Cascade synthesis of spirooxindole δ-lactone derivatives through N-aryl hydroxymethylacrylamides with xanthates

Article abstract of DOI:10.1016/j.tet.2015.08.039

A novel and highly efficient cascade synthesis of spirooxindole δ-lactone derivatives from N-aryl hydroxymethylacrylamides and xanthates in good yields is described. The reaction proceeds through a radical addition/cyclization and ester exchange, in which two new C-C bonds and one C-O bond were formed.

Full text of DOI:10.1016/j.tet.2015.08.039

Tetrahedron 71 (2015) 8117e8122
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cascade synthesis of spirooxindole d-lactone derivatives through
N-aryl hydroxymethylacrylamides with xanthates
*
Shucheng Wang, Xuhu Huang, Yanzhao Wen, Zemei Ge, Xin Wang, Runtao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2015
Received in revised form 10 August 2015
Accepted 14 August 2015
Available online 21 August 2015
A novel and highly efficient cascade synthesis of spirooxindole d-lactone derivatives from N-aryl hy-
droxymethylacrylamides and xanthates in good yields is described. The reaction proceeds through
a radical addition/cyclization and ester exchange, in which two new CeC bonds and one CeO bond were
formed.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Spirooxindole
d
-Lactone
Xanthate
Radical
Cyclization
1. Introduction
The spirooxindoles are among the most privileged scaffolds in
medicinal chemistry.1,2 Thus, numerous effective methods, in-
cluding formal cycloaddition,3 organocascade,4 Prins cyclization,5
and multicomponent reactions,6 have been developed for the
synthesis of diversely structured spirooxindoles. For example,
Huang et al. disclosed that spirooxazolines could be synthesized
from ynones and isatins using phosphine-catalyzed system.4f Zhu
and co-workers reported a palladium-catalyzed oxidative carbo-
heterofunctionalization of alkenes for the preparation of azaspir-
ooxindoles.12c Very recently, Tu’s group succeeded construction of
spiro[indoline-3,20-pyrrole] framework via catalytic asymmetric
1,3-dipolar cycloadditions of isatin-derived azomethine ylide with
allenes.3g All of these methods result in a different class of spi-
rocyclic oxindoles.7,8 However, to the best of our knowledge, there
Scheme 1. Design of new approach for spirooxindole d-lactones.
is only one report on the synthesis of spirooxindole
d
-lactones
(Scheme 1, Eq. 1),9 though
d-lactone is vital and useful subunit in
been used as a powerful tool for building up diversity bioactive
compounds. Even so, a cascade synthesis of spirooxindole de-
rivatives employing acrylamides with other reactants have scarcely
been reported.12
Xanthate-based radical addition reactions developed by Zard
and co-workers are powerful tools for the construction CeC bonds
without utilizing potentially toxic metal agents.13 It is well known
that the intermediates generated by xanthate based radical re-
actions can be readily trapped by alkenes. Inspired by Lu’s work and
as part of our ongoing program to explore efficient methodologies
for synthesize heterocyclic compounds,14 we report herein a novel
many bioactive natural products.10
Nowadays, the cascade reaction has received much attention
because the ability to undertake more than one synthetic step in
a reaction vessel represents a useful method for saving time and
energy, as well as for reducing the use of organic solvents in the
purification the intermediates.11 Thus, the cascade reaction has
* Corresponding author. Tel.: þ86 10 82801504; e-mail address: lirt@bjmu.edu.cn
(R. Li).
http://dx.doi.org/10.1016/j.tet.2015.08.039
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

8118
S. Wang et al. / Tetrahedron 71 (2015) 8117e8122
Table 2
transition-metal-free tandem radical cyclization of olefinic amides
with xanthates to the construction of highly functionalized spi-
Reaction scope for the synthesis of substrate 3a
rooxindole d-lactones under mild conditions, in which two new
CeC bonds and one CeO bond were formed. (Scheme 1, Eq. 2).
2. Results and discussion
Initially, the starting material 2-hydroxymethyl-N-methyl-N-
phenylacrylamide (1a) was firstly synthesized from N-methylani-
line with two steps in a high yield.15 1a was then allowed to react
with xanthate (2a) in the presence of 1.5 equiv of dilauroyl peroxide
(DLP) in DCE at 84 ꢀC for 12 h14 To our delight, the desired product
3a was isolated in 87% yield (Table 1, entry 1). This result encour-
aged us to further optimize the reaction conditions. Several oxi-
dants, including PhI(OAc)2, TBHP, H2O2, K2S2O8, were thoroughly
examined, and the DLP remained as the best one (Table 1, entries
1e5). The solvent screening results revealed that DCE was the best
choice (Table 1, entries 6e10). By altering the temperature to
120 ꢀC, the yield of 3a was slightly reduced due to the instability of
DLP at high temperature (Table 1, entry 11). In addition, decreasing
the amount of DLP and 2a seems to dramatically reduce the re-
action efficiency (Table 1, entry 12e14). Therefore, the best reaction
conditions were concluded as follows: N-aryl hydrox-
ymethylacrylamide 1a (0.1 M), xanthate 2a (1.5 equiv), DLP (oxi-
dant, 1.5 equiv) in DCE at 84 ꢀC in an open flask.
With the optimized reaction conditions in hand, we next ex-
amined the scope of this reaction (Table 2). The reactions of dif-
ferent N-aryl-N-methyl hydroxymethylacrylamides (1) with
xanthate (2a) proceeded efficiently to deliver the spirooxindole
lactones 3a-j in good yields.12d,15,16 The property and position of
substituents R1 in substrates 1 did not significantly effect to the
reactions. Such as, 1b (R1¼4-Me), 1d (R1¼4-CF3) and 1g (R1¼6-Me)
gave the products 3b, 3d and 3g in 81%, 78% and 86% yields, re-
spectively. The good tolerance of substrate bearing Cl and Br pro-
vides
a
convenient platform for further elaboration via
conventional Pd-catalyzed cross-coupling (3e, 3f, 3h). Interestingly,
Table 1
Optimization of reaction conditionsa
a Reaction conditions 1 (0.3 mmol, 1 eq.), 2 (0.45 mmol, 1.5 eq.),
oxidant (0.45 mmol, 1.5 eq.), DCE (3 mL) at 84 oC for 12 hours
under air. The d.r. value is given in parenthesis.
Entry
Oxidant
Temp (ꢀC)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
DLP
84
84
84
84
84
65
60
80
100
130
120
84
84
84
DCE
DCE
DCE
DCE
DCE
THF
EA
CH3CN
Dioxane
C6H5Cl
DCE
DCE
DCE
87
NRc
62
NR
NR
65
15
21
53
22
80
73
71
58
the reaction of 2-hydroxymethyl-N-acryloyltetrahydroquinoline 1k
and 2a produced a tetracyclic oxindole product 3k in 86% yield. For
2-hydroxymethyl-N-methyl-N-naphthylacrylamide 1l, the desired
product 3l was also formed in moderate yield (63%). Next, changing
the N-substituent group R2 of 1a from the methyl group to iso-
propyl, phenyl and benzyl also gave the desired products 3m, 3n
and 3o in 90%, 75% and 94% yields, respectively. Much to our de-
light, replacing R3¼H in 1a with bulkier alkyl groups (R3¼n-Pr, i-Pr,
cyclohexyl) also react smoothly with xanthate 2a affording the
products 3per in 67e74% yields. However, 1s (R3¼Ph) as substrate
did not result any desired product 3s under the same reaction
conditions. The probable reason is the formation of stable benzylic
carbocation, which easy leave away to form monosubstituted
oxindole. Finally, the reactions of a variety of xanthates 2 with 1a
were investigated under the optimized reaction conditions. It was
found that steric bulk of R4 of xanthates 2 significantly influenced
the yields of the reactions.
PhI(OAc)2
TBHP
H2O2
K2S2O8
DLP
DLP
DLP
DLP
DLP
DLP
DLP
DLP
DLP
9
10
11
12d
13e
14d,e
DCE
a
Reaction conditions: 1a (0.3 mmol, 1 equiv), 2a (0.45 mmol, 1.5 equiv), oxidant
(1.5 equiv), solvent (3 mL), 12 h.
b
Isolated yields.
c
NR¼no reaction.
d
Oxidant (1.2 equiv).
e
2a (1.2 equiv).
For examples, the reactions of 2b (R4¼Me), 2c (R4¼Et) and 2d
(R4¼di-Me) afforded the corresponding products (3t, 3u,3v) in 84%,

S. Wang et al. / Tetrahedron 71 (2015) 8117e8122
8119
72% and 38% yields, respectively. However, we are happy to find
4.2. General procedure for the synthesis of compounds 3
that 2e (R4¼CO2Et) could be smoothly transformed into product 3w
in 84% yield with 3:1 dr value.
DLP (0.45 mmol, 1.5 equiv) was added to a solution of 1
(0.3 mmol, 1 equiv) and 2 (0.45 mmol, 1.5 equiv) in DCE (3 mL) in
one portion. The solution was stirred at 84 ꢀC for 12 h. Water
(10 mL) was added to the solution and the mixture was extracted
with DCM (2ꢁ10 mL). The combined organic phase was dried over
Na2SO4. After removal of solvents with a rotary evaporator, the
residue was purified on a silica gel column with petroleum ether
and ethyl acetate as eluents to afford the desired product 3.
Based on these experiments and the previous reports,13,14c
a plausible mechanism is presented in Scheme 2. Initially, xan-
thate 2a reacts with DLP to give radical 4, which would promptly
add to acrylamide 1 to generate radical species 5. Subsequently, this
intermediate 5 undergoes intramolecular carbocyclization to afford
6, followed by DLP oxidation to produce oxindole cation 7. De-
protonation of 7 generates the intermediate 8. Finally, the desired
product 3 was formed via the intramolecular ester exchange re-
action of 8 with the presence of carboxylic acid. To confirm this
possible mechanism, we carefully separated the key intermediate
8o (R2¼Bn, see Supplementary data), which could be converted to
the 3o under our reaction conditions.
4.2.1. 1-Methyl-40,50-dihydrospiro[indoline-3,30-pyran]-2,60(20H)-di-
one (3a). 87% yield, white solid, mp¼121e123 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.37 (t, J¼7.6 Hz, 1H), 7.30 (d, J¼6.8 Hz, 1H), 7.12
(t, J¼7.6 Hz, 1H), 6.93 (d, J¼7.6 Hz, 1H), 4.55 (d, J¼11.2 Hz, 1H), 4.26
(d, J¼11.2 Hz, 1H), 3.25 (s, 3H), 3.13e2.99 (m, 1H), 2.88e2.75 (m,
1H), 2.52e2.45 (m, 1H), 2.16e2.04 (m, 1H); 13C NMR (101 MHz,
CDCl3)
d 176.6, 170.9, 143.0, 131.1, 129.1, 123.5, 123.3, 108.7, 72.8,
46.0, 28.6, 27.3, 26.5. HRMS (ESI): m/z calcd for C13H13NNaO3
[MþNa]þ: 254.0788; found: 254.0792.
4.2.2. 1,5-Dimethyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3b). 81% yield, white solid, mp¼153e155 ꢀC; 1H
NMR (400 MHz, CDCl3)
d
7.17 (d, J¼7.9 Hz, 1H), 7.12 (s, 1H), 6.81 (d,
J¼7.9 Hz, 1H), 4.55 (d, J¼11.2 Hz, 1H), 4.24 (d, J¼11.2 Hz, 1H), 3.23 (s,
3H), 3.13e2.99 (m, 1H), 2.85e2.78 (m, 1H), 2.56e2.43 (m, 1H), 2.36
(s, 3H), 2.14e2.01 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 176.5, 171.0,
140.5, 133.0, 131.3, 129.3 (s), 124.4, 108.4, 72.9, 46.1, 28.6, 27.3, 26.5,
21.1. HRMS (ESI): m/z calcd for C14H15NNaO3 [MþNa]þ: 268.0944;
found: 268.0945.
4.2.3. 5-Methoxy-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3c). 83% yield, white solid, mp¼113e115 ꢀC; 1H
NMR (400 MHz, CDCl3)
d
6.92e6.87 (m, 2H), 6.82 (d, J¼8.4 Hz, 1H),
4.55 (d, J¼11.4 Hz, 1H), 4.25 (d, J¼11.4 Hz, 1H), 3.81 (s, 3H), 3.23 (s,
3H), 3.15e2.96 (m, 1H), 2.85e2.78 (m, 1H), 2.52e2.45 (m, 1H),
2.11e2.04 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 176.3, 171.0, 156.5,
Scheme 2. Plausible reaction pathway.
136.3, 132.5, 113.3, 111.1, 109.0, 72.7, 55.9, 46.4, 28.7, 27.3, 26.6.
HRMS (ESI): m/z calcd for C14H15NNaO4 [MþNa]þ: 284.0893;
found: 284.0896.
3. Conclusion
In summary, we have developed a novel cascade synthesis of
spirooxindole
d-lactone derivatives from N-aryl hydrox-
4.2.4. 1-Methyl-5-(trifluoromethyl)-40,50-dihydrospiro[indoline-3,30-
ymethylacrylamides with xanthates via a radical addition/cycliza-
tion and ester exchange process. The advantages of this method
include available starting materials, broad substrate scope, high
yields and mild reaction conditions. Further application to other
heterocyclic systems is underway.
pyran]-2,60(20H)-dione
(3d). 78%
yield,
white
solid,
mp¼154e156 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.68 (d, J¼8.2 Hz,1H),
7.53 (s, 1H), 7.01 (d, J¼8.2 Hz, 1H), 4.55 (d, J¼11.6 Hz, 1H), 4.30 (d,
J¼11.6 Hz, 1H), 3.30 (s, 3H), 3.14e3.05 (m, 1H), 2.87e2.76 (m, 1H),
2.57e2.43 (m, 1H), 2.23e2.09 (m, 1H); 13C NMR (101 MHz, CDCl3)
d
176.6, 170.5, 145.9, 131.8, 128.0, 126.9 (q, J¼4.0 Hz, 1C), 125.5 (q,
4. Experimental section
4.1. General information
J¼16.8 Hz, 1C), 120.4 (q, J¼3.7 Hz, 1C), 108.5, 72.2, 46.0, 28.6, 27.2,
26.7. HRMS (ESI): m/z calcd for
C
14H12F3NNaO3 [MþNa]þ:
322.0661; found: 322.0667.
All melting points (mp) were measured on a melting point ap-
paratus with a microscope and a hot stage and were uncorrected.
1H NMR spectra were determined in CDCl3 on a Bruke 400 MHz
spectrometer and chemical shifts were reported in parts per million
4.2.5. 5-Chloro-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3e). 80% yield, white solid, mp¼184e186 ꢀC; 1H
NMR (400 MHz, CDCl3)
d
7.36 (dd, J¼8.3, 2.0 Hz, 1H), 7.32e7.25 (m,
1H), 6.85 (d, J¼8.3 Hz,1H), 4.54 (d, J¼11.5 Hz,1H), 4.25 (d, J¼11.5 Hz,
1H), 3.25 (s, 3H), 3.14e2.95 (m, 1H), 2.92e2.74 (m, 1H), 2.53e2.47
from internal TMS (
d
). Data for 1H NMR are recorded as follows:
ppm), multiplicity (integration, s¼singlet,
chemical shift
(
d,
(m,1H), 2.16e2.00 (m,1H); 13C NMR (101 MHz, CDCl3)
d 176.1,170.6,
d¼doublet, dd¼doublets, t¼triplet, q¼quartet, m¼multiplet or
unresolved, coupling constant(s) in Hertz). 13C NMR spectra were
obtained by using the same NMR spectrometers. High-resolution
mass spectra (HRMS) was recorded using a Bruker Apex IV FTMS
instrument. Column chromatography was performed with
200e300 mesh silica gel using flash column techniques. All of the
reagents obtained commercially were used directly unless other-
wise noted.
141.5, 132.8, 129.1, 128.7, 124.1, 109.6 (s), 72.3, 46.3, 28.5, 27.2, 26.6.
HRMS (ESI): m/z calcd for C13H12ClNNaO3 [MþNa]þ: 288.0398;
found: 288.0401.
4.2.6. 5-Bromo-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3f). 75% yield, white solid, mp¼125e127 ꢀC; 1H
NMR (400 MHz, CDCl3)
J¼1.6 Hz, 1H), 6.81 (d, J¼8.3 Hz, 1H), 4.54 (d, J¼11.5 Hz, 1H), 4.25 (d,
d
7.51 (dd, J¼8.3, 1.6 Hz, 1H), 7.42 (d,

8120
S. Wang et al. / Tetrahedron 71 (2015) 8117e8122
J¼11.5 Hz, 1H), 3.24 (s, 3H), 3.10e3.01 (m, 1H), 2.85e2.79 (m, 1H),
2.52e2.45 (m, 1H), 2.13e2.05 (m, 1H); 13C NMR (101 MHz, CDCl3)
d
7.35e7.28 (m, 2H), 7.09 (t, J¼7.5 Hz, 2H), 4.63 (h, 7.0 Hz, 1H), 4.53
(d, J¼11.4 Hz, 1H), 4.25 (d, J¼11.4 Hz, 1H), 3.09e3.01 (m, 1H),
2.82e2.77 (m, 1H), 2.52e2.42 (m, 1H), 2.12e2.02 (m, 1H), 1.50 (d,
d
176.0, 170.6, 142.0, 133.1, 132.0, 126.8, 115.9, 110.1, 72.3, 46.2, 28.5,
27.2, 26.6. HRMS (ESI): m/z calcd for C13H12BrNNaO3 [MþNa]þ:
J¼7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 176.3, 171.1, 141.6, 131.7,
331.9893; found: 331.9898.
128.8, 123.8, 122.7, 110.3, 73.0, 45.7, 44.2, 28.7, 27.3, 19.4, 19.4. HRMS
(ESI): m/z calcd for C15H18NO3 [MþH]þ: 260.1281; found: 260.1281.
4.2.7. 1,7-Dimethyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3g). 86% yield, white solid, mp¼125e127 ꢀC; 1H
4.2.14. 1-Phenyl-40,50-dihydrospiro[indoline-3,30-pyran]-2,60(20H)-di-
NMR (400 MHz, CDCl3)
d
7.14e7.09 (m, 2H), 7.01 (t, J¼7.6 Hz, 1H),
one (3n). 75% yield, white solid, mp¼151e153 ꢀC; 1H NMR
4.52 (d, J¼11.6 Hz, 1H), 4.25 (d, J¼11.6 Hz, 1H), 3.54 (s, 3H),
(400 MHz, CDCl3)
d
7.57 (t, J¼7.6 Hz, 2H), 7.51e7.35 (m, 4H), 7.31 (t,
3.16e3.00 (m, 1H), 2.86e2.73 (m, 1H), 2.62 (s, 3H), 2.52e2.37 (m,
J¼7.8 Hz, 1H), 7.17 (t, J¼7.5 Hz, 1H), 6.92 (d, J¼7.9 Hz, 1H), 4.68 (d,
J¼11.4 Hz, 1H), 4.42 (d, J¼11.4 Hz, 1H), 3.16e3.05 (m, 1H), 2.95e2.79
(m, 1H), 2.71e2.57 (m, 1H), 2.32e2.17 (m, 1H); 13C NMR (101 MHz,
1H), 2.16e2.01 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 177.5, 171.1,
140.1, 132.8, 131.9, 123.2, 121.3, 120.3, 73.0, 45.2, 29.8, 29.0, 27.3,
19.0. HRMS (ESI): m/z calcd for C14H15NNaO3 [MþNa]þ: 268.0944;
found: 268.0946.
CDCl3)
d 176.1, 170.9, 142.9, 133.8, 131.0, 129.8, 129.0, 128.5, 126.4,
123.8, 123.7, 110.0, 72.9, 46.2, 29.1, 27.3. HRMS (ESI): m/z calcd for
C
18H15NNaO3 [MþNa]þ: 316.0944; found: 316.0944.
4.2.8. 7-Bromo-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3h). 82% yield, white solid, mp¼69e71 ꢀC; 1H NMR
4.2.15. 1-Benzyl-40,50-dihydrospiro[indoline-3,30-pyran]-2,60(20H)-di-
(400 MHz, CDCl3)
d
7.48 (d, J¼8.2 Hz,1H), 7.22 (d, J¼7.0 Hz,1H), 6.97 (t,
one (3o). 94% yield, light yellow solid, mp¼42e44 ꢀC; 1H NMR
J¼7.8 Hz, 1H), 4.53 (d, J¼11.5 Hz, 1H), 4.24 (d, J¼11.5 Hz, 1H), 3.64 (s,
(400 MHz, CDCl3)
d
7.40e7.21 (m, 7H), 7.09 (t, J¼7.5 Hz, 1H), 6.84 (d,
3H), 3.13e2.98 (m, 1H), 2.88e2.72 (m, 1H), 2.58e2.39 (m, 1H),
J¼7.8 Hz, 1H), 4.94 (s, 2H), 4.61 (d, J¼11.4 Hz, 1H), 4.33 (d, J¼11.4 Hz,
1H), 3.16e2.99 (m, 1H), 2.89e2.80 (m, 1H), 2.59e2.50 (m, 1H),
2.16e2.01 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 177.1, 170.8, 140.3,
134.7,134.4,124.4,122.5,103.0, 72.5, 45.7, 30.2, 29.0, 27.3. HRMS (ESI):
2.26e2.08 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 176.8, 170.9, 142.0,
m/z calcd for C13H12BrNNaO3 [MþNa]þ: 331.9893; found: 331.9898.
135.4, 131.0, 129.0, 129.0, 127.9, 127.3, 123.6, 123.3, 109.7, 72.8, 46.0,
43.9, 28.8, 27.3. HRMS (ESI): m/z calcd for C19H17NNaO3 [MþNa]þ:
330.1101; found: 330.1104.
4.2.9. 7-Methoxy-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3i). 83% yield, white solid, mp¼111e113 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.11e7.02 (t, J¼8.2 Hz, 1H), 6.95e6.90 (m, 2H),
4.2.16. Ethyl
3-(1-benzyl-3-(hydroxymethyl)-2-oxoindolin-3-yl)
7.41e7.15
4.53(d, J¼11.4Hz,1H), 4.24 (d, J¼11.4Hz,1H), 3.89 (s, 3H), 3.52(s, 3H),
propanoate (8o). Yellow oil, 1H NMR (400 MHz, CDCl3)
d
3.13e2.98 (m, 1H), 2.83e2.75 (m, 1H), 2.56e2.38 (m, 1H), 2.17e1.99
(m, 7H), 7.07 (t, J¼7.5 Hz, 1H), 6.76 (d, J¼7.8 Hz, 1H), 5.03e4.87 (m,
2H), 4.06e3.85 (m, 4H), 2.45e2.37 (m, 1H), 2.27e2.12 (m, 2H),
2.01e1.92 (m, 1H), 1.18 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
(m, 1H); 13C NMR (101 MHz, CDCl3)
d 176.8, 171.1, 145.6, 132.8, 130.8,
123.9, 116.0, 112.8, 72.9, 56.0, 46.0, 29.8, 28.8, 27.3. HRMS (ESI): m/z
calcd for C14H15NNaO4 [MþNa]þ: 284.0893; found: 284.0896.
d
178.6, 172.7, 143.4, 135.6, 129.1, 128.8, 128.6, 127.7, 127.2, 123.4,
122.9, 109.4, 67.2, 60.5, 54.0, 43.8, 29.2, 27.9, 14.1.
4.2.10. 5,7-Dimethoxy-1-methyl-40,50-dihydrospiro[indoline-3,30-py-
ran]-2,60(20H)-dione (3j). 78% yield, white solid, mp¼45e47 ꢀC; 1H
4.2.17. 1-Methyl-20-propyl-40,50-dihydrospiro[indoline-3,30-pyran]-
NMR (400 MHz, CDCl3)
d
6.50 (d, J¼2.2 Hz, 1H), 6.47 (d, J¼2.2 Hz,
2,60(20H)-dione (3p). 74% yield, d.r.¼1.1:1. Major; Colorless oil, 1H
1H), 4.53 (d, J¼11.5 Hz, 1H), 4.24 (d, J¼11.5 Hz, 1H), 3.87 (s, 3H), 3.80
(s, 3H), 3.47 (s, 3H), 3.11e3.01 (m,1H), 2.83e2.74 (m,1H), 2.52e2.40
NMR (400 MHz, CDCl3)
d
7.36 (dt, J¼7.6, 1.2 Hz, 1H), 7.21e7.04 (m,
2H), 6.90 (d, J¼7.8 Hz, 1H), 4.56 (dd, J¼10.4, 1.8 Hz, 1H), 3.30e3.11
(m, 4H), 2.79e2.70 (m, 1H), 2.39e2.29 (m, 1H), 2.15e2.03 (m, 1H),
1.59e1.44 (m, 2H), 0.96e0.84 (m, 2H), 0.76 (t, J¼7.3 Hz, 3H); 13C
(m,1H), 2.12e2.02 (m,1H); 13C NMR (101 MHz, CDCl3)
d 176.6,171.4,
157.2, 146.3, 133.5, 124.2, 100.9, 100.1, 72.8, 55.9, 55.9, 46.5, 29.7,
28.9, 27.4. HRMS (ESI): m/z calcd for C15H18NO5 [MþH]þ: 292.1180;
found: 292.1182.
NMR (101 MHz, CDCl3)
d 176.1, 170.3, 143.6, 129.9, 129.1, 123.0,
122.0, 108.6, 83.1, 48.2, 32.4, 29.1, 26.4, 26.1, 18.8, 13.4. HRMS (ESI):
m/z calcd for C16H20NO3 [MþH]þ: 274.1438; found: 274.1440. Mi-
4.2.11. 4,5,50,60-Tetrahydrospiro[pyran-3,10-pyrrolo[3,2,1-ij]quino-
nor; Colorless oil, 1H NMR (400 MHz, CDCl3)
d
7.36 (dt, J¼7.6,
line]-20,6(2H,40H)-dione
(3k). 86%
yield,
white
solid,
1.2 Hz, 1H), 7.22 (d, J¼7.6 Hz, 1H), 7.10 (t, J¼7.6 Hz, 1H), 6.93 (d,
J¼7.6 Hz, 1H), 4.65 (dd, J¼10.0, 2.4 Hz, 1H), 3.25 (s, 3H),3.02e2.92
(m, 1H), 2.82e2.74 (m, 1H), 2.64e2.49 (m, 1H), 1.94e1.87 (m, 1H),
1.35e1.28 (m, 1H), 1.22e1.07 (m, 1H), 1.00e0.84 (m, 2H), 0.78 (t,
mp¼147e149 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.19e7.08 (m, 2H),
7.01 (t, J¼7.6 Hz, 1H), 4.59 (d, J¼11.3 Hz, 1H), 4.27 (d, J¼11.3 Hz, 1H),
3.76 (t, J¼5.8 Hz, 2H), 3.13e2.95 (m, 1H), 2.87e2.79 (m, 3H),
2.56e2.49 (m, 1H), 2.15e1.98 (m, 3H); 13C NMR (101 MHz, CDCl3)
J¼7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 177.0, 171.8, 143.3,
d
175.2, 170.8, 138.7, 129.7, 127.9, 122.7, 121.4, 120.8, 72.9, 47.4, 39.1,
129.5, 128.8, 124.5, 123.2, 108.6, 82.4, 50.4, 32.7, 29.7, 27.2, 26.4,
18.6, 13.6.
28.3, 27.3, 24.5, 21.0. HRMS (ESI): m/z calcd for C15H16NO3 [MþH]þ:
258.1125; found: 258.1126.
4.2.18. 20-Isopropyl-1-methyl-40,50-dihydrospiro[indoline-3,30-py-
4.2.12. 1-Methyl-40,50-dihydrospiro[benzo[g]indole-3,30-pyran]-
ran]-2,60(20H)-dione (3q). 68% yield, d.r.¼1.2:1. Major, white solid,
2,60(1H,20H)-dione (3l). 63% yield, yellow oil; 1H NMR (400 MHz,
mp¼103e106 ꢀC; 1H NMR (400 MHz, CDCl3)
7.35 (td, J¼7.7, 1.6 Hz,
d
CDCl3)
d
7.84 (dd, J¼8.0, 1.2 Hz 1H), 7.68e7.44 (m, 4H), 7.07 (d,
1H), 7.20e7.07 (m, 2H), 6.90 (d, J¼7.7 Hz, 1H), 4.54 (d, J¼3.7 Hz, 1H),
3.33e3.13 (m, 4H), 2.89e2.67 (m, 1H), 2.41e2.21 (m, 1H), 2.14e1.91
(m, 1H), 1.76e1.52 (m, 1H), 0.85 (d, J¼6.7 Hz, 3H), 0.77 (d, J¼7.0 Hz,
J¼7.8 Hz, 1H), 4.88 (d, J¼11.6 Hz, 1H), 4.43 (d, J¼11.6 Hz, 1H), 3.59 (s,
3H), 3.15e2.99 (m, 1H), 2.98e2.83 (m, 1H), 2.75e2.70 (m, 1H),
2.37e2.20 (m, 1H); 13C NMR (101 MHz, CDCl3)
d
172.4, 170.4, 136.2,
3H); 13C NMR (101 MHz, CDCl3)
d 176.4, 170.6, 143.3, 130.2, 129.0,
135.3, 133.4, 127.4, 127.3, 126.7, 123.6, 123.1, 118.8, 109.4, 75.4, 45.6,
34.0, 30.2, 28.8. HRMS (ESI): m/z calcd for C17H16NO3 [MþH]þ:
282.1125; found: 282.1128.
123.0, 122.0, 108.6, 87.8, 47.5, 30.8, 29.8, 26.3, 26.2, 21.1, 16.6. HRMS
(ESI): m/z calcd for C16H20NO3 [MþH]þ: 274.1438; found: 274.1440.
Minor, white solid, mp¼108e110 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.37 (t, J¼8.2 Hz, 1H), 7.27 (d, J¼7.5 Hz, 1H), 7.11 (t, J¼7.4 Hz, 1H),
4.2.13. 1,3-Dimethyl-3-(3-(naphthalen-2-yl)-3-oxopropyl)indolin-2-
6.94 (d, J¼7.8 Hz, 1H), 4.45 (d, J¼8.1 Hz, 1H), 3.25 (s, 3H), 3.01e2.93
(m, 1H), 2.80e2.68 (m, 1H), 2.51e2.44 (m, 1H), 1.90e1.77 (m, 1H),
one (3m). 90% yield, yellow oil; 1H NMR (400 MHz, CDCl3)

S. Wang et al. / Tetrahedron 71 (2015) 8117e8122
8121
1.68e1.61 (m, 1H), 0.89 (d, J¼6.6 Hz, 3H), 0.56 (d, J¼6.8 Hz, 3H); 13
C
45.7, 44.8, 31.4, 26.5, 14.1. HRMS (ESI): m/z calcd for C16H17NNaO5
[MþNa]þ: 326.0999; found: 326.1004.
NMR (101 MHz, CDCl3) d 177.6, 171.8,143.0,129.6,128.9,124.7,123.1,
108.7, 87.2, 49.7, 31.9, 30.9, 27.2, 26.5, 19.3, 18.3.
Acknowledgements
4.2.19. 20-Cyclohexyl-1-methyl-40,50-dihydrospiro[indoline-3,30-py-
ran]-2,60(20H)-dione (3r). 67% yield, d.r.¼1.4:1. Major, white solid,
The authors thank the National Natural Science Foundation of
China (No. 81172915) for financial support.
mp¼129e131 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.36 (td, J¼7.8, 1.9 Hz,
1H), 7.18e7.07 (m, 2H), 6.90 (d, J¼7.8 Hz, 1H), 4.51 (d, J¼3.9 Hz, 1H),
3.23 (s, 3H), 3.22e3.11 (m, 1H), 2.82e2.67 (m, 1H), 2.39e2.27 (m,
1H), 2.08e2.00 (m, 1H), 1.63 (d, J¼10.4 Hz, 2H), 1.49e1.47 (m, 1H),
1.42e1.29 (m, 2H), 1.20e1.13 (m, 3H),1.01e0.94 (m, 3H); 13C NMR
Supplementary data
Supplementary data (The original data of 1H NMR and 13C NMR
of all products are supplied. The supplementary data files are to be
used as an aid for the refereeing of the paper only.) associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2015.08.039.
(101 MHz, CDCl3)
d 176.5, 170.6, 143.2, 130.3, 128.9, 122.9, 122.0,
108.6, 87.6, 47.3, 39.7, 31.1, 30.6, 27.1, 26.3, 26.2, 25.8, 25.7. HRMS
(ESI): m/z calcd for C19H24NO3 [MþH]þ: 314.1751; found: 314.1775.
Minor, yellow oil; 1H NMR (400 MHz, CDCl3)
d 7.43e7.34 (m, 1H),
7.29e7.24 (m, 1H), 7.11 (t, J¼7.7 Hz, 1H), 6.93 (d, J¼7.7 Hz, 1H), 4.51
(d, J¼8.0 Hz, 1H), 3.25 (s, 3H), 2.99e2.91 (m, 1H), 2.81e2.64 (m, 1H),
2.48e2.40 (m, 2H), 1.84e1.75 (m, 1H), 1.52e1.49 (m, 2H), 1.02e1.00
References and notes
(m, 4H), 0.91e0.88 (m, 4H); 13C NMR (101 MHz, CDCl3)
d 177.6,
1. For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127; (b)
Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36; (c) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209; (d) Galliford, C. V.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 8748; (e) Yang, J.; Wearing, X. Z.; Le Quesne, P.
W.; Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2008, 71, 1431; (f) Badillo, J. J.;
Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug Discov. Dev. 2010, 13, 758; (g) Zhou,
F.; Liu, Y. L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381; (h) Santos, M. M. M.
Tetrahedron 2014, 70, 9735; (i) Song, R. J.; Liu, Y.; Xie, Y. X.; Li, J. H. Synthesis
2015, 47, 1195.
2. (a) Shia, K.; Li, W.; Chang, C.; Hsu, C. J.; Leong, M. K.; Tseng, S.; Lee, C.; Lee, Y.;
Chen, S.; Peng, K.; Tseng, H.; Chang, Y.; Tai, C.; Shih, S. J. Med. Chem. 2002, 45,
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Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.;
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Gong, L. Z. Org. Lett. 2010, 12, 1008; (e) Zhao, Y.; Liu, L.; Sun, W.; Lu, J.;
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171.8, 142.8, 129.7, 128.8, 124.6, 123.1, 108.8, 86.5, 49.5, 40.2, 32.1,
29.0, 27.9, 27.2, 26.5, 25.9, 25.8, 25.4.
4.2.20. 1,50-Dimethyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3t). 84% yield, d.r.¼1.2:1. Major, yellow solid,
mp¼95e97 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.42e7.29 (m, 2H), 7.12
(t, J¼7.6 Hz, 1H), 6.90 (d, J¼7.8 Hz, 1H), 4.61 (d, J¼11.3 Hz, 1H), 4.14
(d, J¼11.3 Hz, 1H), 3.25 (s, 3H), 3.23e3.12 (m, 1H), 2.56 (dd, J¼14.1,
6.7 Hz, 1H), 1.88e1.75 (m, 1H), 1.31 (d, J¼6.7 Hz, 3H); 13C NMR
(101 MHz, CDCl3)
d 176.9, 175.4, 142.6, 133.1, 128.8, 123.5, 123.4,
108.5, 71.8, 47.5, 37.2, 32.7, 26.5, 15.3. HRMS (ESI): m/z calcd for
C
14H15NNaO3 [MþNa]þ: 268.0944; found: 268.0946. Minor, yellow
oil; 1H NMR (400 MHz, CDCl3)
d
7.43e7.31 (m, 2H), 7.13 (t, J¼7.5 Hz,
1H), 6.94 (d, J¼7.8 Hz,1H), 4.52 (d, J¼11.5 Hz,1H), 4.32 (d, J¼11.5 Hz,
1H), 3.26 (s, 3H), 3.10e2.92 (m, 1H), 2.33e2.27 (m, 1H), 2.17e2.03
(m, 1H), 1.49e1.36 (d, J¼6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
176.6, 173.2, 143.1, 130.1, 129.2, 123.6, 122.9, 108.6, 72.5, 46.8, 36.7,
32.6, 26.6, 16.8.
4.2.21. 50-Ethyl-1-methyl-40,50-dihydrospiro[indoline-3,30-pyran]-
2,60(20H)-dione (3u). 72% yield, d.r.¼1.4:1; The mixture of isomers
cannot be separated by column chromatography on silica gel. Yel-
low oil; Major diastereoisomer, 1H NMR (400 MHz, CDCl3)
4. (a) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49,
846; (b) Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song,
M. P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200; (c) Hari
Babu, T.; Abragam Joseph, A.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett.
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2852; (f) Yang, L. H.; Xie, P. Z.; Li, E. Q.; Li, X.; Huang, Y.; Chen, R. Y. Org. Biomol.
Chem. 2012, 10, 7628.
d
7.39e7.24 (m, 2H), 7.13e7.06 (m, 1H), 6.89 (d, J¼7.8 Hz, 1H), 4.54
(d, J¼11.3 Hz,1H), 4.09 (d, J¼11.3 Hz,1H), 3.23 (s, 3H), 3.02e2.76 (m,
1H), 2.58e2.52 (m, 1H), 2.09e1.93 (m, 1H), 1.81e1.68 (m, 1H),
1.59e1.48 (m, 1H), 1.01 (m, 3H); 13C NMR (101 MHz, CDCl3)
d 176.9,
5. Castaldi, M. P.; Troast, D. M.; Porco, J. A. Org. Lett. 2009, 11, 3362.
174.7, 142.6, 133.0, 128.8, 123.7, 123.4, 108.5, 71.5, 47.4, 38.8, 34.7,
26.5, 23.2, 11.3. HRMS (ESI): m/z calcd for C15H17NNaO3 [MþNa]þ:
282.1101; found: 282.1103.
6. (a) Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S. J. J. Comb. Chem. 2010, 12, 231; (b)
Gu, Y. L. Green. Chem. 2012, 14, 2091; (c) Liu, Y.; Wang, H.; Wan, J. Asian J. Org.
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RSC Adv. 2013, 3, 10875; (e) Chen, X. B.; Liu, X. M.; Huang, R.; Yan, S. J.; Lin, J. Eur.
ꢀ
4.2.22. 1,50,50-Trimethyl-40,50-dihydrospiro[indoline-3,30-pyran]-
J. Org. Chem. 2013, 4607; (f) Lopez-Alvarado, P.; Steinhoff, J.; Miranda, S.;
~
ꢀ
Avendano, C.; Menendez, J. C. Tetrahedron 2009, 65, 1660.
2,60(20H)-dione (3v). 38% yield, light yellow oil; 1H NMR (400 MHz,
7. For selected reviews of azaspirooxindoles, see: (a) Ready, J. M.; Reisman, S. E.;
Hirata, M.; Weiss, M. M.; Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int.
Ed. 2004, 43, 1270; (b) Rehn, S.; Bergman, J.; Stensland, B. Eur. J. Org. Chem. 2004,
413; (c) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.;
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Wang, S. J. Am. Chem. Soc. 2005, 127, 10130; (d) Bella, M.; Kobbelgaard, S.;
JØrgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670; (e) Chen, X. H.; Wei, Q.; Luo,
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M. Chem. Commun. 2013, 8842; (g) Huang, Y. M.; Zheng, C. W.; Zhao, G. RSC Adv.
2013, 3, 16999; (h) Badillo, J. J.; Riberiro, C. J. A.; Olmstead, M. M.; Franz, A. K.
Org. Lett. 2014, 16, 6270; (i) Xu, J.; Shao, L. D.; Li, D. S.; Liu, Y. C.; Zhao, Q. S.; Xia,
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Liu, H. Chem. Commun. 2014, 14771.
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Asaumi, T.; Amako, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122,
12663; (b) Nair, V.; Biju, A. T.; Vinod, A. U.; Suresh, E. Org. Lett. 2005, 7, 5139; (c)
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CDCl3)
d
7.36 (td, J¼7.8, 1.1 Hz, 1H), 7.30 (d, J¼7.8 Hz, 1H), 7.11 (td,
J¼7.6, 1.1 Hz, 1H), 6.91 (d, J¼7.8 Hz, 1H), 4.64 (d, J¼11.2 Hz, 1H), 4.24
(d, J¼11.2 Hz, 1H), 3.25 (s, 3H), 2.44 (d, J¼14.4 Hz, 1H), 2.02 (d,
J¼14.4 Hz, 1H), 1.58 (s, 3H), 1.44 (s, 3H). HRMS (ESI): m/z calcd for
C
15H17NNaO3 [MþNa]þ: 282.1101; found: 282.1103.
4.2.23. Ethyl
1-methyl-2,60-dioxo-20,40,50,60-tetrahydrospiro[indo-
line-3,30-pyran]-50-car-Boxylate (3w). 84% yield, d.r.¼3:1; The
mixture of isomers cannot be separated by column chromatogra-
phy on silica gel. Yellow oil; Major diastereoisomer, 1H NMR
(400 MHz, CDCl3) d 7.43e7.29 (m, 2H), 7.16e7.11 (m, 1H), 6.96e6.89
(m, 1H), 4.46 (d, J¼11.6 Hz, 1H), 4.35e4.24 (m, 3H), 3.25 (s, 3H),
2.68e2.50 (m, 2H), 1.34 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
176.6, 168.2, 167.9, 142.9, 130.7, 129.3, 123.7, 123.5, 108.7, 72.4, 62.1,

8122
S. Wang et al. / Tetrahedron 71 (2015) 8117e8122
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