Eosin Y-catalyzed one-pot synthesis of spiro[4H-pyran-oxindole] under visible light irradiation

Article abstract of DOI:10.1016/j.tet.2020.131059

An efficient and simple synthetic approach has been developed for the preparation of biologically interesting spiro[oxindole-3,4’-(4′H-pyran)] derivatives via visible light-mediated one-pot, three-component reaction of isatins, 1,3-dicarbonyl compounds an

Full text of DOI:10.1016/j.tet.2020.131059

Journal Pre-proof
Eosin Y-catalyzed one-pot synthesis of spiro[4H-pyran-oxindole] under visible light
irradiation
Meng-Nan Chen, Jia-Qi Di, Jiao-Mian Li, Li-Ping Mo, Zhan-Hui Zhang
PII:
S0040-4020(20)30174-5
https://doi.org/10.1016/j.tet.2020.131059
TET 131059
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 January 2020
Revised Date: 3 February 2020
Accepted Date: 18 February 2020
Please cite this article as: Chen M-N, Di J-Q, Li J-M, Mo L-P, Zhang Z-H, Eosin Y-catalyzed one-pot
synthesis of spiro[4H-pyran-oxindole] under visible light irradiation, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2020.131059.
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Graphical Abstract
Eosin Y-catalyzed one-pot synthesis of
spiro[4H-pyran-oxindole]
under visible light irradiation
Meng-Nan Chen, Jia-Qi Di, Jiao-Mian Li, Li-Ping Mo*, Zhan-Hui Zhang*
National Demonstration Center for Experimental Chemistry Education, Hebei Key Laboratory of Organic Functional Molecules,
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China

Tetrahedron
1
Eosin Y-catalyzed one-pot synthesis of spiro[4H-pyran-oxindole]
under visible light irradiation
Meng-Nan Chen, Jia-Qi Di, Jiao-Mian Li, Li-Ping Mo*, Zhan-Hui Zhang*
National Demonstration Center for Experimental Chemistry Education, Hebei Key Laboratory of Organic Functional Molecules, College
of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China
Abstract—An efficient and simple synthetic approach has been developed for the preparation of biologically interesting spiro[oxindole-
3,4'-(4'H-pyran)] derivatives via visible light-mediated one-pot, three-component reaction of isatins, 1,3-dicarbonyl compounds and
malononitrile by using an inexpensive organic dye, Na2 eosin Y, as the photocatalyst in aqueous ethyl lactate at ambient temperature. The
substrate scope of this three-component reaction is expanded to linear 1,3-dicarbonyl compounds as viable starting materials. All rights
reserved.
Keywords:
Spiro[4H-pyran-oxindole]
Linear 1,3-dicarbonyl compounds
Multicomponent reaction
Eosin Y
Visible light
spirooxindole-fused thiazolidine (compound A) [15],
1. Introduction
spirooxindole-dihydroquinazolinone (compound B) [16],
spirooxindole pyrrolone (compound C) [17], bridged
O,O-ketals with spirooxindole skeleton (compound D)
[18], spirooxindole-fused thiaindan (compound E) [19],
spirooxindole-urazole (compound F) [20], as listed in the
Figure 1.
In recent years, the use of light as a rich, readily
available and almost inexhaustible source of clean
energy in green organic synthesis has attracted
considerable attention. Visible light-promoted organic
reactions have enormous advantages such as low cost,
safety, environmental friendliness, good compatibility
with functional groups and wide substrate suitability [1-
7]. In addition, multicomponent reactions (MCRs) have
become useful synthetic tools for the preparation of
novel and structurally diverse compounds in which at
least three different starting materials join through
covalent bonds in a single operation to form multiple
bond with high efficiency, atomic economy and low
synthesis cost [8-10]. Therefore, the exploration of
practical and eco-friendly visible light-promoted MCRs
is highly desirable in green and sustainable chemistry
[11-12].
Spirooxindoles are versatile structural motifs and
they are found in many natural products or synthetic
Figure 1. Selected representative compounds containing spirooxindole
compounds
with
important
biological
or
frameworks
pharmacological activities [13]. Due to their increased
structural complexity and important biological activities,
significant attention has been focused on the efficient
and selective construction of various spirooxindole
frameworks [14]. In very years, some complex
spirooxindoles have been assembled, such as
_____________
Spiro[4H-pyran-oxindole] derivatives, which belong
to the spirooxindole family of compounds, exhibit
various biological activities such as anticancer,
antifungal, and antibacterial, antioxidant, spasmolytic,
diuretic, and anti-anaphylactic properties [21]. Because
of the importance of such compounds, enormous effort
has been made to synthesize these spiro compounds.
Although many strategies have been developed for the
* Corresponding author.
E-mail
addresses:
moliping@126.com
(L.-P.
Mo);
zhanhui@mail.nankai.edu.cn (Z.-H. Zhang)

Tetrahedron
2
preparation of spiro[4H-pyran-oxindole], the classical
method is by reaction of isatins with active methylene
compounds and malononitrile in the presence of various
chosen as a model reaction for the optimization of the
reaction conditions (Table 1). When the model reaction
was performed in water-ethyl lactate at room
temperature under white light emitting diode (LED)
irradiation at ambient temperature, no desired product 4a
was formed, and only two component product of isatin
catalysts such as sodium stearate [22], L-proline [23], L-
proline-melamine [24], C4(DABCO-SO3H)2·4Cl [25],
trisodium citrate dehydrate [26], basic ionic liquid [27-
28], hexamethylenetetramine [29], triethylamine [30-31],
borax [32], α-amylase [33], or barium (S)-prolinate [34]
(Scheme 1a). While such methods have facilitated the
synthesis of spiro[4H-pyran-oxindole], they showed
varying grades of success as well as limitations such as
high temperature, longer reaction time, poor substrate
scope, low yields, use of toxic solvents, or complex
catalyst preparation. Thus, the development of more
efficient, economical and general method for the
synthesis of such important compounds is highly
desirable.
and
malononitrile,
2-(2-oxoindolin-3-
ylidene)malononitrile (I), was detected. In order to
promote this reaction, various organic photocatalysts
including rose bengal, rhodamine B, riboflavin, basic
fuchsine, erythrosin B, rhodamine 6G, alizarin,
fluorescein, sodium anthraquinone sulfonate, xanthene,
perylene, phenanthrenequinone, acenaphthenequinone,
9H-xanthen-9-one, 9-fluorenone, and Na2 eosin Y
(Figure 2) were examined under the same conditions. We
are pleased to find this three-component reaction can be
proceed and the corresponding product 4a was obtained
in 40–90% yields (Table 1, entries 2–17). These results
In the past few years, ruthenium and iridium
complexes are the most commonly used
photocatalysts in organic photosynthesis [35-36]
Although these complexes have excellent catalytic
properties, they are expensive, unstable, and
potentially toxic. Recently, eosin Y, a metal-free and
readily available organic dye, has been widely used
as an attractive alternative to transition metal
complexes in various visible-light promoted organic
transformations because it is usually relatively cheap
and less toxic [37]. Inspired by aforementioned
findings and as a part of our ongoing research in the
field of green chemistry [38], herein, we report the
visible light-mediated one-pot, three-component
reaction of isatins, linear 1,3-dicarbonyl compounds
indicated that Na2 eosin
Y exhibited the best
performance for this reaction (entry 17). Besides organic
photocatalysts, semiconductor materials such as
mesoporous graphitic carbon nitride (g-C3N4) [39] and
CdS [40] were also tested, which delivered 4a in 52%
and 78% yields, respectively (Table 1, entries 18 and 19).
and
malononitrile
for
the
synthesis
of
spiro[oxindole-3,4'-(4'
H
-pyran)] derivatives by using
Na2 eosin Y as a photocatalyst in aqueous ethyl
lactate (EL) at room temperature (Scheme 1b). The
reaction is a fruitful one-pot approach under highly
effective, mild and facile reaction conditions.
Scheme 1 Different strategies for the synthesis of spiro[oxindole-3,4'-(4'H-
pyran)] compounds
2. Results and discussion
To commence our studies, three-component reaction
of isatin, malononitrile and ethyl acetoacetate was
Figure 2 Photocatalysts tested in this stud
y

Tetrahedron
3
Table 1
CH3OH resulted in lower yields (Table 2, entries 1–6).
Further study found that the EL/H2O solvent system was
better for improving the yield of the corresponding
product. Its ratio of 3:1 was found suitable for this three-
component reaction, giving the expected product in 90%
yield (entry 15). The screening with different light sources
revealed that green light slightly increased the yield (entry
16). A control experiment showed that only a trace of the
product 4a was detected in the absence of light source
(entry 19). The yield was decreased to 79% by using 0.5
mol% Na2 eosin Y (Table 1, entry 20). These results imply
that eosin Y and visible light are essential for the
successful formation of product 4a.
Catalyst Screen for the Reaction of Isatin, Ethyl Acetoacetate and
Malononitrilea
Entry Phocatalyst
Time (h) Yield (%)b
1
no
12
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
0
2
Rose bengal
76
75
72
65
40
68
70
72
65
38
39
48
52
51
36
90
52
78
3
4
Rhodamine B
Riboflavin
5
6
Basic fuchsine
Erythrosin B
Table 3.
7
8
Rhodamine 6G
Alizarin
Synthesis of spiro[oxindole-3,4'-(4'H-pyran)] compounds from various
isatins and β-keto estera
9
Fluorescein
10
11
12
13
14
15
16
17
Sodium anthraquinone sulfonate
Xanthene
Perylene
H2N
O
CH3
O
Na2 eosin Y
Green LED
NC
O
O
OEt
CN
CN
Phenanthrenequinone
Acenaphthenequinone
9H-Xanthen-9-one
9-Fluorenone
Na2 eosin Y
R
O
O
+
OEt
+
R
H3C
EL/H2O (3:2), r. t.
O
4
N
O
N
1
H
2
3
H
H2N
NC
H2N
H2N
NC
O
18[c] g-C3N4
19 CdS
O
Me
OEt
Me
Me
NC
R
F
OEt
OEt
a
Reaction condition: isatin (1 mmol), malononitrile (1 mmol) and ethyl
O
O
O
O
N
H
N
O
O
F
N
H
Br
acetoacetate (1 mmol) in EL/H2O (3:2, 2 ml), catalyst (2 mol%), room
temperature, 10 W white LED.
4a
4b
4c
4d
4e
H
R = H, 4 h, 94%
R = Me, 4 h, 93%
R = F, 2 h, 92%
R = Br, 4 h, 92%
R = NO2, 2 h, 94%
4g
4 h, 88%
4f
3 h, 89%
b Isolated yield.
c
H2N
NC
H2N
20 mg.
O
O
H2N
Et
Me
OR2
O
Table 2
Me
NC
R
NC
OEt
Further optimization of the reaction conditions for the synthesis of 4aa
OEt
O
O
O
O
N
N
Entry Light Source
1
2
3
4
5
6
7
Time (h)
CHCl3
CH3CN
THF
DMF
EtOAc
CH3OH
H2O
Yield (%)[b]
10
16
29
31
74
75
76
80
O
O
H
H
N
2 = Me, 4 h, 93%
R2 = CH2CHMe2, 2 h, 94%
4m R2 = CH2CH2OMe, 4 h, 93%
4n R2 = CH2CH=CH2, 4 h, 93%
H
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
Green light
Blue light
4k
4l
R
4o
4p
4q
4r
R = H, 4 h, 92%
R = Me, 4 h, 85%
R = Cl, 4 h, 93%
R = NO2,4 h, 93%
R
4h
4i
4j
R = F, 4 h, 88%
R = Cl, 4 h, 90%
R = CF3, 2 h, 92%
H2N
H2N
O
O
H2N
Me
O
Me
Me
NC
NC
NC
R
Br
OMe
OMe
OMe
8
9
EtOH
EL
O
O
O
O
N
N
O
O
81
N
H
H
R
4x
4y
4s
4t
4u
4v
4w
H
R = Me, 4 h, 92%
R = F, 2 h, 93%
R = Cl, 3 h, 92%
R = Br, 4 h, 93%
R = NO2, 2 h, 91%
10
11
12
13
14
15
16
17
18
19
20[c]
EtOH:H2O (1:1)
EtOH:H2O (2:1)
EL:H2O (1:1)
EL:H2O (2:1)
EL:H2O (1:2)
EL:H2O (3:2)
EL:H2O (3:2)
EL:H2O (3:2)
EL:H2O (3:2)
EL:H2O (3:2)
EL:H2O (3:2)
EL:H2O (3:2)
86
83
90
85
80
90
94
88
4aa 3 h, 94%
R = F, 4 h, 91%
R = Cl, 4 h, 90%
4z R = CF3, 2 h, 91%
H2N
O
H2N
H2N
O
O
Me
Me
Me
NC
NC
NC
O(CH2)2OMe
Br
OMe
O(CH2)2OMe
O
O
O
O
O
O
N
N
N
H
Br
Ultraviolet light
no
Green light
Green light
90
trace
79
H
H
CF3
4ac
4 h, 90%
4ab
3 h, 89%
H2N
4ad
2 h, 93%
21[d]
85
H2N
NC
O
Me
OCH2CHMe2
O
Me
OCH2CHMe2
a
NC
Reaction condition: isatin (1 mmol), malononitrile (1 mmol) and ethyl
Br
O2N
acetoacetate (1 mmol) in solvent (2 ml), Na2 eosin Y (2 mol%), room
O
O
N
H
O
O
N
temperature.
H
4ae
4 h, 91%
4af
3 h, 93%
b Isolated yield.
H2N
O
c
H2N
0.5 mol% Na2 eosin Y.
O
Me
OCH2CH=CH2
Me
OCH2CH=CH2
d 1 mol% Na2 eosin Y.
NC
NC
Br
O
O
O
N
H
O
N
A screening of solvents revealed that ethyl lactate (EL)
was the best solvent for this transformation. Other
solvents, such as CHCl3, CH3CN, THF, DMF, EtOAc,
H
CF3
4ag
4 h, 90%
4ah
2 h, 92%

Tetrahedron
4
a
Reaction condition: isatin (1 mmol), β-keto esters (1 mmol) and
which is comparable with the performance of the 1.0
mmol scale reaction (Scheme 2).
malononitrile (1 mmol) in EL/H2O (3:2, 2 ml), Na2 eosin Y (2 mol%), 10
W green LED, room temperature, isolated yields.
Under the established reaction conditions (Table 2,
entry 16), the substrate scope of this three-component
reaction was investigated. First, the reactivity of different
isatins with ethyl acetoacetate and malononitrile was
explored. As illustrated in Table 3, isatins containing
electron-donating or electron-withdrawing groups on the
aryl ring were able to undergo the three-component
reaction. The position and electronic properties of
substituents on the isatin skeleton have no apparent effect
on the reaction and furnished the desired products 4 in
high to excellent yields. Gratifyingly, the halogen
substituted isatins are well tolerated in the transformation,
which would offer the potential for further molecular
complexity via post-functionalization.
Scheme 2 Large-scale synthesis of product 4a
To elucidate the possible reaction mechanism, some
preliminary studies were carried out. The Knoevenagel
condensation of isatin with malononitrile took place in
standard condition with the elimination of water to give
the
corresponding
2-(2-oxoindolin-3-
ylidene)malononitrile (I) in 94% yield. Carrying out the
reaction of I with ethyl acetoacetate generated the
expected product 4a in 93% yield (Scheme 3, a).
Subsequently, we further examined the reactivity of
1,3-dicarbonyl compounds. The results show β-ketoesters
o
Moreover, when the reaction was heated at 50 C in the
with different ester groups such as methyl acetoacetate, dark, product 4a was obtained in very low yield (Scheme
isobutyl 3-oxobutanoate, 2-methoxyethyl acetoacetate,
allyl acetoacetate all reacted smoothly under the standard
conditions, furnishing the corresponding products in
excellent yields. Methyl 3-oxopentanoate underwent the
desired reaction, rendering the corresponding products 4o-
4r effectively.
In addition, the present method was equally effective
for acetylacetone and led to the desired products in high
yields (Table 4). In order to further extend the scope of the
3, b). In addition, this three-component reaction was
completely suppressed in the presence of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) as a radical
scavenger. The reaction did not work in the presence of
2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 3, c).
Meanwhile, we found that the BHT-trapped product II
could be separated and identified by IR, MNR and MS
spectra. These results support the hypothesis that radical
pathway is likely involved in the current reaction.
reaction,
1,3-diphenylpropane-1,3-dione
was
also
employed in this transformation; however, the expected
product was not isolated.
Table 4.
Synthesis of spiro[oxindole-3,4'-(4'H-pyran)] compounds from various
isatins and acetylacetone a
H2N
O
O
Na2 eosin Y
Green LED
Me
Me
O
O
NC
CN
+
O
R
+
EL/H2O (3:2), r. t.
Me
Me
CN
3
R
N
O
O
1
H
2
N
H
4
H2N
NC
H2N
NC
H2N
NC
O
O
O
Me
Me
Me
Me
Me
OMe
Br
R
O
4aq
O
O
O
N
H
O
N
O
N
H
3 h, 86%
H
H2N
NC
R
4ai
4aj
4ak
R = H, 4 h, 93%
R = OMe, 4 h, 93%
R = F, 4 h, 91%
O
Me
4an
R = F, 4 h, 85%
4ao R = Cl, 4 h, 88%
4ap R = CF3, 2 h, 91%
F
F
Me
4al R = Br, 4 h, 90%
4amR = NO2, 2 h, 93%
O
O
N
4ar
4 h, 87%
H
a
Reaction condition: isatin (1 mmol), acetylacetone (1 mmol) and
malononitrile (1 mmol) in EL/H2O (3:2, 2 ml), Na2 eosin Y (2 mol%), 10
W green LED, room temperature, isolated yields.
Furthermore, to demonstrate the scalability of this
visible light-promoted three-component reaction, we
carried out the model reaction on the gram scale. When
the reaction was conducted at a 10 mmol scale, the
desired product 4a was generated in 93% yield (3.02 g),
Scheme 3 Control reaction experiments
On the basis of these experimental results, a plausible
reaction mechanism is proposed as shown in Scheme 4.
According to previous report about the Knoevenagel

Tetrahedron
5
reaction [41], malononitrile undergoes tautomerization in
the presence of aqueous ethyl lactate to give A. After this,
Knoevenagel condensation of A and isatin occurs with
the elimination of one molecule of water to give the
intermediate I. In this step, visible light may exert a
partial effect by applying additional energy to speed up
the reaction. According to literature reports [42], eosin
Y-derived photoexcited states can serve as direct
hydrogen atom transfer (HAT) catalysts in the activation
of C-H bonds. The formation of a α-carbonyl carbon
radical 2a-A is promoted by visible light activated Na2
eosin Y* through a HAT process. The derived carbon
radical 2a-A is subsequently trapped by an electron
deficient 2-(2-oxoindolin-3-ylidene)malononitrile (I) to
form radical adduct III. A reverse hydrogen atom
transfer (RHAT) process between eosin Na2 Y-H and
radical adduct III occurs to regenerate ground-state Na2
eosin Y and the intermediate IV. Subsequently, the
intermediate IV is further subjected to intramolecular
cyclization to form the desired product 4a.
lactate at room temperature under green LED irradiation
under an air atmosphere, generating the desired products
in high to excellent yields. This new approach meets the
requirements of green chemistry and opens up a new
way to develop more sustainable multicomponent
reaction under visible light irradiation for constructing
biological and synthetic important molecules. Detailed
mechanisms and applications for this transformation are
currently being studied in our laboratory.
4. Experimental
4.1 General information
All solvents and reagents were purchased from
commercial suppliers and were used without further
purification. Melting points were measured on X-5
apparatus and were uncorrected. The IR spectra were
obtained on a Thermo Fisher is50 spectrometer using KBr
pellets in the range of 400-4000 cm-1. The 1H NMR and 13
C
NMR spectra were recorded on a Zhongke Niujin AS 400
spectrometer using TMS as internal standard. The mass
spectra were performed on a 3200 Qtrap instrument with an
ESI source. High resolution mass spectra (HR-MS) were
measured on a Brukter Impact II instrument using ESI
source. The WP-VLH-1020 photoreactor from Xi'an
WATTECS experimental equipment co. LTD was used for
the irradiation experiment.
4.2
General Procedure for synthesis of spiro[oxindole-
3,4'-(4'H-pyran)] (4)
In a 15 mL quartz tube equipped with a magnetic stirrer
bar, isatin (1 mmol), 1,3-dicarbonyl compound (1 mmol),
malononitrile (1 mmol), and Na2 eosin Y (0.02 mmol) were
added successively in ethyl lactate/water (3:1, 2 mL). The
reaction tube was exposed to green LED (520–525 nm, 10
W) irradiation at a distance of approximately 3 mm from
bottom of the tube (SI, Figure S1) at room temperature in
air with stirring for an appropriate time. The reaction
progress was monitored by TLC. Upon completion, water
was added to the mixture and the solid precipitate was
filtered and washed with ethanol to obtain the desired pure
product.
4.2.1
Ethyl
2'-amino-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4a)
o
White solid (305.5 mg, 94% yield); m.p.: 272-273 C
(lit. 270-272 °C [22]); IR (KBr): 3381, 3134, 2190, 1722,
1675, 1618, 1596, 1470, 1416, 1381, 1329, 1288, 1212,
Scheme 4 Proposed plausible mechanism
1
1134, 1072, 755 cm-1; H NMR (400 MHz, DMSO-d6) δ
3. Conclusion
10.42 (s, 1H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 7.18 (s, 2H),
7.08 (dd, J = 7.6, 1.2 Hz, 1H), 6.96 (td, J = 7.6, 1.2 Hz, 1H),
6.82 (d, J = 7.6 Hz, 1H), 3.79 (m, 2H), 2.34 (s, 3H), 0.81 (t,
J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
179.1, 165.0, 159.4, 159.0, 142.6, 135.0, 129.0, 123.9,
122.3, 118.0, 109.8, 105.1, 60.7, 57.0, 49.4, 19.1, 13.5 ppm;
ESI-MS: m/z = 325 (M + H)+.
In summary, we have developed a simple and mild
method for the preparation of spiro[oxindole-3,4'-(4'H-
pyran)] derivatives via visible light-promoted one-pot,
three-component reaction of isatins, linear 1,3-
dicarbonyl compounds and malononitrile. The reaction
proceeds smoothly in the presence of commercially
available and inexpensive Na2 eosin Y in aqueous ethyl
4.2.2
Ethyl
2'-amino-3'-cyano-5,6'-dimethyl-2-

Tetrahedron
6
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4b)
NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.27 (s, 2H),
7.16 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.97
(d, J = 2.0 Hz, 1H), 4.08–3.61 (m, 2H), 2.35 (s, 3H), 0.88 (t,
J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
178.9, 164.8, 159.7, 159.4, 144.3, 134.5, 125.8, 125.0,
121.5, 117.8, 112.6, 104.4, 60.9, 56.3, 49.3, 19.1, 13.5 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C17H14BrN3O4Na,
426.0065; found, 426.0072.
o
White solid (315.3 mg, 93% yield); m.p.: 292-293 C;
IR (KBr): 3375, 3116, 2978, 2928, 2187, 1724, 1678, 1628,
1592, 1392, 1374, 1287, 1211, 1152, 1073, 745 cm-1; H
1
NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.12 (s, 2H),
7.02 (dd, J = 8.0, 1.6 Hz, 1H), 6.87 (s, 1H), 6.68 (d, J = 7.6
Hz, 1H), 3.95–3.59 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 0.80
(t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
179.1, 165.0, 159.34, 159.0, 140.1, 135.2, 131.1, 129.3,
124.4, 118.0, 109.5, 105.2, 60.7, 57.2, 49.5, 21.1, 19.0, 13.5
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C18H17N3O4Na,
362.1117; found, 362.1109.
4.2.7 Ethyl 2'-amino-3'-cyano-5,6-difluoro-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4g)
o
White solid (317.7 mg, 88% yield); m.p.: 284-285 C;
IR (KBr): 3376, 3141, 2184, 1729, 1678, 1632, 1591, 1511,
1
4.2.3
Ethyl
2'-amino-3'-cyano-5-fluoro-6'-methyl-2-
1465, 1378, 1331, 1290, 1137, 1089, 1070, 778 cm-1; H
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4c)
NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.34 (dd, J =
10.0, 8.0 Hz, 1H), 7.25 (s, 2H), 6.85 (dd, J = 10.4, 6.8 Hz,
1H), 4.01–3.63 (m, 2H), 2.33 (s, 3H), 0.87 (t, J = 7.6 Hz,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 179.2, 164.8,
159.9, 159.4, 151.2 (dd, JCF=248.2, 13.7 Hz), 147.1 (dd,
JCF=237.6, 13.4 Hz), 139.2 (d, 3JCF = 10.0 Hz), 131.2, 117.8,
113 (dd, JCF=14.6, 3.5 Hz), 104.1, 99.7, 60.9, 56.3, 49.6,
19.2, 13.7 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C17H13F2N3O4Na, 384.0772; found, 384.0766.
o
White solid (315.7 mg, 92% yield); m.p.: 265-266 C
(lit. 264-266 oC [24]); IR (KBr): 3280, 3161, 2193, 1731,
1699, 1680, 1631, 1599, 1482, 1416, 1381, 1315, 1290,
1215, 1122, 1089, 745 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 10.43 (s, 1H), 7.21 (s, 2H), 7.07–6.95 (m, 2H), 6.78 (dd, J
= 8.4, 4.4 Hz, 1H), 3.94–3.63 (m, 2H), 2.33 (s, 3H), 0.82 (t,
J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
1
179.1, 164.9, 159.4, 158.7 (d, JCF = 235.1 Hz), 157.5,
3
2
138.8, 136.8 (d, JCF = 7.4 Hz), 117.8, 115.2 (d, JCF = 25.5
Hz), 104.4, 60.8, 56.5, 50.0, 19.3, 13.6 ppm; ESI-MS: m/z
= 343 (M + H)+.
4.2.8
Ethyl
2'-amino-3'-cyano-7-fluoro-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4h)
o
White solid (301.8 mg, 88% yield); m.p.: >300 C; IR
(KBr): 3321, 3194, 2199, 1730, 1717, 1680, 1651, 1604,
1491, 1473, 1415, 1378, 1330, 1289, 1207, 1145, 1078, 741
4.2.4
Ethyl
2'-amino-5-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4d)
o
1
White solid (370.8 mg, 92% yield); m.p.: 259-260 C
cm-1; H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.27
o
(lit. 257-259 C [24]); IR (KBr): 3379, 3189, 2207, 1715,
(s, 2H), 7.17–7.12 (m, 1H), 7.00–6.96 (m, 2H), 3.98–3.64
1652, 1615, 1596, 1472, 1417, 1380, 1282, 1223, 1137,
1073, 747, 687, 575 cm-1; 1H NMR (400 MHz, DMSO-d6) δ
10.58 (s, 1H), 7.40 (dd, J = 8.4, 2.4 Hz, 1H), 7.33 (d, J =
2.0 Hz, 1H), 7.27 (s, 2H), 6.80 (d, J = 8.0 Hz, 1H), 3.85 (m,
2H), 2.37 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 178.7, 164.8, 160.0, 159.4, 141.9,
137.7, 131.8, 126.7, 117.9, 113.9, 111.8, 104.2, 60.9, 56.4,
49.7, 19.2, 13.5 ppm; ESI-MS: m/z = 403 (M + H)+.
(m, 2H), 2.36 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H) ppm; 13
C
NMR (100 MHz, DMSO-d6) δ 178.9, 164.5, 159.6, 159.4,
146.7 (d, 1JCF = 240.7 Hz), 138.0, 129.6 (d, 3JCF = 12.4 Hz),
4
2
123.3 (d, JCF = 4.1 Hz), 120.0, 117.8, 116.0 (d, JCF = 22.5
Hz), 104.6, 60.8, 56.5, 49.8, 19.2, 13.4 ppm; HRMS (ESI)
m/z: [M + Na]+ calcd for C17H14FN3O4Na, 366.0866; found,
366.0870.
4.2.9
Ethyl
2'-amino-7-chloro-3'-cyano-6'-methyl-2-
4.2.5
Ethyl
2'-amino-3'-cyano-6'-methyl-5-nitro-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4i)
o
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4e)
White solid (347.8 mg, 94% yield); m.p.: 245-246 C
(lit. 245-247 C [24]); IR (KBr): 3300, 3130, 2205, 1721,
White solid (323.1 mg, 90% yield); m.p.: >300 C; IR
(KBr): 3378, 3193, 2199, 1728, 1677, 1625, 1605, 1478,
o
o
1
1416, 1286, 1213, 1127, 1078, 765, 743 cm-1; H NMR
1667, 1626, 1591, 1480, 1457, 1379, 1362, 1282, 1224,
(400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.28 (s, 2H), 7.27 (d,
J = 1.2 Hz, 1H), 7.10 (d, J = 6.8 Hz, 1H), 6.99 (t, J = 7.6,
1H), 4.09–3.61 (m, 2H), 2.36 (s, 3H), 0.83 (t, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 179.1, 164.8,
159.7, 159.40, 140.4, 136.9, 129.0, 123.7, 122.6, 117.8,
114.2, 104.6, 60.9, 56.4, 50.3, 19.2, 13.4 ppm; HRMS (ESI)
m/z: [M + K]+ calcd for C17H14ClN3O4K, 398.0310; found,
398.0306.
1
1129, 1081, 757 cm-1; H NMR (400 MHz, DMSO-d6) δ
11.18 (s, 1H), 8.19 (dd, J = 8.8, 2.4 Hz, 1H), 8.04 (d, J =
2.4 Hz, 1H), 7.36 (s, 2H), 7.03 (d, J = 8.8 Hz, 1H), 3.95–
3.71 (m, 2H), 2.38 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 179.6, 164.7, 161.0, 159.5,
149.1, 142.9, 136.5, 126.5, 119.6, 117.7, 110.1, 103.5, 61.1,
55.7, 49.7, 19.4, 13.6 ppm; ESI-MS: m/z = 370 (M + H)+.
4.2.6
Ethyl
2'-amino-6-bromo-3'-cyano-6'-methyl-2-
4.2.10
Ethyl
2'-amino-3'-cyano-6'-methyl-2-oxo-7-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4f)
(trifluoromethyl)spiro[indoline-3,4'-pyran]-5'-carboxylate
(4j)
White solid (361.6 mg, 92% yield); m.p.: 265-266 C;
IR (KBr): 3302, 3178, 2197, 1731, 1674, 1622, 1487, 1459,
o
White solid (358.7 mg, 89% yield); m.p.: 284-285 C;
IR (KBr): 3265, 3153, 2194, 1705, 1670, 1607, 1476, 1415,
1378, 1363, 1288, 1222, 1132, 1071, 742, 679, 644 cm-1; 1H
o

Tetrahedron
7
1382, 1336, 1315, 1293, 1219, 1170, 1142, 1083, 751 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.49 (d, J
= 8.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.30 (s, 2H), 7.13 (t,
J = 8.4 Hz, 1H), 4.02–3.57 (m, 2H), 2.36 (s, 3H), 0.78 (s,
6.93 (m, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.56–5.46 (m, 1H),
5.18–4.87 (m, 2H), 4.32–4.30 (m, 2H), 2.35 (s, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) δ 179.0, 164.8, 159.4,
159.2, 142.5, 134.9, 132.0, 129.0, 123.9, 122.3, 118.4,
117.9, 109.9, 105.1, 65.4, 57.0, 49.5, 19.2 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C18H15N3O4Na, 360.0960;
found, 360.0951.
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 179.6, 164.7,
1
160.3, 159.5, 140.0, 137.1, 125.5, 122.6, 124.1 (q, JCF
=
2
270.2 Hz), 117.6, 111.1 (q, JCF = 22.6 Hz), 104.1, 60.9,
56.2, 48.7, 19.2, 13.2 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C18H14F3N3O4Na, 416.0834; found, 416.0839.
4.2.15
Ethyl
2'-amino-3'-cyano-6'-ethyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4o)
o
4.2.11
Methyl
2'-amino-3'-cyano-6'-methyl-2-
White solid (311.9 mg, 92% yield); m.p.: 222-223 C;
IR (KBr): 3389, 3177, 2197, 1712, 1682, 1600, 1405, 1364,
1224, 1149, 1081, 752 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 10.43 (s, 1H), 7.32–7.12 (m, 3H), 7.10–7.03 (m, 1H),
6.98–6.94 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.86–3.69 (m,
2H), 2.75–2.62 (m, 2H), 1.20 (t, J = 6.8 Hz, 3H), 0.81 (t, J
= 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
179.0, 164.8, 163.0, 159.7, 142.6, 134.9, 129.1, 123.8,
122.4, 118.0, 109.8, 104.7, 60.8, 56.8, 49.4, 25.4, 13.5, 12.1
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C18H17N3O4Na,
362.1117; found, 362.1122.
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4k)
White solid (289.2 mg, 93% yield); m.p.: 244-245 oC(lit.
245-247 oC [25]); IR (KBr): 3390, 3307, 3195, 2199, 1715,
1621, 1586, 1487, 1416, 1379, 1268, 1095, 1076, 762, 618
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.28–
7.11 (m, 3H), 7.12–7.01 (m, 1H), 7.05–6.90 (m, 1H), 6.82
(d, J = 7.6 Hz, 1H), 3.36 (s, 3H), 2.33 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 179.0, 165.6, 159.4, 158.9,
142.4, 134.9, 129.1, 123.8, 122.4, 118.0, 109.8, 105.3, 56.9,
51.9, 49.5, 19.3 ppm; ESI-MS: m/z = 311 (M + H)+.
4.2.12
Isobutyl
2'-amino-3'-cyano-6'-methyl-2-
4.2.16
Ethyl
2'-amino-3'-cyano-6'-ethyl-5-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4l)
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4p)
o
o
White solid (331.8 mg, 94% yield); m.p.: 232-234 C;
IR (KBr): 3208, 3096, 2968, 2920, 2873, 2230, 1724, 1713,
White solid (300.1 mg, 85% yield); m.p.: 247-249 C;
IR (KBr): 3389, 3198, 2200, 1709, 1667, 1625, 1583, 1493,
1653, 1472, 1407, 1365, 1283, 1220, 1127, 754 cm-1; H
1409, 1305, 1203, 1100, 1064, 734 cm-1; H NMR (400
1
1
NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.89 (d, J =
7.6 Hz, 1H), 7.59–7.55 (m, 1H), 7.16–7.11 (m, 1H), 6.94 (d,
J = 7.6 Hz, 1H), 3.85 (d, J = 6.4 Hz, 2H), 3.61 (s, 2H), 2.18
(s, 3H), 1.91–1.83 (m, 1H), 0.89 (d, J = 2.8 Hz, 3H), 0.87 (d,
J = 2.8 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
174.6, 167.7, 166.2, 164.2, 151.1, 147.0, 143.6, 138.2,
126.3, 123.4, 119.1, 113.5, 112.0, 81.1, 70.7, 50.0, 27.7,
19.3 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C19H19N3O4Na, 376.1273; found, 376.1280.
MHz, DMSO-d6) δ 10.32 (s, 1H), 7.16 (s, 2H), 7.07–6.96
(m, 1H), 6.87 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 3.84–3.76
(m, 2H), 2.85–2.60 (m, 2H), 2.25 (s, 3H), 1.20 (t, J = 7.2
Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 179.0, 164.9, 163.0, 159.6, 140.1, 135.1, 131.2,
129.3, 124.3, 118.0, 109.6, 104.7, 60.8, 57.0, 49.4, 25.4,
21.2, 13.5, 12.1 ppm; HRMS (ESI) m/z: [M + K]+ calcd for
C19H19N3O4K, 392.1013; found, 392.1007.
4.2.17
Ethyl
2'-amino-5-chloro-3'-cyano-6'-ethyl-2-
4.2.13 2-Methoxyethyl 2'-amino-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4m)
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4q)
o
White solid (346.9 mg, 93% yield); m.p.: 250-251 C;
IR (KBr): 3390, 3188, 2200, 1713, 1620, 1584, 1476, 1413,
o
Yellow solid (330.2 mg, 93% yield); m.p.: 179-181 C
(lit. 179-181 oC [29]); IR (KBr): 3304, 3189, 2197, 1682,
1652, 1622, 1558, 1472, 1417, 1378, 1288, 1211, 1134,
1340, 1283, 1212, 1174, 1072, 825 cm-1; H NMR (400
1
MHz, DMSO-d6) δ 10.59 (s, 1H), 7.32–7.23 (m, 3H), 7.18
(d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.91–3.72 (m,
2H), 2.72 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.86
(t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
178.8, 164.7, 163.9, 159.7, 141.5, 137.2, 129.0, 126.3,
123.9, 117.9, 111.3, 103.8, 60.93, 6.2, 49.7, 25.5, 13.4, 12.1
1
1072, 753 cm-1; H NMR (400 MHz, DMSO-d6) δ 10.36 (s,
1H), 7.18 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 (s, 2H), 7.06–6.99
(m, 1H), 6.94–6.90 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.04–
3.68 (m, 2H), 3.20–3.12 (m, 2H), 3.12 (s, 3H), 2.32 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 178.9, 165.1, 159.2,
142.6, 134.9, 129.0, 123.8, 122.3, 117.9, 109.9, 105.2, 69.5,
63.8, 58.4, 57.1, 49.5, 19.4 ppm; ESI-MS: m/z = 355 (M +
H)+.
ppm; HRMS (ESI) m/z: [M
+
Na]+ calcd for
C18H16ClN3O4Na, 396.0727; found, 396.0718.
4.2.18
Ethyl
2'-amino-3'-cyano-6'-ethyl-5-nitro-2-
4.2.14
Allyl
2'-amino-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4r)
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4n)
Brown solid (357.1 mg, 93% yield); m.p.: 258-259 oC;
IR (KBr): 3399, 3188, 2196, 1716, 1668, 1626, 1528, 1455,
o
White solid (313.4 mg, 93% yield); m.p.: 242-244 C;
IR (KBr): 3298, 3185, 2197, 1732, 1682, 1635, 1623, 1603,
1473, 1410, 1377, 1331, 1284, 1212, 1131, 1091, 753 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.21 (dd, J
= 7.6, 1.2 Hz, 1H), 7.18 (s, 2H), 7.12–7.04 (m, 1H), 6.97–
1416, 1363, 1341, 1279, 1212, 1138, 1082, 752 cm-1; H
NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.22 (dd, J =
8.8, 2.4 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.41 (s, 2H), 7.06
(d, J = 8.4 Hz, 1H), 3.88–3.82 (m, 2H), 2.83–2.71 (m, 2H),
1

Tetrahedron
8
1.22 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 179.6, 164.9, 164.5, 159.8,
149.1, 142.9, 136.3, 126.6, 119.5, 117.7, 110.1, 103.1, 61.2,
55.5, 49.6, 25.7, 13.4, 11.9 ppm; HRMS (ESI) m/z: [M +
Na]+ calcd for C18H16N4O6Na, 407.0968; found, 407.0972.
IR (KBr): 3308, 3171, 2189, 1727, 1673, 1626, 1606, 1480,
1
1456, 1338, 1193, 840, 787 cm-1; H NMR (400 MHz,
DMSO-d6) δ 11.20 (s, 1H), 8.21 (dd, J = 8.6, 2.4 Hz, 1H),
8.06 (d, J = 2.4 Hz, 1H), 7.40 (s, 2H), 7.06 (d, J = 8.4 Hz,
1H), 3.44 (s, 3H), 2.40 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 179.6, 165.4, 160.9, 159.5, 148.9, 142.9, 136.4,
126.5, 119.5, 117.6, 110.0, 103.8, 55.6, 52.2, 49.8, 19.7
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C16H12N4O6Na,
379.0655; found, 379.0661.
4.2.19
Methyl
2'-amino-3'-cyano-5,6'-dimethyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4s)
o
White solid (299.0 mg, 92% yield); m.p.: 289-290 C;
IR (KBr): 3387, 3148, 2188, 1724, 1674, 1626, 1604, 1418,
1
1375, 1290, 1100, 809, 792, 567 cm-1; H NMR (400 MHz,
4.2.24 Methyl 2'-amino-3'-cyano-7-fluoro-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4x)
DMSO-d6) δ 10.32 (s, 1H), 7.15 (s, 2H), 7.03–6.95 (m, 1H),
6.92–6.85 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 3.38 (s, 3H),
2.34 (s, 3H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 179.0, 165.6, 159.3, 159.0, 139.9, 135.1, 131.1,
129.3, 124.4, 118.0, 109.5, 105.4, 57.2, 51.9, 49.6, 21.1,
19.3 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C17H15N3O4Na, 348.0960; found, 348.0954.
o
Yellow solid (299.4 mg, 91% yield); m.p.: 248-249 C;
IR (KBr): 3335, 3184, 2192, 1733, 1678, 1635, 1540, 1416,
1
1381, 1379, 1267, 1215, 1158, 1073, 650 cm-1; H NMR
(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.29 (s, 2H), 7.16–
7.12 (m, 1H), 7.04–6.93 (m, 2H), 3.42 (s, 3H), 2.36 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 178.8, 165.5, 159.5,
1
3
159.4, 146.6 (d, JCF4 = 240.7 Hz), 137.9, 129.4 (d, JCF
=
4.2.20 Methyl 2'-amino-3'-cyano-5-fluoro-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4t)
12.4 Hz), 123.3 (d, JCF = 4.0 Hz), 119.9, 117.8, 116.1 (d,
2JCF = 17.3 Hz), 104.9, 56.5, 52.0, 49.9, 19.3 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C16H12FN3O4Na, 352.0710;
found, 352.0716.
o
White solid (306.0 mg, 93% yield); m.p.: 254-255 C;
IR (KBr): 3391, 3159, 2191, 1727, 1674, 1606, 1489, 1418,
1377, 1381, 1291, 1091, 800, 604 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 10.46 (s, 1H), 7.25 (s, 2H), 7.11–6.98 (m, 2H),
6.82–6.80 (m, 1H), 3.41 (s, 3H), 2.35 (s, 3H) ppm; 13C
4.2.25 Methyl 2'-amino-7-chloro-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4y)
1
o
NMR (100 MHz, DMSO-d6) δ 179.1, 165.5, 159.6 (d, JCF
White solid (310.5 mg, 90% yield); m.p.: 261-262 C;
3
= 236.0 Hz), 157.5, 138.6, 136.8 (d, JCF = 7.5 Hz), 117.8,
IR (KBr): 3395, 3301, 2192, 1733, 1683, 1618, 1598, 1473,
2
1
115.3 (d, JCF = 23.1 Hz), 111.8, 110.6, 110.5, 104.7, 56.5,
1412, 1380, 1327, 1225, 1194, 1124, 1070, 740 cm-1; H
52.0, 50.1, 19.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C16H12FN3O4Na, 352.0710; found, 352.0702.
NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.33–7.24 (m,
3H), 7.08 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.42
(s, 3H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6)
δ 179.0, 165.5, 159.6, 159.4, 140.2, 136.8, 129.1, 123.7,
122.6, 117.8, 114.1, 104.9, 56.4, 52.1, 50.5, 19.5 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C16H12ClN3O4Na,
368.0414; found, 368.0426.
4.2.21 Methyl 2'-amino-5-chloro-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4u)
o
White solid (317.4 mg, 92% yield); m.p.: 280-281 C
(lit. >260 oC [30]); IR (KBr): 3378, 3291, 3154, 2190, 1728,
1674, 1604, 1479, 1375, 1290, 1175, 1107, 1083, 689 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.33–7.18
(m, 4H), 6.84 (d, J = 8.0 Hz, 1H), 3.43 (s, 3H), 2.36 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 178.8, 165.5, 160.0,
159.5, 141.3, 137.2, 128.9, 126.3, 124.0, 117.8, 111.2, 104.5,
56.4, 52.1, 49.9, 19.5 ppm; ESI-MS: m/z = 345 (M + H)+.
4.2.26
Methyl
2'-amino-3'-cyano-6'-methyl-2-oxo-7-
(trifluoromethyl)spiro[indoline-3,4'-pyran]-5'-carboxylate
(4z)
o
White solid (344.9 mg, 91% yield); m.p.: 246-247 C;
IR (KBr): 3352, 3190, 2202, 1716, 1682, 1623, 1603, 1456,
1
1337, 1122, 1097, 809, 739 cm-1; H NMR (400 MHz,
4.2.22 Methyl 2'-amino-5-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4v)
DMSO-d6) δ 10.91 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (d,
J = 7.6 Hz, 1H), 7.31 (s, 2H), 7.12 (t, J = 7.6 Hz, 1H), 3.36
o
White solid (361.8 mg, 93% yield); m.p.: 242-243 C
(s, 3H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6)
(lit. 240-242 oC [32]); IR (KBr): 3377, 3168, 2202, 1716,
1670, 1616, 1591, 1475, 1416, 1378, 1385, 1219, 1176,
δ 179.5, 165.4, 160.1, 159.5, 139.9, 136.9, 126.7 (d, JCF
=
1
2
241.6 Hz), 122.8, 117.6, 111.3 (d, JCF = 32.5 Hz), 104.6,
56.5, 56.1, 52.0, 48.8, 19.5 ppm; HRMS (ESI) m/z: [M +
Na]+ calcd for C17H12F3N3O4Na, 402.0678; found, 402.0685.
1
1136, 1079, 747 cm-1; H NMR (400 MHz, DMSO-d6) δ
10.58 (s, 1H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 7.35–7.20 (m,
3H), 6.79 (d, J = 8.4 Hz, 1H), 3.42 (s, 3H), 2.36 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 178.7, 165.5, 160.0,
159.4, 141.7, 137.6, 131.8, 126.7, 117.8, 113.9, 111.8, 104.4,
56.4, 52.0, 49.8, 19.7 ppm; ESI-MS: m/z = 389 (M + H)+.
4.2.27 Methyl 2'-amino-4-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4aa)
o
White solid (365.7 mg, 94% yield); m.p.: >300 C; IR
(KBr): 3427, 3308, 3184, 2198, 1704, 1672, 1606, 1446,
1
4.2.23
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4w)
White solid (324.0 mg, 91% yield); m.p.: 256-257 C;
Methyl
2'-amino-3'-cyano-6'-methyl-5-nitro-2-
1416, 1326, 1171, 1219, 1171, 1073, 907, 655 cm-1; H
NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.28 (s, 2H),
7.20–7.06 (m, 2H), 6.85 (dd, J = 7.2, 1.2 Hz, 1H), 3.45 (s,
o

Tetrahedron
9
3H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
178.2, 165.4, 160.6, 160.2, 144.6, 131.5, 131.0, 125.8,
118.8, 117.7, 109.4, 103.3, 54.3, 52.1, 51.4, 19.5 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C16H12BrN3O4Na,
411.9909; found, 411.9908.
104.1, 71.1, 56.6, 49.7, 27.4, 19.1 ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C19H18BrN3O4Na, 454.0378; found,
454.0385.
4.2.32 Isobutyl 2'-amino-3'-cyano-6'-methyl-5-nitro-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4af)
o
4.2.28 Methyl 2'-amino-6-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4ab)
White solid (370.1 mg, 93% yield); m.p.: 270-271 C;
IR (KBr): 3305, 3187, 2192, 1723, 1674, 1630, 1584, 1480,
o
1
White solid (346.2 mg, 89% yield); m.p.: 286-287 C;
1377, 1346, 1293, 1213, 1133, 1076, 754 cm-1; H NMR
IR (KBr): 3388, 3307, 3191, 2199, 1716, 1673, 1586, 1435,
1416, 1321, 1285, 1187, 1074, 911, 632 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 10.63 (s, 1H), 7.30 (s, 2H), 7.18 (dd, J =
7.6, 1.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.0
Hz, 1H), 3.46 (s, 3H), 2.56 (s, 3H) ppm; 13C NMR (100
MHz, DMSO-d6) δ 178.9, 165.5, 159.6, 159.4, 144.1, 134.4,
125.7, 125.0, 121.5, 117.8, 112.6, 104.7, 56.3, 52.1, 49.4,
19.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C16H12BrN3O4Na, 411.9909; found, 411.9903.
(400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.21 (dd, J = 8.8, 2.0
Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.38 (s, 2H), 7.05 (d, J =
8.4 Hz, 1H), 3.68–3.59 (m, 2H), 2.43 (s, 3H), 1.61–1.59 (m,
1H), 0.72 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) δ 179.5, 164.9, 161.1,
159.4, 148.9, 143.0, 136.5, 126.6, 119.7, 117.6, 110.1,
103.4, 71.3, 55.8, 49.6, 27.4, 19.1, 14.5 ppm; HRMS (ESI)
m/z: [M + Na]+ calcd for C19H18N4O6Na, 421.1124; found,
421.1120.
4.2.29 2-Methoxyethyl 2'-amino-5-bromo-3'-cyano-6'-
methyl-2-oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4ac)
4.2.33
Allyl
2'-amino-5-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4ag)
o
o
Brown solid (389.7 mg, 90% yield); m.p.: 220-221 C
Yellow solid (373.5 mg, 90% yield); m.p.: 259-260 C
(lit. >265 oC [31]); IR (KBr): 3314, 3203, 2204, 1720, 1653,
1617, 1592, 1476, 1414, 1380, 1280, 1220, 1138, 1066, 742
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.35
(dd, J = 8.0, 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.25 (s,
2H), 6.74 (d, J = 8.0 Hz, 1H), 5.60–5.50 (m, 1H), 5.14–4.91
(m, 2H), 4.34–4.32 (m, 2H), 2.34 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 178.6, 164.6, 160.3, 159.3, 141.8,
137.6, 132.0, 126.8, 118.6, 117.8, 113.9, 111.9, 104.2, 65.5,
56.5, 49.7, 19.6 ppm; ESI-MS: m/z = 415 (M + H)+.
(lit. 221-222 oC [29]); IR (KBr): 3292, 2196, 1670, 1474,
1376, 1289, 1086, 974, 746, 627 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 10.51 (s, 1H), 7.35 (dd, J = 8.0, 2.0 Hz, 1H),
7.28 (d, J = 2.0 Hz, 1H), 7.23 (s, 2H), 6.76 (d, J = 8.4 Hz,
1H), 4.03–3.80 (m, 2H), 3.23 (t, J = 4.8 Hz, 2H), 3.13 (s,
3H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
178.6, 165.0, 160.3, 159.3, 141.8, 137.6, 131.7, 126.7,
117.8, 113.9, 111.9, 104.2, 69.6, 64.0, 58.4, 56.5, 49.7, 19.4
ppm; ESI-MS: m/z = 433 (M + H)+.
4.2.30 2-Methoxyethyl 2'-amino-3'-cyano-6'-methyl-2-oxo-
7-(trifluoromethyl)spiro[indoline-3,4'-pyran]-5'-
carboxylate (4ad)
4.2.34
Allyl
2'-amino-3'-cyano-6'-methyl-2-oxo-7-
(trifluoromethyl)spiro[indoline-3,4'-pyran]-5'-carboxylate
(4ah).
o
o
White solid (393.4 mg, 93% yield); m.p.: 190-191 C;
White solid (372.6 mg, 92% yield); m.p.: 262-263 C;
IR (KBr): 3171, 2205, 1735, 1672, 1623, 1604, 1489, 1377,
IR (KBr): 3306, 3176, 2194, 1733, 1674, 1636, 1620, 1600,
1
1
1279, 1217, 1132, 1073, 769 cm-1; H NMR (400 MHz,
1487, 1417, 1384, 1315, 1199, 1138, 1080, 708 cm-1; H
DMSO-d6) δ 10.88 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (d,
J = 7.2 Hz, 1H), 7.30 (s, 2H), 7.12 (t, J = 8.0 Hz, 1H), 3.98–
3.83 (m, 2H), 3.27–3.14 (m, 2H), 3.08 (s, 3H), 2.37 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 179.4, 164.8, 160.4,
NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.47 (d, J =
8.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.31 (s, 2H), 7.12 (t, J
= 7.6 Hz, 1H), 5.41–5.51 (m, 1H), 5.05–4.91 (m, 2H), 4.38–
4.18 (m, 2H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 179.5, 164.5, 160.5, 159.4, 139.9, 137.0, 131.7,
1
159.4, 139.9, 137.0, 124.2 (q, JCF = 270.6 Hz), 122.6,
2
1
117.6, 111.4 (q, JCF = 32.5 Hz), 104.3, 69.4, 63.9, 58.4,
124.1 (q, JCF = 270.4 Hz), 122.6, 118.9, 117.6, 111.0 (q,
56.3, 48.7, 19.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C19H16F3N3O5Na, 446.0940; found, 446.0936.
2JCF = 32.5 Hz), 104.2, 65.6, 56.3, 48.7, 19.4 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C19H14F3N3O4Na, 428.0834;
found, 428.0840.
4.2.31 Isobutyl 2'-amino-5-bromo-3'-cyano-6'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carboxylate (4ae)
4.2.35
3'-Acetyl-6'-amino-2'-methyl-2-oxospiro[indoline-
o
Yellow solid (392.2 mg, 91% yield); m.p.: 245-246 C;
3,4'-pyran]-5'-carbonitrile (4ai)
o
IR (KBr): 3313, 3198, 2207, 1706, 1652, 1617, 1593, 1474,
White solid (274.4 mg, 93% yield); m.p.: 247-248 C
(lit. 242-243 oC [29]); IR (KBr): 3345, 3118, 2188, 1709,
1681, 1653, 1619, 1605, 1481, 1467, 1377, 1319, 1258,
1211, 1120, 1051, 768 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 10.38 (s, 1H), 7.15 (m, 1H), 7.11 (s, 2H), 7.03 (d, J = 7.2
Hz, 1H), 6.92 (m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 2.28 (s,
3H), 2.09 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
198.0, 179.0, 159.7, 156.6, 142.5, 134.6, 129.0, 123.8,
1
1417, 1378, 1298, 1222, 1135, 1068, 777, 688 cm-1; H
NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.38 (dd, J =
8.4, 3.2 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.26 (s, 2H), 6.79
(d, J = 8.4 Hz, 1H), 3.70–3.56 (m, 2H), 2.38 (s, 3H), 3.67–
3.58 (m, 1H), 0.72 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 178.6, 165.1,
160.3, 159.3, 141.7, 137.8, 126.6, 117.8, 114.0, 111.9,

Tetrahedron
10
122.3, 118.0, 115.3, 110.0, 57.2, 49.9, 31.7, 19.8 ppm; ESI-
MS: m/z = 295 (M + H)+.
265 oC [34]); IR (KBr): 3288, 3151, 2197, 1711, 1687, 1653,
1642, 1605, 1467, 1405, 1385, 1355, 1312, 1247, 1218,
1050, 780 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s,
1H), 7.20 (s, 2H), 7.10–7.05 (m, 1H), 6.96–6.86 (m, 2H),
4.2.36
3'-Acetyl-6'-amino-5-methoxy-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4aj)
2.34 (s, 3H), 2.16 (s, 3H) ppm; 13C NMR (100 MHz,
o
1
White solid (295.8 mg, 91% yield); m.p.: 278-279 C
(lit. 276-277 oC [33]); IR (KBr): 3257, 3176, 2193, 1697,
1653, 1592, 1492, 1466, 1437, 1418, 1378, 1297, 1155,
1055, 785 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s,
1H), 7.10 (s, 2H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (d, J
= 8.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 3.67 (s, 3H), 2.28 (s,
3H), 2.09 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
198.0, 178.9, 159.7, 156.5, 155.5, 135.82, 135.8, 118.0,
115.2, 113.6, 110.3, 57.4, 55.9, 50.3, 31.8, 31.7, 19.8 ppm;
ESI-MS: m/z = 325 (M + H)+.
DMSO-d6) δ 197.7, 178.8, 159.6, 157.8, 146.3 (d, JCF
=
=
240.8 Hz), 137.8, 129.5 (d, 3JCF = 12.4 Hz), 123.1 (d, 4JCF
4.1 Hz), 119.7, 117.8, 116.0 (d, 2JCF = 16.1 Hz), 115.2, 56.8,
50.3, 32.0, 31.9, 20.2, 20.0 ppm; ESI-MS: m/z = 313 (M +
H)+.
4.2.41
3'-Acetyl-6'-amino-7-chloro-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4ao)
o
White solid (289.5 mg, 88% yield); m.p.: 278-279 C
(lit. 276-277 oC [33]); IR (KBr): 3285, 3168, 2193, 1725,
1671, 1644, 1620, 1601, 1475, 1418, 1379, 1362, 1303,
1220, 1166, 1062, 775 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 10.82 (s, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.24 (s, 2H), 7.04
(dd, J = 7.2, 1.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 2.38 (s,
3H), 2.21 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
197.74, 179.0, 159.6, 158.0, 140.3, 136.7, 128.9, 123.5,
122.3, 117.8, 115.2, 114.0, 56.7, 50.8, 32.1, 20.2 ppm; ESI-
MS: m/z = 329 (M + H)+.
4.2.37
3'-Acetyl-6'-amino-5-fluoro-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4ak)
o
White solid (284.8 mg, 91% yield); m.p.: 298-300 C
(lit. 260 oC [34]); IR (KBr): 3284, 3140, 2196, 1705, 1687,
1651, 1628, 1605, 1487, 1456, 1405, 1384, 1357, 1265,
1
1220, 1153, 1082, 792, 624 cm-1; H NMR (400 MHz,
DMSO-d6) δ 10.38 (s, 1H), 7.18 (s, 2H), 7.03–6.90 (m, 2H),
6.76 (dd, J = 8.4, 4.4 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 197.7, 179.1, 159.6,
4.2.42
3'-Acetyl-6'-amino-2'-methyl-2-oxo-7-
1
3
158.6 (d, JCF = 235.6 Hz), 157.7, 138.7, 136.6 (d, JCF
=
(trifluoromethyl)spiro[indoline-3,4'-pyran]-5'-carbonitrile
2
7.6 Hz), 117.9, 115.2, 115.0, 111.4 (d, JCF = 23.4 Hz),
110.6, 56.8, 50.4, 31.9, 20.2 ppm; ESI-MS: m/z = 313 (M +
H)+.
(4ap)
o
White solid (330.3 mg, 91% yield); m.p.: 283-285 C;
IR (KBr): 3348, 3187, 2192, 1732, 1674, 1650, 1624, 1602,
1488, 1418, 1380, 1317, 1299, 1219, 1116, 1061, 754 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.43 (d, J
= 8.0 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.25 (s, 2H), 7.08 (t,
J = 8.0 Hz, 1H), 2.38 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 197.6, 179.5, 159.6, 158.7, 140.0,
4.2.38
3'-Acetyl-6'-amino-5-bromo-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4al)
White solid (335.7 mg, 90% yield); m.p.: 224-225oC (lit.
220-222 oC [32]); IR (KBr): 3356, 3235, 2192, 1703, 1653,
1617, 1593, 1478, 1419, 1378, 1300, 1215, 1175, 1053, 817,
1
137.0, 127.5, 125.3, 124.2 (q, JCF = 270.2 Hz), 122.3,
1
2
605 cm-1; H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H),
117.7, 115.1, 110.7 (q, JCF = 32.5 Hz), 56.6, 49.1, 32.1,
7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.20
(s, 2H), 6.74 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 2.20 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 197.5, 178.7, 159.5,
158.6, 141.8, 137.6, 131.6, 126.3, 117.9, 114.9, 113.8, 111.7,
56.7, 50.1, 32.1, 20.2 ppm; ESI-MS: m/z = 373 (M + H)+.
20.4 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C17H12F3N3O3Na, 386.0728; found, 386.0717.
4.2.43
3'-Acetyl-6'-amino-4-bromo-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4aq)
o
Yellow solid (320.8 mg, 86% yield); m.p.: >300 C; IR
(KBr): 3445, 3164, 2196, 1733, 1682, 1653, 1609, 1584,
4.2.39
3'-Acetyl-6'-amino-2'-methyl-5-nitro-2-
1
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4am)
1473, 1415, 1301, 1218, 1207, 1133, 1071, 630 cm-1; H
o
White solid (316.2 mg, 93% yield); m.p.: >300 C
(lit. >300 oC [33]); IR (KBr): 3367, 3179, 2195, 1744, 1682,
1626, 1505, 1482, 1379, 1361, 1335, 1304, 1257, 1219,
NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.26 (d, J =
8.0 Hz, 1H), 7.23 (s, 2H), 7.07 (dd, J = 8.0, 1.2 Hz, 1H),
6.82 (d, J = 6.4 Hz, 1H), 2.38 (s, 3H), 2.25 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 197.4, 178.2, 160.3, 158.9,
144.7, 131.4, 127.2, 125.6, 118.6, 117.7, 114.0, 109.3, 54.6,
51.7, 31.8, 20.3 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C16H12N3O3Na, 317.0776; found, 317.0764.
1
1177, 1120, 1060, 988, 829 cm-1; H NMR (400 MHz,
DMSO-d6) δ 11.10 (s, 1H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H),
7.94 (d, J = 2.4 Hz, 1H), 7.32 (s, 2H), 6.99 (d, J = 8.4 Hz,
1H), 2.43 (s, 3H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 197.4, 179.6, 160.1, 159.6, 149.1, 142.8, 136.5,
126.2, 119.1, 117.6, 114.7, 109.9, 56.1, 50.0, 32.2, 20.7
ppm; ESI-MS: m/z = 340 (M + H)+.
4.2.44
3'-Acetyl-6'-amino-5,6-difluoro-2'-methyl-2-
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4ar)
o
White solid (288.0 mg, 87% yield); m.p.: 289-291 C;
IR (KBr): 3310, 3198, 2190, 1721, 1695, 1667, 1636, 1597,
1473, 1422, 1395, 1380, 1337, 1284, 1206, 1160, 1086, 775
4.2.40
oxospiro[indoline-3,4'-pyran]-5'-carbonitrile (4an)
Yellow solid (266.1 mg, 85% yield); m.p.: >300 C (lit.
3'-Acetyl-6'-amino-7-fluoro-2'-methyl-2-
o
1
cm-1; H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.25

Tetrahedron
11
(dd, J = 9.6, 8.0 Hz, 1H), 7.21 (s, 2H), 6.81 (dd, J = 10.4,
6.4 Hz, 1H), 2.34 (s, 3H), 2.19 (s, 3H) ppm; 13C NMR (100
MHz, DMSO-d6) δ 197.7, 179.2, 159.6, 158.2, 151.1 (dd,
JCF =242.6, 14.1 Hz), 147.1 (dd, JCF =237.8, 13.3 Hz),
[4] Zhang, Q. B.; Ban, Y. L.; Yuan, P. F.; Peng, S. J.; Fang, J.
G.; Wu, L. Z.; Liu, Q. Green Chem. 2017, 19, 5559-5563.
[5] Li, G.; He, R.; Liu, Q.; Wang, Z. W.; Liu, Y. X.; W. J.
Org. Chem. 2019, 84, 8646-8660.
[6] Xie, L.-Y.; Fang, T.-G.; Tan, J.-X.; Zhang, B.; Cao, Z.; Yang,
L.-H.; He, W.-M. Green Chem. 2019, 21, 3858-3863.
[7] (a) Chen, Y. J.; He, Y. H.; Guan, Z. Tetrahedron 2019, 75,
3053-3061;
3
139.2 (d, JCF = 9.8 Hz), 131.0, 117.8, 114.9,113.6 (dd, JCF
=18.3, 7.1 Hz), 99.6, 56.5, 50.0, 32.1, 20.3 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C16H11F2N3O3Na, 354.0666;
found, 354.0672.
(b) Shu, Q.; Li, Y. M.; Liu, T.; Zhang, S. Y.; Jiang, L. L.;
Jin, K.; Zhang, R.; Duan, C. Y. Tetrahedron 2019, 75, 3636-
3642;
(c) Li, W. P.; Zhu, Y. C.; Zhou, Y. J.; Yang, H. W.; Zhu, C. J.
Tetrahedron 2019, 75, 1647-1651;
(d) Tang, N. N.; Yang, S.; Wu, X. X.; Zhu, C. Tetrahedron
2019, 75, 1639-1646;
(e) Zhang, X. D.; Li, Y. M.; Hao, X. Y.; Jin, K.; Zhang, R.;
Duan, C. Y. Tetrahedron 2018, 74, 7358-7363.
4.3 Synthesis of intermediate II
A mixture of ethyl acetoacetate (1 mmol) and Na2
eosin Y (0.02 mmol) in ethyl lactate/water (3:1, 2 mL) was
taken in a reaction tube, radical inhibitor BHT (3.0 mmol)
was added. The reaction tube was exposed to green LED
(450–455 nm, 10 W) irradiation at room temperature in air
with stirring for 5 h. Then, the reaction mixture was poured
into H2O (15 mL) and extracted with EtOAc ( (3 × 20 mL).
The combined organic layer was washed with brine (15 mL)
and dried over sodium sulfate. The solvent was removed
under reduced pressure, and the crude reaction mixture was
purified by flash chromatography using ethyl
acetate/hexane as an eluent to give intermediate II.
[8] Heravi, M. M.; Zadsirjan, V.; Dehghani, M.; Ahmadi, T.
Tetrahedron 2018, 74, 3391-3457.
[9] Jian, H.; Wang, Q.; Wang, W. H.; Li, Z. J.; Gu, C. Z.; Dai,
B.; He, L. Tetrahedron 2018, 74, 2876-2883.
[10] Wu, J. R.; Luo, H.; Wang, T.; Sun, H. M.; Zhang, Q.; Chai,
Y. H. Tetrahedron 2019, 75, 1052-1063.
4.3.1
Ethyl
2-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-
oxobutanoate (intermediate II) [43]
[11] (a) Tiwari, J.; Saquib, M.; Singh, S.; Tufail, F.; Singh, M.;
Colorless oil (63.0 mg, 18% yield); IR (KBr): 2920,
1718, 1470, 1435, 1363, 1274, 1212, 1143, 1024, 883 cm-1;
1H NMR (400 MHz, CDCl3) δ 6.95 (s, 2H), 5.08 (s, 1H),
4.15 (q, J = 7.2 Hz, 2H), 3.73 (t, J = 7.6 Hz, 1H), 3.08 (d, J
= 7.6 Hz, 2H), 2.19 (s, 3H), 1.41 (s, 18H), 1.19 (t, J = 6.8
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 207.3, 187.5,
135.9, 128.7, 125.4, 125.2, 34.3, 30.4, 30.3, 29.8, 14.2 ppm;
ESI-MS: m/z = 371 (M + Na)+.
Singh, J.; Singh, J. Green Chem. 2016, 18, 3221-3231;
(b) Zhang, M.; Chen, M. N.; Zhang, Z. H. Adv. Synth. Catal.
2019, 36, 5182-5190;
(c) Zhang, M.; Chen, M. N.; Li, J. M.; Liu, N.; Zhang, Z. H.
ACS Comb. Sci. 2019, 21, 685-691.
[12] Wu, J. R.; Luo, H.; Wang, T.; Sun, H. M.; Zhang, Q.; Chai,
Y. H. Tetrahedron 2019, 75, 1052-1063.
[13] Yang, Y. T.; Zhu, J. F.; Liao, G. C.; Xu, H. J.; Yu, B. T. Curr.
Med.Chem. 2018, 25, 2233-2244.
[14] Mei, G. J.; Shi, F. Chem. Commun. 2018, 54, 6607-6621.
[15] Rainoldi, G.; Begnini, F.; de Munnik, M.; Lo Presti, L.;
Vande Velde, C. M. L.; Orru, R.; Lesma, G.; Ruijter, E.;
Silvani, A. ACS Comb. Sci. 2018, 20, 98-105.
[16] Wang, L. L.; Jiang, T.; Li, P. H.; Sun, R. J.; Zuo, Z. L. Adv.
Synth. Catal. 2018, 360, 4832-4836.
Acknowledgement
We are very grateful to the National Natural Science
Foundation of China (No. 21272053) and the Science
and Technology Research Foundation of Hebei Normal
University (L2018Z06) for financial support.
[17] Ma, B.; Wu, P.; Wang, X.; Wang, Z. Y.; Lin, H. X.; Dai, H.
X. E. Angew. Chem. Int. Ed. 2019, 58, 13335-13339.
[18] Balha, M.; Soni, C.; Pan, S. C. Eur. J. Org. Chem. 2019,
2552-2559.
[19] Xiao, G. L.; Chen, T. T.; Ma, C. Q.; Xing, D.; Hu, W. H. Org.
Lett. 2018, 20, 4531-4535.
[20] Zhang, L. L.; Zhang, J. W.; Xiang, S. H.; Guo, Z.; Tan, B.
Org. Lett. 2018, 20, 6022-6026.
[21] Han, C.; Zhang, T.; Zhang, A. Q.; Wang, D. D.; Shi, W. M.;
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[22] Wang, L. M.; Jiao, N.; Qiu, J.; Yu, J. J.; Liu, J. Q.; Guo, F. L.;
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ꢀ A pot, atom and step economy, three-component reaction has been developed.
ꢀ The use of an inexpensive organic dye, Na2 eosin Y, as the photocatalyst, avoiding of any
metal or acid catalysts.
ꢀ High yields and pure product formation at ambient temperature.
ꢀ Environmentally benign, simple, and highly efficient procedure with no purification needs.
ꢀ The use of light as a rich, readily available and almost inexhaustible source of clean
energy.
ꢀ Wide range of substrates, good product diversity and easy scalability.
ꢀ No toxic and hazardous solvents are used.

Declaration of interests
☐ √ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
The authors declare no competing financial interest.