Facile construction of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines via one-pot three-component reactions of tryptamines, propiolate, and α,β-unsaturated aromatic aldehydes or ketones

Article abstract of DOI:10.1016/j.tet.2013.04.100

In the presence of anhydrous ZnCl₂ the one-pot three-component reaction of tryptamines, propiolates, and α,β-unsaturated aldehydes as well as arylideneacetones afforded the functionalized 1,2,6,7,12,12b- hexahydroindolo[2,3-a]quinolizines in moderate to high yields and with high diastereoselectivity. The reaction mechanism involved the sequential Michael addition and Pictet-Spengler reactions of β-enamino ester generated in situ.

Full text of DOI:10.1016/j.tet.2013.04.100

Accepted Manuscript
Facile construction of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines via one-pot
three-component reactions of tryptamines, propiolate and #,#-unsaturated aromatic
aldehydes or ketones
Jing Sun, Li-Li Zhang, Chao-Guo Yan
PII:
S0040-4020(13)00660-1
10.1016/j.tet.2013.04.100
TET 24300
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 January 2013
Revised Date: 19 April 2013
Accepted Date: 23 April 2013
Please cite this article as: Sun J, Zhang L-L, Yan C-G, Facile construction of 1,2,6,7,12,12b-
hexahydroindolo[2,3-a]quinolizines via one-pot three-component reactions of tryptamines, propiolate and
#,#-unsaturated aromatic aldehydes or ketones, Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.100.
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ACCEPTED MANUSCRIPT
Facile construction of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines via
one-pot three-component reactions of tryptamines, propiolate and
α,β-unsaturated aromatic aldehydes or ketones
Jing Sun, Li-Li Zhang, Chao-Guo Yan*
College of Chemistry & Chemical Engineering Yangzhou University, Yangzhou 225002, China
Tel: 86-514-87975531; Fax: 86-514-87975244; e-mail: cgyan@yzu.edu.cn
Abstract. In the presence of anhydrous ZnCl2 the one-pot three-component reaction of
tryptamines, propiolates and α,β-unsaturated aldehydes as well as arylideneacetones afforded the
functionalized 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines in moderate to high yields and
with high diastereoselectivity. The reaction mechanism involved the sequential Michael addition
and Pictet-Spengler reactions of β-enamino ester generated in situ.
Keywords: multicomponent reaction; Pictet-Spengler reaction; electron-deficient alkyne; enamino
ester; indolo[2,3-a]quinolizine.
Introduction
1
Indole alkaloids constitute an important class of natural products. As one class of indole
derivatives, the indolo[2,3-a]quinolizidine framework is a particular structural motif found within
2
numerous natural products and pharmaceuticals. Therefore, many efficient methodologies for the
preparation of indolo[2,3-a]quinolizidine and its derivatives have been developed. The traditional
3
4
5
synthetic methods included Bischler–Napieralski, Pictet–Spengler, Fischer indole synthesis and
6
others. The Pictet–Spengler reaction has long been known as an efficient method for the
7,8
preparation of tetrahydro-β-carboline frameworks. In recent years, many developments have
been made to incorporate Pictet–Spengler reaction into cascade sequence or multicomponent

ACCEPTED MANUSCRIPT
9
-12
13
reactions based on the use of tryptamine-derived substrates.
Recently Cao and Zhao
successfully developed an organocatalytic three-component synthesis of indoloquinolizidines
based on conjugate addition of β-enaminoesters generated in situ from alkyl propiolates and
α,β-enals, and subsequent substrate controlled Pictet–Spengler cyclization. In this work only
aliphatic α,β-enals could give the satisfactory results, while aromatic α,β-unsaturated aldehydes
were not suitable substrates for this cascade reaction. In the past few years we also reported
several new domino reactions by using the in situ formed β-enamino esters derived from the
reactions of arylamines with electron-deficient alkynes such as dimethyl acetylenedicarboxylate
14,15
and methyl propiolate.
Encouraged by these results and hunting for new efficient
multicomponent reactions, we investigated the one-pot domino reactions of tryptamines,
propiolate and α,β-unsaturated aldehydes as well as arylideneacetones with catalysis of Lewis acid
and successfully developed
,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines.
Results and Discussion
At first the reaction conditions were examined. According to our previously reported synthetic
a
facile synthetic procedure for the functionalized
1
15
procedure of β-enamino ester from the reaction of arylamine with methyl propiolate,
tryptamine was treated with methyl propiolate in ethanol at room temperature rapidly to give the
desired β-enamino ester. Then cinnamaldehyde and a Lewis acid were added and the mixture was
stirred at room temperature for several hours. In the absence of Lewis catalyst, no further reaction
3 2 2
was observed. Several Lewis acids such as FeCl , I , ZnCl , as well as solvent and temperature
were examined to set up a standard reaction condition. The experimental results showed that the
reaction proceeded with highest yields at room temperature in 48 hours when anhydrous ZnCl
2
2

ACCEPTED MANUSCRIPT
Table 1 Synthesis of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 1a-1q
Entry Compd
R
R’
Ar (H)
C H
Yield (%)
78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1a
1b
1c
1d
1e
1f
H
CH3
6
5
H
CH
CH
CH
CH
3
3
3
3
p-CH
3
C
6
H
4
87
H
m-CH
3
C
6
H
4
81
H
p-CH
3
OC
6
H
4
83
H
p-ClC
6
H
4
84
H
CH3
m-ClC H4
77
6
1g
1h
1i
OCH
3
CH
CH
CH
CH
3
3
3
3
C
6
H
5
83
OCH
OCH
OCH
H
3
3
3
p-CH
3
C
6
H
4
86
m-CH
m-ClC
H
3
C
6
H
4
79
0
1
2
3
4
5
6
7
1j
6
H
4
80
1k
1l
CH3
80
OCH
H
3
CH
CH
CH
CH
3
2
2
2
H
76
1m
1n
1o
1p
1q
CH
CH
CH
3
3
3
C
6
H
5
84
H
p-CH
3
C
6
H
4
85
H
m-ClC
6
H
4
75
OCH3 CH CH3 p-CH C H
81
2
3
6
4
OCH
3
CH
2
CH
3
m-ClC
6
H
4
76
(1.0 mmol) was used as catalyst and ethanol as solvent. With the optimal conditions established, a
variety of substituted cinnamaldehydes were employed in the reaction. All the reaction proceeded
smoothly to give the corresponding 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines (1a-1j) in
satisfactory yields (Table 1, entries 1-10). Under this reaction condition acrolein and ethyl
propiolate also afforded good yields of products (Table 1, entries 11-17). These results indicated
that this one-pot domino reaction had a wide range of substrates. The structures of 1a-1q were
1
13
characterized by IR, H, C NMR, and HRMS spectra and were further confirmed by
1
single-crystal X-ray diffraction determination of the two compounds 1a (Fig. 1) and 1l (Fig. 2). H
NMR spectra clearly showed one set of absorption peaks for each characteristic groups in the
molecule, which indicated that there was only one isomer existed in each sample. As showed in
3

ACCEPTED MANUSCRIPT
molecular structure of compound 1a (Fig.1), the aryl group and indole moiety were in
trans-orientation in the new formed dihydropyridyl ring. Thus compounds 1a-1q except 1k and 1l,
were all belonging to this trans-isomer. It is obvious that there is no cis/trans-isomers for
compounds 1k and 1l (Fig. 2).
Fig. 1 Molecular structure of compound 1a
Fig. 2 Molecular structure of compound 1l
When α-methylcinnamaldehyde was used in this domino reaction under similar conditions,
only the polysubstituted 1,4-dihydropyridines 2a,b were obtained as main products at room
temperature (Scheme 1). Tryptamine acted as a primary amine to construct the dihydropyridyl
16
ring and the expected Pictet-Spengler cyclization was not observed. The molecular structure of
4

ACCEPTED MANUSCRIPT
2
a was successfully determined by X-ray diffraction method (Fig. 3). We were pleased to find that
a,b could be transferred to indolo[2,3-a]quinolizines 3a,b in alcoholic by reflux in the presence
2
of anhydrous zinc chloride for several hours. Under this condition a intramolecular
Pictet-Spengler cyclization at C-2 position of indole proceeded to give the desired cyclized
products 3a,b. This result not only indicated this one-pot domino reaction had wide range of scope,
but also shed light on the mechanism of this reaction.
Scheme 1 synthesis of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 3a,b
Fig. 3 Molecular structure of compound 2a
In order to further illustrate the synthetic value of this domino reaction, arylideneacetones
5

ACCEPTED MANUSCRIPT
were employed in the reaction. At first, tryptamine was treated with methyl or ethyl propiolate in
ethanol to give β-enamino esters. Then arylideneacetones and catalytic ZnCl were added to the
2
system and the mixture was heated to 50ꢀ for about 36 hours. After workup the expected
hexahydroindolo[2,3-a]quinolizines 4a-4g were obtained in 64-81% yields (Table 2). The
structures of 4a-4g were established by the spectroscopic methods and confirmed by single-crystal
1
structure determination of compounds 4d (Fig. 4) and 4g (Fig. 5). H NMR spectra of compounds
4d, 4e, 4f and 4g indicated that two isomers existed within each sample, which is clearly due to
methyl group and aryl group in cis or trans position in tetrahydropyridyl ring. But there is only
1
one isomer existed in compounds 4a, 4b and 4c from their H NMR spectra. it is clearly to see that
phenyl group exists in the trans-orientation to the larger indole moiety in the molecular structures
of 4d and 4g. On the other hand the methyl and phenyl groups are in cis-position in the twist-chair
conformation of tetrahydropyridyl ring. Thus hexahydroindolo[2,3-a]quinolizines 4a-4g existed
mainly in the same isomer as that of compounds 1a-1q, in which the phenyl group and indole
moiety exist in trans-position, while the phenyl group and indole moiety exist in cis-position in
the minor isomer. Here the presence of methyl group might decrease the steric effect of
Pictet-Spengler cyclization and caused the more easily formation of the relatively unstable
cis-isomer.
Table 2 Synthesis of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 4a-4g
4
a-4g (cis/trans-isomer)
Entry Compd
4a
R
H
R’
Ar
Yield (%, cis/trans)
1
CH
3
p-CH
3
C
6
H
4
70
6

ACCEPTED MANUSCRIPT
2
3
4
5
6
7
4b
4c
4d
4e
4f
H
CH
CH
CH
CH
CH
CH
3
3
3
3
3
2
m-CH OC H
4
72
3
6
H
p-BrC
H
4
67
6
CH
CH
CH
H
3
3
3
O
O
O
p-CH
OC
H
4
73 (1:8)
81 (1:8)
73 (1:5)
64 (1:5)
3
6
6 5
C H
6 4
p-ClC H
4g
CH
3
6 5
C H
Fig. 4 Molecular structure of compound 4d (trans-isomer)
Fig. 5 Molecular structure of compound 4g (trans-isomer)
With regard to the mechanism of this reaction sequence (Scheme 2), we assumed that the first
step was the formation of β-enamino ester (A) from the reaction of tryptamine with methyl
1
5
propiolate. The second step was the Michael addition of β-enamino ester (A) to α,β-unsaturated
7

ACCEPTED MANUSCRIPT
aldehydes to give the adduct (B). Thirdly the intramolecular condensation of amino group with
carbonyl group formed the nitrogen-containing cyclic intermediate (C). At last Pictet-Spengler
cyclization gave the final products 1. In the cyclization process the thermodynamically stable
trans-isomer would be preferentially formed due to the steric effect of aryl group.
Scheme 2 The proposed mechanism for ont–pot domino reaction
In conclusion, we have developed a Lewis acid catalyzed one-pot sequential reaction of
tryptamines, propiolate and α,β-unsaturated aldehydes as well as arylideneacetones for the
efficient synthesis of functionalized 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines in good
yields. This protocol has advantages of mild reaction conditions, easily accessible starting
materials, easy purification of the products and wide range of substrates, which makes it a useful
and attractive method for the synthesis of the complex indolo[2,3-a]quinolizines in synthetic and
medicinal chemistry. Further expansion of the reaction scope and synthetic applications of this
methodology are in progress in our laboratory.
Experimental section
1
1
.
General
procedure
for
the
preparation
of
,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 1a-1q: In a round bottom flask a mixture of
8

ACCEPTED MANUSCRIPT
tryptamines (2.0 mmol) and methyl or ethyl propiolate (2.0 mmol) in 5.0mL ethanol was stirred at
room temperature for 20 minutes. Then α,β-unsaturated aldehydes (2.0 mmol) and anhydrous zinc
chloride (1.0 mmol, 0.136 g) were added. The mixture was stirred at room temperature for
additional 48 hours. The resulting precipitate was collected by filtration and washed with cold
alcohol to give the pure product.
Methyl 2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate (1a):
1
yellow solid, 78%, m.p.279~281℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.94 (s, 1H, NH), 7.88
(brs, 1H, CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.36~7.34 (m, 2H, ArH), 7.27 (d, J = 7.8Hz, 2H,
ArH), 7.23~7.21 (m, 2H, ArH), 7.02 (t, J = 7.2Hz, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH), 4.21 (d,
J = 11.4Hz, 1H, CH), 4.01~4.00 (m, 1H, CH), 3.98~3.95 (m, 1H, CH), 3.55~3.51 (m, 1H, CH),
3
.49 (s, 3H, OCH ), 2.81~2.77 (m, 1H, CH), 2.73~2.71 (m, 1H, CH), 2.57 (d, J = 13.2Hz, 1H,
3
13
1 2 6
CH), 1.79 (td, J = 12.6Hz, J = 4.8Hz, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.3, 147.2,
1
4
1
46.6, 136.2, 133.0, 128.1, 127.8, 126.3, 125.9, 121.0, 118.5, 117.7, 111.0, 106.9, 94.0, 50.2, 50.0,
7.1, 36.2, 35.7, 21.6; IR (KBr) υ: 3235, 2965, 2911, 1664, 1597, 1494, 1471, 1428, 1357, 1323,
-1
301, 1205, 1185, 1163, 1109, 1038, 1021, 942, 852, 790 cm ; HRMS (ESI) Calcd. for
+
C H
23 22
N
2
NaO
2
([M+Na] ): 381.1573. Found: 381.1575.
Methyl 2-(4-methxylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1b): yellow solid, 87%, m.p.260~262℃ ; H NMR (600 MHz, DMSO-d ) δ: 10.93 (s, 1H, NH),
6
7
.85 (brs, 1H, CH), 7.40 (d, J = 7.2Hz, 1H, ArH), 7.23 (d, J = 7.8Hz, 1H, ArH), 7.14 (brs, 4H,
ArH), 7.02~7.01 (m, 1H, ArH), 6.97~6.96 (m, 1H, ArH), 4.20 (d, J = 12.0Hz, 1H, CH), 3.96 (brs,
2
H, CH), 3.54~3.50 (m, 1H, CH), 3.48 (s, 3H, OCH ), 2.81~2.77 (m, 1H, CH), 2.72~2.70 (m, 1H,
3
13
3
CH), 2.53 (d, J = 13.2Hz, 1H, CH), 2.29 (s, 3H, CH ), 1.77 (t, J = 12.6Hz, 1H, CH); C NMR
(
150 MHz, DMSO-d
6
) δ: 167.3, 147.0, 143.5, 136.2, 134.8, 133.1, 128.7, 127.6, 126.3, 120.9,
1
1
18.5, 117.6, 111.0, 106.8, 94.1, 50.1, 50.0, 47.0, 35.8, 35.7, 21.6, 20.5; IR (KBr) υ: 3252, 2959,
-1
668, 1560, 1510, 1427, 1358, 1321, 1302, 1206, 1184, 1165, 1109, 1039, 939, 855, 803, 777 cm ;
+
HRMS (ESI) Calcd. for C24
H
24
N
2
NaO
2
([M+Na] ): 395.1730. Found: 395.1732.
Methyl 2-(3-methxylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1c): yellow solid, 81%, m.p.282~284℃ ; H NMR (600 MHz, DMSO-d ) δ: 10.94 (s, 1H, NH),
6
7
7
.87 (brs, 1H, CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.23~7.21 (m, 2H, ArH), 7.09 (brs, 1H, ArH),
.04~7.02 (m, 3H, ArH), 6.97~6.95 (m, 1H, ArH), 4.22 (d, J = 11.4Hz, 1H, CH), 3.96 (brs, 2H,
9

ACCEPTED MANUSCRIPT
CH), 3.56~3.52 (m, 1H, CH), 3.48 (s, 3H, OCH ), 2.79~2.77 (m, 1H, CH), 2.73~2.70 (m, 1H, CH),
3
1
3
2
.54 (d, J = 12.6Hz, 1H, CH), 2.33 (s, 3H, CH
3
), 1.79~1.76 (m, 1H, CH); C NMR (150 MHz,
DMSO-d ) δ: 167.3, 147.1, 146.6, 137.1, 136.2, 133.1, 128.4, 128.0, 126.6, 126.3, 124.8, 120.9,
6
1
2
9
3
18.5, 117.6, 111.0, 106.9, 94.0, 50.1, 50.0, 47.0, 36.1, 35.7, 21.6, 21.2; IR (KBr) υ: 3451, 3236,
908, 2849, 1667, 1599, 1424, 1354, 1320, 1302, 1231, 1214, 1199, 1184, 1169, 1110, 1063, 1038,
-1
+
24, 882, 778 cm ; HRMS (ESI) Calcd. for C24
24 2 2
H N NaO ([M+Na] ): 395.1730. Found:
95.1728.
Methyl 2-(4-methoxyphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1d): yellow solid, 83%, m.p.256~257℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.91 (s, 1H, NH),
7
2
4
.84 (brs, 1H, CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.23 (d, J = 7.8Hz, 1H, ArH), 7.17 (d, J = 7.8Hz,
H, ArH), 7.02 (t, J = 7.2Hz, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH), 6.90 (d, J = 7.8Hz, 2H, ArH),
.20 (d, J = 11.4Hz, 1H, CH), 3.95~3.94 (m, 2H, CH), 3.74 (s, 3H, OCH ), 3.54~3.52 (m, 1H,
), 2.81~2.77 (m, 1H, CH), 2.73~2.70 (m, 1H, CH), 2.53 (d, J = 12.6Hz,
3
CH), 3.49 (s, 3H, OCH
3
1
3
1
1
5
1
1 2 6
H, CH), 1.75 (td, J = 12.6Hz, J = 3.6Hz, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.3,
57.6, 147.0, 138.4, 136.2, 133.1, 128.6, 126.3, 120.9, 118.5, 117.6, 113.5, 111.0, 106.8, 94.3,
5.0, 50.1, 50.0, 47.0, 35.9, 35.3, 21.6; IR (KBr) υ: 3449, 2958, 1663, 1598, 1509, 1429, 1358,
-1
323, 1303, 1277, 1250, 1207, 1186, 1109, 1037, 832 cm ; HRMS (ESI) Calcd. for
+
C H N NaO ([M+Na] ): 411.1679. Found: 411.1682.
2
4
24
2
3
Methyl 2-(4-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1e): yellow solid, 84%, m.p.267~268℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.93 (s, 1H, NH),
7
.88 (brs, 1H, CH), 7.41~7.40 (m, 3H, ArH), 7.30~7.28 (m, 2H, ArH), 7.24 (d, J = 6.6Hz, 1H,
ArH), 7.03 (brs, 1H, ArH), 6.96 (brs, 1H, ArH), 4.20 (d, J = 10.2Hz, 1H, CH), 4.00~3.95 (m, 2H,
CH), 3.53 (brs, 1H, CH), 3.49 (s, 3H, OCH ), 2.79~2.71 (m, 2H, CH), 2.55 (d, J = 12.6Hz, 1H,
CH), 1.79 (brs, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.2, 147.3, 145.6, 136.2, 132.9,
30.5, 129.6, 128.0, 126.3, 120.9, 118.5, 117.8, 111.0, 106.9, 93.6, 50.1, 50.0, 46.9, 35.6, 21.6; IR
KBr) υ: 3447, 3232, 2962, 2822, 1669, 1599, 1489, 1427, 1356, 1320, 1304, 1207, 1185, 1164,
3
1
3
6
1
(
-1
1
2 2
111, 1037, 1012, 876, 854, 832, 796, 758 cm ; HRMS (ESI) Calcd. for C23H21ClN NaO
+
(
[M+Na] ): 415.1184. Found: 415.1184.
Methyl 2-(3-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1f): yellow solid, 77%, m.p.258~260℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.95 (s, 1H, NH),
1
0

ACCEPTED MANUSCRIPT
7
.90 (brs, 1H, CH), 7.40~7.38 (m, 2H, ArH), 7.32~7.30 (m, 2H, ArH), 7.23 (brs, 2H, ArH), 7.03
(
brs, 1H, ArH), 6.96 (brs, 1H, ArH), 4.20 (d, J = 10.8Hz, 1H, CH), 4.02 (brs, 1H, CH), 3.98~3.96
m, 1H, CH), 3.55~3.53 (m, 1H, CH), 3.50 (s, 3H, OCH ), 2.78~2.77 (m, 1H, CH), 2.73~2.71 (m,
6
H, CH), 2.59 (d, J = 12.0Hz, 1H, CH), 1.79 (brs, 1H, CH); C NMR (150 MHz, DMSO-d ) δ:
(
3
1
3
1
1
1
1
67.2, 149.2, 147.5, 136.2, 132.9, 132.8, 130.0, 127.6, 126.5, 126.3, 126.0, 121.0, 118.5, 117.7,
11.0, 106.9, 93.2, 50.2, 50.1, 47.0, 35.9, 35.5, 21.5; IR (KBr) υ: 3497, 3263, 2919, 2853, 2809,
-1
668, 1600, 1472, 1424, 1355, 1324, 1302, 1205, 1184, 1167, 1113, 1038, 890, 862, 773 cm ;
+
HRMS (ESI) Calcd. for C H ClN NaO ([M+Na] ): 415.1184. Found: 415.1184.
2
3
21
2
2
Methyl 9-methoxy-2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1g): yellow solid, 83%, m.p.252~253℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.76 (s, 1H, NH),
7
.87 (brs, 1H, CH), 7.36~7.33 (m, 2H, ArH), 7.26 (d, J = 6.6Hz, 2H, ArH), 7.21 (t, J = 7.2Hz, 1H,
ArH), 7.11 (d, J = 8.4Hz, 1H, ArH), 6.90 (brs, 1H, ArH), 6.67~6.65 (m, 1H, ArH), 4.19 (d, J =
2.0Hz, 1H, CH), 4.00~3.99 (m, 1H, CH), 3.97~3.94 (m, 1H, CH), 3.73 (s, 3H, OCH ), 3.55~3.50
m, 1H, CH), 3.48 (s, 3H, OCH ), 2.79~2.74 (m, 1H, CH), 2.69 (d, J = 12.6Hz, 1H, CH), 2.54 (d,
J = 12.6Hz, 1H, CH), 1.78 (td, J
δ: 167.3, 153.2, 147.2, 146.5, 133.7, 131.2, 128.1, 127.8, 126.6, 125.9, 111.6, 110.7, 106.7, 99.9,
1
3
(
3
13
1
2 6
= 12.6Hz, J = 4.8Hz, 1H, CH); C NMR (150 MHz, DMSO-d )
93.9, 55.4, 50.2, 50.0, 47.1, 36.1, 35.7, 21.7; IR (KBr) υ: 3244, 2913, 2826, 1665, 1584, 1490,
-1
1
444, 1426, 1362, 1321, 1301, 1222, 1205, 1179, 1159, 1106, 1061, 1036, 945, 934, 805, 756 cm ;
+
HRMS (ESI) Calcd. for C24
H
24
N
2
NaO
3
([M+Na] ): 411.1679. Found: 411.1670.
Methyl 9-methoxy-2-(4-methylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (1h): yellow solid, 86%, m.p.238~240℃ ; H NMR (600 MHz, DMSO-d ) δ: 10.76 (s,
6
1H, NH), 7.85 (brs, 1H, CH), 7.14 (brs, 4H, CH), 7.12~7.10 (m, 1H, ArH), 6.90 (brs, 1H, CH),
6
.66 (d, J = 9.0Hz, 1H, ArH), 4.17 (d, J = 12.0Hz, 1H, CH), 3.95 (brs, 2H, CH), 3.73 (s, 3H,
OCH
CH), 2.46 (brs, 1H, CH), 2.28 (s, 3H, CH
DMSO-d ) δ: 167.3, 153.2, 147.0, 143.6, 134. 8, 133.8, 131.3, 128.7, 127.6, 126.6, 111.6, 110.7,
3 3
), 3.53~3.51 (m, 1H, CH), 3.48 (s, 3H, OCH ), 2.78~2.74 (m, 1H, CH), 2.70~2.67 (m, 1H,
13
3
), 1.76 (t, J = 12.0Hz, 1H, CH); C NMR (150 MHz,
6
1
1
8
06.7, 99.9, 94.1, 55.3, 50.2, 50.0, 47.1, 35.8, 35.7, 21.7, 20.5; IR (KBr) υ: 3237, 2945, 1665,
583, 1510, 1485, 1452, 1432, 1373, 1318, 1296, 1205, 1181, 1163, 1135, 1106, 1026, 855, 823,
-1
+
02, 774 cm ; HRMS (ESI) Calcd. for C25
26 2 3
H N NaO ([M+Na] ): 425.1836. Found: 425.1826.
Methyl 9-methoxy-2-(3-methylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
11

ACCEPTED MANUSCRIPT
1
carboxylate (1i): yellow solid, 79%, m.p.226~228℃ ; H NMR (600 MHz, DMSO-d ) δ: 10.77 (s,
6
1
6
3
H, NH), 7.86 (brs, 1H, CH), 7.22 (brs, 1H, ArH), 7.11~7.08 (m, 2H, ArH), 7.02 (brs, 2H, CH),
.90 (brs, 1H, CH), 6.66~6.65 (m, 1H, ArH), 4.19 (d, J = 10.2Hz, 1H, CH), 3.95 (brs, 2H, CH),
.73 (s, 3H, OCH
3
), 3.56~3.53 (m, 1H, CH), 3.48 (s, 3H, OCH
3
), 2.76~2.68 (m, 2H, CH), 2.54
), 1.76 (brs, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.3,
53.2, 147.1, 146.6, 137.1, 133.7, 131.2, 128.4, 128.0, 126.6, 124.8, 111.6, 110.7, 106.7, 99.9,
4.0, 55.3, 50.2, 50.0, 47.1, 36.1, 35.7, 21.7, 21.2; IR (KBr) υ: 3236, 2947, 2847, 1663, 1584,
1
3
(brs, 1H, CH), 2.32 (s, 3H, CH
3
6
1
9
1
-1
483, 1435, 1361, 1317, 1301, 1214, 1196, 1182, 1160, 1107, 1058, 1034, 888, 831, 800, 776 cm ;
+
HRMS (ESI) Calcd. for C25
H
26
N
2
NaO
3
([M+Na] ): 425.1836. Found: 425.1827.
Methyl 9-methoxy-2-(3-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (1j): white solid, 80%, m.p.244~245ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.75 (s,
1
H, NH), 7.88 (brs, 1H, CH), 7.37 (t, J = 7.2Hz, 1H, ArH), 7.31 (brs, 1H, ArH), 7.28 (d, J = 7.8Hz,
H, ArH), 7.21 (d, J = 7.8Hz, 1H, ArH), 7.12 (t, J = 8.4Hz, 1H, ArH), 6.91 (brs, 1H, ArH), 6.67 (d,
1
J = 8.4Hz, 1H, ArH), 4.17 (d, J = 11.4Hz, 1H, CH), 4.01 (brs, 1H, CH), 3.96~3.94 (m, 1H, CH),
3
.73 (s, 3H, OCH
.70~2.68 (m, 1H, CH), 2.55 (d, J = 12.6Hz, 1H, CH), 1.88~1.77 (m, 1H, CH); C NMR (150
) δ: 167.2, 153.2, 149.2, 147.5, 133.5, 132.9, 131.2, 130.0, 127.6, 126.6, 126.4,
25.9, 111.6, 110.8, 106.8, 100.0, 93.2, 55.4, 50.2, 50.1, 47.0, 35.9, 35.5, 21.6; IR (KBr) υ: 3499,
244, 2950, 2838, 1666, 1586, 1484, 1429, 1360, 1335, 1312, 1207, 1183, 1161, 1110, 1061, 1034,
3 3
), 3.56~3.52 (m, 1H, CH), 3.50 (s, 3H, OCH ), 2.78~2.74 (m, 1H, CH),
13
2
MHz, DMSO-d
6
1
3
8
-1
+
2 3
88, 858, 832, 797, 768 cm ; HRMS (ESI) Calcd. for C24H23ClN NaO ([M+Na] ): 445.1289.
Found: 445.1284.
Methyl 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate (1k): yellow solid,
1
8
0%, m.p.156~158℃ ; H NMR (600 MHz, DMSO-d
6
) δ: 10.96 (s, 1H, NH), 7.53 (brs, 1H, CH),
7
.41 (d, J = 7.8Hz, 1H, ArH), 7.32 (d, J = 7.2Hz, 1H, ArH), 7.07~7.05 (m, 1H, ArH), 6.99~6.98
),
.46~3.43 (m, 1H, CH), 2.78~2.74 (m, 1H, CH), 2.71~2.69 (m, 1H, CH), 2.57 (d, J = 12.0Hz, 1H,
(
m, 1H, ArH), 4.99 (d, J = 10.2Hz, 1H, CH), 3.82 (d, J = 12.0Hz, 1H, CH), 3.56 (s, 3H, OCH
3
3
1
3
CH), 2.39~2.36 (m, 1H, CH), 2.31~2.27 (m, 1H, CH), 1.60~1.58 (m, 1H, CH); C NMR (150
MHz, DMSO-d ) δ: 167.6, 146.5, 136.1, 133.6, 126.4, 120.9, 118.5, 117.7, 111.1, 106.5, 93.4,
1.5, 50.0, 49.9, 27.4, 21.6, 20.1; IR (KBr) υ: 3293, 2938, 2849, 1654, 1610, 1493, 1439, 1418,
6
5
1
2

ACCEPTED MANUSCRIPT
-1
1
356, 1332, 1301, 1244, 1205, 1182, 1154, 1095, 1063, 1037, 1002, 933, 829 cm ; HRMS (ESI)
+
Calcd. for C17
18
H N
2
NaO
2
([M+Na] ): 305.1260. Found: 305.1255.
Methyl 9-methoxy-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate (1l):
1
yellow solid, 76%, m.p.204~206ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.78 (s, 1H, NH), 7.52
(brs, 1H, CH), 7.20 (d, J = 8.4Hz, 1H, ArH), 6.91 (brs, 1H, ArH), 6.70 (d, J = 8.4Hz, 1H, ArH),
4
.46 (d, J = 10.2Hz, 1H, CH), 3.81 (d, J = 12.0Hz, 1H, CH), 3.74 (s, 3H, OCH
3
), 3.55 (s, 3H,
OCH
2.0Hz, 1H, CH), 2.38~2.35 (m, 1H, CH), 2.29~2.25 (m, 1H, CH), 1.59~1.57 (m, 1H, CH); C
NMR (150 MHz, DMSO-d ) δ: 167.6, 153.2, 146.5, 134.3, 131.2, 126.7, 111.7, 110.7, 106.4,
00.0, 93.4, 55.3, 51.6, 50.0, 27.4, 21.7, 20.1; IR (KBr) υ: 3229, 2942, 2902, 2843, 1664, 1587,
3
), 3.45~3.41 (m, 1H, CH), 2.75~2.71 (m, 1H, CH), 2.68~2.66 (m, 1H, CH), 2.54 (d, J =
1
3
1
6
1
1
-1
487, 1436, 1356, 1303, 1211, 1180, 1151, 1106, 1060, 1031, 940, 913, 834, 794 cm ; HRMS
+
(
ESI) Calcd. for C18
H
20
N
2
NaO
3
([M+Na] ): 335.1366. Found: 335.1364.
Ethyl 2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate (1m):
1
yellow solid, 84%, m.p.256~258ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.92 (s, 1H, NH), 7.84
(brs, 1H, CH), 7.40 (d, J = 7.2Hz, 1H, ArH), 7.34~7.33 (m, 2H, ArH), 7.27~7.26 (m, 2H, ArH),
7
.23~7.22 (m, 2H, ArH), 7.02 (t, J = 6.6Hz, 1H, ArH), 6.97~6.96 (m, 1H, ArH), 4.22 (d, J =
11.4Hz, 1H, CH), 4.00~3.96 (m, 4H, CH), 3.55~3.52 (m, 1H, CH), 2.80~2.78 (m, 1H, CH),
2
.73~2.71 (m, 1H, CH), 2.57 (d, J = 12.6Hz, 1H, CH), 1.82~1.79 (m, 1H, CH), 1.10 (brs, 3H,
13
3 6
CH ); C NMR (150 MHz, DMSO-d ) δ: 166.8, 146.9, 146.7, 136.2, 133.1, 128.1, 127.9, 127.8,
126.3, 125.8, 120.9, 118.5, 117.7, 111.0, 106.9, 94.4, 58.1, 50.2, 47.1, 36.2, 35.7, 21.6, 14.6; IR
(KBr) υ: 3450, 3232, 2978, 2911, 2851, 1663, 1588, 1494, 1473, 1438, 1363, 1320, 1300, 1209,
-1
+
1
24 2 2
185, 1166, 1108, 1039, 1018, 940, 789 cm ; HRMS (ESI) Calcd. for C24H N NaO ([M+Na] ):
395.1730. Found: 395.1727.
Ethyl 2-(4-methylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1n): yellow solid, 85%, m.p.226~227ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.91 (s, 1H, NH),
7
.82 (brs, 1H, CH), 7.39 (d, J = 7.8Hz, 1H, ArH), 7.23 (d, J = 8.4Hz, 1H, ArH), 7.14 (brs, 4H,
ArH), 7.02 (t, J = 7.8Hz, 1H, ArH), 6.95 (t, J = 7.2Hz, 1H, ArH), 4.20 (d, J = 12.0Hz, 1H, CH),
3
2
.97~3.92 (m, 4H, CH), 3.54~3.50 (m, 1H, CH), 2.82~2.78 (m, 1H, CH), 2.72~2.70 (m, 1H, CH),
.53 (d, J = 13.2Hz, 1H, CH), 2.29 (s, 3H, CH ), 1.77 (td, J = 12.6Hz, J = 4.8Hz, 1H, CH), 1.10
3
1
2
1
3

ACCEPTED MANUSCRIPT
1
3
(
t, J = 7.2Hz, 3H, CH ); C NMR (150 MHz, DMSO-d ) δ: 166.8, 146.8, 143.6, 136.2, 134.8,
3 6
1
2
1
33.1, 128.7, 127.6, 126.3, 120.9, 118.5, 117.6, 111.0, 106.9, 94.6, 58.0, 50.1, 47.1, 35.8, 35.7,
1.6, 20.5, 14.6; IR (KBr) υ: 3449, 2967, 2915, 2852, 2804, 1662, 1587, 1509, 1473, 1442, 1363,
-1
320, 1301, 1208, 1166, 1107, 1040, 1016, 940, 875, 808, 775 cm ; HRMS (ESI) Calcd. for
+
C H
25 26
N
2
NaO
2
([M+Na] ): 409.1886. Found: 409.1885.
Ethyl 2-(3-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1o): yellow solid, 75%, m.p. >300ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.93 (s, 1H, NH), 7.86
(brs, 1H, CH), 7.41~7.39 (m, 1H, ArH), 7.37 (d, J = 7.8Hz, 1H, ArH), 7.31 (brs, 1H, ArH), 7.28 (d,
J = 7.8Hz, 1H, ArH), 7.23 (t, J = 7.8Hz, 2H, ArH), 7.04~7.39 (m, 1H, ArH), 6.97~6.95 (m, 1H,
ArH), 4.21 (d, J = 12.0Hz, 1H, CH), 4.02~3.98 (m, 2H, CH), 3.97~3.94 (m, 2H, CH), 3.58~3.53
(
m, 1H, CH), 2.82~2.77 (m, 1H, CH), 2.72 (d, J = 12.0Hz, 1H, CH), 2.59 (d, J = 13.2Hz, 1H, CH),
1
3
1
.80 (td, J
) δ: 166.7, 149.3, 147.3, 136.2, 132.9, 129.9, 127.7, 126.5, 126.3, 125.9, 1209, 118.5,
17.7, 111.0, 106.9, 93.6, 58.1, 50.2, 47.0, 36.0, 35.4, 21.5, 14.6; IR (KBr) υ: 3448, 2990, 2914,
1 2 3
= 12.6Hz, J = 5.4Hz, 1H, CH), 1.11 (t, J = 7.2Hz, 3H, CH ); C NMR (150 MHz,
DMSO-d
6
1
1
-1
660, 1586, 1474, 1440, 1363, 1325, 1303, 1193, 1165, 1108, 1038, 886, 776 cm ; HRMS (ESI)
+
Calcd. for C24
H23ClN
2
NaO
2
([M+Na] ): 429.1340. Found: 429.1334.
Ethyl 9-methoxy-2-(4-methoxyphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (1p): white solid, 81%, m.p.249~250ꢀ; H NMR (600 MHz, DMSO-d ) δ: 10.72 (s,
6
1
H, NH), 7.81 (brs, 1H, CH), 7.13~7.10 (m, 5H, ArH), 6.90 (brs, 1H, ArH), 6.66 (d, J = 7.8Hz, 1H,
ArH), 4.17 (d, J = 10.8Hz, 1H, CH), 3.94 (brs, 4H, CH), 3.73 (s, 3H, 0CH ), 3.53~3.49 (m, 1H,
CH), 2.77~2.75 (m, 1H, CH), 2.69~2.67 (m, 1H, CH), 2.54 (brs, 1H, CH), 2.28 (s, 3H, CH ), 1.76
) δ: 166.8, 153.2, 146.8, 143.7,
34.7, 133.8, 131.2, 128.7, 127.6, 126.6, 111.6, 110.7, 106.7, 99.9, 94.5, 58.0, 56.0, 55.3, 50.2,
7.1, 35.8, 21.7, 20.5, 18.5, 14.6; IR (KBr) υ: 3453, 2982, 2907, 2828, 1660, 1583, 1484, 1443,
3
3
13
(
brs, 1H, CH), 1.10 (brs, 3H, CH); C NMR (150 MHz, DMSO-d
6
1
4
1
-1
365, 1318, 1298, 1209, 1162, 1107, 1035, 821, 799, 776 cm ; HRMS (ESI) Calcd. for
+
C H
26 28
N
2
NaO
3
([M+Na] ): 439.1992. Found: 439.1988.
Ethyl 9-methoxy-2-(3-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (1q): white solid, 76%, m.p.241~243ꢀ; H NMR (600 MHz, DMSO-d ) δ: 10.75 (s,
6
1H, NH), 7.85 (brs, 1H, CH), 7.37 (t, J = 7.8Hz, 1H, ArH), 7.30~7.27 (m, 2H, ArH), 7.22 (d, J =
1
4

ACCEPTED MANUSCRIPT
7
4
3
1
.8Hz, 1H, ArH), 7.12 (d, J = 8.4Hz, 1H, ArH), 6.91 (brs, 1H, ArH), 6.67 (d, J = 8.4Hz, 1H, ArH),
.18 (d, J = 12.0Hz, 1H, CH), 4.01~3.97 (m, 2H, CH), 3.96~3.93 (m, 2H, CH), 3.73 (s, 3H, 0CH
3
),
.57~3.52 (m, 1H, CH), 2.79~2.74 (m, 1H, CH), 2.69 (d, J = 12.6Hz, 1H, CH), 2.56 (d, J =
1
3
3.2Hz, 1H, CH), 1.79 (td, J
) δ: 166.7, 153.2, 149.3, 147.3, 133.5, 132.9, 131.2, 129.9, 127.6,
26.6, 126.4, 125.9, 111.6, 110.7, 106.8, 100.0, 93.6, 58.1, 55.3, 50.2, 47.1, 36.0, 35.4, 21.6, 14.5;
IR (KBr) υ: 3449, 2956, 2836, 1660, 1586, 1480, 1438, 1365, 1305, 1210, 1162, 1108, 1037, 889,
1 2 3
= 12.6Hz, J = 5.4Hz, 1H, CH), 1.11 (t, J = 7.2Hz, 3H, CH ); C
NMR (150 MHz, DMSO-d
6
1
-
1
+
8
2
1
30, 775 cm ; HRMS (ESI) Calcd. for C H ClN NaO ([M+Na] ): 459.1446. Found: 459.1440.
25 25 2 3
.
General procedure for the preparation of 1,4-dihydropyridines 2a,b and
,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 3a,b: The same procedure as described
above was used by using α-methylcinnamaldehyde. A mixture of 5-methoxytryptamine (2.0 mmol)
and methyl or ethyl propiolate (2.0 mmol) in 5.0mL ethanol was stirred at room temperature for
20 minutes. Then α-methylcinnamaldehyde (2.0 mmol) and anhydrous zinc chloride (1.0 mmol,
0
.136 g) were added. The mixture was stirred at room temperature for additional 48 hours. The
resulting precipitates were collected by filtration and washed with cold alcohol to give the pure
product. Then a solution of compound 2a in a mixture of methanol and toluene (V/V = 1:1)
containing zinc chloride was refluxed for 48 hours to give the product 3a. On the other hand a
solution of compound 2b in ethanol containing zinc chloride was refluxed for 48 hours to give the
product 3b.
Methyl 1-[2-(5-Methoxy-1H-indol-3-yl)-ethyl]-5-methyl-4-phenyl-1,4-dihydropyridine-3-
1
6
carboxylate (2a): white solid, 82%, m.p.158~159ꢀ; H NMR (600 MHz, DMSO-d ) δ: 10.72 (s,
1H, NH), 7.27 (brs, 1H, CH), 7.24 (d, J = 9.0Hz, 1H, ArH), 7.18~7.16 (m, 3H, ArH), 7.11~7.10
(
m, 2H, ArH), 7.08~7.06 (m, 2H, ArH), 6.73 (d, J = 9.0Hz, 1H, ArH), 6.09 (brs, 1H, CH), 4.13
(
brs, 1H, CH), 3.77 (s, 3H, OCH ), 3.70~3.66 (m, 1H, CH), 3.63~3.60 (m, 1H, CH), 3.41 (s, 3H,
3
13
3 3 6
OCH ), 2.97~2.96 (m, 2H, CH), 1.43 (s, 3H, CH ); C NMR (150 MHz, DMSO-d ) δ: 167.3,
1
1
1
53.1, 146.5, 139.9, 131.4, 127.8, 127.6, 127.5, 125.9, 124.0, 123.1, 115.0, 112.0, 111.1, 110.2,
00.4, 98.2, 55.4, 53.7, 50.1, 43.4, 25.6, 18.5; IR (KBr) υ: 3343, 3074, 2989, 2849,1686, 1660,
-1
597, 1450, 1421, 1367, 1312, 1260, 1193, 1158, 1093, 1024, 923, 844, 825, 795, 762 cm ;
+
HRMS (ESI) Calcd. for C25
H
26
N
2
NaO
3
([M+Na] ): 425.1836. Found: 425.1832.
1
5

ACCEPTED MANUSCRIPT
Ethyl 1-[2-(5-Methoxy-1H-indol-3-yl)-ethyl]-5-methyl-4-phenyl-1,4-dihydropyridine-3-
1
carboxylate (2b): white solid, 89%, m.p.138~140ꢀ; H NMR (600 MHz, DMSO-d ) δ: 10.74 (s,
6
1
6
3
H, NH), 7.25~7.21 (m, 2H, CH, ArH), 7.19~7.16 (m, 3H, ArH), 7.11~7.06 (m, 4H, ArH),
.74~6.72 (m, 1H, ArH), 6.10 (brs, 1H, CH), 4.12 (brs, 1H, CH), 3.90~3.87 (m, 1H, CH),
3
.83~3.79 (m, 1H, CH), 3.77 (s, 3H, OCH ), 3.69~3.61 (m, 2H, CH), 2.99~2.94 (m, 2H, CH), 1.42
13
(
3 3 6
s, 3H, CH ), 1.02 (t, J = 6.6Hz, 3H, CH ); C NMR (150 MHz, DMSO-d ) δ: 166.9, 153.1, 146.6,
1
5
1
39.7, 131.5, 127.7, 127.6, 127.5, 125.8, 124.0, 123.1, 114.9, 112.0, 111.1, 110.3, 100.4, 98.6,
8.3, 55.4, 53.7, 43.5, 25.6, 18.5, 14.2; IR (KBr) υ: 3437, 3075, 2989, 1687, 1661, 1597, 1487,
-1
455, 1430, 1371, 1307, 1261, 1240, 1216, 1190, 1158, 1092, 1027, 976, 922, 843, 794, 758 cm ;
+
HRMS (ESI) Calcd. for C26
H
28
N
2
NaO
3
([M+Na] ): 439.1992. Found: 439.1993.
Methyl 9-methoxy-1-methyl-2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (3a): white solid, 78%, m.p.264~265ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.25 (s,
1
8
3
3
H, NH), 7.27 (brs, 1H, CH), 7.32~7.29 (m, 2H, ArH), 7.22~7.19 (m, 3H, ArH), 7.15 (d, J =
.4Hz, 1H, ArH), 6.93 (brs, 1H, ArH), 6.68~6.66 (m, 1H, ArH), 4.31 (d, J = 13.8Hz, 1H, CH),
.94~3.91 (m, 1H, CH), 3.78~3.77 (m, 1H, CH), 3.74 (s, 3H, OCH ), 3.45 (s, 3H, OCH ),
.42~3.41 (m, 1H, CH), 2.77~2.73 (m, 2H, CH), 1.94~1.91 (m, 1H, CH), 1.02 (d, J = 6.6Hz, 3H,
3
3
13
CH ); C NMR (150 MHz, DMSO-d ) δ: 166.9, 153.2, 146.7, 143.0, 132.7, 131.4, 129.4, 127.6,
3
6
126.5, 126.0, 111.8, 110.9, 99.8, 96.5, 55.4, 53.6, 51.7, 49.9, 43.9, 37.2, 22.3, 16.3; IR (KBr) υ:
3313, 3029, 2999, 2956, 2918, 2824, 1657, 1624, 1485, 1459, 1415, 1335, 1245, 1214, 1178, 1154,
-1
1
26 2 3
122, 1095, 1033, 993, 938, 916, 879, 848, 795, 754 cm ; HRMS (ESI) Calcd. for C25H N NaO
+
(
[M+Na] ): 425.1836. Found: 425.1837.
Ethyl 9-methoxy-1-methyl-2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (3b): white solid, 87%, m.p.226~228ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.28 (s,
1
H, NH), 7.81 (brs, 1H, CH), 7.32~7.29 (m, 2H, ArH), 7.22~7.19 (m, 3H, ArH), 7.15 (d, J =
.4Hz, 1H, ArH), 6.93 (brs, 1H, ArH), 6.68~6.66 (m, 1H, ArH), 4.34~3.31 (m, 1H, CH),
.93~3.89 (m, 3H, CH), 3.77~3.76 (m, 1H, CH), 3.74 (s, 3H, OCH ), 3.45~3.42 (m, 1H, CH),
.79~2.73 (m, 2H, CH), 1.94~1.93 (m, 1H, CH), 1.07~1.05 (m, 3H, CH ), 1.02 (d, J = 6.6Hz, 3H,
8
3
3
2
3
13
3 6
CH ); C NMR (150 MHz, DMSO-d ) δ: 166.5, 153.2, 146.5, 143.1, 132.8, 131.4, 129.4, 127.5,
126.5, 125.9, 111.8, 110.9, 109.2, 99.8, 96.8, 58.0, 55.4, 53.7, 51.7, 43.9, 37.1, 22.3, 18.5, 16.3,
1
6

ACCEPTED MANUSCRIPT
1
8
4
2
1
4.5; IR (KBr) υ: 3108, 1728, 1587, 1487, 1460, 1367, 1312, 1244, 1213, 1160, 1123, 1032, 909,
-1
+
43, 783, 750 cm ; HRMS (ESI) Calcd. for C26
H
28
N
2
3
NaO ([M+Na] ): 439.1992. Found:
39.1997.
.
General
procedure
for
the
preparations
of
,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines 4a-4g: A mixture of tryptamines (2.0 mmol)
and methyl or ethyl propiolate (2.0 mmol) in 10.0mL ethanol was stirred at room temperature for
0 minutes. Then arylideneacetones (2.0 mmol) and anhydrous zinc chloride (1.0 mmol, 0.136 g)
2
were added to it. The solution was stirred at about 50C for additional 36 hours. The solvent was
removed by rotator evaporation and the residue was titrated with cold alcohol to give the pure
product.
Methyl 12b-methyl-2-(4-methylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (4a): white solid, 70%, m.p.288~290ꢀ; H NMR (600 MHz, DMSO-d ) δ: 10.97 (s,
6
1H, NH), 7.82 (brs, 1H, CH), 7.39 (d, J = 7.2Hz, 1H, ArH), 7.28 (d, J = 7.8Hz, 1H, ArH), 7.16 (d,
J = 7.8Hz, 2H, ArH), 7.12 (d, J = 7.2Hz, 2H, ArH), 7.04 (t, J = 7.2Hz, 1H, ArH), 6.96 (t, J =
7
3
2
1
9
1
.2Hz, 1H, ArH), 3.98~3.97 (m, 1H, CH), 3.83~3.81 (m, 1H, CH), 3.63~3.59 (m, 1H, CH), 3.50 (s,
H, OCH ), 2.88 (d, J = 13.8Hz, 1H, CH), 2.77~2.73 (m, 1H, CH), 2.67 (d, J = 12.6Hz, 1H, CH),
.28 (s, 3H, CH
3
1
3
3
3 6
), 1.97~1.93 (m, 1H, CH), 0.99 (s, 3H, CH ); C NMR (150 MHz, DMSO-d ) δ:
67.7, 146.7, 142.3, 139.0, 135.9, 134.2, 128.5, 127.4, 126.0, 120.9, 118.5, 117.9, 111.0, 104.3,
2.7, 54.2, 50.0, 47.6, 40.5, 34.6, 24.3, 21.9, 20.5; IR (KBr) υ: 3446, 2916, 2849, 1664, 1582,
-1
425, 1353, 1311, 1217, 1183, 1142, 1093, 1039, 923, 853, 818, 795, 774 cm ; HRMS (ESI)
+
Calcd. for C H N NaO ([M+Na] ): 409.1886. Found: 409.1878.
25
26
2
2
Methyl 12b-methyl-2-(3-methoxyphenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (4b): white solid, 72%, m.p.272~274ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: 10.99 (s,
1H, NH), 7.83 (brs, 1H, CH), 7.39 (d, J = 7.2Hz, 1H, ArH), 7.28 (d, J = 8.4Hz, 1H, ArH), 7.23 (t,
J = 7.8Hz, 1H, ArH), 7.05 (t, J = 7.8Hz, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH), 6.87~6.84 (m, 2H,
ArH), 6.75 (d, J = 7.2Hz, 1H, ArH), 3.99~3.98 (m, 1H, CH), 3.85~3.82 (m, 1H, CH), 3.76 (s, 3H,
OCH ), 3.64~3.60 (m, 1H, CH), 3.52 (s, 3H, OCH ), 2.91 (d, J = 13.8Hz, 1H, CH), 2.77~2.72 (m,
3
3
1H, CH), 2.69~2.66 (m, 1H, CH), 1.95 (dd, J
1
2 3
= 13.8Hz, J = 6.6Hz, 1H, CH), 1.02 (s, 3H, CH );
13
6
C NMR (150 MHz, DMSO-d ) δ: 167.7, 159.1, 147.1, 146.7, 139.0, 135.9, 128.9, 126.0, 120.9,
1
7

ACCEPTED MANUSCRIPT
119.9, 118.5, 117.9, 113.9, 111.0, 110.2, 104.3, 92.5, 54.9, 54.2, 50.1, 47.6, 35.0, 24.2, 21.9; IR
(KBr) υ: 3452, 2930, 2853, 1637, 1485, 1424, 1383, 1349, 1308, 1268, 1221, 1185, 1141, 1092,
-1
+
1
053, 879, 776 cm ; HRMS (ESI) Calcd. for C25
26 2 3
H N NaO ([M+Na] ): 425.1836. Found:
425.1831.
Methyl 9-methoxy-12b-methyl-2-(4-bromophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]-
1
quinolizine-3-carboxylate (4c): white solid, 67%, m.p.299~300ꢀ; H NMR (600 MHz,
6
DMSO-d ) δ: 11.00 (s, 1H, NH), 7.86 (brs, 1H, CH), 7.52~7.51 (m, 2H, ArH), 7.40~7.39 (m, 1H,
ArH), 7.29~7.25 (m, 3H, ArH), 7.05~6.96 (m, 2H, ArH), 3.98 (brs, 1H, CH), 3.84 (brs, 1H, CH),
3
1
1
2
3
.62 (brs, 1H, CH), 3.52 (s, 3H, OCH ), 2.87 (d, J = 12.0Hz, 1H, CH), 2.75~2.68 (m, 2H, CH),
13
3 6
.98 (brs, 1H, CH), 1.00 (s, 3H, CH ); C NMR (150 MHz, DMSO-d ) δ: 167.6, 146.9, 144.9,
38.8, 135.9, 130.7, 129.9, 126.0, 120.9, 118.5, 117.9, 111.0, 104.3, 92.0, 54.2, 50.1, 47.6, 34.7,
4.3, 21.9; IR (KBr) υ: 3448, 2926, 2854, 2025, 1663, 1582, 1485, 1426, 1353, 1309, 1219, 1185,
-1
+
1
143, 1094, 1039, 1011, 823, 782 cm ; HRMS (ESI) Calcd. for C24
2 2
H23BrN NaO ([M+Na] ):
473.0835. Found: 473.0822.
Methyl 9-methoxy-12b-methyl-2-(4-methoxyphenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]-
1
quinolizine-3-carboxylate (4d): white solid, 73%, m.p.266~267 ꢀ; H NMR (600 MHz,
DMSO-d ) δ: cis/trans = 1:8; trans-isomer: 10.80 (s, 1H, NH), 7.81 (brs, 1H, CH), 7.16 (brs, 3H,
6
ArH), 6.89 (brs, 3H, ArH), 6.68 (d, J = 7.2Hz, 1H, ArH), 4.18 (d, J = 12.0Hz, 1H, CH), 3.99~3.94
(
m, 1H, CH), 3.81~3.80 (m, 1H, CH), 3.73 (s, 6H, 0CH
3 3
), 3.51 (s, 3H, 0CH ), 2.83 (d, J = 13.2Hz,
1
3
1
1
2
8
H, CH), 2.71~2.70 (m, 1H, CH), 2.65 (d, J = 13.2Hz, 1H, CH), 1.92~1.91 (m, 1H, CH), 0.98 (s,
13
3 3 6
H, CH ); cis-isomer: 7.78 (brs, 1H, CH), 3.94 (s, 3H, OCH ); C NMR (150 MHz, DMSO-d ) δ:
67.7, 157.1, 153.2, 146.7, 139.8, 137.2, 130.9, 128.4, 126.3, 113.4, 113.3, 111.6, 110.7, 104.2,
00.1, 92.8, 55.4, 54.9, 54.2, 50.0, 47.6, 40.6, 34.2, 24.4, 22.0; IR (KBr) υ: 3451, 3240, 2949,
831, 1662, 1579, 1510, 1461, 1426, 1357, 1314, 1253, 1216, 1180, 1139, 1091, 1036, 984, 910,
-1
+
28 2 4
29, 774 cm ; HRMS (ESI) Calcd. for C26H N NaO ([M+Na] ): 455.1941. Found: 455.1937.
Methyl 9-methoxy-12b-methyl-2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (4e): white solid, 81%, m.p. >300ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: cis/trans =
1
:8; trans-isomer: 10.81 (s, 1H, NH), 7.84 (brs, 1H, CH), 7.33~7.27 (m, 4H, ArH), 7.17~7.15 (m,
H, ArH), 6.89 (brs, 1H, ArH), 6.69~6.67 (m, 1H, ArH), 4.02~3.98 (m, 1H, CH), 3.83~3.80 (m,
2
1
8

ACCEPTED MANUSCRIPT
1
2
3
1
2
1
H, CH), 3.73 (s, 3H, 0CH ), 3.63~3.59 (m, 1H, CH), 3.51 (s, 3H, 0CH ), 2.89~2.85 (m, 1H, CH),
3
3
3
.75~2.63 (m, 2H, CH), 2.00~1.96 (m, 1H, CH), 0.97 (s, 3H, CH ); cis-isomer: 7.78 (brs, 1H, CH),
13
3 6
.94 (s, 3H, OCH ); C NMR (150 MHz, DMSO-d ) δ: 167.6, 153.2, 146.9, 144.5, 139.5, 131.0,
29.9, 129.4, 127.8, 126.4, 111.6, 110.8, 104.3, 100.3, 92.2, 55.4, 54.3, 50.0, 47.7, 40.4, 34.6, 24.4,
2.0; IR (KBr) υ: 3453, 3291, 2976, 2924, 2865, 2828, 2733, 1647, 1610, 1488, 1436, 1416, 1329,
-1
311, 1219, 1183, 1139, 1113, 1091, 1030, 1012, 952, 913, 889, 822, 797, 783 cm ; HRMS (ESI)
+
Calcd. for C25
26
H N
2
NaO
3
([M+Na] ): 425.1836. Found: 425.1840.
Methyl 9-methoxy-12b-methyl-2-(4-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]-
1
quinolizine-3-carboxylate (4f): white solid, 73%, m.p.䟟300ꢀ; H NMR (600 MHz, DMSO-d
6
)
δ: cis/trans = 1:5; trans-isomer: 10.81 (s, 1H, NH), 7.84 (brs, 1H, CH), 7.38 (d, J = 7.8Hz, 2H,
ArH), 7.29 (d, J = 7.8Hz, 2H, ArH), 7.17 (d, J = 9.0Hz, 1H, ArH), 6.90 (brs, 1H, ArH), 6.69 (d, J
=
8.4Hz, 1H, ArH), 3.99~3.98 (m, 1H, CH), 3.84~3.81 (m, 1H, CH), 3.74 (s, 3H, 0CH
.63~3.59 (m, 1H, CH), 3.52 (s, 3H, 0CH ), 2.86~2.82 (m, 1H, CH), 2.75~2.70 (m, 1H, CH),
.68~2.64 (m, 1H, CH), 1.99~1.98 (m, 1H, CH), 0.98 (s, 3H, CH ); cis-isomer: 7.81 (brs, 1H, CH);
3
),
3
2
3
3
13
C NMR (150 MHz, DMSO-d
6
) δ: 167.7, 153.2, 146.7, 145.4, 139.7, 131.0, 127.9, 127.8, 127.5,
126.4, 125.4, 111.6, 110.7, 104.2, 100.2, 92.6, 55.4, 54.3, 50.0, 47.7, 40.6, 35.1, 24.3, 22.0; IR
(KBr) υ: 3446, 3273, 2950, 2926, 2864, 2826, 1642, 1611, 1489, 1418, 1335, 1315, 1219, 1185,
-1
1
2 3
139, 1093, 1033, 953, 914, 879, 829, 800, 769 cm ; HRMS (ESI) Calcd. for C25H25ClN NaO
+
(
[M+Na] ): 459.1992. Found: 459.1945.
Ethyl 9-methoxy-12b-methyl-2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-
1
carboxylate (4g): white solid, 64%, m.p.266~268ꢀ; H NMR (600 MHz, DMSO-d
6
) δ: cis/trans
=
1:5; trans-isomer: 10.98 (s, 1H, NH), 7.81 (brs, 1H, CH), 7.41~7.38 (m, 1H, ArH), 7.33~7.28
m, 5H, ArH), 7.18~7.15 (m, 1H, ArH), 7.06~7.02 (m, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH),
.01~3.98 (m, 3H, CH), 3.83~3.81 (m, 1H, CH), 3.65~3.60 (m, 1H, CH), 2.89 (d, J = 13.2Hz, 1H,
CH), 2.76~2.73 (m, 1H, CH), 2.69~2.66 (m, 1H, CH), 2.00 (dd, J = 13.2Hz, J = 6.6Hz, 1H, CH),
); cis-isomer: 10.87 (s, 1H, NH), 7.66 (brs, 1H, CH),
.24~7.23 (m, 1H, ArH), 7.20~7.19 (m, 1H, ArH), 7.12~7.09 (m, 3H, ArH), 3.80~3.77 (m, 2H,
(
4
1
2
1
7
3 3
.10 (t, J = 6.6Hz, 3H, CH ), 0.99 (s, 3H, CH
CH), 3.73~2.70 (m, 1H, CH), 3.69~3.67 (m, 1H, CH), 3.29 (brs, 1H, CH), 2.81~2.77 (m, 1H, CH),
13
2
3 3
.61~2.58 (m, 1H, CH), 1.55 (s, 3H, CH ), 0.85 (t, J = 6.6Hz, 3H, CH ); C NMR (150 MHz,
1
9

ACCEPTED MANUSCRIPT
DMSO-d ) δ: 167.2, 146.6, 145.5, 139.0, 135.9, 127.8, 127.5, 126.6, 126.1, 125.3, 125.2, 120.9,
6
1
3
8
18.5, 117.9, 111.0, 104.3, 93.2, 58.0, 54.2, 47.6, 40.6, 35.1, 24.3, 21.9, 14.6; IR (KBr) υ: 3417,
241, 2978, 2911, 2856, 1664, 1585, 1445, 1363, 1308, 1221, 1187, 1142, 1090, 1038, 960, 923,
-1
+
26 2 2
82 cm ; HRMS (ESI) Calcd. for C25H N NaO ([M+Na] ): 409.1886. Found: 409.1893.
Supporting Information: The Detailed experiments and characterization data for all compounds
can be found in Supporting Information. Crystallographic data 1a (CCDC 916908), 1c (CCDC
916909), 3a (CCDC 916911), 4d (CCDC 916910) and 4g (CCDC 932055) have been deposited at
the Cambridge Crystallographic Database Centre. These data can be obtained free of charge via
www.ccdc.ac.ck./data_request/cif.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Grant
No. 21172189) and the Priority Academic Program Development of Jiangsu Higher Education
Institutions.
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1. (a) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc.
2009, 131, 10796-10797; (b) Jakubec, P.; Helliwell, M.; Dixon, D. J. Org. Lett. 2008, 10, 4267-4270; (c)
2
1

ACCEPTED MANUSCRIPT
Rueping, M.; Volla, C. M. R.; Bolte, M.; Raabe, G. Adv. Synth. Catal. 2011, 353, 2853–2859; (d) Rueping, M.;
Volla, C. M. R. RSC advances 2011, 1. 79-91.
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2. (a) Jin, Z. C.; Wang, X.; Huang, H. C.; Liang, X. M.; Ye, J. X. Org. Lett. 2011, 13, 564-567; (b) Jin, Z. C.;
Huang, H. C.; Li, W. J.; Luo, X. Y.; Liang X. M.; Ye, J. X. Adv. Synth. Catal. 2011, 353, 343-348; (c) Zhou, H.
L.; Ling, J. B. Xu, P. F. J. Org. Chem. 2012, 77, 7737-7743.
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1
3. Wu, X. Y.; Dai, X. Y.; Fang, H. H.; Nie, L. L.; Chen, J.; Cao, W. G.; Zhao, G. Chem. Eur. J. 2011, 17,
1
0510-10514.
4. (a) Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. Org. Lett. 2010, 12, 3678-3681; (b) Sun, J.; Sun, Y.; Gao, H.; Yan, C.
G. Eur. J. Org. Chem.2011, 6952–6956; (c) Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. ACS Comb. Sci. 2011, 13,
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21-416; (d) Sun, J.; Sun, Y.; Gao, H.; Yan, C. G. Eur. J. Org. Chem. 2012, 1976-1983; (e) Sun, J.; Sun, Y.;
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5. (a) Sun, J.; Sun, Y.; Xia, E. Y.; Yan, C. G. ACS Comb. Sci. 2011, 13, 436-441; (b) Sun, J.; Sun, Y.; Gao, H.; Yan,
C. G. Synthesis, 2012, 1069-1073; (c) Sun, Y.; Sun, J.; Yan, C. G. Mol. Divers. 2012, 16, 163–171; (d) Zhang, L.
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1
1
Graphic abstract
Facile construction of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines via
one-pot three-component reactions of tryptamines, propiolate and
2
2

ACCEPTED MANUSCRIPT
α,β-unsaturated aromatic aldehydes or ketones
Jing Sun, Li-Li Zhang, Chao-Guo Yan*
2
3

ACCEPTED MANUSCRIPT
Facile construction of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizines via
domino Pictet-Spengler reaction of tryptamines, propiolate and α,β-unsaturated
aldehydes or ketones
Jing Sun, Li-Li Zhang, Chao-Guo Yan*
Supporting Information
General Experimental Methods and
Characterization of compounds
1-29
1
. General procedure for the preparation of 1,2,6,7,12,12b-hexahydroindolo[2,3-a]-
quinolizines 1a-1q: In a round bottom flask a mixture of tryptamines (2.0 mmol) and methyl or
ethyl propiolate (2.0 mmol) in 5.0mL ethanol was stirred at room temperature for 20 minuts. Then
α,β-unsaturated aldehydes (2.0 mmol) and anhydrous zinc chloride (1.0 mmol, 0.136 g) were
added to it. The solution was stirred at room temperature for additional 48 hours. The resulting
precipitates were collected by filtration and washed with cold alcohol to give the pure product.

ACCEPTED MANUSCRIPT
methyl 2-phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate (1a): yellow
1
solid, 78%, m.p.279~281� ; H NMR (600 MHz, DMSO-d ) δ: 10.94 (s, 1H, NH), 7.88 (brs, 1H,
6
CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.36~7.34 (m, 2H, ArH), 7.27 (d, J = 7.8Hz, 2H, ArH),
7
.23~7.21 (m, 2H, ArH), 7.02 (t, J = 7.2Hz, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH), 4.21 (d, J =
1.4Hz, 1H, CH), 4.01~4.00 (m, 1H, CH), 3.98~3.95 (m, 1H, CH), 3.55~3.51 (m, 1H, CH), 3.49
s, 3H, OCH ), 2.81~2.77 (m, 1H, CH), 2.73~2.71 (m, 1H, CH), 2.57 (d, J = 13.2Hz, 1H, CH),
1
(
3
1
3
1
1
4
1
.79 (td, J = 12.6Hz, J = 4.8Hz, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.3, 147.2,
1 2 6
46.6, 136.2, 133.0, 128.1, 127.8, 126.3, 125.9, 121.0, 118.5, 117.7, 111.0, 106.9, 94.0, 50.2, 50.0,
7.1, 36.2, 35.7, 21.6; IR (KBr) υ: 3235, 2965, 2911, 1664, 1597, 1494, 1471, 1428, 1357, 1323,
-1
301, 1205, 1185, 1163, 1109, 1038, 1021, 942, 852, 790 cm ; HRMS (ESI) Calcd. for
+
C
H
23 22
N
2
NaO
2
([M+Na] ): 381.1573. Found: 381.1575.
N
N
H
CO CH3
2
N
N
H
CO CH3
2
2

ACCEPTED MANUSCRIPT
methyl 2-(4-methxylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1b): yellow solid, 87%, m.p.260~262� ; H NMR (600 MHz, DMSO-d ) δ: 10.93 (s, 1H, NH),
6
7
.85 (brs, 1H, CH), 7.40 (d, J = 7.2Hz, 1H, ArH), 7.23 (d, J = 7.8Hz, 1H, ArH), 7.14 (brs, 4H,
ArH), 7.02~7.01 (m, 1H, ArH), 6.97~6.96 (m, 1H, ArH), 4.20 (d, J = 12.0Hz, 1H, CH), 3.96 (brs,
H, CH), 3.54~3.50 (m, 1H, CH), 3.48 (s, 3H, OCH ), 2.81~2.77 (m, 1H, CH), 2.72~2.70 (m, 1H,
CH), 2.53 (d, J = 13.2Hz, 1H, CH), 2.29 (s, 3H, CH
2
3
13
3
), 1.77 (t, J = 12.6Hz, 1H, CH); C NMR
(
150 MHz, DMSO-d ) δ: 167.3, 147.0, 143.5, 136.2, 134.8, 133.1, 128.7, 127.6, 126.3, 120.9,
6
1
18.5, 117.6, 111.0, 106.8, 94.1, 50.1, 50.0, 47.0, 35.8, 35.7, 21.6, 20.5; IR (KBr) υ: 3252, 2959,
-1
1668, 1560, 1510, 1427, 1358, 1321, 1302, 1206, 1184, 1165, 1109, 1039, 939, 855, 803, 777 cm ;
+
HRMS (ESI) Calcd. for C24
H
24
N
2
NaO
2
([M+Na] ): 395.1730. Found: 395.1732.
N
N
H
CO CH
2
3
CH3
N
N
H
CO CH
2
3
CH3
3

ACCEPTED MANUSCRIPT
methyl 2-(3-methxylphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1c): yellow solid, 81%, m.p.282~284� ; H NMR (600 MHz, DMSO-d ) δ: 10.94 (s, 1H, NH),
6
7
7
.87 (brs, 1H, CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.23~7.21 (m, 2H, ArH), 7.09 (brs, 1H, ArH),
.04~7.02 (m, 3H, ArH), 6.97~6.95 (m, 1H, ArH), 4.22 (d, J = 11.4Hz, 1H, CH), 3.96 (brs, 2H,
CH), 3.56~3.52 (m, 1H, CH), 3.48 (s, 3H, OCH
.54 (d, J = 12.6Hz, 1H, CH), 2.33 (s, 3H, CH
DMSO-d ) δ: 167.3, 147.1, 146.6, 137.1, 136.2, 133.1, 128.4, 128.0, 126.6, 126.3, 124.8, 120.9,
3
), 2.79~2.77 (m, 1H, CH), 2.73~2.70 (m, 1H, CH),
1
3
2
3
), 1.79~1.76 (m, 1H, CH); C NMR (150 MHz,
6
1
2
9
3
18.5, 117.6, 111.0, 106.9, 94.0, 50.1, 50.0, 47.0, 36.1, 35.7, 21.6, 21.2; IR (KBr) υ: 3451, 3236,
908, 2849, 1667, 1599, 1424, 1354, 1320, 1302, 1231, 1214, 1199, 1184, 1169, 1110, 1063, 1038,
-1
+
24, 882, 778 cm ; HRMS (ESI) Calcd. for C24
24 2 2
H N NaO ([M+Na] ): 395.1730. Found:
95.1728.
N
N
H
CO CH
2
3
CH3
N
N
H
CO CH
2
3
CH3
4

ACCEPTED MANUSCRIPT
methyl 2-(4-methoxyphenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1d): yellow solid, 83%, m.p.256~257� ; H NMR (600 MHz, DMSO-d ) δ: 10.91 (s, 1H, NH),
6
7
2
4
.84 (brs, 1H, CH), 7.40 (d, J = 7.8Hz, 1H, ArH), 7.23 (d, J = 7.8Hz, 1H, ArH), 7.17 (d, J = 7.8Hz,
H, ArH), 7.02 (t, J = 7.2Hz, 1H, ArH), 6.96 (t, J = 7.2Hz, 1H, ArH), 6.90 (d, J = 7.8Hz, 2H, ArH),
.20 (d, J = 11.4Hz, 1H, CH), 3.95~3.94 (m, 2H, CH), 3.74 (s, 3H, OCH
3
), 3.54~3.52 (m, 1H,
CH), 3.49 (s, 3H, OCH
3
), 2.81~2.77 (m, 1H, CH), 2.73~2.70 (m, 1H, CH), 2.53 (d, J = 12.6Hz,
13
1
1
5
1
H, CH), 1.75 (td, J = 12.6Hz, J = 3.6Hz, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.3,
1
2
6
57.6, 147.0, 138.4, 136.2, 133.1, 128.6, 126.3, 120.9, 118.5, 117.6, 113.5, 111.0, 106.8, 94.3,
5.0, 50.1, 50.0, 47.0, 35.9, 35.3, 21.6; IR (KBr) υ: 3449, 2958, 1663, 1598, 1509, 1429, 1358,
-1
323, 1303, 1277, 1250, 1207, 1186, 1109, 1037, 832 cm ; HRMS (ESI) Calcd. for
+
C H
24 24
N
2
NaO
3
([M+Na] ): 411.1679. Found: 411.1682.
N
N
H
CO CH3
2
OCH3
N
N
H
CO CH3
2
OCH3
5

ACCEPTED MANUSCRIPT
methyl 2-(4-chlorophenyl)-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate
1
(
1e): yellow solid, 84%, m.p.267~268� ; H NMR (600 MHz, DMSO-d ) δ: 10.93 (s, 1H, NH),
6
7
.88 (brs, 1H, CH), 7.41~7.40 (m, 3H, ArH), 7.30~7.28 (m, 2H, ArH), 7.24 (d, J = 6.6Hz, 1H,
ArH), 7.03 (brs, 1H, ArH), 6.96 (brs, 1H, ArH), 4.20 (d, J = 10.2Hz, 1H, CH), 4.00~3.95 (m, 2H,
CH), 3.53 (brs, 1H, CH), 3.49 (s, 3H, OCH ), 2.79~2.71 (m, 2H, CH), 2.55 (d, J = 12.6Hz, 1H,
CH), 1.79 (brs, 1H, CH); C NMR (150 MHz, DMSO-d ) δ: 167.2, 147.3, 145.6, 136.2, 132.9,
30.5, 129.6, 128.0, 126.3, 120.9, 118.5, 117.8, 111.0, 106.9, 93.6, 50.1, 50.0, 46.9, 35.6, 21.6; IR
KBr) υ: 3447, 3232, 2962, 2822, 1669, 1599, 1489, 1427, 1356, 1320, 1304, 1207, 1185, 1164,
3
1
3
6
1
(
-1
1
2 2
111, 1037, 1012, 876, 854, 832, 796, 758 cm ; HRMS (ESI) Calcd. for C23H21ClN NaO
+
([M+Na] ): 415.1184. Found: 415.1184.
N
N
H
CO CH
2
3
Cl
N
N
H
CO CH
2
3
Cl
6