Synthesis of Tetrahydropyrazolo[4',3':5,6]pyrano[3,4- c ]quinolones by Domino Knoevenagel/Hetero Diels-Alder Reactions

Article abstract of DOI:10.1055/s-0039-1690189

An efficient Lewis acid mediated domino Knoevenagel/hetero Diels-Alder (DKHDA) reaction of pyrazolone derivatives with N -acrylated anthranilic aldehydes was developed, which afforded functionalized tetracyclic tetrahydropyrazolo[4',3':5,6]pyrano[3,4- c ]quinolones. The products were formed in good yields and with excellent regio- and stereoselectivity in favor of the cis-configured isomer.

Full text of DOI:10.1055/s-0039-1690189

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
M. Kiamehr et al.
Letter
Synlett
SynthesisofTetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones
by Domino Knoevenagel/Hetero Diels–Alder Reactions
Mostafa Kiamehr*a
Leyla Mohammadkhania
Mohammad Reza Khodabakhshib
Behzad Jafaric
Me
CHO
R1
Me
N
N
O
H
ZnBr2 (50 mol%)
EtOH, reflux, 5 h
8 examples
cis/trans > 98:2
(80–92%)
+
N
N
O
N
R3
R2
R1
R1 = Me, Et
2 = H, Me
H
R2
O
Peter Langer*c,d
0
0
0
0-
0
0
0
2-7
6
6
5-8
9
1
2
N
R3
O
H
a Department of Chemistry, Faculty of Science, University of
Qom, Ghadir Blvd, P.O. Box 37146-6611, Qom, Iran
m.kiamehr@qom.ac.ir
R
3 = Ph, 4-Cl-Ph
R
b Applied Biotechnology Research Center, Baqiyatallah University
of Medical Sciences, Mollasadra Street, P.O. Box 1435916471,
Tehran, Iran
c Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a,
18059 Rostock, Germany
peter.langer@uni-rostock.de
d Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
A.-Einstein-Str. 29a, 18059 Rostock, Germany
Received: 25.06.2019
Accepted after revision: 06.08.2019
Published online: 14.08.2019
The pyrazole moiety represents an important heterocy-
clic core structure because of its presence in many biologi-
cally active compounds,6 pharmaceuticals,7 agrochemicals,8
and natural products.9 Among pyrazole derivatives,
Viagra®,10 Celebrex®,11 Acomplia®,12 and Fipronil®13 are
commercial drugs. Pyrazoles display antimicrobial,14 anti-
tubercular,15 antitumor,16 anticancer,17 and antihyperglyce-
mic activities, and also inhibit IL-1 synthesis and HIV-1 re-
verse transcriptase.18 Likewise, tetrahydropyranopyrazoles
represent an important core structure because of their
presence in various biologically active compounds (Figure
1, top).19 On the other hand, functionalized 3,4-dihydro-
quinolone structures are privileged scaffolds that can be
found in many synthetic and natural products (Figure 1,
bottom).20 They show cardiovascular effects and also exhib-
it phosphodiesterase inhibitory and anti-inflammatory ac-
DOI: 10.1055/s-0039-1690189; Art ID: st-2019-d0328-l
Abstract An efficient Lewis acid mediated domino Knoevenagel/hete-
ro Diels–Alder (DKHDA) reaction of pyrazolone derivatives with N-acry-
lated anthranilic aldehydes was developed, which afforded functional-
ized tetracyclic tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones.
The products were formed in good yields and with excellent regio- and
stereoselectivity in favor of the cis-configured isomer.
Key words domino reaction, regioselectivity, cyclizations, heterocy-
cles, Diels–Alder reaction, Knoevenagel reaction
Domino reactions represent an important tool in organ-
ic chemistry.1a In this context, domino Knoevenagel/hetero
Diels–Alder (DKHDA) reactions are of special interest as
they proceed by formation of two or more rings in only one
synthetic step.1 Tetra- and pentacyclic heterocycles, con-
taining a pyran or chroman moiety, have been synthesized
through DKHDA reactions of internal O-allylated- and O-
propargylated salicylic aldehydes with 1,3-dicarbonyl com-
pounds.2 There have also been reported DKHDA reactions of
2-formylphenyl-N-alkyl-2-phenylethenesulfonamides and
2-formylphenyl-2-phenylethenesulfonatesforthesynthesis
of annelated benzosultams or benzosultones, respectively.3
Furthermore, DKHDA reactions of O-acrylated salicylic al-
dehydes and 1,3-dicarbonyl or thiocarbonyl compounds al-
low the synthesis of polycyclic dihydrocoumarines.4 We
have recently reported the DKHDA reaction of N-acrylated
anthranilic aldehydes and indolin-2-thiones, which provides
a convenient access to pentacyclic 3,4-dihydroquinolones.5
Cl
OEt
Me
O
Me
O
Me
Me
Me
Me
N
O
N
O
N
N
N
H
O
N
H
Cl
anti-inflammatory and
analgesic activities
antitubercular agent
fungicide
Me
Me
HO
OMe
Me
NO2
F3C
O
Cl
O
N
OMe
O
Cl
N
O
H
N
O
H
NMDA antagonist
N
H
HIV-1 reverse transcriptase
inhibitor
insecticidal antibiotic
Figure 1 Biologically active annulated pyrazoles (top) and 3,4-dihydro-
quinolones (bottom)
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Kiamehr et al.
Letter
Synlett
tivities.21 3,4-Dihydroquinolones have been prepared by Sk-
raup–Doebner–von Miller reactions,22 Friedlander–Friedel–
Crafts cyclizations,23 radical-mediated reactions,24 oxidative
cyclizations,25 photochemical reactions,26 transition-metal-
catalyzed reactions,27 and asymmetric synthetic approaches.28
An important concept in medicinal chemistry relies on
the synthesis of hybrid molecules containing a combination
of known pharmacophores.29 Tetrahydropyrazolo[4',3':5,6]-
pyrano[3,4-c]quinolones combine the structural units of
pyrazoles, tetrahydropyranopyrazoles, and 3,4-dihydro-
quinolones as pharmacophoric core structures. This type of
molecule has, to the best of our knowledge, not been re-
ported in the literature so far. Following our general interest
in the development of new synthetic methods and their ap-
plication in heterocyclic chemistry,30 we herein wish to re-
port a new and convenient synthesis of tetrahydropyrazo-
lo[4',3':5,6]pyrano[3,4-c]quinolones 3 by DKHDA reaction
of pyrazolones 2 with N-acrylated anthranilic aldehydes 1
(Scheme 1).
The synthesis of the desired target molecules was next
studied. To optimize the conditions of the DKHDA reaction,
the synthesis of product 3a by reaction of N-acrylanthranil-
ic aldehyde 1a with N-phenylpyrazolone 2a was investigat-
ed (Table 1). Initially, the effect of the solvent, such as water,
acetonitrile, methanol, ethanol, acetic acid, and toluene,
was studied. The reactions were carried out under reflux
and catalyst-free conditions at a reaction time of 15 hours
Table 1 Optimization of the Synthesis of 3aa,b
Me
Me
CHO
Me
H
N
O
N
N
N
N
O
O
N
H
Me
O
1a
2a
3a
Entry
Solvent
Additive (mol%)
Temp (°C)
Yieldb(%)
1
2
H2O
–
refluxc
refluxc
refluxc
refluxc
refluxc
refluxc
refluxd
refluxd
refluxd
refluxd
refluxd
refluxd
refluxd
refluxd
13
15
30
32
5
R1
MeCN
MeOH
EtOH
AcOH
PhCH3
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
–
Me
N
Me
CHO
N
H
O
3
–
O
+
N
N
R3
N
R1
H
R2
4
–
N
R3
R2
O
O
H
5
–
1
2
3
6
–
18
48
67
85
10
20
25
85
80
Scheme 1 DKHDA reaction of N-acrylated anthranilaldehydes with pyr-
7
ZnO (100)
ZnCl2 (100)
ZnBr2 (100)
NEt3 (100)
L-proline (100)
ZnBr2 (100)
ZnBr2 (50)
ZnBr2 (40)
azolones
8
9
N-Acrylated anthranilic aldehydes 1a–d were synthe-
sized in three steps as shown in Scheme 2. The alkylation of
quinoline with alkyl iodides (1,4-dioxane, reflux) afforded
the N-alkylquinolinium salts 5a,b. Oxidation of the latter
with H2O2 gave N-alkylanthranilic aldehydes 6a,b.31 Finally,
products 1a–d were obtained by reaction of 6a,b with acry-
loyl chloride (7a) or (E)-crotonyl chloride (7b) according to
a known methodology.5
10
11
12
13
14
EtOH
EtOH
a Reagents and conditions: 1a (0.5 mmol, 1.0 equiv), 2a (0.5 mmol,
1.0 equiv), and solvent (5.0 mL).
b Yields of isolated products.
c Reaction time: 15 h.
d Reaction time: 5 h.
O
R1 Yield (%)
a
b
H
Me
Et
84
78
6a
6b
N
N
R1
NH
R1
I
4
5a–b
6a–b
O
O
R2 Yield (%)
R1
Me
Me
Et
O
H
H
85
80
78
73
H
1a
1b
1c
c
+
R1
Cl
R2
N
Me
NH
R1
H
O
7a–b
6a–b
R2
Me
1d Et
1a–d
R2 = H, Me
R1 = Me, Et
Scheme 2 Synthesis of 1a–d. Reagents and conditions: (a) R1I, 1,4-dioxane, reflux, 1 h; (b) 1,2-dichloroethane/H2O (1:1), KOH, H2O2, 72 h; (c) NaHCO3,
CH2Cl2, 2–5 h.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
M. Kiamehr et al.
Letter
Synlett
(entries 1–6, Table 1). The best yields were obtained in eth-
anol (32% yield, entry 4). Subsequently, the effect of the
Lewis acid, such as ZnO, ZnCl2, and ZnBr2, was studied. In
the presence of Lewis acid, the yields were improved to 48,
67, and 85%, respectively, and the reaction time could be re-
duced to five hours (entries 7-9). In fact, employment of Zn-
Br2 in ethanol heated to reflux gave the best yields (85%, en-
try 9). The use of other catalysts, such as the acid L-proline
or the base NEt3, was not successful (entries 10 and 11).
Likewise, the use of ZnBr2 in water heated to reflux was not
successful (entry 12). Reduction of the amount of ZnBr2 to
50 mol% gave equally good yields (85%), but further reduc-
tion of the amount of ZnBr2 (40 mol%) gave lower yields
(entries 13 and 14). Hence, the optimized reaction condi-
tions involved ethanol at reflux with 50 mol% of ZnBr2 and a
reaction time of five hours (entry 13).32 In all cases, analysis
Me
CHO
R1
Me
N
N
O
Hc
ZnBr2 (50 mol%)
+
N
N
R1
O
EtOH, reflux, 5 h
O
N
R3
Hb
R2
R2
N
R3
O
Ha
1a–d
2a–b
3a–h
Me
O
Me
N
Et
N
N
Me
N
Me
Me
H
H
H
O
O
H
H
N
H
N
H
H
N
N
N
O
O
Me
O
H
H
H
3a (85%)
3c (80%)
3b (83%)
Me
Me
1
Et
O
of the H NMR spectrum of 3a revealed that the product
N
H
N
H
Me
Me
N
H
H
Me
N
H
was selectively obtained as the cis-configured isomer.
By using the optimized conditions, the substrate scope
was studied. The cyclization of pyrazolones 2a,b with an-
thranilic aldehydes 1a–d afforded products 3a–h in 80–90%
yield and with very good regio- and diastereoselectivity
(Scheme 3).
O
O
N
N
H
N
N
O
H
O
Me
N
O
Me
H
H
H
3f (90%)
3e (92%)
3d (84%)
Cl
Cl
The structure of the products was confirmed by spec-
troscopic methods. The coupling constants of the adjacent
H atoms clearly indicate the cis configuration of the prod-
Et
O
Et
N
N
Me
Me
H
H
1
ucts (comparison with H NMR data of related molecules
O
N
H
N
N
H
H
1
reported in the literature).1–5 For example, in the H NMR
N
O
Me
O
H
H
spectrum of compound 3d, a one-proton double doublet
with coupling constants of 7.3 Hz and 5.2 Hz is observed for
proton Hb at 2.84 ppm, a three-proton multiplet for the N-
CH2 and Ha protons at 3.88–4.03 ppm, and a one-proton
doublet with a coupling constant of 5.1 Hz for proton Hc at
4.25 ppm. These data indicate that Ha and Hb are in a trans
relationship and Hb and Hc are in a cis relationship (for as-
signment of the protons, see Scheme 3). In all compounds,
Cl
Cl
3g (87%)
3h (80%)
Scheme 3 Preparative scope. Reagents and conditions: 1 (0.5 mmol,
1.0 equiv), 2 (0.5 mmol, 1.0 equiv), ZnBr2 (0.25 mmol, 0.5 equiv), and
EtOH (5.0 mL), reflux, 5 h. Isolated yields are given in parenthesis.
1
similar coupling constants were observed. In the H NMR
R1
Me
N
Me
R1
H
N
exo intermediate
N
O
N
O
N
H
N
O
2
O
R
R3
H
R2
Me
N
R3
CHO
O
ZnBr2 (50 mol%)
EtOH, reflux
trans isomer
+
N
R1
N
R3
O
R2
Me
H
R1
N
R1
2
1
N
Me
endo intermediate
N
O
O
N
H
R2
N
O
R3
N
H
O
R2
R3
cis isomer (3a–h)
Scheme 4 Possible mechanism of the formation of compounds 3a–h
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
M. Kiamehr et al.
Letter
Synlett
spectrum of compound 3d, there are also a three-proton
triplet, doublet, and a singlet at 1.24, 1.49, and 2.27 ppm,
respectively, which can be assigned to the three CH3 groups.
A possible mechanism of the formation of products 3a–
h is illustrated in Scheme 4. The ZnBr2-mediated Knoevena-
gel condensation of N-acrylanthranilic aldehyde 1 with pyr-
azolone 2 leads to the formation of an intermediate which
can exist in an exo or endo orientation. The stereochemistry
of the products depends on the stereochemical orientation
of the dienophile in the transition state of the subsequent
intramolecular hetero Diels–Alder reaction. The reaction
seems to proceed selectively via the endo transition state, as
exclusively the formation of the cis-configured isomers was
observed. This might be explained by electronic reasons.
In conclusion, we have synthesized what are, to the best
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lo[4',3':5,6]pyrano[3,4-c]quinolones through DKHDA reac-
tion of pyrazolones with N-acrylated anthranilic aldehydes.
The reaction proceeds with excellent regio- and stereose-
lectivity and in high yields. The reaction was carried out in
ethanol heated to reflux as a green and environmentally
friendly solvent. The Lewis acid used, ZnBr2, is inexpensive
and commercially available.
Acknowledgement
Financial support by the State of Mecklenburg-Vorpommern, by the
State of Iran, and by the DAAD is gratefully acknowledged.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690189.
S
u
p
p
orit
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gInformati
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n
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gInformati
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(32) Synthesis of Products 3a–h by DKHDA Reaction; General Pro-
cedure
A mixture of N-acrylated anthranilaldehyde 1 (0.5 mmol), N-
phenyl pyrazolone 2 (0.5 mmol), and ZnBr2 (50 mol%) was
stirred in EtOH heated to reflux (5 mL). The progress of the reac-
tion was followed by TLC. After completion (5 h) and cooling
down, ice-cold water (20 mL) was poured into the reaction mix-
ture. The resulting precipitate was filtered after stirring for 5
min and washed with cold water. After air drying at room tem-
perature, the pure product 3 was obtained by column chroma-
tography on silica gel, by eluting with n-hexane/ethyl acetate
(2:1).
(5R*,5aS*,11bS*)-7-Ethyl-1,5-dimethyl-3-phenyl-5,5a,7,11b-
tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolin-6(3H)-
one (3d)
Pale yellow solid; yield: 84% (157 mg); mp 180–182 °C. IR (ATR):
3066, 2930, 1664, 1599, 1496, 1126, 757 cm–1 1H NMR (300
.
MHz, CDCl3):  = 1.24 (t, J = 6.4 Hz, 3 H, CH3), 1.49 (d, J = 6.5 Hz,
3 H, CH3), 2.17 (s, 3 H, CH3), 2.84 (dd, J = 7.3, 5.2 Hz, 1 H, Hb),
3.88–4.03 (m, 3 H, Ha, NCH2), 4.25 (d, J = 5.1 Hz, 1 H, Hc), 7.02–
7.21 (m, 3 H, Ar-H), 7.27–7.40 (m, 4 H, Ar-H), 7.73 (d, J = 8.51
Hz, 2 H, Ar-H). 13C NMR (75 MHz, CDCl3):  = 12.7 (CH3), 13.4
(CH3), 18.8 (CH3), 31.0 (CH), 38.0 (NCH2), 46.3 (CH), 72.4 (OCH),
115.0 (CH), 120.3 (CH), 121.1 (C), 123.3 (CH), 125.6 (CH), 128.3
(CH), 128.9 (CH), 129.1 (CH), 129.8 (C), 137.4 (C), 138.5 (C),
146.8 (C), 149.4 (C), 167.2 (CON). HRMS (EI): m/z calcd for
C
23H23N3O2 [M]+: 373.1785; found: 373.1781.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E