ZnBr2 catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: An efficient route to polycyclic thiopyranoindol annulated [3,4-c]quinolone derivatives

Article abstract of DOI:10.1016/j.tet.2017.04.017

Various novel polycyclic thiopyranoindol annulated [3,4-c]quinolone derivatives were synthesized via domino Knoevenagel-hetero-Diels–Alder reactions of indoline-2-thions and novel N-acrylated anthranilaldehydes in refluxing ethanol as a solvent in the presence of 20?mol% ZnBr₂ as a Lewis acid catalyst. All reactions proceed with high yields with excellent regio- and stereoselectivity.

Full text of DOI:10.1016/j.tet.2017.04.017

Accepted Manuscript
ZnBr catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: An efficient route
2
to polycyclic thiopyranoindol annulated [3,4-c]quinolone derivatives
Mostafa Kiamehr, Batoul Alipour, Leyla Mohammadkhani, Behzad Jafari, Peter
Langer
PII:
S0040-4020(17)30389-7
10.1016/j.tet.2017.04.017
TET 28618
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 February 2017
Revised Date: 26 March 2017
Accepted Date: 10 April 2017
Please cite this article as: Kiamehr M, Alipour B, Mohammadkhani L, Jafari B, Langer P, ZnBr
2
catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: An efficient route to polycyclic
thiopyranoindol annulated [3,4-c]quinolone derivatives, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.04.017.
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Abstract
Leave this area blank for abstract info.
ZnBr2 catalyzed domino Knoevenagel-hetero
-Diels–Alder reaction: an efficient route to
polycyclic thiopyranoindol annulated [3,4-
c]quinolone derivatives
Mostafa Kiamehra,*, Batoul Alipoura, Leyla Mohammadkhania, Behzad Jafarib, Peter Langerb,c

ACCEPTED MANUSCRIPT
ZnBr2 catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: an
efficient route to polycyclic thiopyranoindol annulated [3,4-c]quinolone
derivatives
Mostafa Kiamehr a,*, Batoul Alipour a, Leyla Mohammadkhani a, Behzad Jafari b, Peter Langer b,c
a Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 37146-6611,
Qom, Iran
b Institut für Chemie der Universität Rostock, Albert-Einstein-Straße 3a, D-18059 Rostock, Germany
c Leibniz Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, D-18059
Rostock, Germany
*Corresponding author. Tel.: +98-25-32103093
E-mail address: mkiamehr@yahoo.com, m.kiamehr@qom.ac.ir
Abstract. Various novel polycyclic thiopyranoindol annulated [3,4-c]quinolone
derivatives were synthesized via domino Knoevenagel-hetero-Diels–Alder
reactions of indoline-2-thions and novel N-acrylated anthranilaldehydes in
refluxing ethanol as a solvent in the presence of 20 mol% ZnBr2 as a Lewis
acid catalyst. All reactions proceed with high yields with excellent regio- and
stereoselectivity.
Keywords: Domino reaction, Knoevenagel-hetero-Diels–Alder, Indole,
Indolin-2-thione, 3,4-Dihydroquinolone, ZnBr2 catalyzed
1. Introduction
Indole derivatives are important heterocycles. They are widespread in nature
and have various biological activities,1 such as topical anti-inflammatory,2 anti-
HIV3
and
antitumor
activities.4
Also
compounds
possessing
tetrahydrothiopyrano indole moieties are very important because of their
different biological and medicinal activities.5 On the other hand, the
dihydroquinolone (3,4-dihydroquinolin-2-one) structure is found in many
pharmacologically important natural products and synthetic compounds.6
Simple alkoxydihydroquinolones form the core of the commercial drugs such
as carteolol,7 cilostazol8 and aripiprazole.9 Many 3,4-disubstituted
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dihydroquinolones
have
cardiovascular,
anti-inflammatory
and
phosphodiesterase inhibitory activities.10 The 3,4-dihydroquinolone structure is
also embedded within pentacyclic alkaloids of the Melodinus scandens family,
exemplified by scandine, meloscine and epimeloscine,11 as well as the
structurally unique alkaloids of the Trigolutesin A,12 scandomelonine and
episcandomelonine that have both indole and 3,4-dihydroquinolone moieties.11b
Not surprisingly, methods for the synthesis of 3,4-disubstituted
dihydroquinolones have attracted significant attention. Protocols, such as
Friedlander/Friedel–Crafts
cyclization,13 Skraup–Doebner–Von Miller
reaction,14 oxidative cyclization,15 radical reactions,16 photocyclizations,17
palladium-catalyzed cyclocarbonylation18 and rhodium-catalyzed reaction19
approaches have been reported. Despite their efficiencies, most of the reported
reactions are either multi-step, or are not suited for the synthesis of 3,4-
disubstituted dihydroquinolones containing other heterocyclic groups.
The domino Knoevenagel-hetero-Diels–Alder (DKHDA) reaction is a popular
strategy for the synthesis of polycyclic heterocycles and natural products.20 A
wide range of heterocyclic compounds, especially polycycles with a pyran or
chroman moiety have been synthesized by domino-Knoevenagel-hetero-Diels–
Alder reaction.21 In addition there are some reports of domino-Knoevenagel-
hetero-Diels–Alder reactions for the synthesis of polycycles with a
benzosultone or benzosultam moiety.22 In this regard, previously we reported
domino
Knoevenagel-hetero-Diels–Alder
reactions
of
O-acrylated
salicylaldehyde derivatives for synthesis of pentacycles with
a
dihydrocoumarin ring.23 The goal of the present study was to introduce a new
methodology for synthesis of pentacyclic heterocycles with 3,4-disubstituted
dihydroquinolones, in one step. To the best of our knowledge, this is the first
example of using N-acrylated anthranilaldehydes in the domino Knoevenagel-
hetero-Diels–Alder reaction with indolin-2-thiones. In the context of our
general
interest
in
the
domino
Knoevenagel-hetero-Diels–Alder
reactions,21a,22b,23 and synthesis of heterocyclic compounds using indolin-2-
thiones,24 we herein report a new and highly efficient reaction for the
preparation of pentacyclic compounds 3a-k, which consist of an indole ring
(A), a tetrahydrothiopyran ring (B) annulated to a 3,4-dihydroquinolone ring
(C) (Scheme 1).
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Scheme 1.
2. Results and discussion
2.1. Preparation of N-acrylated anthranilaldehyde derivatives for domino
Knoevenagel-hetero-Diels–Alder reaction
N-alkylanthranilaldehydes 4a-b were prepared from the corresponding N-
alkylquinoline salts on the basis of the previously reported method.25 N-
acrylated anthranilaldehyde derivatives 1a-f were then prepared from
condensation of N-alkylanthranilaldehydes 4a-b and (E)-acryloyl chloride
derivatives (acryloyl chloride, (E)-crotonoyl chloride and (E)-cinnamoyl
chloride) 5a-c in the presence of NaHCO3 in CH2Cl2 within 2-5 h in good
yields (Scheme 2). N-Acrylatedanthranilaldehyde derivatives 1a-f were
completely characterized using their analytical and spectral data. For example,
1
the H NMR spectrum of 1c exhibited characteristic singlet at δ 3.37 ppm for
NMe followed by two doublet at 6.05 and 7.64 for the =CH (J = 15.4 Hz) in
trans-relation with each other, together with a singlet at 10.05 due to CHO.
Yield (%)
R1
R2
85
Me
Me
H
1a
1b
1c
1d
1e
1f
CHO
CHO
O
Me
Ph
H
80
76
78
NaHCO3/ 2ꢀ5 h
CH2Cl2
O
+
R1
N
Me
Et
Cl
R2
N
R1
H
R2
Et
Me
Ph
73
65
4a-b
R1= Me, Et
5a-c
R2= H, Me, Ph
1a-f
Et
Scheme 2.
2.2. Domino Knoevenagel-hetero-Diels–Alder reaction of N-acrylated
anthranilaldehyde derivatives with indolin-2-thiones
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To optimize the reaction conditions, we screened the domino Knoevenagel-
hetero-Diels–Alder reaction of compound 1b with 1-methylindoline-2-thione
2a as a model. The effect of several solvents and catalysts were studied (Table
1). Using refluxing water or acetonitrile as a solvent under catalyst-free
conditions for 24 h, the products were obtained in 10% and 12% yield
respectively (Entries 1 and 2, Table 1). When the reaction was carried out in the
presence of ZnO as a Lewis acid in acetonitrile for 24 h at refluxing
temperature, the yield was increased to 35% (Entry 3). The effect of other
solvents in the presence of ZnO was studied. Using MeOH and EtOH as
solvents did not give the significant influence to the yield of product (Entries 4
and 5). Surprisingly the addition of ZnBr2 as a catalyst and ethanol as solvent
dramatically increased the yield of reaction to 88% and decreased the time of
reaction to 3 hours (Entry 6). Decreasing the ratio of ZnBr2 to 50 mol% and 20
mol% afforded the same results, but with 10 mol% of ZnBr2 in the same times,
gave lower yield (Entries 7, 8 and 9). We also examined other conditions, for
example Lewis base (Entry 10) or ZnCl2 (Entry 11), also we checked ZnBr2 in
water (Entry 12), but the best conditions was entry 9. In all the cases the
product was obtained as a cis isomer.
Table 1
Effect of catalysts and solvents on the domino Knoevenagel-hetero-Diels–Alder reaction of compounds 1b
and 2a
Entry
Solvent
Catalyst
Temp. (°C)
Time
(h)
24
24
24
24
24
3
3
3
3
24
Yielda
(%)
10
12
35
30
48
88
88
1
2
3
4
5
6
7
8
9
H2O
CH3CN
CH3CN
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
-
-
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
ZnO (100%)
ZnO (100%)
ZnO (100%)
ZnBr2 (100%)
ZnBr2 (50%)
ZnBr2 (20%)
ZnBr2 (10%)
Et3N
88
68
0
10
6

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11
12
EtOH
H2O
ZnCl2 (20%)
ZnBr2 (20%)
Reflux
Reflux
24
24
60
22
a Yield of isolated products.
Under the optimized conditions, we next investigated the effect of substitutions
on the yield as well as regio- and stereoselectivity of domino Knoevenagel-
hetero-Diels–Alder reaction of N-acrylated anthranilaldehyde derivatives 1a-f
and indoline-2-thiones 2a–c (Table 2).
Table 2
Domino Knoevenagel-hetero-Diels–Alder reactions of N-acrylated anthranilaldehyde derivatives 1a-f with
indoline-2-thiones 2a-ca
Entry
Aldehydes 1
Indoline-2-thiones 2
Products 3
Yieldb
1
90
2a
1a
3a
2
88
2a
1b
3b
3
95
2a
1c
3c
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4
87
2a
1d
3d
5
83
1e
2a
3e
CHO
6
92
O
N
Ph
Et
2a
1f
3f
CHO
7
90
O
N
Me
1a
2b
3g
8

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8
85
1a
2c
3h
9
90
1b
2c
3i
10
94
2c
1c
3j
11
87
S
N
Ph
2c
1d
3k
a All the reactions were carried out at reflux in the EtOH for 3 h in the presence of ZnBr2 (20 mol%).
b Isolated products.
The structures of the products 3a-k were established on the basis of their
spectral data (1H and 13C NMR, DEPT and IR), as well as HRMS analysis. The
9

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relative configurations were determined from the coupling constants of the
relevant H-atoms and also by direct comparison with the reported data in
1
literature.20-23 For instance, the characteristic peaks for 3b in the H NMR
spectra are a doublet of doublet (J = 9.6, 4.6 Hz) at δ 2.99 ppm for the Hb
followed by a multiplet for the Ha at δ 3.48-3.59 ppm and a doublet for the Hc
with J = 4.5 Hz at δ 4.71 ppm that show trans-relation between Ha and Hb also
cis-relation between Ha and Hc respectively. In all the synthesized products, the
relative orientations of the H-atoms were found to be same.
A plausible mechanism for the domino Knoevenagel-hetero-Diels–Alder
reaction is shown in Scheme 3. Initially aldehydes 1 undergo a Knoevenagel
condensation with indolin-2-thiones 2 in the presence of ZnBr2 (ZnBr2 as a
Lewis acid can facilitate the condensation) to afford an alkene intermediate,
which has not been isolated. The stereochemistry of the final products depends
on the endo- and exo-orientation of the dienophile in the transition state. We
assume that the trans-cycloadducts 6 could form via an exo-transition state
(intermediates 7), whereas the cis-isomers 3a-k resulted from an endo-
transition state (intermediates 8), as represented in Scheme 3. Here only the
products 3a-k were isolated which shows that the endo-transition states are
more stable than exo-transition states, due to secondary orbital interaction, so
reactions proceed via intermediates 8 to produce the cis-isomers 3a-k with
excellent regio- and stereoselectivity.
10

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Scheme 3. A plausible mechanism for the formation of compounds 3a-k.
3. Conclusion
We have reported a ZnBr2-catalyzed domino Knoevenagel-intramolecular-
hetero-Diels–Alder reaction of novel N-acrylated anthranilaldehydes and
indoline-2-thions with high efficiency and excellent regio- and stereoselectivity
to provide various novel pentacyclic thiopyranoindol annulated [3,4-
c]quinolone derivatives in a single step.
The major advantages of this reaction are the ease of the work-up (products can
be isolated without chromatography), clean reactions, high yields of products,
short reaction times, in the presence of 20 mol% ZnBr2 as a commercially
available and inexpensive catalyst, which make it a useful and attractive
strategy for the synthesis of quinolone-indole hybrids.
4. Experimental section
4.1. General
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Commercially available materials were used without any additional
purification. Analytical thin layer chromatography was performed on 0.20 mm
60 A silica gel plates. Column chromatography was performed using 60 A
silica gel (60–200 mesh). Infrared spectra were recorded in an ATR apparatus.
Mass spectrometric data (MS) were obtained by electron ionization (EI, 70 eV),
chemical ionization (CI, isobutane) or electrospray ionization (ESI). Melting
points are uncorrected. 1H NMR, 13C NMR and DEPT spectra in CDCl3 at r.t.;
δ in ppm rel. to Me4Si as internal standard, J in Hz.
4.2. General procedure for preparation of the N-acrylated
anthranilaldehyde derivatives 1a-f
To a stirred solution of N-alkylanthranilaldehydes 4 (10 mmol) and sodium
bicarbonate (NaHCO3) (15 mmol) in dry CH2Cl2 (15 mL) at 0-5 °C, was added
dropwise a solution of acryloyl chloride derivatives 5 (12 mmol) in dry CH2Cl2
(15 mL) at 0-5 °C, over 45 minutes, which was then stirred at room
temperature to 2-5 h. The organic solution was then washed with water (20 mL)
and hydrogen chloride (5%) solution (20 mL) and dried over Na2SO4. The
solvent was evaporated under reduced pressure, and the residue was separated
by column chromatography on a silica gel with petroleum ether/ethyl acetate
(3:1) as an eluent to obtain pure N-acrylated anthranilaldehyde derivatives 1a-f.
4.2.1. N-(2-Formylphenyl)-N-methylacrylamide (1a). Light brown liquid, yield
85% (1.61 g). 1H NMR (250 MHz, CDCl3): δ 3.32 (3H, s, NCH3), 5.47 (1H, dd,
J = 10.3, 1.8 Hz), 5.80 (1H, dd, J = 16.7, 10.3 Hz), 6.33 (1H, dd, J = 16.7, 1.8
Hz), 7.23 (1H, dd, J = 8.0, 0.9 Hz, Ar-H), 7.47(1H, t, J = 7.7 Hz, Ar-H), 7.64
(1H, td, J = 7.7, 1.6 Hz, Ar-H), 7.92 (1H, dd, J = 7.7, 1.6 Hz, Ar-H), 10.00 (1H,
13
s, -CHO); C NMR (62.5 MHz, CDCl3): δ 38.3 (NCH3), 127.6 (CH), 128.9
(CH), 129.0 (CH2), 129.3 (CH), 129.9 (CH), 132.7 (C), 135.6 (CH), 145.2 (C),
165.9 (CON), 189.1 (CHO). IR (ATR, cm–1): ῦ= 3066, 2928, 2852, 2750, 1692,
1652, 1594, 1398, 1349, 1262, 1192, 773. HRMS (ESI): calcd for C11H11O2N1
(M+) 189.0784, found 189.0782.
4.2.2. (E)-N-(2-Formylphenyl)-N-methylbut-2-enamide (1b). Light brown
1
liquid, yield 80% (1.625 g). H NMR (250 MHz, CDCl3): δ 1.70 (3H, dd, J =
6.9, 1.5 Hz, CH3), 3.37 (3H, s, NCH3), 5.53 (1H, dq, J = 15.0, 1.5 Hz), 6.90-
12

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7.05 (1H, m), 7.30 (1H, dd, J = 7.5, 0.7 Hz, Ar-H), 7.53 (1H, t, J = 7.5 Hz, Ar-
H), 7.70 (1H, td, J = 7.8, 1.5 Hz, Ar-H), 7.99 (1H, dd, J = 7.8, 1.5 Hz, Ar-H),
10.07 (1H, s, -CHO); 13C NMR (62.5 MHz, CDCl3): δ 18.0 (CH3), 38.2
(NCH3), 121.9 (CH), 128.7 (CH), 129.3 (CH), 129.5 (CH), 132.8 (C), 135.5
(CH), 143.2 (CH), 145.8 (C), 166.3 (CON), 189.3 (CHO). IR (ATR, cm–1): ῦ=
3055, 2916, 2851, 2750, 1692, 1661, 1629, 1593, 1445, 1370, 1191, 1089, 963,
773, 568. HRMS (ESI): calcd for C12H13O2N1 (M+) 203.0941, found 203.0939.
4.2.3. N-(2-Formylphenyl)-N-methylcinnamamide (1c). Yellow solid, yield
1
76% (2.015 g), mp: 89-90 ºC. H NMR (250 MHz, CDCl3): δ 3.37 (3H, s,
NCH3), 6.05 (1H, d, J = 15.4 Hz), 7.16-7.33 (6H, m, Ar-H), 7.50 (1H, t, J = 7.4
Hz, Ar-H), 7.64 (1H, d, J = 15.4 Hz, =CH), 7.65 (1H, dt, J = 7.7, 1.5 Hz, Ar-
H), 7.95 (1H, dd, J = 7.7, 1.5 Hz, Ar-H), 10.05 (1H, s, -CHO); 13C NMR (62.5
MHz, CDCl3): δ 38.5 (NCH3), 117.5 (CH), 127.9 (CH), 128.7 (CH), 128. 9
(CH), 129.4 (CH), 129.7 (CH), 129.8 (CH), 132.8 (C), 134.6 (C), 135.6 (CH),
143.3 (CH), 145.5 (C), 166.3 (CON), 189.1 (CHO). IR (ATR, cm–1): ῦ= 3061,
3031, 2930, 2850, 2748, 1685, 1656, 1622, 1593, 1419, 1361, 1251, 1089, 968,
821, 756, 699, 563. HRMS (ESI): calcd for C17H15O2N1 (M+) 265.1097, found
265.1094.
4.2.4. N-Ethyl-N-(2-formylphenyl)acrylamide (1d). Light brown liquid, yield
1
78% (1.585 g). H NMR (250 MHz, CDCl3): δ 1.11 (3H, t, J = 7.2 Hz, CH3),
3.61-4.05 (2H, m, NCH2-), 5.46 (1H, dd, J = 10.3, 1.9 Hz), 5.76 (1H, dd, J =
16.7, 10.3 Hz), 6.33 (1H, dd, J = 16.7, 1.9 Hz), 7.21 (1H, dd, J = 7.8, 0.9 Hz,
Ar-H), 7.48 (1H, t, J = 7.6, Ar-H), 7.64 (1H, dt, J = 7.6, 1.7 Hz, Ar-H), 7.94
13
(1H, dd, J = 7.7, 1.6 Hz, Ar-H), 10.02 (1H, s, -CHO); C NMR (62.5 MHz,
CDCl3): δ 12.6 (CH3), 45.3 (NCH2), 128.0 (CH), 128.8 (CH), 129.0 (CH2),
129.5 (CH), 130.0 (CH), 133.3 (C), 135.3 (CH), 143.8 (C), 165.3 (CON), 189.4
(CHO). IR (ATR, cm–1): ῦ= 2972, 2933, 2873, 2750, 1693, 1655, 1593, 1407,
1259, 1188, 979, 769. HRMS (ESI): calcd for C12H13O2N1 (M+) 203.0941,
found 203.0939.
4.2.5. (E)-N-Ethyl-N-(2-formylphenyl)but-2-enamide (1e). Light brown liquid,
1
yield 73% (1.585 g). H NMR (250 MHz, CDCl3): δ 1.09 (3H, t, J = 7.1 Hz,
CH3), 1.62 (3H, dd, J = 6.9, 1.4 Hz, CH3), 3.59-4.02 (2H, m, NCH2-), 5.42 (1H,
dq, J = 15.0, 1.4 Hz), 6.80-6.98 (1H, m), 7.18-7.22 (1H, m, Ar-H), 7.47 (1H, t,
13

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J = 7.5 Hz, Ar-H), 7.64 (1H, td, J = 7.7, 1.4 Hz, Ar-H), 7.94 (1H, dd, J = 7.7,
13
1.3 Hz, Ar-H), 10.01 (1H, s, -CHO); C NMR (62.5 MHz, CDCl3): δ 11.7
(CH3), 17.0 (CH3), 44.2 (NCH2), 121.3 (CH), 127.7 (CH), 128.2 (CH), 129.1
(CH), 132.4 (C), 134.4 (CH), 142.1 (CH), 143.3 (C), 164.7 (CON), 188.6
(CHO). IR (ATR, cm–1): ῦ= 3072, 2979, 2929, 2870, 2855, 2754, 1682, 1661,
1623, 1593, 1445, 1393, 1375, 1246, 1135, 1094, 974, 824, 772, 575. HRMS
(ESI): calcd for C13H15O2N1 (M+) 217.1097, found 217.1097.
4.2.6. N-Ethyl-N-(2-formylphenyl)cinnamamide (1f). Yellow solid, yield 65%
1
(1.815 g), mp: 60-62 ºC. H NMR (250 MHz, CDCl3): δ 1.20 (3H, t, J = 7.2
Hz, CH3), 3.69-4.19 (2H, m, NCH2-), 6.07 (1H, d, J = 15.4 Hz), 7.22-7.33 (6H,
m, Ar-H), 7.57 (1H, t, J = 7.6 Hz, Ar-H), 7.68-7.76 (2H, m, Ar-H & =CH-),
13
8.04 (1H, dd, J = 7.7, 1.6 Hz, Ar-H), 10.14 (1H, s, -CHO); C NMR (62.5
MHz, CDCl3): δ 12.7 (CH3), 45.5 (NCH2), 117.9 (CH), 127.9 (CH), 128.6
(CH), 128.8 (CH), 129.4 (CH), 129.8 (CH), 130.2 (CH), 133.4 (C), 134.7 (C),
135.3 (CH), 143.3 (CH), 144.1 (C), 165.8 (CON), 189.4 (CHO). IR (ATR, cm–
1): ῦ= 3062, 3028, 2974, 2932, 2850, 2752, 1689, 1653, 1616, 1592, 1372,
1233, 971, 759. HRMS (ESI): calcd for C18H17O2N1 (M+) 279.1254, found
279.1253.
4.3. General procedure for domino Knoevenagel-hetero-Diels–Alder
reaction
To a stirred solution of N-acrylated anthranilaldehyde 1 (0.5 mmol) and
indolin-2-thione 2 (0.5 mmol) in EtOH (7 ml) was added ZnBr2 (20 mol%),
Then the reaction mixture was stirred at reflux. The progress of the reaction
was monitored by TLC. After completion of the reaction (3 h), which is with
precipitation of the product, the mixture was poured onto ice-cold water (20
ml) and stirred for 5 min., the precipitate was filtered and washed with water,
after drying, recrystallized from ethanol to produce pure product 3.
4.3.1.
(6aS*,13cR*)-5,9-Dimethyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3a). Pale yellow powder, yield 90%
1
(150 mg), mp: 223-225 ºC. H NMR (250 MHz, CDCl3): δ 3.06-3.27 (3H, m,
Ha & Hb), 3.44 (3H, s, NCH3), 3.64 (3H, s, NCH3), 4.69 (1H, d, J = 4.0 Hz,
14

ACCEPTED MANUSCRIPT
Hc), 6.84-7.23 (6H, m, Ar-H), 7.27-7.40 (2H, m, Ar-H); 13C NMR (62.5 MHz,
CDCl3): δ 24.5 (CH2), 29.9 (NCH3), 30.0 (NCH3), 33.0 (CH), 41.9 (CH), 103.4
(C), 108.3 (CH), 114.7 (CH), 116.7 (CH), 119.7 (CH), 120.6 (CH), 123.5 (CH),
127.7 (CH), 128.2 (C), 128.7 (C), 129.3 (CH), 129.4 (C), 137.3 (C), 138.3 (C),
170.7 (CO). IR (ATR, cm–1): ῦ= 2930, 1664, 1603, 1468, 1374, 1278, 1120,
756. HRMS (ESI): calcd for C20H18N2O1S1 (M+) 334.1134, found 334.1131.
4.3.2. (6aS*,7S*,13cR*)-5,7,9-Trimethyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3b). Pale yellow powder, yield 88%
(154 mg), mp: 238-240 ºC. 1H NMR (250 MHz, CDCl3): δ 1.46 (3H, d, J = 6.8
Hz, CH3), 2.99 (1H, dd, J = 9.6, 4.6 Hz, Hb), 3.44 (3H, s, NCH3), 3.48-3.59
(1H, m, Ha), 3.63 (3H, s, NCH3), 4.71 (1H, d, J = 4.5 Hz, Hc), 6.92-7.24 (6H,
13
m, Ar-H), 7.29-7.35 (2H, m, Ar-H); C NMR (62.5 MHz, CDCl3): δ 19.3
(CH3), 29.8 (CH3), 29.9 (CH3), 33.2 (CH), 33.8 (CH), 48.4 (CH), 103.1 (C),
108.3 (CH), 114.9 (CH), 116.7 (CH), 119.6 (CH), 120.4 (CH), 123.4 (CH),
127.8 (CH), 128.4 (C), 128.9 (C), 129.1 (CH), 130.4 (C), 137.3 (C), 138.4 (C),
169.3 (CO). IR (ATR, cm–1): ῦ= 3053, 2924, 1670, 1596, 1498, 1451, 1367,
751, 698. HRMS (ESI): calcd for C21H20N2O1S1 (M+H) 349.1369, found
349.1367.
4.3.3. (6aS*,7R*,13cR*)-5,9-Dimethyl-7-phenyl-6a,7,9,13c-tetrahydroindolo
[3',2':5,6]thiopyrano[3,4-c]quinolin-6(5H)-one (3c). Light brown powder,
yield 95% (195 mg), mp: 185-186 ºC. 1H NMR (300 MHz, CDCl3): δ 3.19 (3H,
s, NCH3), 3.32 (1H, dd, J = 8.2, 4.5 Hz, Hb), 3.58 (3H, s, NCH3), 4.54 (1H, d, J
= 3.8 Hz, Hc), 4.67 (1H, d, J = 8.5 Hz, Ha), 6.88-7.24 (11H, m, Ar-H), 7.28-
7.34 (2H, m, Ar-H); 13C NMR (75 MHz, CDCl3): δ 29.9 (NCH3), 33.7 (NCH3),
43.5 (CH), 48.1 (CH), 49.0 (CH), 103.2 (C), 108.3 (CH), 109.6 (C), 114.9
(CH), 117.1 (CH), 119.6 (CH), 120.5 (CH), 123.3 (CH), 128.0 (C), 128.1 (CH),
128.3 (C), 128.4 (CH), 128.5 (CH), 128.6 (CH), 129.5 (CH), 130.5 (C), 137.3
(C), 138.8 (C), 168.5 (CO). IR (ATR, cm–1): ῦ= 3047, 2914, 1666, 1598, 1462,
1355, 1088, 753. HRMS (ESI): calcd for C26H22N2O1S1 (M+) 410.1447, found
410.1439.
4.3.4. (6aS*,13cR*)-5-Ethyl-9-methyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3d). Pale white powder, yield 87% (151
1
mg), mp: 200-201 ºC. H NMR (250 MHz, CDCl3): δ 1.31 (3H, t, J = 7.1 Hz,
15

ACCEPTED MANUSCRIPT
CH3), 3.05-3.19 (3H, m, Ha & Hb), 3.64 (3H, s, NCH3), 4.07 (2H, dq, J = 7.1,
2.5 Hz, NCH2-), 4.67 (1H, d, J = 3.1 Hz, Hc), 6.90-7.38 (8H, m, Ar-H); 13C
NMR (62.5 MHz, CDCl3): δ 12.8 (CH3), 24.3 (CH2), 29.9 (NCH3), 33.0 (CH),
37.6 (NCH2) , 41.9 (CH), 103.5 (C), 108.3 (CH), 114.7 (CH), 116.7 (CH),
119.7 (CH), 120.6 (CH), 123.5 (CH), 127.7 (CH), 128.5 (C), 128.7 (C), 129.3
(C), 129.6 (CH), 137.1 (C), 137.3 (C), 170.1 (CO). IR (ATR, cm–1): ῦ= 3045,
2929, 1663, 1596, 1461, 1379, 750, 729. HRMS (ESI): calcd for C21H20N2O1S1
(M+) 348.1291, found 348.1284.
4.3.5.
(6aS*,7S*,13cR*)-5-Ethyl-7,9-dimethyl-6a,7,9,13c-tetrahydroindolo
[3',2':5,6]thiopyrano[3,4-c]quinolin-6(5H)-one (3e). Cream powder, yield 83%
(150 mg), mp: 165-167 ºC. 1H NMR (250 MHz, CDCl3): δ 1.32 (3H, t, J = 7.1
Hz, CH3), 1.45 (3H, d, J = 6.9 Hz, CH3), 2.95 (1H, dd, J = 10.0, 4.5 Hz, Hb),
3.49-3.55 (1H, m, Ha), 3.63 (3H, s, NCH3), 3.85-4.27 (2H, m, NCH2-), 4.71
(1H, d, J = 4.5 Hz, Hc), 6.88-7.25 (5H, m, Ar-H), 7.27-7.37 (3H, m, Ar-H); 13C
NMR (62.5 MHz, CDCl3): δ 13.0 (CH3), 19.0 (CH3), 29.9 (NCH3), 33.1 (CH),
33.9 (CH), 38.0 (NCH2), 48.6 (CH), 103.4 (C), 108.3 (CH), 114.7 (CH), 116.7
(CH), 119.6 (CH), 120.4 (CH), 123.3 (CH), 127.7 (CH), 128.5 (C), 129.2 (C),
129.3 (CH), 130.4 (C), 137.30 (C), 137.34 (C), 168.8 (CO). IR (ATR, cm–1):
ῦ= 2926, 1662, 1597, 1492, 1457, 1370, 1312, 1248, 748, 737. HRMS (ESI):
calcd for C22H22N2O1S1 (M+) 362.1447, found 362.1441.
4.3.6.
(6aS*,7R*,13cR*)-5-Ethyl-9-methyl-7-phenyl-6a,7,9,13c-
tetrahydroindolo[3',2':5,6]thiopyrano[3,4-c]quinolin-6(5H)-one (3f). Yellow
powder, yield 92% (195 mg), mp: 139-140 ºC. 1H NMR (250 MHz, CDCl3): δ
0.99 (3H, t, J = 7.1 Hz, CH3), 3.31 (1H, dd, J = 9.4, 4.4 Hz, Hb), 3.58 (3H, s,
NCH3), 3.50-4.05 (2H, m, NCH2), 4.56-4.59 (2H, m, Ha & Hc), 6.90 (1H, dt,
J = 7.5, 0.9 Hz, Ar-H), 7.00 (2H, t, J = 6.9 Hz, Ar-H), 7.06-7.13 (2H, m, Ar-H),
13
7.18-7.30 (8H, m, Ar-H); C NMR (62.5 MHz, CDCl3): δ 12.8 (CH3), 29.9
(NCH3), 34.0 (CH), 38.2 (NCH2), 43.5 (CH), 48.2 (CH), 103.4 (C), 108.4
(CH), 114.5 (C), 114.7 (CH), 116.9 (CH), 119.7 (CH), 120.5 (CH), 123.2 (CH),
128.0 (CH), 128.4 (C), 128.5 (CH), 128.6 (CH), 128.8 (CH), 128.9 (C), 129.7
(CH), 130.6 (C), 137.3 (C), 137.8 (C), 167.8 (CO). IR (ATR, cm–1): ῦ= 3047,
2929, 1667, 1595, 1454, 1355, 1312, 1088, 747. HRMS (ESI): calcd for
C27H24N2O1S1 (M+) 424.1604, found 424.1592.
16

ACCEPTED MANUSCRIPT
4.3.7. (6aS*,13cR*)-9-Ethyl-5-methyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3g). Cream powder, yield 90% (157
1
mg), mp: 189-190 ºC. H NMR (300 MHz, CDCl3): δ 1.30 (3H, t, J = 7.2 Hz,
CH3), 2.97-3.20 (3H, m, Ha & Hb), 3.37 (3H, s, NCH3), 3.95-4.10 (2H, m,
NCH2-), 4.63 (1H, d, J = 4.4 Hz, Hc), 6.85-7.35 (8H, m, Ar-H); 13C NMR (75
MHz, CDCl3): δ 14.9 (CH3), 24.4 (CH2), 30.0 (NCH3), 33.0 (CH), 38.7
(NCH2), 42.0 (CH), 103.4 (C), 108.4 (CH), 114.7 (CH), 116.8 (CH), 119.6
(CH), 120.5 (CH), 123.6 (CH), 127.7 (CH), 128.2 (C), 128.4 (C), 128.9 (C),
129.3 (CH), 136.2 (C), 138.3 (C), 170.8 (CO). IR (ATR, cm–1): ῦ= 3045, 2971,
2930, 1656, 1596, 1461, 1443, 1375, 1119, 755, 726. HRMS (ESI): calcd for
C21H20N2O1S1 (M+) 348.1291, found 348.1285.
4.3.8. (6aS*,13cR*)-5-Methyl-9-phenyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3h). Pale white powder, yield 85% (168
1
mg), mp: 135-136 ºC. H NMR (300 MHz, CDCl3): δ 2.98-3.14 (2H, m, Ha),
3.25-3.31 (1H, m, Hb), 3.46 (3H, s, NCH3), 4.77 (1H, d, J = 4.7 Hz, Hc), 6.97-
7.23 (5H, m, Ar-H), 7.29-7.56 (8H, m, Ar-H); 13C NMR (75 MHz, CDCl3): δ
24.7 (CH2), 30.0 (NCH3), 33.1 (CH), 42.0 (CH), 105.2 (C), 109.6 (CH), 114.8
(CH), 116.8 (CH), 117.0 (C), 120.5 (C), 121.3 (CH), 123.6 (CH), 127.2 (CH),
127.7 (CH), 127.8 (CH), 127.9 (C), 128.1 (CH), 129.2 (C), 129.3 (CH), 129.6
(CH), 129.7 (C), 138.3 (C), 170.7 (CO). IR (ATR, cm–1): ῦ= 3049, 2925, 1661,
1595, 1497, 1449, 1363, 740, 697. HRMS (ESI): calcd for C25H20N2O1S1 (M+)
396.1291, found 396.1287.
4.3.9. (6aS*,7S*,13cR*)-5,7-Dimethyl-9-phenyl-6a,7,9,13c-tetrahydroindolo
[3',2':5,6]thiopyrano[3,4-c]quinolin-6(5H)-one (3i). Cream powder, yield 90%
(185 mg), mp: 153-154 ºC. 1H NMR (300 MHz, CDCl3): δ 1.38 (3H, d, J = 6.8
Hz, CH3), 3.05 (1H, dd, J = 10.0, 4.6 Hz, Hb), 3.42-3.54 (4H, m, NCH3 & Ha),
4.81 (1H, d, J = 4.4 Hz, Hc), 6.96-7.25 (6H, m, Ar-H), 7.27-7.56 (7H, m, Ar-
H); 13C NMR (75 MHz, CDCl3): δ 19.0 (CH3), 30.1 (NCH3), 33.3 (CH), 34.0
(CH), 48.6 (CH), 105.1 (C), 109.7 (CH), 114.9 (CH), 116.8 (CH), 120.5 (CH),
121.2 (CH), 123.5 (CH), 127.2 (CH), 127.8 (CH), 128.1 (CH), 128.7 (C), 128.9
(C), 129.1 (CH), 129.5 (CH), 130.7 (C), 136.7 (C), 137.8 (C), 138.4 (C), 169.4
(CO). IR (ATR, cm–1): ῦ= 3053, 2927, 1668, 1597, 1490, 1454, 1367, 749.
HRMS (ESI): calcd for C26H22N2O1S1 (M+) 410.1447, found 410.1444.
17

ACCEPTED MANUSCRIPT
4.3.10. (6aS*,7R*,13cR*)-5-Methyl-7,9-diphenyl-6a,7,9,13c-tetrahydroindolo
[3',2':5,6]thiopyrano[3,4-c]quinolin-6(5H)-one (3j). Cream powder, yield 94%
(223 mg), mp: 255-256 ºC. 1H NMR (300 MHz, CDCl3): δ 3.30 (3H, s, NCH3),
3.52 (1H, dd, J = 9.3, 4.4 Hz, Hb), 4.64 (1H, d, J = 9.3 Hz, Ha), 4.79 (1H, d, J
= 3.7 Hz, Hc), 7.05-7.30 (5H, m, Ar-H), 7.35-7.57 (13H, m, Ar-H); 13C NMR
(75 MHz, CDCl3): δ 29.9 (NCH3), 34.1 (CH), 43.8 (CH), 48.3 (CH), 105.1 (C),
109.7 (CH), 114.9 (CH), 117.1 (CH), 120.5 (CH), 121.3 (CH), 123.4 (CH),
127.2 (CH), 128.12 (CH), 128.14 (CH), 128.4 (C), 128.5 (CH), 128.6 (CH),
128.9 (CH), 129.5 (CH), 129.6 (CH), 130.9 (C), 136.6 (C), 137.4 (C), 137.5
(C), 137.7 (C), 138.7 (C), 168.4 (CO). IR (ATR, cm–1): ῦ= 3061, 2937, 1670,
1595, 1497, 1365, 762, 750, 696. HRMS (ESI): calcd for C31H24N2O1S1 (M+H)
473.1682, found 473.1677.
4.3.11. (6aS*,13cR*)-5-Ethyl-9-phenyl-6a,7,9,13c-tetrahydroindolo[3',2':5,6]
thiopyrano[3,4-c]quinolin-6(5H)-one (3k). Light brown powder, yield 87%
(178 mg), mp: 135-136 ºC. 1H NMR (300 MHz, CDCl3): δ 1.33 (3H, t, J = 7.0
Hz, CH3), 2.98-3.15 (2H, m, Ha), 3.22-3.28 (1H, m, Hb), 4.02-4.16 (2H, m,
NCH2-), 4.74 (1H, d, J = 4.2 Hz, Hc), 6.96-7.22 (5H, m, Ar-H), 7.28-7.58 (8H,
m, Ar-H); 13C NMR (75 MHz, CDCl3): δ 12.8 (CH3), 24.5 (CH2), 33.1 (CH),
37.7 (NCH2), 42.0 (CH), 105.4 (C), 109.6 (CH), 114.8 (CH), 116.8 (CH), 120.5
(CH), 121.3 (CH), 123.5 (CH), 127.2 (CH), 127.8 (CH), 127.9 (C), 128.1
(CH), 129.2 (C), 129.4 (C), 129.5 (CH), 129.6 (CH), 136.7 (C), 137.2 (C),
137.7 (C), 170.2 (CO). IR (ATR, cm–1): ῦ= 3044, 2964, 2928, 1663, 1593,
1496, 1447, 739, 694. HRMS (ESI): calcd for C26H22N2O1S1 (M+) 410.1447,
found 410.1436.
Supplementary data
13
1H NMR, C NMR and DEPT 135 spectra of compounds 1a-f and 3a-k are
submitted in separated file as supplementary data.
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J. Org. Chem., 2016, 81, 4955–4964; (k) Sutariya, T. R.; Labana, B.
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23519-23529.
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Kubicki, M. J. Iran. Chem. Soc. 2013, 10, 1057–1065;
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Table 1
Effect of catalysts and solvents on the domino Knoevenagel-hetero-Diels–Alder reaction of compounds 1b
and 2a
Entry
Solvent
Catalyst
Temp. (°C)
Time
(h)
Yielda
(%)
22

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1
2
3
4
5
6
7
8
9
H2O
CH3CN
CH3CN
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
-
-
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
24
24
24
24
24
3
3
3
3
10
12
35
30
48
88
88
88
68
0
ZnO (100%)
ZnO (100%)
ZnO (100%)
ZnBr2 (100%)
ZnBr2 (50%)
ZnBr2 (20%)
ZnBr2 (10%)
Et3N
10
11
12
24
24
24
ZnCl2 (20%)
ZnBr2 (20%)
60
22
a Yield of isolated products.
Table 2
Domino Knoevenagel-hetero-Diels–Alder reactions of N-acrylated anthranilaldehyde derivatives 1a-f with
indoline-2-thiones 2a-ca
Entry
Aldehydes 1
Indoline-2-thiones 2
Products 3
Yieldb
1
90
2a
1a
3a
2
88
2a
1b
3b
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3
95
2a
1c
3c
4
87
2a
1d
3d
5
83
1e
2a
3e
CHO
6
92
O
N
Ph
Et
2a
1f
3f
24

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CHO
7
90
O
N
Me
1a
2b
3g
8
85
1a
2c
3h
9
90
1b
2c
2c
25
3i
10
94
1c
3j

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11
87
S
N
Ph
2c
1d
3k
a All the reactions were carried out at reflux in the EtOH for 3 h in the presence of ZnBr2 (20 mol%).
b Isolated products.
Scheme 1.
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R1
R2
Yield (%)
85
Me
Me
Me
Et
H
1a
1b
1c
1d
1e
1f
CHO
CHO
O
Me
Ph
H
80
76
NaHCO3/ 2ꢀ5 h
CH2Cl2
O
+
R1
N
Cl
R2
N
R1
78
73
65
H
R2
Et
Me
Ph
4a-b
R1= Me, Et
5a-c
R2= H, Me, Ph
1a-f
Et
Scheme 2.
Scheme 3. A plausible mechanism for the formation of compounds 3a-k.
27