Formal [4 + 2] Annulation of Oxindole-Embedded ortho-Quinone Methides with 1,3-Dicarbonyls: Synthesis of Spiro[Chromen-4,3′-Oxindole] Scaffolds

Article abstract of DOI:10.1021/acs.joc.8b03260

The oxindole-embedded ortho-quinone methides were employed as reactive intermediates in formal [4 + 2] annulation with 1,3-dicarbonyls, providing an efficient access to spiro[chromen-4,3′-oxindole] scaffolds via a cascade conjugate addition/ketalization/d

Full text of DOI:10.1021/acs.joc.8b03260

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Article
Formal [4 + 2] Annulation of Oxindole-Embedded ortho-Quinone Methides
with 1,3-Dicarbonyls: Synthesis of Spiro[Chromen-4,3´-Oxindole] Scaffolds
Yao-Bin Shen, Shuai-Shuai Li, Yun-Ming Sun, Xicheng Liu, Liping Yu, Qing Liu, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Feb 2019
Downloaded from http://pubs.acs.org on February 19, 2019
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Formal [4 + 2] Annulation of Oxindole-Embedded
ortho-Quinone Methides with 1,3-Dicarbonyls: Synthesis of
Spiro[Chromen-4,3´-Oxindole] Scaffolds
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Yao-Bin Shen,† Shuai-Shuai Li,† Yun-Ming Sun,*,† Xicheng Liu,§ Liping Yu,† Qing Liu,┴ Jian
Xiao*,†,‡
† College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
‡ College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
§ College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China
┴ College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao
266590, China.
Corresponding author: Yun-Ming Sun, Jian Xiao
E-mail address: sunymtch@163.com； chemjianxiao@163.com
Graphic Abstract
Abstract: The oxindole-embedded ortho-quinone methides, in situ generated from
oxindole-embedded ortho-hydroxybenzyl alcohols, were employed as reactive intermediates in
formal [4
+ 2] annulation with 1,3-dicarbonyls, providing an efficient access to
spiro[chromen-4,3´-oxindole] scaffolds via a cascade conjugate addition/ketalization/dehydration
process. This protocol featured metal-free conditions, wide substrate scope and excellent yields.
INTRODUCTION
Spirooxindoles and 4H-chromenes are privileged skeletons in an array of natural products and
pharmaceutical agents (Figure 1).1-2 Due to their structural complexities and diverse bioactivities,
considerable efforts have been devoted to assembling these frameworks.3-4 According to the
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Figure 1. Natural products and bioactive compounds containing the spirooxindole or
4H-chromene core.
principle of superposition in drug discovery, incorporation of these two motifs would provide
potential bioactivity from spiro[chromen-4,3´-oxindole] scaffolds (Scheme 1a). So far, although
spirooxindoles have been successfully hybridized with various heterocyclic rings,3 there are
sporadic reports related to the synthesis of spiro[chromen-4,3´-oxindole] scaffolds. And the
limited examples were realized by cascade [3 + 3] annulation-type reactions (Scheme 1b).5
Therefore, it is appealing to develop new methods for efficient construction of these intriguing
molecules.
Scheme 1. Synthesis of Spiro[Chromen-4,3´-Oxindole] Scaffolds.
ortho-Quinone methides (o-QMs) have emerged as highly reactive synthons for the synthesis of
complex molecules and naturally occurring products, especially for chromanes and related
analogues.6 Owing to their inherent tendency of rearomatization, o-QMs have been commonly
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exploited as electron-deficient species to participate in conjugate addition7 and [4 + n] cyclization
reactions.8-10 In spite of these significant progresses, to the best of our knowledge, there are no
examples of o-QMs-involved reactions for one-pot assembly of spiro[chromen-4,3´-oxindole]
scaffolds. In this context, we envisaged the introduction of an oxindole unit into the o-QMs would
furnish a new class of oxindole-embedded o-QMs, which could undertake a formal [4 + 2]
annulation with 1,3-dicarbonyls for rapid buildup of spiro[chromen-4,3´-oxindole] skeletons via a
cascade conjugate addition/ketalization/dehydration sequence. As our continuing interest in the
one-step assembly of molecular complexity,11 herein, we reported a formal [4 + 2] annulation of in
situ generated oxindole-embedded o-QMs with 1,3-dicarbonyls for one-pot synthesis of
spiro[chromen-4,3´-oxindole] compounds (Scheme 1c). This reaction featured metal-free
conditions, wide substrate scope and high yields.
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RESULTS AND DISCUSSION
To test the feasibility of our proposal, we commenced our investigations with the reaction
between oxindole-embedded ortho-hydroxybenzyl alcohol 1a and 1,3-cyclohexanedione 2a
(Table 1). To our delight, the reaction proceeded smoothly and delivered the desired product 3aa
in 94% yield when 10 mol % of trifluoromethanesulfonic acid (TfOH) was used as the catalyst in
DCE at 80 °C (Table 1, entry 1). Then a series of Brønsted acids were screened, such as
p-toluenesulfonic acid monohydrate (TsOH·H2O), methanesulfonic acid (MsOH) and
trifluoroacetic acid (TFA). However, all of them led to inferior results (Table 1, entries 2-7).
Afterwards, Lewis acids were evaluated and it was found that Sc(OTf)3 also exhibited a high
efficiency to furnish 3aa in 93% yield (Table 1, entries 8 and 9). Subsequently, decreasing the
catalyst loading to 5 mol % resulted in a diminished yield (Table 1, entry 10). Finally, the
exploration of solvents such as THF, toluene and MeCN indicated that DCE was the best solvent
(Table 1, entries 11-13). Consequently, TfOH was selected as the best catalyst to catalyze this
reaction in DCE.
With the optimized conditions in hand, the substrate scope and generality of the developed
formal [4 + 2] annulation were evaluated. At first, a wide range of oxindole-embedded
ortho-hydroxybenzyl alcohols 1 bearing various substituents were subjected to the reactions with
1,3-cyclohexanedione 2a, which proceeded efficiently and afforded the corresponding
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Table 1. Optimization of the Reaction Conditionsa
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entry
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catalyst
TfOH
TsOH·H2O
MsOH
TFA
(−)-CSA
PhCO2H
HOAc
Sc(OTf)3
Cu(OTf)2
TfOH
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
yield b (%)
94
77
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14
<10
93
86
85
9
10c
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TfOH
TfOH
TfOH
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83
toluene
MeCN
aReaction conditions: 1a (0.1 mmol), 2 (0.12 mmol) and catalyst (10 mol %) in solvent (1 mL) at 80 °C for 8 h.
TfOH
=
trifluoromethanesulfonic acid, TsOH·H2O
=
p-toluenesulfonic acid monohydrate, MsOH =
b
methanesulfonic acid, TFA = trifluoroacetic acid, (–)-CSA = (–)-10-camphorsulfonic acid. Isolated yield after
column chromatography. cCatalyst (5 mol %), 24 h.
spiro[chromen-4,3´-oxindole] products in good to excellent yields (Table 2). With respect to the
R1 groups, electron-donating methoxy and methyl groups were well tolerated and furnished the
desired products 3ba and 3ca in 88% and 95% yields, respectively. Moreover,
electron-withdrawing halogens (fluoro, chloro, and bromo) at different positions had negligible
influence on the transformations, giving the expected products 3da-3ja in 67-94% yields. It is
noted that the decreased yield of 3ha might be ascribed to the steric hindrance of in situ generated
oxindole-embedded o-QM intermediate. Remarkably, the substrate incorporating the stronger
electron-withdrawing nitro group was also an ideal candidate and delivered product 3ka in 88%
yield, which could hardly be realized in previously reported o-QMs-involved reactions. It was
worth mentioning that the achievement of fluorine- and nitro-containing substrates indicated the
great potential in the medicinal industry. With regard to the R2 groups, in addition to methyl and
ethyl groups, the allyl and propargyl substituents functioned efficiently, providing the desired
products 3la-3oa in 85-97% yields. Notably, the alcohols carrying highly strained cyclopropyl and
cyclopropylmethyl groups also worked well and produced the products 3pa and 3qa in 94% and
92% yields, correspondingly. Moreover, the substrate without a protecting group was examined
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and afforded product 3ra in 85% yield. As to the R3 group, satisfyingly, the oxindole-embedded
ortho-naphthoquinone methide was tolerable and gave the corresponding product 3sa in 73%
yield.
Table 2. Substrate Scope of Oxindole-Embedded ortho-Hydroxybenzyl Alcohols 1a
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aReaction conditions: 1 (0.1 mmol), 2a (0.12 mmol) and TfOH (10 mol %) in DCE (1 mL) at 80 °C for 8 h.
Isolated yield after column chromatography. bTfOH (20 mol %), 12 h. c24 h.
Next, the substrate scope of 1,3-dicarbonyls 2 was further examined, as shown in Table 3.
Substituted 1,3-cyclohexanediones were fully compatible with the reaction conditions, yielding
3ab and 3ac in 97% and 90% yields, respectively. Notably, other 1,3-dicarbonyls such as
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1,3-cyclopentanedione, 2,4-pentanedione and 1,3-diphenyl-1,3-propanedione are also good
reaction partners for this reaction, delivering products 3ad-3af in 75-93% yields. Gratifyingly, the
employment of benzyl acetoacetate and ethyl benzoylacetate could proudce products 3ag and 3ah
in moderate yields.
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Table 3. Substrate Scope of 1,3-Dicarbonyls 2a
aReaction conditions: 1a (0.1 mmol), 2 (0.12 mmol) and TfOH (10 mol %) in DCE (1 mL) at 80 °C for 8 h.
Isolated yield after column chromatography. b3 h. cTfOH (20 mol %).
To substantiate the practicality of this protocol, the formal [4 + 2] annulation of 1p with 2a was
performed on a gram scale, which reacted smoothly and gave spiro[chromen-4,3´-oxindole] 3pa in
95% yield (Scheme 2).
Scheme 2. Gram-Scale Synthesis
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On the basis of the above experimental results, a plausible mechanism was proposed, as shown
in Scheme 3. Under the catalysis of Brønsted acid, the oxindole-embedded o-QM intermediate A
is in situ generated via the dehydration of oxindole-embedded ortho-hydroxybenzyl alcohol 1a. At
the same time, 1,3-cyclohexanedione 2a tautomerizes to the enol species 2a´. Then the conjugate
addition of 2a´ to intermediate A occurs and affords intermediate B, which subsequently
undertakes the intramolecular ketalization to provide intermediate C. Finally, Brønsted
acid-catalyzed dehydration of C gives the desired product 3aa. Intriguingly, intermediates A and
C have been isolated and characterized by NMR, which fully proves this hypothesis.
Scheme 3. Proposed Mechanism
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CONCLUSION
In summary, the oxindole-embedded o-QMs, in situ generated from oxindole-embedded
ortho-hydroxybenzyl alcohols, were designed as reactive intermediates in formal [4 + 2]
annulation with 1,3-dicarbonyls, which offered an efficient route to pharmaceutically important
spiro[chromen-4,3´-oxindole] scaffolds via a domino conjugate addition/ketalization/dehydration
process. This method featured metal-free conditions, wide substrate scope and excellent yields,
which exhibited promising prospects in organic synthesis and drug discovery.
Experimental Section
All commercially available reagents, unless otherwise indicated, were used without further
purification. All solvents were purified and dried according to standard methods prior to use.
Reactions were monitored by thin layer chromatography (TLC) with 0.2 mm silica gel-coated
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HSGF 254 plates, visualized by UV light at 254 or 365 nm. Products were isolated and purified by
column chromatography on 200-300 mesh silica gel. 1H, 13C, and 19F NMR spectra were recorded
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on a Bruker AMX 500 (500 MHz for H NMR, 125 MHz for 13C NMR and 470 MHz for 19F
9
NMR) spectrometer at room temperature. The chemical shifts (δ) were reported in ppm with
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1
respect to an internal standard, tetramethylsilane (0 ppm), and the solvent (CDCl3, H: δ = 7.26
ppm, 13C: δ = 77.16 ppm). Coupling constants (J) are given in Hertz. Splitting patterns of apparent
multiplets associated with an averaged coupling constants were designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br (broadened). All
13C spectra were recorded with broadband proton decoupling. HRMS were performed on a Waters
XEVO QTOF mass spectrometer.
General Procedure for the Synthesis of Oxindole-Embedded ortho-Hydroxybenzyl Alcohols
1.12
A round-bottom flask was charged with isatin (1 mmol), phenol (3 mmol) and H2O (6 mL). The
reaction mixture was stirred vigorously at room temperature and monitored by TLC. After the
consumption of isatin, the reaction mixture was extracted with ethyl acetate, and the combined
organic layers were dried over anhydrous Na2SO4. The solvent was concentrated under reduced
pressure, and the residue was purified by flash column chromatography (column chromatography
eluent, petroleum ether/ EtOAc = 8:1) to afford products 1. For the new compounds 1e, 1g, 1h, 1j,
1k, 1m, 1p and 1q, they have been characterized as follows.
General Procedure for Formal [4
+
2] Annulation of Oxindole-Embedded
ortho-Hydroxybenzyl Alcohols 1 with 1,3-Dicarbonyls 2.
An oven-dried reaction tube was charged with oxindole-embedded ortho-hydroxybenzyl
alcohols 1 (1.0 equiv, 0.1 mmol), 1,3-dicarbonyls 2 (1.2 equiv, 0.12 mmol), DCE (1 mL) and
TfOH (10 mol %). The reaction mixture was stirred vigorously at 80 °C in oil bath for appropriate
time and monitored by TLC. After the consumption of 1, the reaction mixture was concentrated
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under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc) to afford products 3.
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General Procedure for Gram-Scale Synthesis of 3pa.
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An oven-dried round-bottomed flask was charged with oxindole-embedded
ortho-hydroxybenzyl alcohol 1p (3.0 mmol, 1017 mg), 1,3-dicarbonyl 2a (3.6 mmol, 403 mg),
DCE (30 mL) and TfOH (0.3 mol, 45 mg). The reaction mixture was stirred vigorously at 80 °C in
oil bath for 8 h, and monitored by TLC. After the consumption of 1p, the reaction mixture was
concentrated under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc = 6:1) to afford product 3pa as white solid in 95%
yield (1180 mg).
1-benzyl-7-fluoro-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1e). White
solid; 358 mg, 91% yield; mp 124‒126 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 7.29–7.20 (m, 6H), 7.11–6.98 (m,
2H), 6.50 (s, 1H), 6.25 (s, 1H), 5.85 (s, 2H), 4.99 (s, 2H), 4.87 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 179.0, 151.7, 148.9, 147.8 (d, J = 244.6 Hz), 141.5, 136.0, 132.3, 129.0 (d, J = 8.8 Hz),
128.8 (2C), 127.8, 127.3 (2C), 124.8 (d, J = 6.3 Hz), 121.8, 118.5 (d, J = 19.4 Hz), 116.7, 106.5,
101.5 (comb, 2C), 79.1, 45.8 (d, J = 4.5 Hz); 19F NMR (470 MHz, CDCl3) δ –132.6; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C22H17FNO5 394.1085; found 394.1086.
1-benzyl-6-chloro-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1g). White
solid; 364 mg, 89% yield; mp 120‒122 °C; column chromatography eluent, petroleum
1
ether/EtOAc = 8:1; H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 7.38–7.22 (m, 6H), 7.12 (d, J =
7.7 Hz, 1H), 6.76 (s, 1H), 6.55 (s, 1H), 6.29 (s, 1H), 5.88 (s, 2H), 4.90 (d, J = 15.8 Hz, 1H), 4.79
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(d, J = 15.8 Hz, 1H), 4.68 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.2, 151.7, 149.0, 143.6,
141.6, 136.2, 134.3, 129.1 (2C), 128.1, 127.7, 127.1 (2C), 126.9, 123.9, 116.7, 110.8, 106.5, 101.7,
101.6, 78.7, 44.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H17ClNO5 410.0790; found
410.0795.
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1-benzyl-4-bromo-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1h). White
solid; 408 mg, 90% yield; mp 129‒131 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 7.28 (m, 4H), 7.22 (d, J = 7.3 Hz,
2H), 7.14 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 6.21 (s, 1H), 5.90 (s, 1H), 5.87
(s, 1H), 4.88 (d, J = 15.8 Hz, 1H), 4.82 (d, J = 15.8 Hz, 1H), 4.37 (s, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ177.8, 152.5, 149.2, 144.5, 141.4, 134.4, 131.7, 129.0 (2C), 128.0, 127.9, 127.7,
127.1 (2C), 120.8, 113.7, 109.2, 106.7, 101.6, 101.5, 80.5, 44.2; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H17BrNO5 454.0285; found 454.0283.
1-benzyl-6-bromo-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1j). White
solid; 381 mg, 84% yield; mp 116‒118 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 7.32 (m, 5H), 7.24 (m, 2H), 6.93
(s, 1H), 6.62 (s, 1H), 6.27 (s, 1H), 5.90 (s, 1H), 5.89 (s, 1H), 4.91 (d, J = 15.8 Hz, 1H), 4.82 (d, J =
15.8 Hz, 1H), 4.44 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.2, 152.0, 149.2, 143.7, 141.7,
134.2, 129.1 (2C), 128.2, 127.9, 127.4, 127.1 (2C), 126.9, 124.1, 116.9, 113.7, 106.6, 102.2, 101.6,
78.9, 44.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H17BrNO5 454.0285; found 454.0291.
1-benzyl-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-5-nitroindolin-2-one (1k). Yellow
solid; 365 mg, 87% yield; mp 140‒142 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.03 (s,
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1H), 7.32 (m, 3H), 7.25 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.56 (s, 1H), 6.42 (s, 1H), 5.92 (s, 2H),
5.00 (d, J = 15.8 Hz, 1H), 4.93 (d, J = 15.8 Hz, 1H), 4.46 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 179.1, 150.9, 149.3, 144.3, 142.0, 133.8, 130.4, 130.3, 129.2, 128.4, 127.2, 127.1, 121.7,
116.3, 109.9, 106.2, 101.8, 101.7, 78.1, 44.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H17N2O7 421.1030; found 421.1034.
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1-ethyl-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1m). White solid; 297
mg, 95% yield; mp 119‒121 °C; column chromatography eluent, petroleum ether/EtOAc = 8:1; 1H
NMR (500 MHz, CDCl3) δ 9.37 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.18 (t,
J = 7.5 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 6.25 (s, 1H), 5.86 (s, 1H), 5.84 (s, 1H),
4.63 (s, 1H), 3.73 (qq, J = 14.3, 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 178.7, 152.3, 148.8, 142.2, 141.3, 130.4, 129.4, 126.2, 123.8, 117.1, 109.4, 106.8, 101.8,
101.4, 79.3, 35.2, 12.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H16NO5 314.1023; found
314.1026.
1-(cyclopropylmethyl)-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one
(1p).
White solid; 305 mg, 90% yield; mp 108‒110 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 9.38 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.39 (t, J
= 7.8 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 6.26 (s, 1H), 5.86 (s,
1H), 5.84 (s, 1H), 4.68 (s, 1H), 3.60 (dd, J = 14.5, 6.9 Hz, 1H), 3.52 (dd, J = 14.5, 7.0 Hz, 1H),
1.21–1.10 (m, 1H), 0.58–0.48 (m, 2H), 0.42–0.31 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
179.0, 152.3, 148.8, 142.8, 141.3, 130.3, 129.4, 126.1, 123.8, 117.1, 109.7, 106.7, 101.7, 101.4,
79.3, 44.8, 9.4, 4.0, 4.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NO5 340.1179; found
340.1180.
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1-cyclopropyl-3-hydroxy-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)indolin-2-one (1q). White
solid; 299 mg, 92% yield; mp 108‒110 °C; column chromatography eluent, petroleum
ether/EtOAc = 8:1; 1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 7.42 (m, 2H), 7.18 (m, 2H), 6.55
(s, 1H), 6.21 (s, 1H), 5.86 (s, 1H), 5.84 (s, 1H), 4.53 (s, 1H), 2.69–2.60 (m, 1H), 1.12–1.00 (m,
2H), 0.96–0.84 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 180.0, 152.2, 148.8, 143.6, 141.3,
130.4, 128.6, 125.9, 123.9, 117.2, 110.5, 106.8, 101.8, 101.4, 79.3, 22.5, 6.0, 6.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H16NO5 326.1023; found 326.1020.
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1-benzyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione
(3aa). White solid; 42.4 mg, 94% yield; mp 237–239 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.4 Hz, 2H), 7.37 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.15‒7.07 (m, 1H), 6.94–6.85 (m, 2H), 6.74 (d, J = 7.8 Hz,
1H), 6.59 (s, 1H), 6.00 (s, 1H), 5.86 (d, J = 1.2 Hz, 1H), 5.84 (d, J = 1.2 Hz, 1H), 5.09 (d, J = 15.7
Hz, 1H), 5.00 (d, J = 15.7 Hz, 1H), 2.83–2.67 (m, 2H), 2.48–2.29 (m, 2H), 2.17–2.08 (m, 1H),
2.07–1.96 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.6, 167.9, 147.8, 145.3, 143.5,
142. 7, 136.5, 136.2, 128.8 (2C), 128.2, 127.6 (2C), 127.5, 123.0, 122.9, 114.0, 111.0, 109.3,
105.1, 101.7, 98.5, 48.7, 44.6, 36.9, 28.1, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C28H22NO5 452.1492; found 452.1497.
1-benzyl-5-methoxy-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-
dione (3ba). White solid; 42.3 mg, 88% yield; mp 261–263 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.3 Hz, 2H), 7.37 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 6.62 (m, 2H), 6.59 (s, 1H), 6.52–6.48 (m, 1H), 6.02 (s, 1H),
5.88 (d, J = 1.4 Hz, 1H), 5.86 (d, J = 1.4 Hz, 1H), 5.05 (d, J = 15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz,
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1H), 3.65 (s, 3H), 2.81–2.68 (m, 2H), 2.47–2.32 (m, 2H), 2.18–2.08 (m, 1H), 2.08–1.97 (m, 1H);
13C NMR{1H} (125 MHz, CDCl3) δ 195.8, 178.3, 167.9, 156.2, 147.8, 145.3, 143.4, 137.8, 136.3,
136.2, 128.8 (2C), 127.6 (2C), 127.5, 113.9, 112.0, 110.9, 110.9, 109.6, 105.2, 101.7, 98.5, 55.6,
49.1, 44.7, 36.9, 28.1, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H24NO6 482.1598;
found 482.1605.
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1-benzyl-5-methyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-d
ione (3ca). White solid; 44.2 mg, 95% yield; mp 250‒252 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.5 Hz, 2H), 7.36 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 6.90 (dd, J = 7.9, 0.8 Hz, 1H), 6.70 (d, J = 0.6 Hz, 1H), 6.62
(d, J = 7.9 Hz, 1H), 6.59 (s, 1H), 6.01 (s, 1H), 5.87 (d, J = 1.3 Hz, 1H), 5.86 (d, J = 1.3 Hz, 1H),
5.07 (d, J = 15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 2.82–2.68 (m, 2H), 2.47–2.32 (m, 2H), 2.18
(s, 3H), 2.12 (dt, J = 17.6, 5.9 Hz, 1H), 2.09–1.99 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
195.9, 178.5, 167.8, 147.7, 145.2, 143.5, 140.3, 136.5, 136.3, 132.4, 128.7 (2C), 128.5, 127.6 (2C),
127.5, 123.9, 114.2, 111.1, 109.0, 105.3, 101.7, 98.4, 48.8, 44.7, 36.9, 28.1, 21.1, 20.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C29H24NO5 466.1649; found 466.1657.
1-benzyl-5-fluoro-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3da). White solid; 44.1 mg, 94% yield; mp 233‒235 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.3 Hz, 2H), 7.38 (t, J =
7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 6.79 (td, J = 8.9, 2.6 Hz, 1H), 6.68–6.62 (m, 2H), 6.60 (s,
1H), 5.99 (s, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.87 (d, J = 1.3 Hz, 1H), 5.06 (d, J = 15.7 Hz, 1H),
4.99 (d, J = 15.7 Hz, 1H), 2.82–2.68 (m, 2H), 2.48–2.31 (m, 2H), 2.19–2.09 (m, 1H), 2.09–1.99
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.3, 168.2, 159.5 (d, J = 239.6 Hz), 148.0,
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145.4, 143.5, 138.6 (d, J = 1.9 Hz), 137.9 (d, J = 7.5 Hz), 135.9, 128.8 (2C), 127.7, 127.5 (2C),
114.4 (d, J = 23.4 Hz), 113.3, 111.2 (d, J = 24.8 Hz), 110.6, 109.8 (d, J = 8.0 Hz), 105.0, 101.8,
98.6, 49.1 (d, J = 1.6 Hz), 44. 8, 36.9, 28.1, 20.4; 19F NMR (470 MHz, CDCl3) δ -120.2; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C28H21FNO5 470.1398; found 470.1403.
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1-benzyl-7-fluoro-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3ea). White solid; 40.8 mg, 87% yield; mp 256‒258 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.4 Hz, 2H), 7.35 (t, J =
7.4 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 6.95–6.86 (m, 1H), 6.84 (td, J = 7.8, 4.6 Hz, 1H), 6.68 (d, J
= 7.2 Hz, 1H), 6.58 (s, 1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.84 (s, 1H), 5.22 (d, J = 15.3 Hz, 1H), 5.09
(d, J = 15.3 Hz, 1H), 2.82–2.65 (m, 2H), 2.47–2.27 (m, 2H), 2.12 (dt, J = 11.9, 5.6 Hz, 1H),
2.07–1.94 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.7, 178.2, 168.0, 147.9, 147.3 (d, J =
243.1 Hz), 145.3, 143.3, 139.3 (d, J = 2.9 Hz), 137.5, 129.3 (d, J = 8.6 Hz), 128.5 (2C), 127.8,
127.8, 127.5, 123.5 (d, J = 6.4 Hz), 119.0 (d, J = 2.9 Hz), 116.4 (d, J = 19.8 Hz), 113.5, 110.8,
104.9, 101.8, 98.5, 48.9 (d, J = 2.1 Hz), 46.0 (d, J = 4.4 Hz), 36.8, 28.1, 20.4; 19F NMR (470 MHz,
CDCl3) δ -133.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H21FNO5 470.1398; found
470.1401.
1-benzyl-5-chloro-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3fa). White solid; 43.7 mg, 90% yield; mp 249‒251 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2H), 7.38 (t, J =
7.6 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.07 (dd, J = 8.3, 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.65
(d, J = 8.3 Hz, 1H), 6.60 (s, 1H), 5.97 (s, 1H), 5.89 (d, J = 0.9 Hz, 1H), 5.88 (s, 1H), 5.06 (d, J =
15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 2.84–2.69 (m, 2H), 2.49–2.33 (m, 2H), 2.21–2.10 (m, 1H),
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2.09–1.98 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.1, 168.2, 148.0, 145.4, 143.5,
141.3, 138.0, 135.7, 128.9 (2C), 128.2, 128.1, 127.7, 127.5 (2C), 123.6, 113.2, 110.5, 110.2, 104.9,
101.8, 98.6, 48.8, 44.8, 36.8, 28.1, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H21ClNO5
486.1103; found 486.1106.
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1-benzyl-6-chloro-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3ga). White solid; 40.8 mg, 84% yield; mp 253‒255 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2H), 7.39 (t, J =
7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 6.88 (dd, J = 7.9, 1.8 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.74
(d, J = 1.8 Hz, 1H), 6.59 (s, 1H), 5.97 (s, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.86 (d, J = 1.3 Hz, 1H),
5.07 (d, J = 15.7 Hz, 1H), 4.94 (d, J = 15.7 Hz, 1H), 2.81–2.67 (m, 2H), 2.47–2.30 (m, 2H),
2.17–2.08 (m, 1H), 2.02 (ddq, J = 10.8, 8.3, 5.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
195.8, 178.4, 168.1, 148.0, 145.4, 143.9, 143.5, 135.6, 134.9, 133.8, 128.9 (2C), 127.8, 127.5 (2C),
124.0, 122.8, 113.3, 110.6, 109.8, 104.9, 101.8, 98.5, 48.4, 44.7, 36.9, 28.1, 20.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C28H21ClNO5 486.1103; found 486.1103.
1-benzyl-4-bromo-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3ha). White solid; 35.4 mg, 67% yield; mp 247‒249 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.6 Hz, 2H), 7.38 (t, J =
7.5 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.02–6.96 (m, 2H), 6.70 (dd, J = 5.9, 2.7 Hz, 1H), 6.60 (s,
1H), 5.99 (s, 1H), 5.92–5.86 (m, 2H), 5.08 (d, J = 15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H),
2.80–2.67 (m, 2H), 2.47–2.34 (m, 2H), 2.18–1.97 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
196.0, 177.9, 169.1, 148.1, 145.2, 144.7, 144.6, 135.8, 132.8, 129.7, 128.9 (2C), 127.7, 127.6 (2C),
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126.7, 118.9, 111.4, 109.0, 108.4, 104.6, 101.8, 98.3, 50.3, 44.8, 36.8, 28.2, 20.5; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C28H21BrNO5 530.0598; found 530.0599.
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one (3ia). White solid; 48.6 mg, 92% yield; mp 265‒267 °C; column chromatography eluent,
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petroleum ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 2H), 7.38 (m,
2H), 7.29 (t, J = 7.4 Hz, 1H), 7.22 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.60 (m, 2H),
5.97 (s, 1H), 5.89 (d, J = 1.3 Hz, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.05 (d, J = 15.7 Hz, 1H), 4.98 (d,
J = 15.7 Hz, 1H), 2.84–2.67 (m, 2H), 2.50–2.32 (m, 2H), 2.21–2.09 (m, 1H), 2.10–1.99 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.0, 168.2, 148.0, 145.4, 143.5, 141.8, 138.3, 135.7,
131.0, 128.9 (2C), 127.7, 127.5 (2C), 126.4, 115.6, 113.1, 110.7, 110.5, 105.0, 101.8, 98.6, 48.7,
44.7, 36.8, 28.1, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H21BrNO5 530.0598; found
530.0604.
1-benzyl-6-bromo-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-di
one (3ja). White solid; 45.0 mg, 85% yield; mp 272‒274 °C; column chromatography eluent,
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petroleum ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.39 (m,
2H), 7.30 (t, J = 7.4 Hz, 1H), 7.04 (dd, J = 7.9, 1.7 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 6.76 (d, J =
7.9 Hz, 1H), 6.59 (s, 1H), 5.96 (s, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.86 (d, J = 1.3 Hz, 1H), 5.06 (d,
J = 15.7 Hz, 1H), 4.94 (d, J = 15.7 Hz, 1H), 2.82–2.67 (m, 2H), 2.46–2.30 (m, 2H), 2.17–2.07 (m,
1H), 2.07–1.96 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.3, 168.1, 148.0, 145.4,
144.1, 143.5, 135.6, 135.4, 128.9 (2C), 127.8, 127.5 (2C), 125.8, 124.4, 121.7, 113.2, 112.5, 110.6,
104.9, 101.8, 98.5, 48.4, 44.7, 36.8, 28.1, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C28H21BrNO5 530.0598; found 530.0597.
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1-benzyl-5-nitro-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dio
ne (3ka). Yellow solid; 43.6 mg, 88% yield; mp 292‒294 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 8.7, 2.2 Hz, 1H), 7.79
(d, J = 2.2 Hz, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H),
6.83 (d, J = 8.7 Hz, 1H), 6.64 (s, 1H), 5.91 (s, 1H), 5.90 (s, 1H), 5.89 (s, 1H), 5.12 (d, J = 15.7 Hz,
1H), 5.05 (d, J = 15.7 Hz, 1H), 2.80 (t, J = 6.3 Hz, 2H), 2.47–2.34 (m, 2H), 2.23–2.03 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 196.1, 178.7, 168. 9, 148.5, 148.4, 145.6, 143.7, 143.6, 137.2,
135.0, 129.1 (2C), 128.1, 127.6 (2C), 125.5, 119.1, 112.2, 110.1, 108.8, 104.5, 102.0, 98.9, 48.6,
45.0, 36.7, 28.1, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H21N2O7 497.1343; found
497.1355.
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1-methyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione (3la).
White solid; 31.9 mg, 85% yield; mp 244‒246 °C; column chromatography eluent, petroleum
ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.25 (td, J = 7.7, 1.4 Hz, 1H), 6.94 (td, J = 7.4,
0.8 Hz, 1H), 6.92–6.88 (m, 2H), 6.58 (s, 1H), 6.02 (s, 1H), 5.85 (s, 2H), 3.35 (s, 3H), 2.78–2.66
(m, 2H), 2.42–2.26 (m, 2H), 2.15–2.06 (m, 1H), 2.05–1.96 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 195.8, 178.6, 167.8, 147.7, 145.2, 143.6, 143.6, 136.5, 128.4, 123.0, 122.9, 113.8, 111.2,
108.1, 105.2, 101.7, 98.4, 48.8, 36.9, 28.1, 26.8, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H18NO5 376.1179; found 376.1188.
1-ethyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione (3ma).
White solid; 36.2 mg, 93% yield; mp 193‒195 °C; column chromatography eluent, petroleum
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ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 7.23 (td, J = 7.5, 1.7 Hz, 1H), 6.96–6.87 (m,
3H), 6.57 (s, 1H), 6.02 (s, 1H), 5.85 (s, 2H), 3.94 (dq, J = 14.4, 7.2 Hz, 1H), 3.83 (dq, J = 14.3, 7.2
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Hz, 1H), 2.80–2.66 (m, 2H), 2.43–2.26 (m, 2H), 2.15–2.06 (m, 1H), 2.05–1.94 (m, 1H), 1.40 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 178.0, 167.7, 147.7, 145.2, 143.5, 142.6,
136.8, 128.3, 123.2, 122.6, 114.0, 111.2, 108.3, 105.1, 101.7, 98.4, 48.7, 36.9, 35.1, 28.1, 20.4,
12.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20NO5 390.1336; found 390.1335.
1-allyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione (3na).
White solid; 38.9 mg, 97% yield; mp 192‒194 °C; column chromatography eluent, petroleum
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ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 7.21 (td, J = 7.7, 1.4 Hz, 1H), 6.98–6.87 (m,
3H), 6.58 (s, 1H), 6.03 (s, 1H), 6.03–5.95 (m, 1H), 5.86 (s, 2H), 5.52 (dd, J = 17.2, 1.2 Hz, 1H),
5.31 (dd, J = 10.3, 1.1 Hz, 1H), 4.52 (ddt, J = 16.1, 4.8, 1.5 Hz, 1H), 4.41 (dd, J = 16.2, 5.7 Hz,
1H), 2.81–2.65 (m, 2H), 2.43–2.26 (m, 2H), 2.17–2.06 (m, 1H), 2.06–1.95 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 195.8, 178.2, 167.8, 147.8, 145.3, 143.6, 142.7, 136.5, 131.8, 128.2,
123.1, 122.8, 118.0, 113.9, 111.1, 109.2, 105.2, 101.7, 98.5, 48.7, 43.1, 36.9, 28.1, 20.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H20NO5 402.1336; found 402.1337.
1-(prop-2-yn-1-yl)-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-d
ione (3oa). White solid; 36.3 mg, 91% yield; mp 211‒213 °C; column chromatography eluent,
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petroleum ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 7.31–7.26 (m, 1H), 7.13 (d, J = 7.9
Hz, 1H), 6.98 (td, J = 7.5, 0.5 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 6.09 (d,
J = 1.6 Hz, 1H), 5.87 (d, J = 1.6 Hz, 2H), 4.92–4.79 (m, 1H), 4.51–4.38 (m, 1H), 2.81–2.67 (m,
2H), 2.46–2.27 (m, 3H), 2.11 (tt, J = 10.7, 5.3 Hz, 1H), 2.06–1.95 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ 195.9, 177.5, 167.9, 147.8, 145.31, 143.5, 141.6, 136.3, 128.3, 123.3, 123.1, 113.7,
110.9, 109.2, 105.2, 101.7, 98.4, 77.2, 72.4, 48.6, 36.8, 29.9, 28.1, 20.4; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C24H18NO5 400.1179; found 400.1182.
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1-(cyclopropylmethyl)-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'
H)-dione (3pa). White solid; 39.0 mg, 94% yield; mp 184‒186 °C; column chromatography
eluent, petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.23 (td, J = 7.7, 1.6 Hz, 1H),
6.99 (d, J = 7.8 Hz, 1H), 6.95–6.86 (m, 2H), 6.57 (s, 1H), 6.10 (s, 1H), 5.86 (d, J = 1.2 Hz, 1H),
5.85 (d, J = 1.2 Hz, 1H), 3.73 (qd, J = 14.4, 6.8 Hz, 2H), 2.79–2.65 (m, 2H), 2.44–2.26 (m, 2H),
2.16–2.06 (m, 1H), 2.00 (dtt, J = 10.8, 8.2, 5.5 Hz, 1H), 1.38–1.28 (m, 1H), 0.67–0.54 (m, 2H),
0.51–0.38 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.7, 178.4, 167.7, 147.7, 145.2, 143.5,
143.1, 136.7, 128.2, 123.1, 122.6, 114.1, 111.1, 108.6, 105.1, 101.7, 98.4, 48. 7, 44.7, 36.8, 28.1,
20.4, 9.6, 4.0, 3.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H22NO5 416.1492; found
416.1496.
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1-cyclopropyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione
(3qa). White solid; 36.9 mg, 92% yield; mp 243‒245 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.24 (dd, J = 7.7, 1.2 Hz, 1H), 7.16
(d, J = 7.7 Hz, 1H), 6.93 (td, J = 7.4, 0.9 Hz, 1H), 6.86 (dd, J = 7.3, 0.8 Hz, 1H), 6.57 (s, 1H), 5.96
(s, 1H), 5.86 (d, J = 0.8 Hz, 2H), 2.83 (dq, J = 6.8, 4.0 Hz, 1H), 2.77–2.65 (m, 2H), 2.39–2.25 (m,
2H), 2.14–2.05 (m, 1H), 1.99 (dtt, J = 11.0, 8.1, 5.7 Hz, 1H), 1.14–1.06 (m, 3H), 1.03 (ddd, J =
13.4, 6.3, 3.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.9, 179.1, 167.6, 147.7, 145.2,
144.0, 143.6, 136.0, 128.2, 123.0, 122.7, 114.1, 111.4, 109.5, 105.1, 101.7, 98.4, 48.9, 36.9, 28.0,
22.7, 20.4, 6.3, 6.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H20NO5 402.1336; found
402.1335.
7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-dione (3ra). White
solid; 30.7 mg, 85% yield; mp 294‒296 °C; column chromatography eluent, petroleum
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ether/EtOAc = 3:1; 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.90 (m,
3H), 6.58 (s, 1H), 6.20 (s, 1H), 5.87 (s, 1H), 5.87 (s, 1H), 2.81–2.66 (m, 2H), 2.48–2.30 (m, 2H),
2.13 (tt, J = 10.6, 5.2 Hz, 1H), 2.08–1.97 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 196.0,
180.0, 168.0, 147.8, 145.4, 143.4, 140.5, 137.1, 128.3, 123.4, 122.8, 113.6, 111.0, 110.0, 105.4,
101.7, 98.4, 49.1, 36.9, 28.1, 20.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H16NO5
362.1023; found 362.1027.
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1'-benzyl-10,11-dihydrospiro[benzo[c]xanthene-7,3'-indoline]-2',8(9H)-dione (3sa). White
solid; 33.4 mg, 73% yield; mp 272‒274 °C; column chromatography eluent, petroleum
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ether/EtOAc = 6:1; H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.1 Hz,
1H), 7.57 (m, 3H), 7.50 (t, J = 7.3 Hz, 1H), 7.43–7.35 (m, 3H), 7.30 (t, J = 7.3 Hz, 1H), 7.17–7.07
(m, 1H), 6.94–6.84 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 5.18 (d, J = 15.7
Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 2.94 (t, J = 6.2 Hz, 2H), 2.55–2.36 (m, 2H), 2.20 (tt, J = 11.7,
5.7 Hz, 1H), 2.15–2.05 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 195.9, 178.6, 167.7, 143.7,
142.9, 136.7, 136.4, 133.5, 128.8 (2C), 128.3, 127.7 (2C), 127.6, 127.6, 127.0, 126.8, 125.3, 123.8,
123.5, 123.3, 123.0, 121.3, 116.5, 112.1, 109.3, 48.9, 44.8, 37.0, 28.2, 20.5; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C31H24NO3 458.1751; found 458.1748.
1-benzyl-7',7'-dimethyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'
H)-dione (3ab). White solid; 46.5 mg, 97% yield; mp 221‒223 °C; column chromatography
eluent, petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.37
(t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.14–7.07 (m, 1H), 6.92–6.86 (m, 2H), 6.74 (d, J =
7.8 Hz, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 5.86 (d, J = 1.2 Hz, 1H), 5.84 (d, J = 1.2 Hz, 1H), 5.08 (d,
J = 15.7 Hz, 1H), 5.00 (d, J = 15.7 Hz, 1H), 2.66 (d, J = 17.3 Hz, 1H), 2.55 (d, J = 17.4 Hz, 1H),
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2.31 (d, J = 16.2 Hz, 1H), 2.19 (d, J = 16.2 Hz, 1H), 1.16 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 195.6, 178.5, 166.2, 147.8, 145.3, 143.6, 142.6, 136.4, 136.2, 128.8 (2C),
128.2, 127.6 (2C), 127.5, 122.9 (2C), 114.0, 109.7, 109.3, 105.1, 101.7, 98.5, 50.7, 48.7, 44.6,
41.8, 32.2, 29.0, 27.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H26NO5 480.1805; found
480.1814.
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1-benzyl-7'-methyl-7',8'-dihydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthene]-2,9'(6'H)-
dione (3ac). White solid; 41.9 mg, 90% yield; mp 224‒226 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.5 Hz, 2H), 7.37 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.15–7.06 (m, 1H), 6.94–6.84 (m, 2H), 6.74 (d, J = 7.8 Hz,
1H), 6.59 (s, 1H), 6.00 (d, J = 2.7 Hz, 1H), 5.85 (d, J = 7.9 Hz, 2H), 5.15–4.93 (m, 2H), 2.75 (m,
1H), 2.55–2.22 (m, 3H), 2.11 (m, 1H), 1.11 (t, J = 6.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3)
δ 195.8, 178.5, 166.9, 147.8, 145.3, 143.6, 142.7, 136.5, 136.2, 128.8 (2C), 128.2, 127.6 (2C), 127.
6, 123.0, 123.0, 113.9, 110.4, 109.3, 105.2, 101.7, 98.5, 48.8, 45.1, 44.7, 36.0, 28.0, 20.7; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C29H24NO5 466.1649; found 466.1659.
1'-benzyl-6,7-dihydro-8H-spiro[cyclopenta[b][1,3]dioxolo[4,5-g]chromene-9,3'-indoline]-2',8
-dione (3ad). White solid; 40.6 mg, 93% yield; mp 224‒226 °C; column chromatography eluent,
petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.3 Hz, 2H), 7.37 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.16 (ddd, J = 8.9, 7.6, 1.7 Hz, 1H), 6.99–6.91 (m, 2H), 6.75
(d, J = 7.9 Hz, 1H), 6.70 (s, 1H), 6.00 (s, 1H), 5.91 (s, 2H), 5.12 (d, J = 15.8 Hz, 1H), 4.95 (d, J =
15.8 Hz, 1H), 2.95–2.81 (m, 2H), 2.49 (qdd, J = 18.1, 6.7, 3.2 Hz, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 200.5, 179.4, 176.9, 148.2, 145.7, 145.5, 142.8, 135.5, 134.0, 128.8 (3C), 127.6, 127.3
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(2C), 124.1, 123.3, 114.2, 113.6, 109.6, 105.9, 102.0, 99.1, 48.7, 44.5, 33.3, 25.9; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C27H20NO5 438.1336; found 438.1347.
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(3ae).
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White solid; 32.9 mg, 75% yield; mp 212‒214 °C; column chromatography eluent, petroleum
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2H), 7.27 (t, J = 7.3 Hz, 1H), 7.13 (td, J = 7.7, 1.4 Hz, 1H), 6.98–6.88 (m, 2H), 6.77 (d, J = 7.8 Hz,
1H), 6.56 (s, 1H), 5.91 (s, 1H), 5.84 (s, 1H), 5.83 (s, 1H), 5.08 (d, J = 15.6 Hz, 1H), 4.91 (d, J =
15.6 Hz, 1H), 2.46 (s, 3H), 2.17 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.3, 178.9, 159.9,
147.7, 144.9, 143.9, 142.8, 136.3, 136.1, 128.8 (2C), 128.3, 127.7 (2C), 127.6, 123.1 (2C), 113.7,
113.5, 109.2, 104.8, 101.6, 98.2, 51.3, 44.6, 31.6, 20.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C27H22NO5 440.1492; found 440.1489.
7'-benzoyl-1-benzyl-6'-phenylspiro[indoline-3,8'-[1,3]dioxolo[4,5-g]chromen]-2-one
(3af).
White solid; 46.7 mg, 83% yield; mp 227‒229 °C ; column chromatography eluent, petroleum
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ether/EtOAc = 15:1; H NMR (500 MHz, CDCl3) δ 7.57–7.51 (m, 2H), 7.48 (d, J = 7.4 Hz, 2H),
7.44–7.39 (m, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.18–7.06 (m, 6H), 7.02 (t, J
= 7.7 Hz, 2H), 6.87 (t, J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 5.89 (s,
2H), 5.14 (d, J = 15.7 Hz, 1H), 4.94 (d, J = 15.7 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
195.6, 178.1, 158.7, 148.0, 145.3, 145.0, 143.2, 138.7, 136.1, 134.6, 133.7, 131.8, 130.3, 129.7
(2C), 129.2 (2C), 128.8 (2C), 128.7, 127.9 (2C), 127.6 (2C), 127.6, 127.5 (2C), 123.7, 123.1,
113.9, 110.2, 109.4, 105.2, 101.7, 98.8, 52.7, 44.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C37H26NO5 564.1805; found 564.1811.
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1-benzyl-6'-methyl-2-oxospiro[indoline-3,8'-[1,3]dioxolo[4,5-g]chromene]-7'-carboxylate (3ag).
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White solid; 37.2 mg, 70% yield; mp 150‒152 °C; column chromatography eluent, petroleum
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ether/EtOAc = 40:1; H NMR (500 MHz, CDCl3) δ 7.36–7.27 (m, 7H), 7.26 (dt, J = 3.7, 2.0 Hz,
1H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 7.01–6.98 (m, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.91–6.87 (m, 2H),
6.55 (t, J = 3.8 Hz, 2H), 5.84 (d, J = 1.3 Hz, 1H), 5.83 (s, 1H), 5.82 (d, J = 1.3 Hz, 1H), 4.90 (d, J
= 15.4 Hz, 1H), 4.77 (d, J = 11.9 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 3.78 (d, J = 15.4 Hz, 1H),
2.52 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 178.9, 165.9, 162.7, 147.8, 144.9, 143.7, 142.5,
137.0, 136.4, 135.2, 128.9 (2C), 128.7 (2C), 128.4 (2C), 128.1, 128.1, 127.8 (2C), 127.7, 123.5,
123.1, 112.9, 109.3, 104.8, 101.6, 101.3, 98.4, 66.6, 50.8, 43.9, 20.2; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C33H26NO6 532.1755; found 532.1769.
ethyl
1-benzyl-2-oxo-6'-phenylspiro[indoline-3,8'-[1,3]dioxolo[4,5-g]chromene]-7'-carboxylate (3ah).
White solid; 32.4 mg, 61% yield; mp 183‒185 °C ; column chromatography eluent, petroleum
ether/EtOAc = 15:1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 6.5 Hz, 2H), 7.47 (d, J = 7.5 Hz,
2H), 7.45–7.39 (m, 3H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H),
7.14 (d, J = 7.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 5.95 (s,
1H), 5.87 (d, J = 4.2 Hz, 2H), 5.12 (d, J = 15.5 Hz, 1H), 4.88 (d, J = 15.5 Hz, 1H), 3.71 (dq, J =
10.8, 7.1 Hz, 1H), 3.60 (dq, J = 10.8, 7.1 Hz, 1H), 0.56 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 178.3, 166.1, 159.9, 147.9, 145.0, 144.8, 143.0, 136.1, 135.6, 134.8, 129.8, 128.8
(2C), 128.6 (3C), 128.0 (2C), 127.8 (2C), 127.7, 123.9, 123.2, 113.2, 109.1, 105.0, 103.8, 101.7,
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98.7, 60.3, 51.6, 44.6, 13.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H26NO6 532.1755;
found 532.1759.
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(E)-1-benzyl-3-(6-oxobenzo[d][1,3]dioxol-5(6H)-ylidene)indolin-2-one (A). This compound
was detected and obtained by the reaction of oxindole-embedded ortho-hydroxybenzyl alcohol 1a
(0.1 mmol, 37.5 mg) with 1,3-cyclohexanedione 2a (0.12 mmol, 13.5 mg) in the presence of 10
mol % TfOH (0.01 mmol, 1.5 mg) at 80 °C for 5 min. Reddish brown oil; <10% yield; E/Z >20:1;
column chromatography eluent, petroleum ether/EtOAc = 18:1; 1H NMR (500 MHz, CDCl3) δ
8.77 (d, J = 8.0 Hz, 1H), 8.60 (s, 1H), 7.32 (m, 5H), 7.22 (t, J = 7.8 Hz, 1H), 6.93 (t, J = 7.6 Hz,
1H), 6.65 (d, J = 7.7 Hz, 1H), 5.97 (s, 2H), 5.95 (s, 1H), 4.94 (s, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 187.9, 169.2, 159.5, 150.3, 144.2, 136.6, 135.8, 132.7, 130.7, 128.8 (2C), 127.7, 127.6,
127.2 (2C), 122.4, 122.0, 108.7, 102.8, 101.5, 101.2, 43.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C22H16NO4 358.1047; found 358.1043.
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1-benzyl-5a'-hydroxy-5a',7',8',9a'-tetrahydrospiro[indoline-3,10'-[1,3]dioxolo[4,5-b]xanthen
e]-2,9'(6'H)-dione (C). This compound was detected and obtained by the reaction of
oxindole-embedded ortho-hydroxybenzyl alcohol 1a (0.1 mmol, 37.5 mg) with
1,3-cyclohexanedione 2a (0.12 mmol, 13.5 mg) in the presence of 10 mol % TfOH (0.01 mmol,
1.5 mg) at 80 °C for 1 h. White solid; 9.9 mg, 21% yield; mp 228‒230 °C; column
chromatography eluent, petroleum ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H),
7.50 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H),
6.99 (t, J = 7.3 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 5.83 (s,
2H), 5.75 (s, 1H), 5.09 (d, J = 15.6 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 3.72 (s, 1H), 2.53–2.40 (m,
2H), 2.33 (td, J = 13.1, 6.8 Hz, 1H), 2.24–2.08 (m, 2H), 2.03 (m, 1H); 13C{1H} NMR (125 MHz,
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CDCl3) δ 204.1, 181.2, 148.5, 146.3, 143.9, 142.9, 135.4, 133.7, 128.9 (2C), 128.8, 127.9, 127.6
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(2C), 123.7, 122.3, 112.3, 110.0, 105.2, 101.3, 100.2, 98.6, 59.6, 49.3, 44.9, 40.9, 36.8, 20.7;
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HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H24NO6 470.1598; found 470.1592.
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Supporting Information
NMR spectra of products. This material is available free of charge via the Internet at
http://pubs.acs.org.
ORCID
Shuai-Shuai Li: 0000-0001-7279-2885
Jian Xiao: 0000-0003-4272-6865
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to NSFC (21702117 and 21878167) and the Natural Science Foundation of
Shandong Province (JQ201604, ZR2017BB005) as well as the Key Research and
Development Program of Shandong Province (2017GSF218073). We thank the Dr.
Feng-Ying Dong (Central Laboratory of Qingdao Agricultural University) for NMR
determination. We also thank Prof Teck-Peng Loh and Prof Yun-He Xu (University of
Science and Technology of China) for HRMS determination.
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