[2+2+2] cycloaddition reactions of α,β-unsaturated N-arylaldimines, acetylenedicarboxylates and 2-arylidene-1,3-indanediones

Article abstract of DOI:10.1016/j.tet.2017.05.019

The domino [2+2+2] cycloaddition reaction of α,β-unsaturated N-arylaldimines, dialkyl acetylenedicarboxylates and 2-arylidene-1,3-indanediones in dry methylene dichloride at room temperature afforded isomeric 2′-styryl-1,2′,3,4′-tetrahydro-1′H-spiro[inden

Full text of DOI:10.1016/j.tet.2017.05.019

Accepted Manuscript
[2+2+2] cycloaddition reactions of α,β-unsaturated N-arylaldimines,
acetylenedicarboxylates and 2-arylidene-1,3-indanediones
Wen-Juan Yang, Jing Zhang, Jing Sun, Ya-Jing Xie, Chao-Guo Yan
PII:
S0040-4020(17)30485-4
10.1016/j.tet.2017.05.019
TET 28685
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 March 2017
Revised Date: 26 April 2017
Accepted Date: 4 May 2017
Please cite this article as: Yang W-J, Zhang J, Sun J, Xie Y-J, Yan C-G, [2+2+2] cycloaddition reactions
of α,β-unsaturated N-arylaldimines, acetylenedicarboxylates and 2-arylidene-1,3-indanediones,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.019.
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ACCEPTED MANUSCRIPT
[2+2+2] cycloaddition reactions of α,β-unsaturated N-arylaldimines,
acetylenedicarboxylates and 2-arylidene-1,3-indanediones
Wen-Juan Yang, Jing Zhang, Jing Sun*, Ya-Jing Xie, Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China.
E-mail: sunjing@yzu.edu.cn; cgyan@yzu.edu.cn
Abstract: The domino [2+2+2] cycloaddition reaction of α,β-unsaturated N-arylaldimines, dialkyl
acetylenedicarboxylates and 2-arylidene-1,3-indanediones in dry methylene dichloride at room
temperature afforded isomeric 2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines] in
good yields. Under similar conditions, the reaction of α,β-unsaturated N-arylaldimines with two
molecules
of
dialkyl
acetylenedicarboxylates
resulted
in
1-aryl-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylates. Additionally, the three-component
reaction of α,β-unsaturated N-arylaldimines, dimethylacetylenedicarboxylate and benzoyl cyanide
also gave isomeric 1,3-oxazine-4,5-dicarboxylates.
Keywords:
cycloaddition;
spiro[indene-2,3'-pyridine];
dihydropyridine;
1,3-oxazine;
α,β-unsaturated aldimine; electron-deficient reaction.
Introduction
Nucleophilic aromatic tertiary amine catalyzed cycloaddition reactions have emerged as one of
the powerful tools for the construction of diverse carbocyclic and heterocyclic systems.1,2 The
synthetic strategy of this type of catalyzed cycloaddition reactions included addition of
nitrogen-containing heterocycles such as pyridine, quinoline and isoquinoline to electron-deficient
alkynes to generate active Huisgen’s 1,4-dipole and its subsequent cyclization with the prevailing
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dipolarophiles to assemble versatile nitrogen-containing heterocyclic systems.3-5 In recent years,
the combination of reactive Huisgen’s 1,4-dipoles with greener synthetic methodology such as
domino and multicomponent reactions has resulted in many elegant and efficient synthetic
protocols for diverse biologically important heterocyclic compounds.6-9 It might be encouraged by
the rapid development of Huisgen’s 1,4-dipolar chemistry, the structurally related reactive
1,4-dipoles, which can be easily generated by addition of N-arylaldimines and its α,β-unsaturated
derivatives to electron-deficient alkynes, were also found to display versatile reactivity in domino
annulation reactions.10-11 These reactive 1,4-dipoles reacted with active carbonyl compounds such
as aromatic aldehydes,12 isatins13 and quinones14 to give corresponding 1,3-oxazine derivatives.
More importantly, these in situ generated 1,4-dipoles reacted with arylidene or isatylidene
malononitriles
to
give
the
corresponding
1,4,5,6-tetrahydropyridine15
or
spiro[indoline-3,4'-pyridine]16 derivatives. Other interesting reactions of these 1,4-dipoles
including reaction with isocyanates to give functionalized pyrimidinones17 and reaction with
2-aminobenzimidazole to give imidazole derivatives.18 The reported results revealed that the
reactive 1,4-dipoles generated from the reaction of aldimines with electron-deficient alkynes are
useful synthons for the construction of various nitrogen-containing heterocycles. In order to
further explore their synthetic values and in continuation our aim to provide efficient protocols for
the spiro compounds,19 herein we wish to report the three-component reaction of α,β-unsaturated
N-arylaldimines, dialkyl acetylenedicarboxylates and several dipolarophiles for the synthesis of
polysubstituted
2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridine],
1,6-hydropyridine-2,3,4,5-tetracarboxylates and 1,3-oxazine derivatives.
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Results and Discussion
According to the previously established reaction conditions for the synthesis of
spiro[indoline-3,4'-pyridine] derivatives16, a mixture of α,β-unsaturated N-arylaldimines, dimethyl
acetylenedicarboxylate and 2-arylidene-1,3-indanedione was carried out in dry methylene
dichloride. Without adding any other catalyst, the reaction proceeded smoothly to give the
expected [2+2+2] cycloaddition products 1a-1p in satisfactory yields (Table 1). It can be seen that
the cinnamaldehyde itself and its m-methyl, p-methoxy, m-fluoro, p-fluoro, and p-nitro derivatives
afforded the products in good yields. The substituents showed a little effect on the yields. However,
aniline with electron-withdrawing substituents such as p-chloro and p-nitro groups cannot be used
in the reaction because the lower reactivity of the corresponding α,β-unsaturated N-arylaldimines
with an electron-withdrawing group. On the other hand, the substituents on the
2-arylidene-1,3-indanediones also showed a little effect on the reaction. It should be pointed out
that non-conjugated N-arylaldimines derived from condensation of aromatic aldehydes with
anilines did not afford the desired product when the similar three-component reaction was carried
out under same reaction conditions. This result indicated that α,β-unsaturated N-arylaldimines
have much high reactivity than that of non-conjugated N-arylaldimines.
Table 1 Synthesis of 1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines] 1a-1pa
Entry
Compd
1a
Ar1
Ph
Ar2
Ar3
Yield (%, cis/trans)b
76 (54:46）
5
6
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
Ph
71 (49:51)
1b
3

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3
Ph
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
p-ClC6H4
p-MeC6H4
Ph
78 (67:33）
75 (54:46）
72 (60:40）
65 (55:45）
65 (48:52）
66 (64:36）
68 (40:60）
64 (55:45）
62 (51:49)
1c
1d
1e
1f
4
Ph
1
Ph
2
Ph
8
m-MeC6H4
m-MeC6H4
m-MeC6H4
1g
1h
1i
7
m-MeC6H4
p-MeOC6H4
m-MeC6H4
m-MeC6H4
m-MeC6H4
m-MeC6H4
Ph
9
10
11
12
13
14
15
16
p-MeOC6H4 Ph
1j
p-MeOC6H4 p-MeOC6H4
1k
1l
m-FC6H4
p-FC6H4
p-MeOC6H4
p-MeC6H4
80 (75:25)
1m
1n
1o
1p
79 (48:52）
78 (46:54）
88 (55:45）
85 (49:51)
p-FC6H4
p-MeC6H4
p-NO2C6H4
p-NO2C6H4
p-MeOC6H4
p-MeOC6H4
p-NO2C6H4
m-MeC6H4
a. Reaction conditions: ɑ,ß-unsaturated N-arylaldimines (1.0 mmol), dimethyl acetylenedicarboxylate (1.0 mmol) and
arylidene indane-1,3-dione (1.0 mmol) in CH2Cl2 (15.0 mL), rt, 12 hrs. b: Isolated yields.
1
The structures of obtained spiro compounds were established by IR, HRMS, H and 13C
1
NMR spectroscopy. H NMR spectra clearly indicated that two isomers existed in the obtained
products. This is obviously attributed to the 2'-styryl group and 4'-aryl group in the
cis/trans-positions in the newly-formed dihydropyridyl ring. In order to determine the
1
cis/trans-isomers, H NMR spectra of the single crystal of the trans-isomer 1b was firstly
1
1
analyzed (Fig. s1 in SI). By comparing H NMR spectra of the single crystal 1b to H NMR
spectra of the isomeric mixture of compound 1b (Fig. s2 in SI), the ratio of cis/trans-isomers in
compound 1b were successfully determined. Then, the ratio of cis/trans-isomers in other
compounds 1a-1p were tentatively assigned by the integration of 1H NMR spectra on the basis of
analysis of 1H NMR spectra of 1b. From the Table 1, it can be seen that the ratios of cis/trans
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isomers are usually comparable in most cases, which also indicated that this reaction did not show
high diastereoselectivity. However, because the cis/trans-isomers have very similar polarity, it is
difficult to separate them by normal chromatography. The single crystal structures of three
compounds 1b, 1d and 1g were successfully determined by X-ray diffraction method. It is
interesting to find that single crystal structures of compounds 1b (Fig. 1) and 1g (Fig. s2) have
trans-configuration, in which 2'-styryl group and 4'-aryl group exist on the trans-position in the
newly-formed dihydropyridyl ring. However, the compound 1d (Fig. 2) has a cis-configuration
with 2'-styryl group and 4'-p-chlorobenzyl group existing on the cis-position. It is also seen that
the 2'-styryl group and 4'-aryl group have very little steric effect, which caused the cis/trans
isomers were formed in nearly equivalent proportions in the cyclized reaction.
Fig. 1 Single crystal structure of compound 1b
Fig. 2 Single crystal structure of compound 1d
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Because electron-deficient alkynes were also reactive dipolarophiles in various cycloaddition
reactions, we envisioned that dialkyl acetylenedicarboxylats might react with the initially
generated 1,4-dipole to accomplish the cycloaddition reaction. Thus, a mixture of α,β-unsaturated
N-arylaldimine and excess dialkyl acetylenedicarboxylate was stirred in dry methylene dichloride
at room temperature for several hours. After workup, we were pleased to find that the expected
1-aryl-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylates 2a-2h were really produced in
moderate to good yields (Table 2). The structures of the 1,6-dihydropyrdines 2a-2h were not only
fully characterized by spectroscopic methods, but also confirmed by single crystal analysis of one
representative compound 2c (Fig. 3).
Table 2 Synthesis of 1,6-dihydropyridine-2,3,4,5-tetracarboxylate 2a-2h a
Entry
1
Compd
Ar
Ar’
R1
Yield (%) b
72
C6H5
C6H5
CH3
2a
2
3
4
5
6
7
8
C6H5
C6H5
p-CH3C6H5
p-CH3OC6H5
p-ClC6H5
CH3
CH3
69
69
75
79
71
66
71
2b
2c
2d
2e
2f
C6H5
CH3
C6H5
p-BrC6H5
CH3
m-CH3C6H5
C6H5
p-CH3C6H5
p-ClC6H5
CH3
CH2CH3
CH2CH3
2g
2h
C6H5
p-BrC6H5
a. Reaction conditions: ɑ,ß-unsaturated N-arylaldimines (1.0 mmol), dialkyl acetylenedicarboxylate (2.2 mmol)
in CH2Cl2 (15.0 mL), rt, 6 hrs. b: Isolated yields.
6

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Fig. 3 Molecular structure of compound 2c
For further demonstrating the synthetic values of this [2+2+2] domino cycloaddition, benzoyl
cyanide was also employed in the reaction. Under similar reaction conditions, the
three-component reaction of α,β-unsaturated N-arylaldimines, dimethyl acetylenedicarboxylate
and benzoyl cyanide afforded the expected polysubstituted 1,3-oxazine-4,5-dicarboxylates 3a-3i
1
in satisfactory yields (Table 3). H NMR spectra also showed that the obtained products contain
cis/trans-isomers. The ratio of the cis/trans isomers are usually nearly equal and in very few case
the molecular ratio of the cis/trans isomer reaches 8:92. The single crystal structure of compound
3e was also determined by X-ray diffraction method, in which the stylyl group and the phenyl
group are in trans-configuration.
Table 3 Synthesis of polysubstituted 1,3-oxazine-4,5-dicarboxylates 3a-3i a
Entry
Compd
3a
Ar
Ar’
Yield (%, cis/trans) b
82 (85:15)
1
2
3
4
C6H5
C6H5
C6H5
C6H5
p-CH3C6H4
p-C(CH3)3C6H4
p-ClC6H4
76 (53:47)
3b
75 (45:55)
3c
p-BrC6H4
70 (52:48)
3d
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5
6
7
8
9
p-MeC6H4
p-CH3OC6H4
p-CH3OC6H4
p-FC6H4
p-ClC6H4
p- CH3C6H4
p-CH3OC6H4
p- CH3C6H4
p- CH3C6H4
84 (44:56)
86 (45:55)
81 (55:45)
72 (92:8)
68(45:55)
3e
3f
3g
3h
3i
p-NO2C6H4
a. Reaction conditions: ɑ,ß-unsaturated N-arylaldimines (1.0 mmol), dialkyl acetylenedicarboxylate (1.0 mmol),
benzoyl cyanide (0.8 mmol) in CH2Cl2 (15.0 mL), rt, 20 hrs. b: Isolated yields.
Fig. 4 Single crystal structure of compound 3e
In order to explain the formation of 1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines] and
the related products, a concise reaction mechanism was proposed on the basis of the previously
reported cyclization reactions (Scheme 1).16-18 At first, the nucleophilic addition of ɑ,ß-unsaturated
N-arylaldimines to dimethyl acetylenedicarboxylate afforded a dipolar intermediate (A). Secondly,
Michael addition of the dipolar intermediate (A) to 2-arylidene-1,3-indanedione gave an addition
intermediate (B). Finally, the intramolecular coupling of the iminium ion with the carbanion
produced
1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines]
1
as
a
mixture
of
cis/trans-diastereoisomers in a nearly non-selective manner. If there is no other dipolarophile in
the reaction, the initially formed dipolar intermediate (A) added to the C-C triple bond of dialkyl
acetylenedicarboxylate to form the intermediate (C). Then, the subsequent intramolecular
8

ACCEPTED MANUSCRIPT
cyclization
of
intermediate
(C)
gave
the
corresponding
1,6-dihydropyridine-2,3,4,5-tetracarboxylate 2. In the alternative pathway, the dipolar intermediate
(A) added to the carbonyl group of benzoyl cyanide gave the intermediate (D). Then, the
cyclization of iminium ion with alkoxide ion in intermediate (D) afforded cis/trans-isomeric
1,3-oxazine-4,5-dicarboxylates 3.
Scheme 1 Proposed reaction mechanism for three-component reaction
Conclusion
In summary, we have successfully demonstrated the potential synthetic application of the
reactive 1,4-dipoles generated from the addition α,β-unsaturated N-arylaldimines to dialkyl
acetylenedicarboxylates.
The
in
situ
to
generated
1,4-dipoles
give
reacted
with
2-arylidene-1,3-indanediones
isomeric
2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines] in good yields. It also reacted with
9

ACCEPTED MANUSCRIPT
dialkyl
acetylenedicarboxylates
and
benzoyl
cyanide
and
to
finish
1-aryl-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylates
polysubstituted
1,3-oxazine-4,5-dicarboxylates. The advantages of these reactions are the readily available starting
reagents, mild reaction conditions and high efficiency. This protocol not only provided new
efficient synthetic methodology for diverse nitrogen-containing heterocycles, but also extended
the synthetic values of reactive Huisgen’s 1,4-dipoles.
Experimental section
1. General procedure for the synthesis of 1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridines]
1a-1p: A mixture of α,β-unsaturated N-arylaldimine (1.0 mmol), dimethyl acetylenedicarboxylate
(1.0 mmol) and 2-arylidene-1,3-indanedione (1.0 mmol) in dry methylene dichloride (15.0 mL)
was stirred at room temperature for about twelve hours. After removing the solvent, the resulting
oily residue was subjected to thin-layer chromatography with light petroleum and ethyl acetate
(V/V = 2:1) as eluting solvent to give the pure product for analysis.
Dimethyl
4'-(4-chlorophenyl)-1,3-dioxo-2'-styryl-1'-(p-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-
1
[pyridine]-5',6'-dicarboxylate (1a): light yellow solid, 76%, m.p. 190-192℃; H NMR (400
MHz, CDCl3) δ: cis-isomer: 7.88 (d, J = 7.2 Hz, 1H, ArH), 7.76-7.52 (m, 3H, ArH), 7.28 (d, J =
8.0 Hz, 1H, ArH), 7.24-7.20 (m, 2H, ArH), 7.11-7.00 (m, 7H, ArH), 6.92 (brs, 1H, ArH), 6.65-6.63
(m, 1H, ArH), 6.58 (d, J = 16.0 Hz, 1H, CH), 6.11 (brs, 1H, CH), 4.48 (d, J = 10.8 Hz, 1H, CH),
4.31 (s, 1H, CH), 3.67 (s, 3H, OCH3), 3.38 (s, 3H, OCH3), 2.26 (s, 3H, CH3); trans-isomer:
7.76-7.52 (m, 4H, ArH), 6.41 (d, J = 16.0 Hz, 1H, CH), 5.09-5.02 (m, 1H, CH), 4.75 (d, J = 10.0
Hz, 1H, CH), 4.63 (s, 1H, CH), 3.57 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 2.24 (s, 3H, CH3); ratio
of cis/trans-isomers = 54:46; 13C NMR (100 MHz, CDCl3) δ: 200.2, 198.6, 197.3, 166.5, 166.3,
165.4, 165.3, 150.0, 148.3, 142.9, 142.2, 141.3, 141.0, 138.6, 137.7, 137.5, 137.2, 136.2, 136.0
(2C), 135.8, 135.6, 135.4, 135.3, 135.1, 132.6, 132.1, 130.1, 130.0, 129.5, 129.0, 128.5, 128.3,
128.2, 128.1, 128.0, 126.9, 126.4, 123.5, 123.4, 122.7, 122.6, 122.1, 121.8, 100.0, 65.0, 60.8, 59.0,
52.5, 52.3, 51.2, 51.0, 44.4, 41.7, 31.9, 29.7, 29.7, 29.4, 22.7, 21.1 (2C), 14.1; IR (KBr) υ: 3577,
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3426, 3030, 2947, 2852, 1742, 1700, 1581, 1502, 1438, 1335, 1249, 1124, 1015, 977, 922, 824,
793, 734 cm-1, MS (m/z): HRMS (ESI) Calcd. for C38H30ClNNaO6 ([M+Na]+): 654.1654; found:
654.1650.
Dimethyl
4'-(4-bromophenyl)-1'-(4-methoxyphenyl)-1,3-dioxo-2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro-[
1
indene-2,3'-pyridine]-5',6'-dicarboxylate (1b): light yellow solid, 71%, m.p. 200-202℃; H
NMR (400 MHz, CDCl3) δ cis-isomer: 7.91 (d, J = 7.2 Hz, 1H, ArH), 7.79-7.54 (m, 4H, ArH),
7.35-7.29 (m, 2H, ArH), 7.24-7.20 (m, 3H, ArH), 7.08-7.01 (m, 4H, ArH), 6.80-6.74 (m, 2H, ArH),
6.66 (d, J = 7.6 Hz, 1H, ArH), 6.51 (d, J = 15.2 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.47 (d, J = 6.8
Hz, 1H, CH), 4.29 (s, 1H, CH), 3.75 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.40 (s, 3H, OCH3);
trans-isomer: 7.35-7.29 (m, 3H, ArH), 6.41 (d, J = 15.6 Hz, 1H, CH), 5.09-5.03 (m, 1H, CH), 4.75
(d, J = 10.0 Hz, 1H, CH), 4.63 (s, 1H, CH), 3.73 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.36 (s, 3H,
OCH3); ratio of cis/trans-isomers = 49:51. 13C NMR (100 MHz, CDCl3) δ: 200.2, 198.7, 197.3,
166.5, 166.3, 165.3, 158.7, 150.2, 148.7, 142.9, 142.2, 141.3, 140.9, 138.6, 138.0, 136.3, 136.0,
135.8, 135.6, 135.5, 135.3, 132.5, 131.7, 131.1, 130.9, 130.5, 129.2, 128.5, 128.3, 128.2 (2C),
126.8, 126.4, 123.5 (2C), 122.7, 122.6, 122.0, 121.8, 120.9, 120.3, 113.9, 113.4, 99.6, 65.1, 60.7,
58.7, 55.3 (2C), 52.5, 52.3, 51.2, 51.0, 44.4, 41.8; IR (KBr) υ: 3647, 3368, 3068, 3023, 2948, 2838,
1900, 1743, 1700, 1580, 1504, 1438, 1335, 1241, 1179, 1127, 1068, 1020, 976, 927, 838, 794, 736
cm-1, MS (m/z): HRMS (ESI) Calcd. for C38H30BrNNaO7 ([M+Na]+): 714.1098; found: 714.1087.
Dimethyl
1'-(4-chlorophenyl)-4'-(4-nitrophenyl)-1,3-dioxo-2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[inde
1
ne-2,3'-pyridine]-5',6'-dicarboxylate (1c): light yellow solid, 78%, m.p. 204-206℃; H NMR
(400 MHz, CDCl3) δ cis-isomer: 7.96 (d, J = 8.8 Hz, 1H, ArH), 7.89 (d, J = 7.2 Hz, 1H, ArH),
7.79-7.55 (m, 4H, ArH), 7.37-7.27 (m, 9H, ArH), 7.12-7.03 (m, 1H, ArH), 6.72 (d, J = 16.0 Hz,
1H, CH), 6.67-6.65 (m, 1H, ArH), 6.25-6.22 (m, 1H, CH), 4.48 (s, 1H, CH), 4.46 (d, J = 5.6 Hz,
1H, CH), 3.73 (s, 3H, OCH3), 3.37 (s, 3H, OCH3); trans-isomer: 7.84 (s, 1H, ArH), 7.12-7.03 (m,
2H, ArH), 6.48 (d, J = 16.0 Hz, 1H, CH), 5.01-4.94 (m, 1H, CH), 4.80-4.75 (m, 2H, CH, CH),
3.61 (s, 3H, OCH3), 3.36 (s, 3H, OCH3); ratio of cis/trans-isomers = 67:33. 13C NMR (100 MHz,
CDCl3) δ: 199.4, 198.3, 198.0, 197.0, 166.0, 165.9, 165.1, 164.8, 149.8, 147.7, 147.1, 146.9, 146.7,
146.6, 142.5, 142.0, 140.9, 140.8, 138.2, 137.2, 136.7, 136.5, 136.4, 136.2, 136.0 (2C), 135.6,
11

ACCEPTED MANUSCRIPT
134.8, 133.8, 132.9, 131.6, 129.5, 129.2, 128.7, 128.6, 128.5 (2C), 128.4, 127.0, 126.4, 123.7,
123.5 (2C), 123.4, 123.2 (2C), 123.1, 123.0, 122.7, 121.0, 120.7, 100.6, 65.8, 65.2, 60.6, 59.0,
52.8, 52.6, 51.4, 51.2, 44.7, 41.6, 29.7; IR (KBr) υ: 3424, 3067, 2947, 2846, 1741, 1700, 1586,
1521, 1489, 1425, 1343, 1248, 1120, 1013, 976, 925, 849, 760, 723 cm-1, MS (m/z): HRMS (ESI)
Calcd. for C37H27ClN2NaO8 ([M+Na]+): 685.1348; found: 685.1347.
Dimethyl
1',4'-bis(4-chlorophenyl)-1,3-dioxo-2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-pyridi
1
ne]-5',6'-dicarboxylate (1d): light yellow solid, 75%, m.p. 198-200℃; H NMR (400 MHz,
CDCl3) δ cis-isomer: 7.88 (d, J = 7.2 Hz, 1H, ArH), 7.77-7.70 (m, 2H, ArH), 7.66-7.54 (m, 2H,
ArH), 7.35 (d, J = 8.4 Hz, 1H, ArH), 7.29-7.26 (m, 3H, ArH), 7.23-7.20 (m, 2H, ArH), 7.10-7.03
(m, 4H, ArH), 6.93 (s, 1H, ArH), 6.67-6.63 (m, 2H, ArH, CH), 6.17-6.12 (m, 1H, CH), 4.45 (d, J =
6.8 Hz, 1H, CH), 4.32 (s, 1H, CH), 3.70 (s, 3H, OCH3), 3.38 (s, 3H, OCH3); trans-isomer: 7.35 (d,
J = 8.4 Hz, 2H, ArH), 7.29-7.26 (m, 4H, ArH), 6.93 (s, 2H, ArH), 6.45 (d, J = 15.6 Hz, 1H, CH),
5.05-5.00 (m, 1H, CH), 4.75 (d, J = 10.4 Hz, 1H, CH), 4.62 (s, 1H, CH), 3.59 (s, 3H, OCH3), 3.36
(s, 3H, OCH3); ratio of cis/trans-isomers = 54:46. 13C NMR (100 MHz, CDCl3) δ: 200.0, 198.7,
198.4, 197.4, 166.4, 166.2, 165.3, 165.1, 149.3, 147.3, 142.8, 142.2, 141.2, 141.0, 138.5, 137.5,
137.2, 136.9, 136.1, 135.9, 135.7, 135.6, 135.1, 135.0, 133.6, 132.8, 132.6, 132.3, 131.6, 130.0,
129.1, 128.6, 128.4 (2C), 128.3, 128.2, 128.0, 127.0, 126.4, 123.6, 123.4, 122.8, 122.6, 121.5,
121.2, 101.5, 65.0, 60.8, 59.0, 52.6, 52.5, 51.3, 51.1, 44.4, 41.6; IR (KBr) υ: 3642, 3423, 3066,
3029, 2948, 2891, 1907, 1742, 1700, 1586, 1489, 1423, 1403, 1335, 1251, 1129, 1015, 977, 925,
837, 796, 752, 730 cm-1; MS (m/z): HRMS (ESI) Calcd.forC37H27Cl2NNaO6 ([M+Na]+):674.1108;
found:674.1104.
Dimethyl
1'-(4-bromophenyl)-4'-(4-chlorophenyl)-1,3-dioxo-2'-styryl-1,2',3,4'-tetrahydro-1'H-spiro[in
dene-2,3'-pyridine]-5',6'-dicarboxylate (1e): light yellow solid, 72%, m.p. 212-214℃; 1H NMR
(400 MHz, CDCl3) δ cis-isomer: 7.88 (d, J = 7.2 Hz, 1H, ArH), 7.76-7.70 (m, 2H, ArH), 7.67-7.54
(m, 2H, ArH), 7.41-7.36 (m, 2H, ArH), 7.30-7.28 (m, 4H, ArH), 7.10-7.04 (m, 4H, ArH), 6.93 (brs,
1H, ArH), 6.67 (d, J = 7.6 Hz, 1H, ArH, CH), 6.20 (brs, 1H, CH), 4.45 (d, J = 6.4 Hz, 1H, CH),
4.32 (s, 1H, CH), 3.71 (s, 3H, OCH3), 3.37 (s, 3H, OCH3); trans-isomer: 7.41-7.36 (m, 3H, ArH),
6.46 (d, J = 15.6 Hz, CH), 5.04-4.98 (m, 1H, CH), 4.75 (d, J = 10.0 Hz, 1H, CH), 4.62 (s, 1H, CH),
12

ACCEPTED MANUSCRIPT
3.60 (s, 3H, OCH3), 3.37 (s, 3H, OCH3); ratio of cis/trans-isomers = 60:40. 13C NMR (100 MHz,
CDCl3) δ: 200.0, 198.7, 198.4, 197.3, 166.3, 166.1, 165.3, 165.1, 149.2, 147.2, 142.8, 142.2(2C),
141.0, 139.0, 137.4, 137.1, 136.9, 136.1, 135.9, 135.7(2C), 135.6, 135.1, 135.0, 132.6, 132.3,
132.1, 131.9, 131.6, 130.0, 128.6, 128.4(2C), 128.3 (2C), 128.2, 128.0, 127.0, 126.4, 123.6, 123.4,
122.8, 122.6, 121.7, 121.5, 121.2, 120.7, 101.6, 65.0, 62.6, 60.8, 59.1, 52.7, 52.5, 51.3, 51.1, 44.4,
41.5; IR(KBr) υ: 3610, 3374, 3065, 3028, 2947, 1907, 1742, 1700, 1586, 1486, 1438, 1421, 1402,
1335, 1250, 1128, 1064, 1012, 976, 925, 834, 795, 751, 728 cm-1 ; MS (m/z): HRMS (ESI) Calcd.
for C37H27BrClNNaO6 ([M+Na]+): 718.0602; found: 718.0588.
Dimethyl
1'-(4-bromophenyl)-1,3-dioxo-2'-styryl-4'-(p-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'
1
-pyridine]-5',6'-dicarboxylate (1f): light yellow solid, 65%, m.p. 206-208℃; H NMR (400
MHz, CDCl3) δ cis-isomer: 7.88 (d, J = 7.2 Hz, 1H, ArH), 7.74-7.67 (m, 2H, ArH), 7.58-7.50 (m,
1H, ArH), 7.41-7.30 (m, 4H, ArH), 7.23-7.20 (m, 3H, ArH), 7.10-7.00 (m, 2H, ArH), 6.88-6.86 (m,
3H, ArH), 6.66 (d, J = 6.8 Hz, 1H, ArH), 6.60 (d, J = 16.0 Hz, 1H, CH), 6.13-6.08 (m, 1H, CH),
4.51 (d, J = 6.8 Hz, 1H, CH), 4.27 (s, 1H, CH), 3.70 (s, 3H, OCH3), 3.38 (s, 3H, OCH3), 2.21 (s,
3H, CH3); trans-isomer: 7.65-7.63 (m, 1H, ArH), 7.58-7.50 (m, 2H, ArH), 7.10-7.00 (m, 3H, ArH),
6.71 (d, J = 6.8 Hz, 1H, ArH), 6.47 (d, J = 16.0 Hz, 1H, CH), 5.13-5.07 (m, 1H, CH), 4.77 (d, J =
10.0 Hz, 1H, CH), 4.57 (s, 1H, CH), 3.60 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 2.04 (s, 3H, CH3);
ratio of cis/trans-isomers = 55:45. 13C NMR (100 MHz, CDCl3) δ: 200.3, 198.9, 198.7, 197.5,
166.7, 166.4, 165.4, 165.3, 148.7, 147.1, 143.0, 142.3, 141.5, 141.1, 139.4, 138.6, 138.1, 137.4,
136.7, 135.9, 135.8, 135.6, 135.4, 135.2 (2C), 132.0, 131.9, 131.5, 129.3, 128.5, 128.4, 128.3,
128.2, 127.9, 127.4, 126.8, 126.5, 125.8, 123.4, 123.3, 122.6, 122.4, 121.9, 121.7, 121.6, 120.8,
102.1, 64.6, 61.9, 60.8, 59.0, 52.6, 52.4, 51.3, 51.1, 45.3, 42.7, 29.7, 21.5; IR(KBr) υ: 3622, 3543,
3426, 3031, 2947, 1954, 1740, 1700, 1590, 1486, 1438, 1400, 1334, 1249, 1124, 1061, 1010, 977,
921, 880, 843, 773, 732 cm-1; MS (m/z): HRMS (ESI) Calcd. for C38H30BrNNaO6 ([M+Na]+):
698.1149; found: 698.1152.
Dimethyl
2'-(3-methylstyryl)-1,3-dioxo-4'-phenyl-1'-(p-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'
1
-pyridine]-5',6'-dicarboxylate (1g): light yellow solid, 65%, m.p. 212-214℃; H NMR (600
MHz, CDCl3) δ cis-isomer: 7.89 (d, J = 7.2 Hz, 1H, ArH), 7.74-7.67 (m, 1H, ArH), 7.64-7.58 (m,
13

ACCEPTED MANUSCRIPT
1H, ArH), 7.53-7.48 (m, 1H, ArH), 7.30 (d, J = 8.0 Hz, 1H, ArH), 7.15-6.98 (m, 7H, ArH),
6.93-6.86 (m, 3H, ArH), 6.51-6.34 (m, 2H, ArH, CH), 5.10-5.04 (m, 1H, CH), 6.93-6.86 (m, 1H,
ArH), 6.07 (s, 1H, CH), 4.53 (d, J = 6.8 Hz, 1H, CH), 4.30 (s, 1H, CH), 3.66 (s, 3H, OCH3), 3.37
(s, 3H, OCH3), 2.24 (s, 3H, CH3); trans-isomer: 7.74-7.67 (m, 2H, ArH), 7.15-6.98 (m, 8H, ArH),
4.77 (d, J = 10.0 Hz, 1H, CH), 4.64 (s, 1H, CH), 3.57 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 2.26 (s,
3H, CH3), 2.09 (s, 3H, CH3); ratio of cis/trans-isomers = 48:52. 13C NMR (150 MHz, CDCl3) δ:
200.5, 198.9, 197.4, 166.8, 166.6, 165.5, 149.7, 143.1, 142.4, 141.6, 141.1, 139.4, 138.7, 138.1,
137.9, 137.6, 137.5, 137.2, 136.3, 136.0, 135.8, 135.6, 135.5, 135.3, 135.1, 130.2, 129.5, 129.0,
128.8, 128.4, 128.1, 128.0, 127.8, 127.6, 127.5, 127.0, 126.5, 124.0, 123.5, 123.4 (2C), 122.7,
122.4, 122.3, 122.0, 100.5, 64.9, 61.0, 59.1, 52.4, 52.3, 51.1, 50.9, 45.3, 42.8, 21.3, 21.1; IR (KBr)
υ:3639, 3426, 3027, 2950, 1955, 1740, 1697, 1585, 1505, 1438, 1247, 1134, 1020, 978, 922, 879,
812, 762, 719 cm-1; MS (m/z): HRMS (ESI) Calcd. for C39H33NNaO6 ([M+Na]+): 634.2200; found:
634.2209.
Dimethyl
2'-(3-methylstyryl)-1,3-dioxo-4'-(m-tolyl)-1'-(p-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,
1
3'-pyridine]-5',6'-dicarboxylate (1h): light yellow solid, 66%, m.p. 192-194℃; H NMR (400
MHz, CDCl3) δ cis-isomer: 7.89 (d, J = 7.2 Hz, 1H, ArH), 7.73-7.67 (m, 2H, ArH), 7.54-7.50 (m,
1H, ArH), 7.30 (d, J = 6.0 Hz, 2H, ArH), 7.10-6.98 (m, 6H, ArH), 6.91-6.81 (m, 3H, ArH),
6.50-6.43 (m, 2H, ArH, CH), 6.05 (brs, 1H, CH), 4.53 (d, J = 7.2 Hz, 1H, CH), 4.26 (s, 1H, CH),
3.66 (s, 3H, OCH3), 3.39 (s, 3H, OCH3), 2.25 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.10 (s, 3H, CH3);
trans-isomer: 7.63 (d, J = 7.6 Hz, 1H, ArH), 7.58 (d, J = 6.8 Hz, 1H, ArH), 6.91-6.81 (m, 4H,
ArH), 6.65 (brs, 1H, ArH), 6.38 (d, J = 15.2 Hz, 1H, CH), 5.14-5.08 (m, 1H, CH), 4.77 (d, J =
10.0 Hz, 1H, CH), 4.58 (s, 1H, CH), 3.59 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 2.26 (s, 3H, CH3),
2.00 (s, 3H, CH3); ratio of cis/trans-isomers = 64:36. 13C NMR (100 MHz, CDCl3) δ: 200.2, 198.6,
197.3, 166.5, 166.3, 165.4, 165.3, 150.0, 148.3, 142.9, 142.2, 141.3, 141.0, 138.6, 137.7, 137.5,
137.2, 136.2, 136.0(2C), 135.8, 135.6, 135.4, 135.3, 135.1, 132.6, 132.1, 130.1, 130.0, 129.5,
129.0, 128.5, 128.3, 128.2, 128.1, 128.0, 126.9, 126.4, 123.5, 123.4, 122.7, 122.6, 122.1, 121.8,
100.0, 65.0, 60.8, 59.0, 52.5, 52.3, 51.2, 51.0, 44.4, 41.7, 31.9, 29.7(2C), 29.4, 22.7, 21.1 (2C),
14.1; IR (KBr) υ: 3641, 3426, 3184, 3022, 2949, 1946, 1739, 1697, 1586, 1506, 1433, 1397, 1247,
1128, 978, 913, 877, 817, 780, 719 cm-1; MS (m/z): HRMS (ESI) Calcd. for C40H35NNaO6
14

ACCEPTED MANUSCRIPT
([M+Na]+): 648.2357; found: 648.2350.
Dimethyl
1',4'-bis(4-methoxyphenyl)-2'-(3-methylstyryl)-1,3-dioxo-1,2',3,4'-tetrahydro-1'H-spiro[inde
1
ne-2,3'-pyridine]-5',6'-dicarboxylate (1i): light yellow solid, 68%, m.p. 178-180℃; H NMR
(600 MHz, CDCl3) δ cis-isomer: 7.91 (d, J = 7.8 Hz, 1H, ArH), 7.75-7.73 (m, 1H, ArH), 7.71-7.69
(m, 1H, ArH), 7.54-7.49 (m, 2H, ArH), 7.34 (d, J = 8.4 Hz, 1H, ArH), 7.04 (brs, 2H, ArH),
6.92-6.90 (m, 1H, ArH), 6.82-6.71 (m, 4H, ArH), 6.57-6.55 (m, 3H, ArH), 6.36-6.33 (m, 1H, CH),
5.79 (brs, 1H, CH), 4.52 (d, J = 7.2 Hz, 1H, CH), 4.24 (s, 1H, CH), 3.75 (s, 3H, OCH3), 3.73 (s,
3H, OCH3), 3.64 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 2.28 (s, 3H, CH3); trans-isomer: 7.63 (d, J =
7.2 Hz, 1H, ArH), 7.59 (d, J = 7.2 Hz, 1H, ArH), 7.11-7.08 (m, 1H, ArH), 6.96-6.95 (m, 1H, ArH),
6.82-6.71 (m, 5H, ArH), 6.66-6.63 (m, 3H, ArH), 4.99-4.96 (m, 1H, CH), 4.74 (d, J = 9.6 Hz, 1H,
CH), 4.59 (s, 1H, CH), 3.73 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.39 (s, 3H,
OCH3), 2.06 (s, 3H, CH3); ratio of cis/trans-isomers = 40:60. 13C NMR (150 MHz, CDCl3) δ:
200.7, 199.0, 197.5, 166.8, 166.7, 165.6, 165.4, 159.6, 158.7, 149.8, 143.2, 142.5, 141.7, 141.1,
139.5, 138.6, 137.4, 135.7, 135.5, 135.2, 135.0, 132.9, 131.8, 129.6, 128.8, 128.3, 127.9 (2C),
127.7, 127.3, 126.0, 123.4, 123.3, 122.5, 122.3, 120.1 (2C), 113.8, 113.7, 113.4, 100.1, 65.0, 61.0,
58.9, 55.3(2C), 55.2, 52.4, 52.3, 51.1, 50.9, 45.4, 43.0, 29.7, 26.6, 21.2; IR (KBr) υ: 3566, 3008,
2951, 2837, 1744, 1697, 1593, 1507, 1433, 1338, 1245, 1174, 1107, 1027, 971, 920, 836, 792, 733
cm-1; MS (m/z): HRMS (ESI) Calcd. for C40H35NNaO8 ([M+Na]+): 680.2255; found: 680.2267.
Dimethyl
2'-(4-methoxystyryl)-1,3-dioxo-1'-phenyl-4'-(m-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2
1
,3'-pyridine]-5',6'-dicarboxylate (1j): light yellow solid, 64%, m.p. 186-188℃; H NMR (600
MHz, CDCl3) δ cis-isomer: 7.90 (d, J = 7.8 Hz, 1H, ArH), 7.74-7.71 (m, 1H, ArH), 7.54-7.49 (m,
1H, ArH), 7.69-7.67 (m, 1H, ArH), 7.44-7.38 (m, 2H, ArH), 7.30-7.28 (m, 1H, ArH), 7.23 (d, J =
7.2 Hz, 1H, ArH), 7.19-7.15 (m, 1H, ArH), 7.10-7.05 (m, 1H, ArH), 6.92-6.91 (m, 2H, ArH), 6.82
(s, 1H, ArH), 6.74 (d, J = 9.0 Hz, 1H, ArH), 6.67-6.66 (m, 1H, ArH), 6.46 (d, J = 15.0 Hz, 1H,
CH), 5.90 (s, 1H, CH), 4.57 (d, J = 7.2 Hz, 1H, CH), 4.28 (s, 1H, CH), 3.75 (s, 3H, OCH3), 3.64 (s,
3H, OCH3), 3.41 (s, 3H, OCH3), 2.25 (s, 3H, CH3); trans-isomer: 7.64 (d, J = 7.0 Hz, 1H, ArH),
7.59 (d, J = 4.8 Hz, 1H, ArH), 7.10-7.05 (m, 2H, ArH), 6.74 (d, J = 9.0 Hz, 2H, ArH), 6.63 (d, J =
9.0 Hz, 1H, ArH), 6.56 (d, J = 9.0 Hz, 1H, ArH), 6.37 (d, J = 15.6 Hz, 1H, CH), 5.00-4.95 (m, 1H,
15

ACCEPTED MANUSCRIPT
CH), 4.79 (d, J = 10.2 Hz, 1H, CH), 4.61 (s, 1H, CH), 3.66 (s, 3H, OCH3), 3.55 (s, 3H, OCH3),
3.35 (s, 3H, OCH3), 2.06 (s, 3H, CH3); ratio of cis/trans-isomers = 55:45. 13C NMR (150 MHz,
CDCl3) δ: 200.6, 199.0, 198.7, 197.5, 166.8, 166.6, 165.5, 165.4, 159.6, 149.4, 148.0, 143.2, 142.4,
141.6, 141.1, 140.3, 139.2, 138.5, 137.4, 135.8(2C), 135.5, 135.3, 135.0, 130.5, 129.5, 128.8,
128.3, 128.0, 127.9, 127.8, 127.7, 127.3, 126.0, 123.3, 122.5, 122.3, 120.1, 119.9, 113.9, 113.7,
100.8, 64.8, 61.0, 59.1, 55.3, 55.2, 52.4, 52.2, 51.2, 51.0, 45.4, 42.9, 21.5; IR (KBr) υ: 3779, 3646,
3534, 3427, 3187, 3002, 2949, 2840, 1960, 1892, 1736, 1698, 1587, 1502, 1439, 1394, 1338, 1246,
1180, 1130, 1027, 977, 933, 875, 828, 777, 708 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C39H33NNaO7 ([M+Na]+): 650.2149; found: 650.2161.
Dimethyl
1'-(4-methoxyphenyl)-2'-(4-methoxystyryl)-1,3-dioxo-4'-(m-tolyl)-1,2',3,4'-tetrahydro-1'H-
spiro[indene-2,3'-pyridine]-5',6'-dicarboxylate (1k): light yellow solid, 62%, m.p. 184-186℃;
1H NMR (600 MHz, CDCl3) δ cis-isomer: 7.91 (d, J = 5.2 Hz, 1H, ArH), 7.75-7.73 (m, 1H, ArH),
7.71-7.69 (m, 1H, ArH), 7.54-7.49 (m, 1H, ArH), 7.34 (d, J = 8.4 Hz, 1H, ArH), 7.11-7.08 (m, 1H,
ArH), 6.96-6.90 (m, 2H, ArH), 6.80-6.71 (m, 4H, ArH), 6.66-6.63 (m, 2H, ArH), 6.56 (d, J = 9.0
Hz, 1H, ArH), 6.36-6.33 (m, 1H, CH), 5.79 (brs, 1H, CH), 4.52 (d, J = 10.2 Hz, 1H, CH), 4.24 (s,
1H, CH), 3.75 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 2.28
(s, 3H, CH3); trans-isomer: 7.63 (d, J = 7.2 Hz, 1H, ArH), 7.58 (d, J = 6.8 Hz, 1H, ArH), 7.34 (d, J
= 8.4 Hz, 2H, ArH), 7.04 (brs, 2H, ArH), 4.99-4.96 (m, 1H, CH), 4.74 (d, J = 10.2 Hz, 1H, CH),
4.60 (s, 1H, CH), 3.74 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.34 (s, 3H,
OCH3), 2.06 (s, 3H, CH3); ratio of cis/trans-isomers = 51:49. 13C NMR (150 MHz, CDCl3) δ:
200.7, 199.0, 198.5, 197.5, 166.8, 166.7, 165.5, 165.4, 159.6, 158.7, 149.8, 148.8 (2C), 143.2,
142.5, 141.7, 141.1, 139.5, 138.6, 137.4, 135.7, 135.6, 135.2, 135.0, 132.9, 131.8, 129.8, 129.6,
128.8, 128.3, 127.9 (2C), 127.7, 127.3, 126.0, 123.4, 123.3, 122.5, 122.3, 120.1, 113.8, 113.7,
113.4, 100.1, 65.0, 61.0, 58.9, 55.3 (2C), 55.2, 52.4, 52.3, 51.1, 50.9, 45.4, 43.0, 21.6, 21.2; IR
(KBr) υ: 3636, 3369, 3009, 2951, 2836, 2049, 1743, 1698, 1594, 1507, 1433, 1338, 1244, 1175,
1111, 1028, 972, 922, 837, 817, 793, 733 cm-1; MS (m/z): HRMS (ESI) Calcd. for C40H35NNaO8
([M+Na]+): 680.2255; found: 680.2255.
Dimethyl
2'-(3-fluorostyryl)-1'-(4-methoxyphenyl)-1,3-dioxo-4'-(m-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro
16

ACCEPTED MANUSCRIPT
1
-[indene-2,3'-pyridine]-5',6'-dicarboxylate (1l): light yellow solid, 80%, m.p. 182-184℃; H
NMR (600 MHz, CDCl3) δ cis-isomer: 7.91 (d, J = 7.8 Hz, 1H, ArH), 7.76-7.74 (m, 2H, ArH),
7.72-7.69 (m, 1H, ArH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.17-7.14 (m, 1H, ArH), 7.10-7.07 (m, 1H,
ArH), 6.94 (d, J = 7.2 Hz, 1H, ArH), 6.91-6.84 (m, 6H, ArH), 6.79-6.76 (m, 1H, ArH), 6.43 (d, J =
15.6 Hz, 1H, CH), 6.01 (brs, 1H, CH), 4.53 (d, J = 7.8 Hz, 1H, CH), 4.23 (s, 1H, CH), 3.75 (s, 3H,
OCH3), 3.65 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 2.26 (s, 3H, CH3); trans-isomer: 7.65 (d, J = 6.6
Hz, 1H, ArH), 7.61 (d, J = 7.2 Hz, 1H, ArH), 7.57-7.51 (m, 2H, ArH), 7.02-6.99 (m, 2H, ArH),
6.50 (d, J = 7.8 Hz, 1H, ArH), 6.36 (d, J = 15.6 Hz, 1H, CH), 6.34-6.32 (m, 1H, ArH), 5.20-5.15
(m, 1H, CH), 4.76 (d, J = 10.2 Hz, 1H, CH), 4.58 (s, 1H, CH), 3.74 (s, 3H, OCH3), 3.59 (s, 3H,
OCH3), 3.34 (s, 3H, OCH3), 2.06 (s, 3H, CH3); ratio of cis/trans-isomers = 75:25. 13C NMR (150
MHz, CDCl3) δ: 200.5, 198.7, 198.5, 197.4, 166.8, 166.6, 165.4, 163.7, 162.0, 158.8, 158.7, 149.6,
148.6, 143.1, 142.3, 141.6, 141.1, 139.2, 138.4, 138.3 (d, J = 8.2 Hz), 137.8 (d, J = 7.4 Hz), 137.4,
135.8, 135.7, 135.4, 135.1, 135.0, 134.2, 132.9, 131.7(2C), 130.0, 129.9 (d, J = 8.4 Hz), 128.0
(2C), 127.7, 127.4, 126.0, 124.0, 124.0, 123.4, 123.3, 122.6, 122.5, 122.4, 115.0, 114.9, 114.8,
114.0, 113.5, 113.2 (d, J = 21.9 Hz), 112.9 (d, J = 20.2 Hz), 100.2, 64.6, 61.5, 60.8, 58.9, 55.4,
55.3, 52.4, 52.3, 51.2, 51.0, 45.4, 43.0, 29.7, 21.5, 21.2; IR (KBr) υ: 3638, 3359, 3065, 3012, 2949,
2841, 1738, 1697, 1584, 105, 1439, 1336, 1238, 1177, 1136, 1026, 976, 876, 840, 786, 720 cm-1;
MS (m/z): HRMS (ESI) Calcd. for C39H32FNNaO7 ([M+Na]+): 668.2055; found: 668.2059.
Dimethyl
2'-(3-fluorostyryl)-1'-(4-methylphenyl)-1,3-dioxo-4'-(m-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro-
1
[indene-2,3'-pyridine]-5',6'-dicarboxylate (1m): light yellow solid, 79%, m.p. 172-174℃; H
NMR (600 MHz, CDCl3) δ cis-isomer: 7.90 (d, J = 7.8 Hz, 1H, ArH),7.74-7.67 (m, 1H, ArH),
7.65 (d, J = 6.6 Hz, 1H, ArH), 7.55-7.50 (m, 1H, ArH), 7.30 (d, J = 7.8 Hz, 2H, ArH), 7.15-7.03
(m, 3H, ArH), 6.92-6.82 (m, 4H, ArH), 6.73-6.65 (m, 3H, ArH), 6.49 (d, J = 15.6 Hz, 1H, CH),
6.00 (brs, 1H, CH), 4.52 (d, J = 7.2 Hz, 1H, CH), 4.27 (s, 1H, CH), 3.66 (s, 3H, OCH3), 3.40 (s,
3H, OCH3), 3.24 (s, 3H, OCH3), 2.24 (s, 3H, CH3), 2.06 (s, 3H, CH3); trans-isomer: 7.74-7.67 (m,
2H, ArH), 7.69 (d, J = 7.2 Hz, 1H, ArH), 7.15-7.03 (m, 4H, ArH), 6.39 (d, J = 15.6 Hz, 1H, CH),
5.12-5.06 (m, 1H, CH), 4.47 (d, J = 9.6 Hz, 1H, CH), 4.59 (s, 1H, CH), 3.58 (s, 3H, OCH3), 3.34
(s, 3H, OCH3), 2.28 (s, 3H, CH3), 2.26 (s, 3H, CH3); ratio of cis/trans-isomers = 48:52.13C NMR
(150 MHz, CDCl3) δ: 200.5, 198.8, 197.4, 166.8, 166.6, 165.5 (2C), 163.4 (d, J = 8.4 Hz), 161.7
17

ACCEPTED MANUSCRIPT
(d, J = 10.3 Hz), 149.4, 148.2, 143.1, 142.3, 141.6, 141.1, 139.1, 138.5, 137.7, 137.6, 137.4, 137.3,
135.8, 135.6, 135.3, 135.1, 134.8, 133.9, 132.3, 131.7, 131.7, 130.0, 129.5, 129.0, 128.4, 128.3,
128.1 (d, J = 9.6 Hz), 127.9, 127.8, 127.7, 127.3, 125.9, 123.3, 122.5, 122.4 (2C), 122.1, 115.5 (d,
J = 15.6 Hz), 115.3 (d, J = 16.5 Hz), 100.6, 64.6, 60.9, 59.1, 52.4, 52.2, 51.1, 50.9, 45.3, 42.8,
29.7, 21.5, 21.2, 21.1(2C); IR (KBr) υ:3611, 3424, 3033, 2945, 1740, 1699, 1586, 1507, 1442,
1338, 1239, 1144, 1061, 1019, 978, 864, 821, 725 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C39H32FNNaO6 ([M+Na]+): 652.2106; found: 652.2106.
Dimethyl
2'-(4-fluorostyryl)-1,3-dioxo-4'-phenyl-1'-(p-tolyl)-1,2',3,4'-tetrahydro-1'H-spiro[indene-2,3'-
pyridine]-5',6'-dicarboxylate (1n): light yellow solid, 78%, m.p. 180-182℃; 1H NMR (600 MHz,
CDCl3) δ cis-isomer: 7.90 (d, J = 7.2 Hz, 1H, ArH), 7.74-7.64 (m, 2H, ArH), 7.55-7.50 (m, 1H,
ArH), 7.31 (d, J = 7.2 Hz, 1H, ArH), 7.16-6.88 (m, 10H, ArH), 6.73 (m, 1H, ArH), 6.65-6.63 (m,
1H, ArH), 6.52 (d, J = 15.0 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.52 (d, J = 9.6 Hz, 1H, CH), 4.32 (s,
1H, CH), 3.67 (s, 3H, OCH3), 3.38 (s, 3H, OCH3), 2.28 (s, 3H, CH3); trans-isomer: 7.60 (d, J = 7.2
Hz, 1H, ArH), 6.68 (d, J = 15.6 Hz, 1H, CH), 5.07-5.03 (m, 1H, CH), 4.77 (d, J = 9.6 Hz, 1H, CH),
4.65 (s, 1H, CH), 3.58 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 2.26 (s, 3H, CH3); ratio of
cis/trans-isomers = 46:54. 13C NMR (150 MHz, CDCl3) δ: 200.5, 198.8, 198.7, 197.4, 166.8,
166.5 (d, J = 13.8 Hz), 165.4 (d, J = 10.2 Hz), 161.7(2C), 149.6, 148.2, 143.1, 142.3, 141.5, 141.1,
139.3, 138.7, 137.7, 137.5, 137.2, 135.8, 135.6, 135.4, 135.2, 134.9, 133.9, 133.2, 131.6, 130.1,
129.5, 129.0, 128.8, 128.4 (d, J = 7.9 Hz), 128.0 (d, J = 6.4 Hz), 127.8, 127.0, 126.6, 123.4 (2C),
122.6, 122.5, 122.3, 122.0, 115.5, 115.3 (d, J = 5.4 Hz), 115.2, 100.6, 64.8, 60.9, 59.1, 58.4, 52.4,
52.3, 51.1, 50.9, 45.3, 42.7, 21.1(2C), 18.4; IR(KBr) υ: 3591, 3366, 3035, 2948, 1741, 1700, 1585,
1508, 1441, 1402, 1335, 1240, 1144, 1024, 978, 926, 817, 764, 733 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C38H30FNNaO6 ([M+Na]+):638.1949; found: 638.1951.
Dimethyl
1'-(4-methoxyphenyl)-4'-(4-nitrophenyl)-2'-(4-nitrostyryl)-1,3-dioxo-1,2',3,4'-tetrahydro-1'H
-
spiro[indene-2,3'-pyridine]-5',6'-dicarboxylate (1o): light yellow solid, 88%, m.p. 180-182℃;
1H NMR (600 MHz, CDCl3) δ cis-isomer: 8.16 (d, J = 7.8 Hz, 1H, ArH), 7.98 (d, J = 7.8 Hz, 1H,
ArH), 7.91-7.58 (m, 7H, ArH), 7.47 (s, 1H, ArH), 7.35-7.30 (m, 4H, ArH), 6.83-6.74 (m, 4H, ArH,
18

ACCEPTED MANUSCRIPT
CH),6.41 (brs, 1H, CH), 4.48-4.46 (m, 2H, CH, CH), 3.77 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
3.39 (s, 3H, OCH3); trans-isomer: 7.47 (s, 2H, ArH), 6.49 (d, J = 15.6 Hz, 1H, CH), 5.29-5.24 (m,
1H, CH), 4.82 (d, J = 10.2 Hz, 1H, CH), 4.76 (s, 1H, CH), 3.75 (s, 3H, OCH3), 3.60 (s, 3H, OCH3),
3.36 (s, 3H, OCH3); ratio of cis/trans-isomers = 55:45; 13C NMR (150 MHz, CDCl3) δ: 199.6,
197.9, 196.8, 166.0, 165.1, 164.8, 159.1, 158.8, 150.4, 148.7, 147.4 (2C), 147.1, 146.9, 146.7,
142.6, 142.1, 141.9, 141.2, 141.1, 140.8, 136.5, 136.3, 136.2, 136.1, 134.2, 132.9, 132.2, 129.6,
127.6, 127.0, 126.5, 126.4, 124.0, 123.8, 123.7, 123.6, 123.3, 123.2, 122.9, 114.2, 113.7, 99.2,
64.8, 60.5, 58.8, 55.5, 55.4, 52.7, 52.5, 51.3, 51.2, 44.7, 41.8, 29.7; IR (KBr) υ: 3637, 3379, 3076,
3004, 2951, 2842, 1744, 1703, 1592, 1442, 1403, 1347, 1250, 1135, 1024, 979, 918, 839, 812, 735
cm-1, MS (m/z): HRMS (ESI) Calcd. for C38H29N3NaO11 ([M+Na]+): 726.1694; found: 726.1699.
Dimethyl
1'-(4-methoxyphenyl)-2'-(4-nitrostyryl)-1,3-dioxo-4'-phenyl-1,2',3,4'-tetrahydro-1'H-spiro[in
dene-
2,3'-pyridine]-5',6'-dicarboxylate (1p): light yellow solid, 85%, m.p. 180-182℃; 1H NMR (600
MHz, CDCl3) δ cis-isomer: 8.08 (d, J = 7.8 Hz, 1H, ArH), 7.92-7.89 (m, 2H, ArH), 7.76-7.69 (m,
1H, ArH),7.66 (d, J = 7.8 Hz, 1H, ArH), 7.37-7.33 (m, 2H, ArH), 7.16-7.09 (m, 3H, ArH),
7.01-6.88 (m, 3H, ArH), 6.84-6.81 (m, 2H, ArH), 6.77 (d, J = 8.4 Hz, 1H, ArH), 6.63 (d, J = 16.2
Hz, 1H, CH), 6.31 (brs, 1H, CH), 4.55 (d, J = 6.6 Hz, 1H, CH), 4.31 (s, 1H, CH), 3.74 (s, 3H,
OCH3), 3.59 (s, 3H, OCH3); trans-isomer: 7.76-7.69 (m, 2H, ArH), 7.62 (d, J = 7.2 Hz, 1H, ArH),
7.58-7.52 (m, 1H, ArH), 7.37-7.33 (m, 3H, ArH), 6.67 (d, J = 16.2 Hz, 1H, CH), 5.40-5.36 (m, 1H,
CH), 4.81 (d, J = 10.2 Hz, 1H, CH), 4.63 (s, 1H, CH), 3.76 (s, 3H, OCH3), 3.68 (s, 3H, OCH3),
3.39 (s, 3H, OCH3); ratio of cis/trans-isomers = 49:51. 13C NMR (150 MHz, CDCl3) δ: 200.3,
198.5, 197.3, 166.6, 166.4, 165.4, 165.3, 158.9, 158.7, 149.5, 148.3, 147.3, 143.0, 142.3, 142.1,
141.6, 141.5, 141.0, 139.0, 138.3, 136.0, 135.8, 135.6, 135.4, 133.8, 133.0, 132.8, 131.6, 131.5,
128.7, 128.1, 127.9, 127.4, 127.1, 127.0, 126.7, 123.9, 123.8, 123.4, 122.6(2C), 114.0, 113.6,
100.5, 64.5, 60.6, 58.9, 55.4(2C), 52.5, 52.4, 51.2, 50.9, 45.3, 42.8, 29.7; IR (KBr) υ: 3641, 3426,
3184, 3022, 2949, 1946, 1739, 1697, 1586, 1506, 1433, 1397, 1247, 1128, 978, 913, 877, 817, 780,
719 cm-1; MS (m/z): HRMS (ESI) Calcd. for C38H30N2NaO9 ([M+Na]+): 681.1825; found:
681.1842.
19

ACCEPTED MANUSCRIPT
2. General procedure for the synthesis of 1,6-dihydropyridine-2,3,4,5-tetracarboxylate 2a-2h:
A mixture of α,β-unsaturated N-arylaldimine (1.0 mmol), dimethyl acetylenedicarboxylate (2.2
mmol) in dry methylene dichloride (15.0 mL) was stirred at room temperature for about six hours.
After removing the solvent, the resulting oily residue was subjected to thin-layer chromatography
with light petroleum and ethyl acetate (V/V = 2:1) as eluting solvent to give the pure product for
analysis.
Tetramethyl 1-phenyl-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate (2a): yellow
1
solid, 72%, m.p. 171-173℃; H NMR (400 MHz, CDCl3) δ: 7.45-7.43 (m, 2H, ArH), 7.35-7.27
(m, 8H, ArH), 6.78 (d, J = 16.0 Hz, 1H, CH), 6.30 (dd, J1 = 16.0 Hz, J2 = 5.6 Hz, 1H, CH), 5.49 (d,
J = 5.6 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3) δ: 167.7, 164.1, 163.6, 148.2, 142.8, 137.5, 135.9, 131.9,
129.3, 128.6, 128.3, 128.2, 127.0, 125.1, 122.8, 109.3, 103.5, 61.8, 52.9, 52.6, 52.4, 52.0; IR (KBr)
υ:3020, 2948, 2779, 1742, 1714, 1606, 1497, 1436, 1366, 1301, 1244, 1203, 1172, 1122, 1095,
1024, 835, 796, 763 cm-1; MS (m/z): HRMS (ESI) Calcd. for C27H25NNaO8 ([M+Na]+): 514.1472.
Found: 514.1488.
Tetramethyl
(E)-6-styryl-1-(p-tolyl)-1,6-dihydropyridine-2,3,4,5-tetracarboxylate
(2b):
1
yellow solid, 69%, m.p. 186-188℃; H NMR (400 MHz, CDCl3) δ: 7.44-7.42 (m, 2H, ArH),
7.35-7.32 (m, 2H, ArH), 7.28 (d, J = 7.6 Hz, 1H, ArH), 7.23-7.22 (m, 2H, ArH), 7.16-7.14 (m, 2H,
ArH), 6.75 (d, J = 15.6 Hz, 1H, CH), 6.30 (dd, J1 = 16.0 Hz, J2 = 6.0 Hz, 1H, CH), 5.45 (d, J= 5.6
Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H, OCH3),
2.35 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 167.8, 164.1, 163.7, 148.5, 140.3, 138.4, 137.6,
135.9, 131.9, 129.9, 128.6, 128.2, 127.0, 125.1, 122.9, 108.7, 102.8, 62.0, 52.8, 52.6, 52.4, 52.0,
21.1; IR (KBr) υ:3029, 2948, 1745, 1708, 1577, 1510, 1478, 1434, 1390, 1341, 1299, 1259, 1218,
1182, 1130, 1059, 1018, 965, 814 cm-1; MS (m/z): HRMS (ESI) Calcd. for C28H27NNaO8
([M+Na]+): 528.1629. Found: 528.1629.
20

ACCEPTED MANUSCRIPT
Tetramethyl (E)-1-(4-methoxyphenyl)-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate
(2c): yellow solid, 69%, m.p. 174-176℃; 1H NMR (400 MHz, CDCl3) δ: 7.44-7.43 (m, 2H, ArH),
7.34-7.26 (m, 5H, ArH), 6.85 (d, J = 8.0 Hz, 2H, ArH), 6.73 (d, J = 15.2 Hz, 1H, CH), 6.31 (dd, J1
= 15.2 Hz, J2 = 5.2 Hz, 1H, CH), 5.41 (d, J = 5.2 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
δ: 167.8, 164.1, 163.7, 159.4, 149.0, 137.6, 135.8, 135.6, 132.0, 128.6, 128.3, 127.2, 127.0, 122.9,
114.3, 108.3, 101.7, 62.4, 55.5, 52.9, 52.6, 52.4, 52.0; IR (KBr) υ: 3026, 2952, 1738, 1702, 1594,
1503, 1437, 1357, 1306, 1236, 1169, 1120, 1025, 973, 842, 792 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C28H27NNaO9 ([M+Na]+): 544.1578. Found: 544.1597.
Tetramethyl
(E)-1-(4-chlorophenyl)-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate
(2d): yellow solid, 75%, m.p. 175-177℃; 1H NMR (400 MHz, CDCl3) δ: 7.44-7.42 (m, 2H, ArH),
7.36-7.32 (m, 4H, ArH), 7.30-7.26 (m, 3H, ArH), 6.76 (d, J = 16.0 Hz, 1H, CH), 6.27 (dd, J1 =
16.0 Hz, J2 = 6.0 Hz, 1H, CH), 5.43 (d, J = 5.6 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 3.65 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ: 167.5, 163.9,
163.5, 147.6, 141.3, 137.2, 135.7, 134.0, 132.1, 129.5, 128.6, 128.4, 127.0, 126.3, 122.5, 109.8,
104.2, 61.8, 53.0, 52.7, 52.5, 52.1; IR (KBr) υ:3027, 2955, 2840, 1745, 1699, 1594, 1495, 1435,
1349, 1303, 1220, 1171, 1117, 1093, 1015, 968, 882, 841, 788 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C27H24ClNNaO8 ([M+ Na]+): 548.1083. Found: 548.1087.
Tetramethyl
(E)-1-(4-bromophenyl)-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate
(2e): yellow solid, 79%, m.p. 190-192℃; 1H NMR (400 MHz, CDCl3) δ: 7.49-7.48 (m, 2H, ArH),
7.44-7.42 (m, 2H, ArH), 7.34-7.28 (m, 3H, ArH), 7.22-7.20 (m, 2H, ArH), 6.76 (d, J = 15.6 Hz,
1H, CH), 6.27 (dd, J1 = 15.2 Hz, J2 = 4.0 Hz, 1H, CH), 5.44 (brs, 1H, CH), 3.92 (s, 3H, OCH3),
3.76 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.66 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ:
167.4, 163.9, 163.5, 147.4, 141.8, 137.2, 135.7, 132.5, 132.0, 128.6, 128.4, 127.0, 126.5, 122.5,
121.9, 109.9, 104.4, 61.7, 53.1, 52.7, 52.5, 52.1; IR (KBr) υ: 3021, 2954, 2830, 1744, 1698, 1594,
1501, 1434, 1349, 1219, 1171, 1117, 1072, 1013, 968, 840, 788 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C27H24BrNNaO8 ([M+Na]+): 592.0578. Found: 592.0585.
Tetramethyl (E)-6-(3-methylstyryl)-1-(p-tolyl)-1,6-dihydropyridine-2,3,4,5-tetracarboxylate
(2f): yellow solid, 71%, m.p. 181-183℃; 1H NMR (400 MHz, CDCl3) δ: 7.26-7.21 (m, 5H, ArH),
7.15-7.13 (m, 2H, ArH), 7.10-7.09 (m, 1H, ArH), 6.71 (d, J = 15.6 Hz, 1H, CH), 6.28 (dd, J1 =
21

ACCEPTED MANUSCRIPT
15.6 Hz, J2 = 6.0 Hz, 1H, CH), 5.44 (d, J = 6.0 Hz, 1H, CH), 3.92 (s, 3H, OCH3), 3.74 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 2.35 (brs, 6H, CH3); 13C NMR (100 MHz, CDCl3)
δ: 167.8, 164.1, 163.7, 148.5, 140.3, 138.4, 138.2, 137.6, 135.8, 132.0, 129.9, 129.0, 128.5, 127.7,
125.1, 124.2, 122.7, 108.8, 102.7, 62.1 52.8, 52.6, 52.3, 52.0, 21.3, 21.1; IR (KBr) υ: 3031, 2952,
1749, 1702, 1592, 1494, 1437, 1349, 1210, 1171, 1120, 1026, 986, 878, 804 cm-1; MS (m/z):
HRMS (ESI) Calcd. for C29H29NNaO8 ([M+Na]+): 542.1785. Found: 542.1800.
Tetraethyl (E)-1-(4-chlorophenyl)-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate (2g):
yellow oil, 66%, 1H NMR (400 MHz, CDCl3) δ: 7.44-7.42 (m, 2H, ArH), 7.36-7.28 (m, 7H, ArH),
6.76 (d, J = 16.0 Hz, 1H, CH), 6.31 (dd, J1 = 16.0 Hz, J2 = 6.0 Hz, 1H, CH), 5.41 (d, J = 5.6 Hz,
1H, CH), 4.38-4.34 (m, 2H, CH2), 4.24-4.06 (m, 6H, CH2), 1.38 (t, J = 7.2 Hz, 3H, CH3), 1.28 (t, J
= 7.2 Hz, 3H, CH3), 1.24 (t, J = 7.2 Hz, 3H, CH3), 1.08 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ: 167.0, 163.6, 163.2, 163.0, 147.7, 141.4, 137.1, 135.9, 133.8, 131.8, 129.3, 128.6,
128.3, 127.0, 126.6, 122.9, 110.1, 104.3, 62.3, 62.0, 61.7, 61.4, 61.0, 14.1, 14.0, 13.9, 13.6; IR
(KBr) υ: 3032, 2958, 2922, 1746, 1717, 1698, 1672, 1588, 1509, 1466, 1432, 1398, 1360, 1342,
1321, 1256, 1180, 1127, 1096, 1063, 1018, 965, 878, 812 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C31H32ClNNaO8 ([M+Na]+): 604.1709. Found: 604.1714.
Tetraethyl (E)-1-(4-chlorophenyl)-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylate (2h):
yellow oil, 71%, 1H NMR (400 MHz, CDCl3) δ: 7.48-7.42 (m, 4H, ArH), 7.34 (t, J = 7.2 Hz, 2H,
ArH), 7.29 (d, J = 8.0 Hz, 1H, ArH), 7.24-7.22 (m, 2H, ArH), 6.76 (d, J = 16.0 Hz, 1H, CH), 6.30
(dd, J1 = 16.0 Hz, J2 = 6.0 Hz, 1H, CH), 5.41 (d, J = 5.6 Hz, 1H, CH), 4.38-4.34 (m, 2H, CH2),
4.24-4.07 (m, 6H, CH2), 1.38 (t, J = 7.2 Hz, 3H, CH3), 1.28 (t, J = 7.2 Hz, 3H, CH3), 1.24 (t, J =
7.2 Hz, 3H, CH3), 1.08 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 167.0, 163.6,
163.2, 163.0, 147.5, 141.9, 137.1, 135.9, 132.3, 131.8, 128.6, 128.3, 127.0, 126.8, 122.9, 121.7,
110.2, 104.5, 62.3, 61.9, 61.7, 61.4, 61.0, 14.1, 14.0, 13.9, 13.6; IR (KBr) υ: 3027, 2949, 2922,
1754, 1710, 1684, 1606, 1582, 1501, 1488, 1433, 1356, 1236, 1180, 1136, 1011, 976, 958, 891,
819, 795 cm-1; MS (m/z): HRMS (ESI) Calcd. for C31H32BrNNaO8 ([M+Na]+): 648.1204. Found:
648.1201.
3. General procedure for the synthesis of polysubstituted 1,3-oxazine-4,5-dicarboxylates
3a-3i: A mixture of α,β-unsaturated N-arylaldimine (1.0 mmol), dimethyl acetylenedicarboxylate
22

ACCEPTED MANUSCRIPT
(1.0 mmol) in dry methylene dichloride (15.0 mL) was stirred at room temperature for about half
hour. Then, benzoyl cyanide (0.8 mmol) added and the solution was stirred at room temperature
for about twenty hours. After removing the solvent, the resulting oily residue was subjected to
thin-layer chromatography with light petroleum and ethyl acetate (V/V = 2:1) as eluting solvent to
give the pure product for analysis.
Dimethyl
6-cyano-6-phenyl-2-styryl-3-(p-tolyl)-3,6-dihydro-2H-1,3-oxazine-4,5-
dicarboxylate (3a): white solid, 82%, m.p. 131-133 ; 1H NMR (400 MHz, CDCl3) δ: cis-isomer:
7.76-7.71 (m, 2H, ArH), 7.47-7.41 (m, 4H, ArH), 7.26-7.23 (t, J = 3.2Hz, 2H, ArH), 7.15-7.08 (m,
6H, ArH), 6.78 (d, J = 15.6Hz, 1H, CH), 5.88 (d, J = 7.6Hz, 1H, CH), 5.74-5.68 (m, 1H, CH),
3.58 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 2.32 (s, 3H, CH3); trans-isomer: 6.88 (d, J = 15.6Hz, 1H,
CH), 6.49-6.44 (m, 1H, CH), 5.57 (d, J = 7.6Hz, 1H, CH),3.69 (s, 3H, OCH3), 3.55 (s, 3H, OCH3),
2.34 (s, 3H, CH3); ratio of cis/trans-isomers = 85:15. 13C NMR (100 MHz, CDCl3) δ: 163.6, 163.5,
163.4, 163.2, 150.0, 146.7, 138.8, 138.3, 137.9, 137.8, 137.0, 136.2, 135.3, 135.2, 134.9, 130.0,
129.7, 129.5, 129.4, 129.2, 128.8, 128.7, 128.6, 128.5, 127.3, 126.9, 126.7, 126.4, 125.3, 121.7,
120.9, 118.5, 118.3, 101.6, 101.3, 87.3, 87.2, 73.9, 73.6, 72.4, 52.9, 52.8, 51.6, 51.5, 29.6, 21.2,
21.2, 21.1, 21.0; IR(KBr) υ: 3060, 2959, 2871, 1749, 1699, 1565, 1507, 1427, 1361, 1300, 1263,
1230, 1142, 1015, 976, 843, 756 cm-1; MS (m/z): HRMS (ESI) Calcd. for C30H27N2O5([M+H]+):
495.1920, found: 495.1906.
Dimethyl
3-(4-(tert-butyl)phenyl)-6-cyano-6-phenyl-2-styryl-3,6-dihydro-2H-1,3-oxazine-
1
4,5-dicarboxylate (3b): white solid, 76%, m.p. 160-162 ; H NMR (400 MHz, CDCl3) δ:
cis-isomer: 7.76 (m, 2H, ArH), 7.49-7.41 (m, 4H, ArH), 7.38-7.31 (m, 3H, ArH), 7.22 (d, 2H, J =
3.0Hz, ArH), 7.17-7.12 (m, 1H, ArH), 6.88 (d, J = 16.0Hz, 1H, CH), 5.88 (d, J = 8.0Hz, 1H, CH),
5.66-5.63 (m, 1H, CH), 3.56 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 1.27 (s, 3H, 3CH3); trans-isomer:
6.93 (d, J = 16.0Hz, 1H, CH), 6.54-6.49 (m, 1H, CH), 5.79 (d, J = 8.0Hz, 1H, CH), 3.70 (s, 3H,
OCH3), 3.55 (s, 3H, OCH3), 1.30 (s, 3H, 3CH3); ratio of cis /trans-isomer = 53:47. 13C NMR (100
MHz, CDCl3) δ: 163.6, 163.4, 163.3, 151.9, 150.7, 149.9, 146.3, 138.5, 137.9, 137.7, 137.0, 136.0,
135.3, 135.2, 135.1, 129.4, 129.3, 129.0, 128.8, 128.7, 128.6, 128.6, 128.5, 127.4, 126.9, 126.7,
126.4, 126.4, 125.9, 124.5, 121.8, 121.1, 118.6, 118.2, 102.0, 101.7, 87.4, 87.2, 72.2, 53.0, 53.0,
23

ACCEPTED MANUSCRIPT
52.8, 52.8, 51.6, 51.6, 51.6, 51.5, 34.7, 34.6, 31.2, 31.1; IR(KBr) υ: 3028, 2951, 1746, 1700, 1575,
1493, 1436, 1306, 1259, 1231, 1142, 1092, 1014, 970, 832, 773, 751 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C33H33N2O5([M+H]+): 537.2389, found: 537.2372.
Dimethyl
3-(4-chlorophenyl)-6-cyano-6-phenyl-2-styryl-3,6-dihydro-2H-1,3-oxazine-4,5-
dicarboxylate (3c): white solid, 75%, m.p. 140-142 ; 1H NMR (400 MHz, CDCl3) δ; cis isomer:
7.73-7.69 (m, 2H, ArH), 7.44 (brs, 5H, ArH), 7.30 (t, J = 8.8Hz, 4H, ArH), 7.86 (d, J = 7.2Hz, 3H,
ArH), 6.81 (d, J = 16.0Hz, 1H, CH), 5.88 (d, J = 3.6Hz, 1H, CH), 5.70-5.65 (m, 1H, CH), 3.62 (s,
3H, OCH3), 3.53 (s, 3H, OCH3); trans isomer: 6.88 (d, J = 16.0Hz, 1H, CH), 6.46-6.41 (m, 1H,
CH), 5.58 (d, J = 1.8Hz, 1H, CH), 3.72 (s, 3H, OCH3), 3.57 (s, 3H, OCH3); ratio of cis
/trans-isomer = 45:55. 13C NMR (100 MHz, CDCl3) δ: 163.4, 163.3, 163.2, 163.1, 149.4, 146.0,
139.4, 138.4, 137.6, 136.7, 136.6, 136.4, 135.0, 134.7, 134.6, 133.5, 130.7, 129.7, 129.6, 129.6,
129.3, 129.1, 129.0, 128.8, 128.7, 128.6, 128.6, 128.5, 128.5, 127.3, 126.9, 126.7, 126.5, 126.4,
126.4, 126.3, 121.3, 120.4, 118.4, 118.0, 109.9, 103.0, 102.9, 87.3, 87.0, 72.4, 53.2, 53.1, 53.1,
53.0, 51.9, 51.8, 51.7, 51.6; IR(KBr) υ: 3283, 2928, 2860, 2120, 1710, 1608, 1583, 1500, 1454,
1405, 1369, 1291, 1188, 1115, 1091, 1033, 910, 816 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C29H24ClN2O5([M+H]+): 515.1374, found: 515.1347.
Dimethyl
3-(4-bromophenyl)-6-cyano-6-phenyl-2-styryl-3,6-dihydro-2H-1,3-oxazine-4,5-
dicarboxylate (3d): white solid, 70%, m.p. 124-126 ; 1H NMR (400 MHz, CDCl3) δ: cis-isomer:
7.74-7.69 (m, 2H, ArH), 7.50-7.44 (m, 6H, ArH), 7.38-7.30 (m, 3H, ArH), 7.17-7.15 (m, 1H, ArH),
7.10 (d, J = 4.0Hz, 2H, ArH), 6.82 (d, J = 16.0Hz, 1H, CH), 5.71-5.65 (m, 1H, CH), 5.59 (d, J =
4.8Hz, 1H, CH), 3.73 (s, 3H, OCH3), 3.57 (s, 3H, OCH3); trans-isomer: 6.89 (d, J = 16.0Hz, 1H,
CH), 6.47-6.42 (m, 1H, CH), 5.88 (d, J = 7.6Hz, 1H, CH), 3.62 (s, 3H, OCH3), 3.54 (s, 3H, OCH3);
ratio of cis /trans-isomer = 52:48. 13C NMR (100 MHz, CDCl3) δ: 163.4, 163.3, 163.2, 163.0,
149.3, 145.9, 140.0, 138.4, 137.5, 137.1, 136.6, 136.4, 134.9, 134.6, 132.6, 132.3, 131.0, 129.6,
129.5, 129.1, 129.0, 128.7, 128.7, 128.6, 127.3, 126.9, 126.7, 126.6, 126.4, 122.8, 121.4, 121.3,
120.3, 118.3, 118.0, 103.2, 103.1, 87.3, 87.0, 72.4, 53.2, 53.1, 53.1, 53.0, 53.0, 51.8, 51.8, 51.7,
51.7, 51.7, 51.6, 51.6; IR(KBr) υ: 3030, 2952, 1745, 1703, 1658, 1586, 1489, 1442, 1384, 1301,
1262, 1226, 1142, 1074, 1013, 973, 833, 775 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C29H24BrN2O5([M+H]+): 559.0869, found: 559.0847.
Dimethyl
3-(4-chlorophenyl)-6-cyano-2-(4-methylstyryl)-6-phenyl-3,6-dihydro-2H-1,3-
24

ACCEPTED MANUSCRIPT
oxazine-4,5-dicarboxylate (3e): white solid, 84%, m.p. 136-138 ; 1H NMR (400 MHz, CDCl3) δ:
cis-isomer: 7.74-7.68 (m, 2H, ArH), 7.47-7.40 (m, 3H, ArH), 7.35-7.32 (m, 3H, ArH), 7.16 (d, J =
8.0Hz, 3H, ArH), 7.06 (s, 2H, ArH), 6.77 (d, J = 15.6Hz, 1H, CH), 5.87 (d, J = 7.6Hz, 1H, CH),
5.65-5.59 (m, 1H, CH), 3.61 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 2.30 (s, 3H, CH3); trans-isomer:
6.83 (d, J = 16.0Hz, 1H, CH), 6.39-6.34 (m, 1H, CH), 5.55 (d, J = 5.2Hz, 1H, CH), 3.72 (s, 3H,
OCH3), 3.56 (s, 3H, OCH3), 2.35 (s, 3H, CH3); ratio of cis /trans-isomer = 44:56. 13C NMR (100
MHz, CDCl3) δ: 163.2, 163.1, 162.9, 162.7, 148.2, 147.0, 146.9, 145.5, 144.1, 143.7, 139.1, 136.8,
136.6, 136.2, 134.7, 134.3, 129.8, 129.7, 129.4, 129.2, 128.8, 128.7, 128.6, 127.5, 127.0, 126.5,
126.4, 126.4, 125.3, 124.4, 123.1, 120.7, 119.9, 118.1, 117.4, 107.8, 105.5, 87.5, 87.4, 53.5, 53.5,
53.3, 53.2, 52.2, 52.1, 51.9, 51.9; IR(KBr) υ: 3026, 2953, 2345, 1903, 1747, 1698, 1574, 1493,
1434, 1346, 1312, 1256, 1224, 1140, 1093, 1013, 986, 833, 763, 700 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C30H26ClN2O5([M+H]+): 529.1530, found: 529.1506.
Dimethyl
6-cyano-2-(4-methoxystyryl)-6-phenyl-3-(p-tolyl)-3,6-dihydro-2H-1,3-oxazine-
1
4,5-dicarboxylate (3f): white solid, 86%, m.p. 124-126 ; H NMR (400 MHz, CDCl3) δ:
cis-isomer: 7.30 (t, J = 9.0Hz, 2H, ArH), 7.44-7.39 (m, 4H, ArH), 7.16-7.10 (m, 5H, ArH),
6.89-6.77 (m, 2H, ArH), 6.75-6.71 (m, 1H, CH), 5.86 (d, J = 7.2Hz,1H, CH), 5.58-5.53 (m, 1H,
CH), 3.76 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 2.32 (s, 3H, CH3); trans-isomer:
6.77-6.75 (m, 1H, CH), 6.35-6.30 (m, 1H, CH), 5.58-5.53 (m, 1H, CH), 3.81 (s, 3H, OCH3), 3.69
(s, 3H, OCH3), 3.55 (s, 3H, OCH3), 2.34 (s, 3H, CH3); ratio of cis /trans-isomer = 45:55. 13C NMR
(100 MHz, CDCl3) δ: 163.6, 163.6, 163.5, 163.5, 163.3, 160.1, 160.1, 150.1, 146.8, 138.7, 138.3,
138.0, 137.8, 137.4, 137.1, 135.7, 135.3, 130.0, 129.6, 129.4, 129.4, 129.2, 128.7, 128.6, 128.4,
128.4, 128.4, 128.3, 128.0, 127.7, 126.8, 126.4, 125.3, 119.3, 118.6, 118.5, 118.3, 114.1, 113.9,
113.9, 113.8, 101.6, 101.1, 87.6, 87.4, 72.4, 55.3, 55.2, 55.2, 55.2, 52.9, 52.9, 52.8, 52.7, 51.6,
51.5, 51.5, 51.4, 21.1, 21.0; IR(KBr) υ: 3004, 2951, 2842, 1744, 1701, 1571, 1510, 1440, 1341,
1302, 1248, 1179, 1137, 1029, 978, 854, 820, 760, 705 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C31H29N2O6([M+H]+): 525.2026, found: 525.2014.
Dimethyl
6-cyano-3-(4-methoxyphenyl)-2-(4-methoxystyryl)-6-phenyl-3,6-dihydro-2H-
1
1,3-oxazine-4,5-dicarboxylate (3g): white solid, 81%, m.p. 144-146 ; H NMR (400 MHz,
CDCl3) δ: cis-isomer: 7.75-7.70 (m, 2H, ArH), 7.46-7.41 (m, 3H, ArH), 7.36 (d, J = 8.8Hz, 1H,
ArH), 7.17-7.08 (m, 3H, ArH), 6.89-6.81 (m, 3H, ArH), 6.76 (d, J = 8.4Hz, 1H, ArH), 6.71 (d, J =
25

ACCEPTED MANUSCRIPT
8.8Hz, 1H, CH), 6.28-6.23 (m, 1H, CH), 5.45 (d, J = 5.6Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.79 (s,
3H, OCH3), 3.67 (s, 3H, OCH3), 3.56 (s, 3H, OCH3); trans-isomer: 6.74 (d, J = 6.8Hz, 1H, CH),
5.84 (d, J = 8.0Hz, 1H, CH), 5.59-5.53 (m, 1H, CH), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.59
(s, 3H, OCH3), 3.52 (s, 3H, OCH3); ratio of cis /trans-isomer = 55:45. 13C NMR (100 MHz, CDCl3)
δ: 163.6, 163.3, 160.1, 160.1, 159.4, 159.0, 150.2, 147.5, 137.4, 137.1, 135.8, 133.1, 130.8, 130.5,
129.4, 128.6, 128.6, 128.3, 127.9, 127.8, 127.7, 126.9, 126.4, 119.2, 118.6, 118.5, 114.4, 114.0,
113.9, 101.3, 99.7, 87.7, 87.1, 72.5, 55.4, 55.4, 55.3, 55.3, 55.3, 55.2, 55.2, 55.2, 52.8, 51.4, 51.4,
29.6; IR(KBr) υ: 3004, 2951, 2839, 2350, 1748, 1703, 1576, 1510, 1438, 1303, 1248, 1178, 1136,
1027, 969, 826, 762 cm-1; MS (m/z): HRMS (ESI) Calcd. for C31H29N2O7([M+H]+): 541.1975,
found: 541.1960.
Dimethyl
6-cyano-2-(4-fluorostyryl)-6-phenyl-3-(p-tolyl)-3,6-dihydro-2H-1,3-oxazine-4,5-
dicarboxylate (3h): white solid, 72%, m.p. 152-154 ; 1H NMR (400 MHz, CDCl3) δ cis-isomer:
7.74 (t, J = 9.4Hz, 2H, ArH), 7.46-7.42 (m, 3H, ArH), 7.17-7.08 (m, 6H, ArH), 6.93 (t, J = 8.6Hz,
2H, ArH), 6.75 (d, J = 16.0Hz, 1H, CH), 5.87 (d, J = 7.6Hz, 1H, CH), 5.65-5.60 (m, 1H, CH),
3.59 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 2.33 (s, 3H, CH3). trans-isomer: 3.70
(s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 2.34 (s, 3H, CH3); ratio of cis
/trans-isomer = 92:8. 13C NMR (100 MHz, CDCl3) δ: 164.1, 163.5, 163.2, 161.7, 149.9, 138.8,
136.9, 136.6, 135.2, 131.1, 131.1, 129.7, 129.5, 129.2, 129.1, 128.6, 128.5, 126.4, 120.7, 118.5,
115.7, 115.4, 109.9, 101.7, 87.1, 52.9, 52.8, 51.6, 51.5, 21.1,; IR(KBr) υ: 3036, 2953, 1746, 1702,
1571, 1509, 1428, 1299, 1264, 1229, 1139, 1018, 978, 861, 825, 765 cm-1; MS (m/z): HRMS (ESI)
Calcd. for C30H26FN2O5([M+H]+): 513.1826, found: 513.1815.
Dimethyl
6-cyano-3-(4-methoxyphenyl)-2-(4-nitrostyryl)-6-phenyl-3,6-dihydro-2H-1,3-
oxazine-4,5-dicarboxylate (3i): white solid, 68%, m.p. 132-134 ; 1H NMR (400 MHz, CDCl3) δ
cis-isomer: 8.23-8.10 (m, 2H, ArH), 7.75-7.70 (m, 2H, ArH), 7.60 (d, J = 8.4Hz, 1H, ArH),
7.52-7.42 (m, 4H, ArH), 7.18-7.15 (m, 2H, ArH), 6.87 (t, J = 7.2Hz, 2H, ArH), 6.82 (d, J = 9.6Hz,
1H, CH), 5.93-5.86 (m, 2H, 2CH), 3.79 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.53 (s,3H, OCH3);
trans-isomer: 8.23-8.10 (m, 3H, ArH), 6.97 (d, J = 15.6Hz, 2H, ArH), 6.85 (d, J = 8.4Hz, 1H, CH),
6.65-6.60 (m, 1H, CH), 5.57 (d, J = 5.2Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.56
(s, 3H, OCH3); ratio of cis /trans-isomer = 45:55. 13C NMR (100 MHz, CDCl3) δ: 163.4, 163.4,
163.3, 163.1, 159.6, 159.2, 150.0, 147.6, 147.0, 141.4, 141.1, 137.5, 136.7, 135.0, 133.6, 133.2,
26

ACCEPTED MANUSCRIPT
130.7, 130.2, 129.6, 128.7, 128.0, 127.5, 127.3, 126.7, 126.5, 126.4, 125.4, 124.0, 123.9, 118.4,
118.4, 114.6, 114.3, 101.7, 101.1, 86.5, 86.3, 72.5, 55.5, 55.5, 55.5, 55.4, 53.1, 53.0, 52.9, 52.9,
51.8, 51.7, 51.6, 51.5, 29.6; IR(KBr) υ: 3005, 2952, 2847, 1747, 1704, 1582, 1514, 1440, 1345,
1304, 1242, 1137, 1025, 973, 833, 752 cm-1; MS (m/z): HRMS (ESI) Calcd. for
C30H26N3O8([M+H]+): 556.1720, found: 556.1702.
1
Supporting Information: H and 13C NMR spectra for all new compounds are available free of
charge via the Internet. Crystallographic data 1b (CCDC 1495113), 1d (CCDC 1495114), 1g
(CCDC 1495115), and 2c (CCDC 1495116), and 3e (CCDC 1542024) have been deposited at the
Cambridge Crystallographic Database Centre.
Acknowledgment: This work was financially supported by the National Natural Science
Foundation of China (Grant No. 21572196) and the Priority Academic Program Development of
Jiangsu Higher Education Institutions We also thank the Analysis and Test Center of Yangzhou
University for providing necessary instruments for analysis.
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