; found 414.0922.
Biological Assays
Cells and Reagents: The leukemia cell lines (Du145LNCaP, PC3,
A549, HepG2NCI-N87,MCF-7) were purchased from ATCC and
maintained as recommended by ATCC (Manassas, USA). CCK-8
was purchased from Dojindo Molecular Technologies Inc (Kuma-
moto, Japan). DMSO and Cremophor were purchased from
Sigma–Aldrich (Dorset, USA).
5-Ethyl-7,8,9-trimethoxy-2-(naphthalen-2-ylmethyl)thieno[2,3-c]-
quinolin-4(5H)-one (12b-23): White solid (101 mg, 74 %), m.p.
Antiproliferation Assay Using Cell Counting Kit (CCK-8): Cells in
the logarithmic phase were placed into 96-well culture dishes
(ca. 3000 cells/well). After 24 h, the cells were treated with the com-
pounds or the vehicle control at the indicated concentrations and
left for 72 h. CCK-8 was added to the 96-well plates (10 μL/well)
and incubated with the cells for 3 h. OD450 and OD650 were deter-
mined using a micro-plate reader. Absorbance rate (A) for each
well was calculated as OD450 – OD650. The cell viability rate for
each well was calculated as V [%] = (As – Ac)/(Ab – Ac) ϫ100%,
and the data were further analysed using Graphpad Prism5
(Graphpad Software, Inc.). The data used were the mean values
from three experiments. As, Absorbance rate of the test-compound
well; Ac, absorbance rate of the well with neither cell nor test com-
pound; Ab, absorbance rate of the well with cell and vehicle control.
159.5–161.5 °C. IR (KBr): ν = 2932, 1643, 1568, 1457, 1288, 1243,
˜
1096, 1054, 930, 799 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.81–
7.76 (m, 3 H), 7.73 (s, 1 H), 7.49–7.40 (m, 4 H), 6.66 (s, 1 H), 4.41
(q, J = 7.2 Hz, 2 H), 4.37 (s, 2 H), 4.05 (s, 3 H), 3.98 (s, 3 H), 3.88
(s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.4, 154.0, 148.6, 144.1, 140.4, 137.2, 137.1, 133.6,
133.3, 132.3, 128.9, 128.4, 127.7, 127.6, 127.1, 126.9, 126.1, 125.6,
122.9, 107.6, 93.9, 61.2, 60.7, 56.1, 37.5, 36.4, 12.7 ppm. HRMS
(ESI, ion-trap): calcd. for C27H26NO4S [M + H]+ 460.1577; found
460.1567.
5-Ethyl-2-(4-fluorobenzyl)-7,8,9-trimethoxythieno[2,3-c]quinolin-
4(5H)-one (12b-33): White solid (96 mg, 75%), m.p. 149–150 °C. IR
1
(KBr): ν = 1644, 1508, 1457, 1400, 1286, 1053, 820, 766 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 7.40 (s, 1 H), 7.25–7.22 (m, 2 H),
7.01–6.97 (m, 2 H), 6.67 (s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.17
(s, 2 H), 4.07 (s, 3 H), 3.98 (s, 3 H), 3.89 (s, 3 H), 1.38 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.9, 160.5,
158.4, 154.1, 148.6, 143.9, 140.4, 137.2, 135.4, 135.4, 133.3, 130.2,
130.1, 128.9, 122.7, 115.5, 115.4, 107.5, 93.9, 61.2, 60.7, 56.2, 37.5,
35.4, 12.7 ppm. HRMS (ESI, ion-trap): calcd. for C23H23FNO4S
[M + H]+ 428.1326; found 428.1319.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data along with
1
copies of the H and 13C NMR spectra for all new compounds.
Acknowledgments
This work was supported by the Fundamental Research Funds for
the Central Universities (2012ZZ043), the National Natural Sci-
ence Foundation of China (NSFC) (grant numbers 21072062,
21272078, and 21336002), the Natural Science Foundation of
Guangdong Province, China (grant number 10351064101000000),
and the Program for New Century Excellent Talents in Universities
of China (grant number NCET-12-0189).
5-Ethyl-2-(4-fluorobenzyl)-7,9-dimethoxythieno[2,3-c]quinolin-
4(5H)-one (12b-34): White solid (83 mg, 70 %), m.p. 192.5–
1
194.5 °C. IR (KBr): ν = 1699, 1650, 1518, 1244, 823, 753 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 7.41 (s, 1 H), 7.24–7.22 (m, 2 H),
7.01–6.97 (m, 2 H), 6.54 (s, 1 H), 6.38 (s, 1 H), 4.39 (q, J = 7.2 Hz,
2 H), 4.17 (s, 2 H), 4.00 (s, 3 H), 3.91 (s, 3 H), 1.37 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.9, 160.6, 158.7,
156.4, 143.1, 140.9, 138.6, 135.6, 130.1, 130.0, 127.8, 122.5, 115.5,
115.3, 104.0, 92.2, 91.9, 55.8, 55.6, 37.7, 35.4, 12.6 ppm. HRMS
(ESI, ion-trap): calcd. for C22H21FNO3S [M + H]+ 398.1221; found
398.1217.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: August 17, 2013
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31238
/KAP1
Date: 14-11-13 19:10:05
Pages: 13
Synthesis and Properties of Spirooxindoles
Spiro-Heterocycles
L. Huang, X. Zhang, J. Li, K. Ding,
X. Li, W. Zheng,* B. Yin* .............. 1–13
Synthesis, Skeletal Rearrangement, and
Biological Activities of Spirooxindoles: Ex-
ploration of a Stepwise C-Piancatelli Re-
arrangement
Keywords: Heterocycles
/ Spiro com-
pounds / Rearrangement / Aromatic substi-
tution / Cyclization
We describe the scope of the transform-
ation of 2-furylcarbinols into spiro[furo-ox-
indoles], and the skeletal rearrangements of
spiro[furo-oxindoles] and spiro[thieno-ox-
indoles]. The transformation of 2-furylcarb-
inols into spiro[pentenone-oxindoles] rep-
resents the first stepwise C-Piancatelli re-
arrangement. Some of the spirooxindole
products showed promising cytotoxic ac-
tivities against tumor cell lines.
Eur. J. Org. Chem. 0000, 0–0
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