One-pot Two-step Reaction for Synthesis of Poly-substituted Pyrano[3,2-c]pyridones and Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones in Water

Article abstract of DOI:10.1002/jhet.3646

An efficient four-component approach for the synthesis poly-substituted pyrano[3,2-c]pyridones and spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones in water has been established. During the reaction, the products were readily achieved through one-pot two-step reaction using solid acid as catalyst. The advantages of atom and step economy, the recyclability of heterogeneous solid acid catalyst, easy workup procedure, and the wide scope of substrates make the reaction a powerful tool for assembling pyrano[3,2-c]pyridone skeletons of chemical and medical interest.

Full text of DOI:10.1002/jhet.3646

Month 2019
One-pot Two-step Reaction for Synthesis of Poly-substituted Pyrano[3,2-
c]pyridones and Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-
diones in Water
*
Zhenhang Xu, Yijun Du, Songxiang Wang, Zeru Wu, Yuhao Lou, and Furen Zhang
School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals
Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
*E-mail: frzhang@usx.edu.cn
Received June 12, 2019
DOI 10.1002/jhet.3646
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
An efficient four-component approach for the synthesis poly-substituted pyrano[3,2-c]pyridones and
spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones in water has been established. During the reac-
tion, the products were readily achieved through one-pot two-step reaction using solid acid as catalyst.
The advantages of atom and step economy, the recyclability of heterogeneous solid acid catalyst, easy
workup procedure, and the wide scope of substrates make the reaction a powerful tool for assembling
pyrano[3,2-c]pyridone skeletons of chemical and medical interest.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
acetylation, and multicomponent reactions. During our
continuous efforts on the development of multicomponent
domino reaction using solid acid as catalyst [13], herein,
we would like to report a new one-pot two-step method
for the synthesis of poly-substituted pyrano[3,2-c]
pyridone and spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-
2,5′(6′H)-dione derivatives in water. This reaction was
performed from readily available materials of 4-hydroxy-
6-methyl-2H-pyran-2-one 1, amine 2, aromatic aldehydes
4, and malononitrile 5 in water using solid acid as
catalyst [14] through one-pot two-step four-component
strategy, and the results were shown in Scheme 1. In
addition, only three-component reaction product of 2-
amino-7-methyl-5-oxo-4-phenyl-4H,5H-pyrano[4,3-b]
pyran-3-carbonitrile 7 was obtained when all the substrates
submitted the reaction system through one-pot method.
Pyran-annulated heterocyclic scaffolds, which process
distinct properties of general interest, play an important
role in the building of numerous oxygen-containing
heterocyclic natural compounds [1–3]. The structurally
diverse and intriguing pyranopyridone family has been
found to exist in many natural products and exhibit
important biological activities, such as antibacterial [4],
antifungal and antialgal [5], anti-inflammatory [6],
antileishmanial [7], and anticancer [8]. Among these
skeletons, the selected pyranopyridone derivatives of 2H-
pyrano[3,2-c]pyridines
(I),
YCM1008A(1)
(II),
zanthosimuline (III), and huajiaosimuline (IV) [9], which
exhibit a broad range of biological activities, commonly
exist in nature (Fig. 1). Because of their unique biological
and pharmacological activities, some methodologies for
the formation of pyranopyridone derivatives have been
developed [10]. However, the scopes of bioactive
pyranopyridone molecules are rather limited. Therefore,
the development of an efficient synthetic strategy for
pyranopyridone derivatives is of chemical and biological
importance.
It is an important goal and task of modern organic
chemistry to develop new methods aimed at improving
the efficiency of synthesis and avoiding the introduction
of environmental problems. Because of good stability,
highly catalytic efficiency, environmental friendliness,
low cost, and recyclability, solid acid as catalyst for
organic synthesis has received more and more attention
[11]. At present, many organic synthesis reactions
catalyzed by solid acid have been reported [12], such as
esterification, etherification, dehydration, oxidation,
RESULTS AND DISCUSSION
To begin this study, the compounds 4-hydroxy-6-
methyl-2H-pyran-2-one 1, n-butylamine 2, benzaldehyde
4, and malononitrile 5 were chosen as model substrate to
screen the reaction conditions for the one-pot two-step
reaction. The model reaction was tested under a variety
of conditions, and the representative data were shown in
Table 1. The reaction did not give desired product
without catalyst even at reflux temperature for 24 h
(Table 1, entries 1 and 2). The goal product with 10–47%
yields was obtained when the model reaction was
catalyzed with different heterogeneous catalyst, such as
Amberlyst-15, zeolite (HY), and carbon (the
carbonaceous material from the single furaldehyde). To
© 2019 Wiley Periodicals, Inc.

Z. Xu, Y. Du, S. Wang, Z. Wu, Y. Lou, and F. Zhang
Vol 000
order to evaluate the scope of the protocol. Firstly, the
effect of various groups bearing aromatic aldehydes was
evaluated, after 4 h of the reaction between 4-hydroxy-6-
methyl-2H-pyran-2-one and n-butylamine. To our delight,
a variety of functional groups of aromatic aldehydes were
found to be well tolerated under selected conditions to
give desired products with good to excellent yields
(Table 2). The reactions bearing electron-donating groups,
such as methyl, isopropyl, and methoxyl-substituted
arylaldehyde ring 4, all worked better to provide the
desired products with higher yields than those bearing
electron-withdrawing groups, such as fluoromethyl,
Figure 1. Some of bioactive compounds bearing pyranpyridone-
annulated scaffolds.
chloromethyl,
bromomethyl,
and
trifluoromethyl-
substituted aromatic aldehydes with 3 and 5. The results
indicated that aromatic aldehydes bearing electron-
donating groups were more suitable for the domino
reaction. Bulky o-substituted aromatic aldehydes were
converted into corresponding pyrano[3,2-c]pyridine
derivatives with slightly lower yields 73–80%. Bulky 1-
naphthaldehyde also displays similar activity and gives 2-
amino-6-butyl-7-methyl-4-(naphthalen-1-yl)-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile 6o with
76% yield. Additionally, the heterocyclic 2-
thienylaldehyde also exhibits good activity and gives 2-
amino-6-butyl-7-methyl-5-oxo-4-(thiophen-2-yl)-5,6-
dihydro-4H-pyrano [3,2-c]pyridine-3-carbonitrile 6p with
72% yield. Then, different aliphatic and aromatic amines,
such as n-propylamine, benzylamine, and aniline were
tested to expand the scope of the reaction. Pleasantly, we
found that the reaction can occur smoothly under the
earlier conditions when the aliphatic amines were used.
The results are shown in Table 2. The compounds of 2-
amino-7-methyl-5-oxo-4-aryl-6-propyl-5,6-dihydro-4H-
our delight, up to 91% yield of desired product was
obtained when the solid acid (C─SO3H) was selected to
promote the reaction (Table 1, entry 6). Then, different
homogeneous acidic catalysts, such as HOAc, TsOH,
PhCOOH, CF3COOH, HCl, and H2SO4, were chosen to
catalyze the model reaction, and only 16–51% of goal
product was obtained (Table 1, entries 9–14). The next
loading screening of catalyst indicated that the solid acid
(10 mg) was enough to promote the domino reaction
forward. Subsequently, the model reaction was
carried out with solid acid as catalyst and repeated many
times in different solvents, such as MeOH, EtOH, N,N-
dimethylformamide, tetrahydrofuran, toluene, and
dichloromethane (Table 1, entries 6 and 15–20). The
results indicated that none of other media exhibit better
suitable for the reaction than water. Thus, water was
chosen as the solvent for the following reactions. Finally,
the reaction catalyzed by solid acid was performed and
repeated many times in different temperature. The yield
of product rose when the reaction temperature was
increased from room temperature to 80°C (Table 1,
entries 6 and 21–23). However, a further increase of
reaction temperature failed to improve the yield of the
desired product (Table 1, entry 24).
pyrano[3,2-c]pyridine-3-carbonitrile
and
2-amino-6-
benzyl-7-methyl-5-oxo-4-aryl-5,6-dihydro-4H-pyrano[3,2-
c]pyridine-3-carbonitrile with 82% and 92% yields,
respectively, were obtained. However, the aniline did not
exhibit any activity, and no corresponding target product
was obtained. The earlier cases exhibit the scope and
generality of the four-component one-pot two-step reaction.
With the earlier results in hand, a series of new
pyrano[3,2-c]pyridine derivatives were synthesized in
Scheme 1. Different one-pot procedure for synthesis of pyrano[4,3-b]pyrans and pyrano[3,2-c]pyridones.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis for Poly-substituted Pyrano[3,2-c]pyridones and
Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones
Table 1
Optimization of conditions for one-pot two-step reaction.
Entry
Solvent
Catalyst (mg)
T (°C)
Yielda (%)
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
—
—
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
80
Reflux
80
80
80
80
80
80
80
80
80
80
80
—
—
34
47
10
91
93
51
38
51
32
41
16
34
78
76
42
49
41
14
—
39
77
88
Amberlyst-15 (10)
Zeolite (HY) (10)
Carbon (10)c
C─SO3H (10)
C─SO3H (20)
C─SO3H (5)
HOAc (10)d
TsOH (10)d
PhCOOH (10)d
CF3COOH (10)d
HCl (10)d
H2SO4 (10)d
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
C─SO3H (10)
H2O
80
MeOH
EtOH
DMF
THF
Toluene
DCM
H2O
H2O
H2O
H2O
Reflux
Reflux
80
Reflux
80
Reflux
RT
40
60
Reflux
Reaction conditions: 1 (0.5 mmol) and 2a (0.6 mmol), catalysts (× mg), and solvent (3 mL) were mixed in selected conditions for 4 h, and then 4a (0.5
mmol) and 5a (0.6 mmol) submitted the earlier reaction system for another 4 h.
DMF, dimethylformamide; RT, room temperature; THF, tetrahydrofuran.
aIsolated yields.
bThe reaction was carried out for 24 h.
cThe carbonaceous material from the single furaldehyde.
d10 mol%.
To further expand the scope of the one-pot two-step
four-component reaction, different isatins were used to
replace the aromatic aldehyde (Table 3). A wide range of
substituent isatins including electron-withdrawing groups
and electron-donating groups all furnished the expected
products 9a–9e with 83–89% yields under the earlier
conditions. It is worth mentioning that the protocol
provides a straightforward pathway to prepare a variety
4H-chromene-3-carbonitrile was obtained with 63% yield.
We attributed to the stronger nucleophilicity of oxygen
atom than nitrogen atom to cyano group. The structures
of all the products 6 and 9 were unambiguously
characterized by 1H-NMR, 13C-NMR, and high-
resolution mass spectrometry (HRMS) spectra (see the
Supporting Information).
On the basis of the earlier results, the possible
mechanism for the one-pot two-step reaction is proposed
and shown in Scheme 2. The formation of 6a is expected
to proceed via initial reaction of the compounds 4-
hydroxy-6-methyl-2H-pyran-2-one 1 and n-butylamine 2
to afford 1-butyl-4-hydroxy-6-methylpyridin-2(1H)-one
3a, which undergoes Michael addition with Knoevenagel
condensation indermediate A, formed from benzaldehyde
4 and malononitrile 5, to yield intermediate B, Finally,
intramolecular nucleophilic addition of B afford the
of
poly-substituted
spiro[indoline-3,4′-pyrano[3,2-c]
pyridine]-2,5′(6′H)-diones in one-pot two-step operation.
Additionally, the model reaction was performed again
using 5,5-dimethylcyclohexane-1,3-dione instead of 4-
hydroxy-6-methyl-2H-pyran-2-one. The results indicated
that the desired product 2-amino-1-butyl-7,7-dimethyl-5-
oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile was not obtained; instead, the compound 2-
amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
Journal of Heterocyclic Chemistry
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Z. Xu, Y. Du, S. Wang, Z. Wu, Y. Lou, and F. Zhang
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Table 2
Synthesis of substituted 2-amino-7-methyl-5-oxo-4-aryl-5,6-dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile derivatives.
6a, 91%
6b, 89%
6c, 88%
6d, 87%
6e, 85%
6f, 83%
6g, 82%
6i, 77%
6h, 80%
6j, 79%
6k, 80%
6l, 83%
6o, 76%
6n, 73%
6m, 77%
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis for Poly-substituted Pyrano[3,2-c]pyridones and
Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones
Table 2
(Continued)
6p, 72%
6q, 92%
6r, 85%
6s, 82%
6t, 85%
6u, 86%
6v, 82%
Reaction conditions: 1 (0.5 mmol) and 2 (0.6 mmol), catalysts (10 mg), and water (3 mL) were mixed in selected conditions for 4 h, and then 4 (0.5 mmol)
and 5 (0.6 mmol) submitted the earlier reaction system for another 4 h.
desired product 6a. The function of the solid acid catalyst
is to provide proper acidity for the ammonolysis of
lactone, the Michael addition, and the cyclization for the
formation of 2-amino-6-butyl-7-methyl-5-oxo-4-phenyl-
5,6-dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile 6a.
The main advantages of solid acid catalysis are the
recovery and reusability. The activity of the recovered
solid acid catalyst provides useful information about its
stability during the catalytic cycle. After completion of
one-pot two-step reaction, the solid acid was filtered off
and washed with methanol and water, heated at 100°C
for 4 h, and used for further runs. The regenerated
catalyst was used in the model reaction with a fresh
reaction mixture for four times. The results were shown in
Figure 2. These results indicated that the decrease of 2-
amino-6-butyl-7-methyl-5-oxo-4-phenyl-5,6-dihydro-4H-
pyrano[3,2-c]pyridine-3-carbonitrile 6a yields is mainly
due to the gradual contamination of the active surface of
catalyst by the byproduct.
CONCLUSIONS
In conclusion, a series of poly-substituted pyrano[3,2-c]
pyridone and spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-
2,5′(6′H)-dione derivatives have been obtained with one-
pot two-step reaction using solid acid as catalyst in
water. The mild and environment-friendly conditions, the
efficient and recycle solid acid catalyst, and the
operational simplicity are represented in the one-pot
two-step transformation, which provides
methodology for the preparation of pyrano[3,2-c]
pyridone derivatives.
a
good
EXPERIMENTAL
General.
All reagents were commercial products
without further purification, unless otherwise stated.
Analytical thin-layer chromatography (TLC) was
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Vol 000
Table 3
Synthesis of 2′-amino-6′-butyl-7′-methyl-2,5′-dioxo-5′,6′-dihydrospiro [indoline-3,4′-pyrano[3,2-c]pyridine]-3′-carbonitriles.
9b, 83%
9c, 86%
9a, 89%
9d, 84%
9e, 88%
Reaction conditions: 1 (0.5 mmol) and 2a (0.6 mmol), catalysts (10 mg), and water (3 mL) were mixed in selected conditions for 4 h, and then 8 (0.5
mmol) and 5 (0.6 mmol) submitted the earlier reaction system for another 4 h.
Scheme 2. Probable mechanism for the formation of compound 6a.
performed using Merck silica gel GF254 plates (Merck,
Kenilworth, NJ). Melting points were measured on an X-
4
Figure 2. Studies in recycling of solid acid in the synthesis of 6a. [Color
figure can be viewed at wileyonlinelibrary.com]
melting point apparatus. 1H-NMR spectra were
recorded on a 400-MHz instrument (Bruker Avance 400
Spectrometer; Bruker Corp., Billerica, MA). Chemical
shifts (δ) were given in parts per million relative to
tetramethylsilane (TMS) as the internal reference, with
coupling constants (J) in Hertz. 13C-NMR spectra were
recorded at 100 MHz. Chemical shifts were reported in
parts per million with the internal DMSO-d6 signal at
39.0 ppm as a standard. HRMS (ESI) was measured with
Bruker Daltonics APEXII instrument (Bruker Corp.).
The preparation of substituted 2-amino-7-methyl-5-oxo-4-
aryl-5,6-dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
derivatives 6a–6w. In a 10-mL reaction vial, 1 (0.5 mmol)
and 2 (0.6 mmol), solid acid (10 mg), and water (3 mL)
were mixed and then capped at 80°C for 4 h, and then 4
(0.5 mmol) and 5 (0.6 mmol) submitted the earlier
reaction system for another 4 h, which were monitored
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis for Poly-substituted Pyrano[3,2-c]pyridones and
Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones
by TLC until conversion of the substrates was complete.
The mixture was cooled to room temperature. The
resulted precipitate was filtered and dried along with the
catalyst. The crude product was further purified by
recrystallization from hot ethanol/N,N-dimethylformamide
to give the pure desired product.
The preparation of 2′-amino-6′-butyl-7′-methyl-2,5′-dioxo-
5′,6′-dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
carbonitrile 9. In a 10-mL reaction vial, 1 (0.5 mmol) and
2 (0.6 mmol), solid acid (10 mg), and water (3 mL) were
mixed and then capped at 80°C for 4 h, and then 7 (0.5
mmol) and 5 (0.6 mmol) submitted the earlier reaction
system for another 4 h, which were monitored by TLC
until conversion of the substrates was complete. The
mixture was cooled to room temperature. The resulted
precipitate was filtered and dried along with the catalyst.
The crude product was further purified by
recrystallization from hot ethanol/N,N-dimethylformamide
(ESI) m/z calcd for C23H28N3O2 [M + H]+: 378.2176,
found: 378.2181.
2-Amino-6-butyl-4-(4-methoxyphenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6d).
Pale
yellow powder; mp: 239–240°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.02 (d, J = 8.4 Hz, 2H, ArH), 6.99
(s, 2H, NH2), 6.83 (d, J = 8.0 Hz, 2H, ArH), 6.03 (s, 1H,
CH), 4.28 (s, 1H, CH), 3.80–3.85 (m, 1H, CH2), 3.70 (s,
4H, OMe + CH2), 2.35 (s, 3H, CH3), 1.38–1.46 (m, 2H,
CH2), 1.21–1.26 (m, 2H, CH2), 0.85 (t, J = 7.2 Hz, 3H,
CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.3,
159.4, 158.3, 155.0, 147.1, 137.3, 128.8, 114.0, 106.7,
97.7, 58.4, 55.4, 44.0, 36.5, 30.3, 20.1, 14.0; HRMS
(ESI) m/z calcd for C21H24N3O3 [M + H]+: 366.1812,
found: 366.1809.
2-Amino-6-butyl-4-(4-fluorophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6e).
Pale
yellow powder; mp: 233–234°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.15–7.19 (m, 2H, ArH), 7.08 (d, J
= 8.8 Hz, 2H, ArH), 7.05 (s, 2H, NH2), 6.04 (s, 1H, CH),
4.35 (s, 1H, CH), 3.80–3.88 (m, 1H, CH2), 3.69–3.76 (m,
1H, CH2), 2.36 (s, 3H, CH3), 1.36–1.48 (m, 2H, CH2),
1.21–1.29 (m, 2H, CH2), 0.84 (t, J = 7.2 Hz, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6, TMS): δ 162.5, 161.2,
159.7 (1JCF = 66.0 Hz), 155.2, 147.5, 141.4, 129.6 (3JCF
= 8.0 Hz), 129.6, 120.4, 115.3 (2JCF = 21.0 Hz), 106.2,
97.8, 57.9, 44.0, 36.7, 30.3, 20.1, 14.0; HRMS (ESI) m/z
calcd for C20H21FN3O2 [M + H]+: 354.1612, found:
to give the pure desired product.
2-Amino-6-butyl-7-methyl-5-oxo-4-phenyl-5,6-dihydro-4H-
pyrano[3,2-c]pyridine-3-carbonitrile (6a).
Pale yellow
1
powder; mp: >300°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.26 (t, J = 7.2 Hz, 2H, ArH), 7.13–7.18 (m,
3H, ArH), 7.03 (br, s, 2H, NH2), 6.05 (s, 1H, CH), 4.34
(s, 1H, CH), 3.80–3.86 (m, 1H, CH2), 3.69–3.76 (m, 1H,
CH2), 2.36 (s, 3H, CH3), 1.41–1.44 (m, 2H, CH2), 1.22–
1.27 (m, 2H, CH2), 0.85 (t, J = 7.2 Hz, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.3, 159.5,
155.3, 147.3, 145.3, 128.7, 127.8, 126.9, 120.5, 106.4,
97.7, 58.1, 44.0, 30.3, 20.1, 14.0; HRMS (ESI) m/z calcd
354.1609.
2-Amino-6-butyl-4-(4-chlorophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6f). White
for C20H22N3O2 [M + H]+: 336.1707, found: 336.1711.
2-Amino-6-butyl-7-methyl-5-oxo-4-(p-tolyl)-5,6-dihydro-4H-
solid; mp: >300°C; 1H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.32 (d, J = 8.0 Hz, 2H, ArH), 7.16 (d, J = 8.4
Hz, 2H, ArH), 7.06 (s, 2H, NH2), 6.04 (s, 1H, CH), 4.35
(s, 1H, CH), 3.10–3.84 (m, 1H, CH2), 3.72–3.77 (m, 1H,
CH2), 2.36 (s, 3H, CH3), 1.38–1.43 (m, 2H, CH2), 1.21–
1.26 (m, 2H, CH2), 0.84 (t, J = 7.2 Hz, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.2, 159.4,
155.3, 147.6, 144.2, 131.5, 129.7, 128.6, 120.3, 105.9,
97.8, 57.6, 44.0, 36.9, 30.3, 20.1, 14.0; HRMS (ESI) m/z
calcd for C20H21ClN3O2 [M + H]+: 370.1317, found:
pyrano[3,2-c]pyridine-3-carbonitrile (6b).
White powder;
1
mp: 280–282°C; H-NMR (400 MHz, DMSO-d6, TMS):
δ 6.99–7.07 (m, 6H, ArH + NH2), 6.03 (s, 1H, CH), 4.28
(s, 1H, CH), 3.80–3.87 (m, 1H, CH2), 3.68–3.76 (m, 1H,
CH2), 2.36 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.39–1.46
(m, 2H, CH2), 1.22–1.28 (m, 2H, CH2), 0.85 (t, J = 7.2
Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ
161.2, 159.4, 155.2, 147.2, 142.3, 136.0, 129.2, 127.7,
120.5, 106.6, 97.7, 58.3, 44.0, 36.9, 30.3, 21.1, 20.1,
14.0; HRMS (ESI) m/z calcd for C21H24N3O2 [M + H]+:
370.1321.
2-Amino-6-butyl-4-(4-bromophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6g). White
350.1863, found: 350.1861.
2-Amino-6-butyl-4-(4-isopropylphenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6c). White
powder; mp: 254–256°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 8.01 (d, J = 8.4 Hz, 2H, ArH),
7.66 (d, J = 8.4 Hz, 4H, ArH), 6.61 (s, 1H, CH), 4.90
(s, 1H, CH), 4.35–4.42 (m, 1H, CH2), 4.25–4.32 (m,
1H, CH2), 2.91 (s, 3H, CH3), 1.92–2.01 (m, 2H, CH2),
1.77–1.82 (m, 2H, CH2), 1.40 (t, J = 7.2 Hz, 3H,
CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.2,
159.4, 155.3, 147.6, 144.6, 131.5, 130.1, 120.4, 120.0,
105.8, 97.8, 57.5, 44.0, 36.9, 30.3, 20.1, 14.0; HRMS
1
solid; mp: 245–246°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.04 (d, J = 8.4
Hz, 2H, ArH), 7.01 (s, 2H, NH2), 6.04 (s, 1H, CH), 4.30
(s, 1H, CH), 3.83–3.90 (m, 1H, CH2), 3.67–3.74 (m, 1H,
CH2), 2.78–2.85 (m, 1H, CH), 2.36 (s, 3H, CH3), 1.39–
1.47 (m, 2H, CH2), 1.22–1.28 (m, 2H, CH2), 1.16 (d, J =
7.2 Hz, 6H, CH3), 0.86 (d, J = 7.2 Hz, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.3, 159.5,
155.3, 147.2, 146.9, 142.7.0, 127.6, 126.6, 106.6, 97.8,
58.2, 42.5, 36.9, 33.5, 30.4, 24.3, 20.1, 14.0; HRMS
(ESI) m/z calcd for C20H21BrN3O2 [M
+
H]+:
414.0812, found: 414.0817.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Xu, Y. Du, S. Wang, Z. Wu, Y. Lou, and F. Zhang
Vol 000
2-Amino-6-butyl-7-methyl-5-oxo-4-(4-(trifluoromethyl)
phenyl)-5,6-dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6h). White solid; mp: 265–266°C; 1H-NMR (400 MHz,
2-Amino-6-butyl-7-methyl-4-(3-nitrophenyl)-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6l). White
powder; mp: 289–290°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 8.63 (d, J = 8.0 Hz, 1H, ArH), 8.55
(s, 1H, ArH), 8.23 (d, J = 7.6 Hz, 1H, ArH), 8.15 (t, J =
8.0 Hz, 1H, ArH), 7.77 (s, 2H, NH2), 6.65 (s, 1H, CH),
5.13 (s, 1H, CH), 4.36–4.43 (m, 1H, CH2), 4.25–4.36 (m,
1H, CH2), 2.93 (s, 3H, CH3), 1.93–1.99 (m, 2H, CH2),
1.75–1.80 (m, 2H, CH2), 1.38 (t, J = 7.2 Hz, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.2, 159.6,
155.4, 148.1, 148.0, 147.5, 134.9, 130.3, 122.3, 122.2,
120.2, 105.2, 97.8, 57.0, 44.0, 37.2, 30.3, 20.1, 20.0,
13.9; HRMS (ESI) m/z calcd for C20H21N4O4 [M + H]+:
DMSO-d6, TMS): δ 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.37
(d, J = 8.0 Hz, 2H, ArH), 7.14 (s, 2H, NH2), 6.07 (s,
1H, CH), 4.46 (s, 1H, CH), 3.80–3.86 (m, 1H, CH2),
3.72–3.76 (m, 1H, CH2), 2.37 (s, 3H, CH3), 1.36–1.43
(m, 2H, CH2), 1.20–1.25 (m, 2H, CH2), 0.82 (t, J =
7.2 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6,
TMS): δ 161.3, 159.5, 155.4, 149.8, 147.8, 128.7,
127.8, 126.1, 125.6 (1JCF = 3.3 Hz), 120.3, 105.5,
97.8, 57.3, 44.0, 37.4, 30.3, 20.0, 14.0; HRMS (ESI)
m/z calcd for C21H21F3N3O2 [M + H]+: 404.1580,
found: 404.1577.
2-Amino-6-butyl-7-methyl-4-(4-nitrophenyl)-5-oxo-5,6-
381.1557, found: 381.1556.
2-Amino-6-butyl-4-(2,4-dichlorophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6m).
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6i).
Yellow solid; mp: 261–262°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 8.14 (d, J = 8.4 Hz, 2H, ArH), 7.42
(d, J = 8.8 Hz, 2H, ArH), 7.20 (s, 2H, NH2), 6.08 (s, 1H,
CH), 4.52 (s, 1H, CH), 3.78–3.85 (m, 1H, CH2), 3.72–
3.76 (m, 1H, CH2), 2.37 (s, 3H, CH3), 1.36–1.43 (m, 2H,
CH2), 1.17–1.26 (m, 2H, CH2), 0.82 (t, J = 7.2 Hz, 3H,
CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.2,
159.5, 155.5, 152.9, 148.1, 146.6, 129.2, 124.0, 120.1,
105.1, 97.8, 56.8, 44.1, 37.4, 30.3, 20.1, 13.9; HRMS
(ESI) m/z calcd for C20H21N4O4 [M + H]+: 381.1557,
Yellow solid; mp: 239–240°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.50 (d, J = 2.0 Hz, 1H, ArH),
7.31 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 7.10 (s, 3H, ArH
+ NH2), 6.06 (s, 1H, ArH), 4.82 (s, 1H, CH), 3.77–
3.84 (m, 1H, CH2), 3.67–3.74 (m, 1H, CH2), 2.38 (s,
3H, CH3), 1.34–1.46 (m, 2H, CH2), 1.20–1.27 (m, 2H,
CH2), 0.84 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (100
MHz, DMSO-d6, TMS): δ 161.1, 159.4, 155.8, 147.9,
141.5, 133.7, 133.0, 132.0, 129.1,128.0, 119.9, 104.8,
97.6, 56.2, 44.0, 30.3, 20.1, 20.1, 14.0; HRMS (ESI)
m/z calcd for C20H20Cl2N3O2 [M + H]+: 404.0927,
found: 381.1560.
2-Amino-4-(2-bromophenyl)-6-butyl-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6j). White
found: 404.0930.
2-Amino-6-butyl-4-(2,6-dichlorophenyl)-7-methyl-5-oxo-5,6-
powder; mp: 275–276°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.52 (d, J = 7.2 Hz, 1H, ArH), 7.25
(t, J = 6.8 Hz, 1H, ArH), 7.10 (t, J = 6.0 Hz, 1H, ArH),
7.03 (s, 3H, ArH + NH2), 6.05 (s, 1H, CH), 4.87 (s, 1H,
CH), 3.77–3.83 (m, 1H, CH2), 3.67–3.72 (m, 1H, CH2),
2.37 (s, 3H, CH3), 1.35–1.43 (m, 2H, CH2), 1.20–1.25
(m, 2H, CH2), 0.84 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR
(100 MHz, DMSO-d6, TMS): δ 161.1, 159.4, 155.7,
147.7, 132.9, 130.4, 128.8, 128.5, 123.5, 119.0, 105.6,
97.6, 57.1, 44.0, 36.7, 30.3, 20.1, 14.0; HRMS (ESI) m/z
calcd for C20H21BrN3O2 [M + H]+: 414.0812, found:
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6n).
White solid; mp: >300°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.45 (d, J = 7.2 Hz, 1H, ArH),
7.22–7.27 (m, 2H, ArH), 7.10 (s, 2H, NH2), 5.99 (s,
1H, CH), 5.37 (s, 1H, CH), 3.74–3.81 (s, 1H, CH2),
3.63–3.71 (s, 1H, CH2), 2.36 (s, 3H, CH3), 1.35–1.40
(m, 2H, CH2), 1.22–1.30 (m, 2H, CH2), 0.83 (t, J =
7.2 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6,
TMS):
δ
161.0, 160.2, 156.3, 147.8, 137.1,
136.6, 134.4, 130.5, 129.3, 128.8, 119.8, 103.5, 97.5,
53.5, 43.9, 33.8, 30.3, 20.0, 14.0; HRMS (ESI) m/z
calcd for C20H20Cl2N3O2 [M + H]+: 404.0927, found:
414.0811.
2-Amino-6-butyl-7-methyl-4-(2-nitrophenyl)-5-oxo-5,6-
404.0928.
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6k).
2-Amino-6-butyl-7-methyl-4-(naphthalen-1-yl)-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6o). White
Brown solid; mp: 245–246°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.81 (d, J = 8.0 Hz, 1H, ArH), 7.60
(t, J = 7.6 Hz, 1H, ArH), 7.40 (t, J = 7.6 Hz, 1H, ArH),
7.28 (d, J = 7.2 Hz, 1H, ArH), 7.20 (s, 2H, NH2), 6.06
(s, 1H, CH), 5.11 (s, 1H, CH), 3.73–3.80 (m, 1H, CH2),
3.62–3.69 (m, 1H, CH2), 2.35 (s, 3H, CH3), 1.28–1.42
(m, 2H, CH2), 1.14–1.23 (m, 2H, CH2), 0.83 (t, J = 7.2
Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ
161.2, 160.0, 155.0, 149.8, 148.0, 139.6, 133.8, 131.0,
128.1, 124.0, 119.9, 105.8, 97.7, 56.3, 43.9, 31.7, 30.2,
20.0, 14.0; HRMS (ESI) m/z calcd for C20H21N4O4 [M +
H]+: 381.1557, found: 381.1558.
1
powder; mp: >300°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 8.45 (d, J = 6.8 Hz, 1H, ArH), 7.93 (d, J =
8.0 Hz, 1H, ArH), 7.77 (d, J = 8.0 Hz, 1H, ArH),
7.51–7.59 (m, 2H, ArH), 7.41 (t, J = 7.6 Hz, 1H,
ArH), 7.12 (d, J = 6.8 Hz, 1H, ArH), 7.00 (s, 2H,
NH2), 6.13 (s, 1H, CH), 5.33 (s, 1H, CH), 3.67–3.76
(m, 2H, CH2), 2.38 (s, 3H, CH3), 1.34–1.42 (m, 2H,
CH2), 1.17–1.22 (m, 2H, CH2), 0.81 (t, J = 7.2 Hz,
3H, CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ
161.3, 159.3, 155.8, 147.3, 133.7, 131.6, 128.8, 127.3,
126.2, 126.0, 124.2, 120.4, 107.2, 97.4, 58.9, 44.0,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis for Poly-substituted Pyrano[3,2-c]pyridones and
Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones
30.3, 20.1, 14.0; HRMS (ESI) m/z calcd for C24H24N3O2
J = 8.0 Hz, 2H, ArH), 6.10 (s, 1H, CH), 5.28 (d, J = 16.0
Hz, 1H, CH2), 5.07 (d, J = 16.0 Hz, 1H, CH2), 4.37 (s,
1H, CH), 3.71 (s, 3H, CH3), 2.23 (s, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.8, 159.3,
158.4, 155.4, 147.6, 137.3, 129.1, 128.8, 127.5, 126.5,
120.5, 114.0, 106.9, 98.2, 58.5, 55.5, 46.7, 36.6, 20.2;
HRMS (ESI) m/z calcd for C24H22N3O3 [M + H]+:
[M + H]+: 386.1863, found: 386.1863.
2-Amino-6-butyl-7-methyl-5-oxo-4-(thiophen-2-yl)-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6p).
Yellow powder; mp: 222–224°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.27 (t, J = 3.6 Hz, 1H, ArH),
7.16 (s, 2H, NH2), 6.89 (t, J = 5.2 Hz, 2H, ArH), 6.03
(s, 1H, CH), 4.68 (s, 1H, CH), 3.80–3.87 (m, 2H,
CH2), 2.36 (s, 3H, CH3), 1.42–1.48 (m, 2H, CH2),
1.24–1.30 (m, 2H, CH2), 0.86 (t, J = 7.2 Hz, 3H,
CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.3,
160.0, 155.0, 149.7, 147.7, 127.2, 124.7, 124.5, 106.4,
97.9, 57.7, 44.1, 32.2, 30.3, 20.1, 14.0; HRMS (ESI)
m/z calcd for C18H20N3O2S [M + H]+: 342.1271,
400.1656, found: 400.1660.
2-Amino-6-benzyl-4-(4-chlorophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6u).
White powder; mp: >300°C; 1H-NMR (400 MHz,
DMSO-d6, TMS): δ 7.19–7.35 (m, 7H, ArH), 7.09 (s,
2H, NH2), 7.01 (d, J = 6.8 Hz, ArH), 6.12 (s, 1H, CH),
5.25 (d, J = 16.0 Hz, 1H, CH2), 5.07 (d, J = 16.0 Hz,
1H, CH2), 4.42 (s, 1H, CH), 2.24 (s, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.7, 159.4,
148.1, 144.2, 137.2, 131.6, 129.7, 129.1, 128.6, 127.6,
126.5, 106.1, 98.2, 57.8, 46.7, 36.9, 20.2; HRMS (ESI)
m/z calcd for C23H19ClN3O2 [M + H]+: 404.1160, found:
found: 342.1270.
2-Amino-7-methyl-5-oxo-4-phenyl-6-propyl-5,6-dihydro-4H-
pyrano[3,2-c]pyridine-3-carbonitrile (6q).
White powder;
1
mp: 261–262°C; H-NMR (400 MHz, DMSO-d6, TMS):
δ 7.26 (t, J = 7.2 Hz, 2H, ArH), 7.13–7.18 (m, 3H, ArH),
7.04 (s, 2H, NH2), 6.05 (s, 1H, CH), 4.34 (s, 1H, CH),
3.76–4.34 (m, 1H, CH2), 3.66–3.73 (m, 1H, CH2), 2.36
(s, 3H, CH3), 1.43–1.49 (m, 2H, CH2), 0.81 (t, J = 7.2
Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ
161.3, 159.5, 155.3, 147.4, 145.2, 128.7, 127.0, 120.5,
106.4, 97.7, 58.1, 45.7, 37.3, 21.6, 20.1, 11.5; HRMS
(ESI) m/z calcd for C19H20N3O2 [M + H]+: 322.1550,
404.1161.
2-Amino-6-benzyl-4-(4-bromophenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6v). White
1
powder; mp: >300°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.47 (s, 2H, ArH), 7.21–7.27 (m, 4H, ArH),
7.11–7.16 (m, 4H, ArH + NH2), 7.00 (s, 2H, ArH), 6.12
(s, 1H, CH), 5.25 (d, J = 15.2 Hz, 1H, CH2), 5.07 (d, J =
14.4 Hz, 1H, CH2), 4.42 (s, 1H, CH), 2.23 (s, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6, TMS): δ 161.7, 159.4,
155.7, 148.1, 144.6, 137.2, 131.6, 130.1, 129.1, 127.6,
126.5, 120.2, 120.1, 106.0, 98.3, 57.7, 46.7, 37.0, 20.2;
HRMS (ESI) m/z calcd for C23H19BrN3O2 [M + H]+:
found: 322.1555.
2-Amino-4-(4-chlorophenyl)-7-methyl-5-oxo-6-propyl-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6r). White
powder; mp: 252–254°C; 1H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.31 (d, J = 8.0 Hz, 2H, ArH), 7.16 (d, J = 8.0 Hz,
2H, ArH), 7.06 (s, 2H, NH2), 6.04 (s, 1H, CH), 4.35 (s, 1H,
CH), 3.70–3.78 (m, 2H, CH2), 2.35 (s, 3H, CH3), 1.43–
1.48 (m, 2H, CH2), 0.80 (t, J = 7.2 Hz, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 161.3, 159.5,
155.3, 147.6, 144.2, 131.5, 129.7, 128.6, 120.3, 105.9,
97.8, 57.6, 45.7, 36.9, 21.6, 20.1, 11.5; HRMS (ESI) m/z
calcd for C19H19ClN3O2 [M + H]+: 356.1160, found:
448.0655, found: 448.0652.
2-Amino-7-methyl-5-oxo-4-phenyl-4H,5H-pyrano[4,3-b]
pyran-3-carbonitrile (7a). White powder; mp: 235–236°C;
1H-NMR (400 MHz, DMSO-d6, TMS): δ 7.31 (t, J = 7.2
Hz, 2H, ArH), 7.17–7.24 (m, 5H, ArH + NH2), 6.28 (s,
1H,CH), 4.28 (s, 1H, CH), 2.21 (s, 3H, CH3); 13C-NMR
(100 MHz, DMSO-d6, TMS): δ 163.4, 161.8, 158.6,
158.5, 144.1, 128.9, 127.9, 127.4, 119.8, 101.2, 98.4,
356.1164.
2-Amino-6-benzyl-7-methyl-5-oxo-4-(p-tolyl)-5,6-dihydro-
58.3, 36.7, 19.7.
4H-pyrano[3,2-c]pyridine-3-carbonitrile
(6s).
White
2-Amino-4-(4-bromophenyl)-7-methyl-5-oxo-4H,5H-
pyrano[4,3-b]pyran-3-carbonitrile (7b). White powder; mp:
1
powder; mp: >300°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.24–7.29 (m, 3H, ArH), 7.07 (s, 8H, ArH +
NH2), 6.11 (s, 1H, CH), 5.23–5.29 (m, 1H, CH2),
5.03–5.11 (m, 1H, CH2), 4.38 (s, 1H, CH), 2.24 (s,
6H, CH3); 13C-NMR (100 MHz, DMSO-d6, TMS): δ
159.4, 155.6, 147.7, 142.3, 136.1, 129.2, 129.1, 127.7,
126.5, 98.2, 58.4, 46.7, 37.1, 21.1, 20.2; HRMS (ESI)
m/z calcd for C24H22N3O2 [M + H]+: 384.1707, found:
217–218°C; 1H-NMR (400 MHz, DMSO-d6, TMS): δ 7.49
(d, J = 8.0 Hz, 2H, ArH), 7.26 (s, 2H, NH2), 7.15 (d, J =
8.0 Hz, 2H, ArH), 6.26 (s, 1H,CH), 4.29 (s, 1H, CH),
2.20 (s, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6,
TMS): δ 163.6, 161.9, 158.8, 158.5, 131.7, 130.3, 120.5,
119.7, 100.5, 98.4, 57.7, 36.2, 19.8.
2′-Amino-6′-butyl-7′-methyl-2,5′-dioxo-5′,6′-
dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
384.1711.
1
carbonitrile (9a).
White solid; mp: >300°C; H-NMR
2-Amino-6-benzyl-4-(4-methoxyphenyl)-7-methyl-5-oxo-5,6-
dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (6t). White
(400 MHz, DMSO-d6, TMS): δ 10.23 (s, 1H, NH), 7.01
(s, 1H, NH2), 6.92 (t, J = 7.6 Hz, 1H, ArH), 6.69 (d, J =
6.8 Hz, 1H, ArH), 6.64 (t, J = 7.2 Hz, 1H, ArH), 6.57 (d,
J = 7.6 Hz, 1H, ArH), 5.88 (s, 1H, CH), 3.40–3.54 (m,
1
powder; mp: >300°C; H-NMR (400 MHz, DMSO-d6,
TMS): δ 7.22–7.28 (m, 3H, ArH), 7.11 (d, J = 8.0 Hz,
2H, ArH), 7.02 (d, J = 8.4 Hz, 4H, ArH + NH2), 6.86 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Xu, Y. Du, S. Wang, Z. Wu, Y. Lou, and F. Zhang
Vol 000
2H, CH2), 2.16 (s, 3H, CH3), 1.10–1.15 (m, 2H, CH2),
0.96–1.02 (m, 2H, CH2), 0.60 (t, J = 7.2 Hz, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6, TMS): δ 178.6, 160.2,
159.6, 156.2, 148.2, 142.9, 134.8, 128.5, 123.6, 122.0,
118.2, 109.5, 103.9, 97.6, 57.4, 48.1, 44.1, 30.3, 20.1,
19.9, 14.0; HRMS (ESI) m/z calcd for C21H21N4O3 [M +
6.67 (d, J = 7.6 Hz, 1H, ArH), 6.09 (s, 1H, CH), 3.73–
3.80 (m, 1H, CH2), 3.62–3.69 (m, 1H, CH2), 2.38 (s, 3H,
CH3), 2.17 (s, 1H, CH3), 1.34–1.41 (m, 2H, CH2), 1.19–
1.24 (m, 2H, CH2), 0.83 (t, J = 7.2 Hz, 3H, CH3); 13C-
NMR (100 MHz, DMSO-d6, TMS): δ 178.5, 160.2,
159.6, 156.2, 148.2, 140.5, 134.9, 130.8, 128.8, 124.2,
118.3, 109.3, 104.1, 97.6, 57.6, 48.1, 44.0, 30.3, 21.0,
20.1, 19.9, 14.0; HRMS (ESI) m/z calcd for C22H23N4O3
[M + H]+: 391.1765, found: 391.1769.
H]+: 377.1608, found: 377.1605.
2′-Amino-6′-butyl-5-fluoro-7′-methyl-2,5′-dioxo-5′,6′-
dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
carbonitrile (9b). Gray solid; mp: >300°C; 1H-NMR (400
MHz, DMSO-d6, TMS): δ 10.47 (s, 1H, NH), 7.29 (s, 2H,
NH2), 6.94–6.99 (m, 1H, ArH), 6.88–6.90 (m, 1H, ArH),
6.76–6.79 (m, 1H, ArH), 6.10 (s, 1H, CH), 3.64–3.79 (m,
2H, CH2), 2.38 (s, 1H, CH3), 1.34–1.39 (m, 2H, CH2),
1.16–1.25 (m, 2H, CH2), 0.82 (t, J = 6.4 Hz, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6, TMS): δ 178.6, 160.3
(1JCF = 54.0 Hz), 159.8, 157.5, 156.3, 148.4, 139.1,
136.6 (3JCF = 8.0 Hz), 118.1, 114.7 (2JCF = 23.0 Hz),
111.5 (2′JCF = 24.0 Hz), 110.1 (3′JCF = 8.0 Hz), 103.5,
97.7, 56.8, 48.6, 44.1, 30.3, 20.0, 19.9, 14.0; HRMS
(ESI) m/z calcd for C21H20FN4O3 [M + H]+: 395.1514,
Acknowledgment. We are grateful for the help of undergraduate
of Shaoxing University for this research work.
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found: 395.1516.
2′-Amino-6′-butyl-5-chloro-7′-methyl-2,5′-dioxo-5′,6′-
dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
carbonitrile (9c). Gray solid; mp: >300°C; 1H-NMR (400
MHz, DMSO-d6, TMS): δ 10.59 (s, 1H, NH), 7.31 (s, 2H,
NH2), 7.19 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 7.04 (d, J = 1.2
Hz, 1H, ArH), 6.81 (d, J = 8.0 Hz, 1H, ArH), 6.10 (s, 1H,
CH), 3.73–3.80 (m, 1H, CH2), 3.63–3.70 (m, 1H, CH2),
2.37 (s, 1H, CH3), 1.34–1.41 (m, 2H, CH2), 1.18–1.23
(m, 2H, CH2), 0.82 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR
(100 MHz, DMSO-d6, TMS): δ 178.4, 160.3, 159.8,
156.4, 148.5, 141.9, 136.9, 128.4, 126.0, 123.8, 118.1,
110.9, 103.3, 97.8, 56.6, 48.4, 44.1, 30.3, 20.0, 19.9,
14.0; HRMS (ESI) m/z calcd for C21H20ClN4O3 [M +
H]+: 411.1218, found: 411.1221.
2′-Amino-5-bromo-6′-butyl-7′-methyl-2,5′-dioxo-5′,6′-
dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
carbonitrile (9d). Gray solid; mp: >300°C; 1H-NMR (400
MHz, DMSO-d6, TMS): δ 10.48 (s, 1H, NH), 7.20 (s,
3H, ArH + NH2), 7.04 (s, 1H, ArH), 6.65 (d, J = 7.6
Hz, 1H, ArH), 6.00 (s, 1H, CH), 3.60–3.67 (m, 1H,
CH2), 3.53–3.59 (m, 1H, CH2), 2.27 (s, 3H, CH3),
1.23–1.29 (m, 2H, CH2), 1.07–1.12 (m, 2H, CH2), 0.72
(t, J = 7.6 Hz, 3H, CH3); 13C-NMR (100 MHz,
DMSO-d6, TMS): δ 178.3, 160.3, 159.8, 156.4, 148.5,
142.3, 137.3, 131.3, 126.5, 118.1, 113.7, 111.5, 103.3,
97.8, 56.6, 48.4, 44.1, 30.3, 20.0, 20.0, 14.0; HRMS
(ESI) m/z calcd for C21H20BrN4O3 [M
+
H]+:
455.0713, found: 455.0711.
2′-Amino-6′-butyl-5,7′-dimethyl-2,5′-dioxo-5′,6′-
dihydrospiro[indoline-3,4′-pyrano[3,2-c]pyridine]-3′-
carbonitrile (9e). Gray solid; mp: >300°C; 1H-NMR (400
MHz, DMSO-d6, TMS): δ 10.31 (s, 1H, NH), 7.19 (s, 2H,
NH2), 6.93 (d, J = 8.0 Hz, 1H, ArH), 6.72 (s, 1H, ArH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Efficient Synthesis for Poly-substituted Pyrano[3,2-c]pyridones and
Spiro[indoline-3,4′-pyrano[3,2-c]pyridine]-2,5′(6′H)-diones
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet