Rearrangement Reactions in Aza-Vinylogous Povarov Products: Metal-Free Synthesis of C3-Functionalized Quinolines and Studies on their Synthetic Application

Article abstract of DOI:10.1002/ejoc.201900986

Several types of C⁴-functionalized 4-alkyl-2-aryl-1,2,3,4-tetrahydroquinolines underwent rearrangement of their functional groups to C³, with concomitant aromatization, by simple reflux in 1,2-dichlorobenzene. The functional groups that were shown to undergo the C⁴ to C³ migration were –CH=CH-Z (where Z = CO₂Et, CN, NO₂, COCH₃, CH₂OH) and –CH=C(Y)–Z (where Y = CN and Z = CO₂Et or Y = Z = CN). On the other hand, the dimethylhydrazono group failed to migrate under thermal conditions but was shown to undergo a smooth dehydrogenation/C⁴ to C³ rearrangement/ dehydrogenation sequence at room temperature in the presence of DDQ, with a broad scope that includes 4-alkyl-2-aryl- and 2-acyl-1,2,3,4-tetrahydroquinolines. We also report a computational and experimental study of the mechanism of both reactions, which supports an unusual intramolecular aza-ene pathway. The ready availability by this method of 2,3-difunctionalized quinolines allowed the simple preparation of fused heterocyclic systems derived from the pyrrolo[3,4-b]quinoline framework, using both reductive and non-reductive domino processes.

Full text of DOI:10.1002/ejoc.201900986

A Journal of
Accepted Article
Title: Rearrangement reactions in aza-vinylogous Povarov products:
Metal-free synthesis of C3-functionalized quinolines and studies
on their synthetic application
Authors: José Clerigué, Giulia Bianchini, Pascual Ribelles, Tomás
Tejero, Pedro Merino, María Teresa Ramos, and J. Carlos
Menéndez
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900986
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
Rearrangement reactions in aza-vinylogous Povarov products:
Metal-free synthesis of C3-functionalized quinolines and studies
on their synthetic application
José Clerigué,[a] Giulia Bianchini,[a] Pascual Ribelles,[a] Tomás Tejero,[b] Pedro Merino,*[c] M. Teresa
Ramos[a] and J. Carlos Menéndez*[a]
Abstract: Several types of C4-functionalized 4-alkyl-2-aryl-1,2,3,4-
tetrahydroquinolines underwent rearrangement of their functional
groups to C3, with concomitant aromatization, by simple reflux in 1,2-
dichlorobenzene. The functional groups that were shown to undergo
the C4 to C3 migration were –CH=CH-Z (where Z = CO2Et, CN, NO2,
COCH3, CH2OH) and –CH=C(Y)-Z (where Y = CN and Z = CO2Et or
Y = Z = CN). On the other hand, the dimethylhydrazono group failed
to migrate under thermal conditions but was shown to undergo a
smooth dehydrogenation/ C4 to C3 rearrangement/ dehydrogenation
sequence at room temperature in the presence of DDQ, with a broad
added to the synthetic toolbox.[6] However, in spite of these
advances, there is still a need for general, high-yielding synthetic
routes to functionalized quinoline derivatives. In particular, the
synthesis of aromatic quinoline derivatives based on
rearrangement reactions that involve concomitant aromatization
processes is unknown in the literature. In this context, we
published some years ago a preliminary report of a reaction that
transformed 4-alkyl-2-aryl-1,2,3,4-tetrahydroquinolines bearing a
vinylogous electron-withdrawing functional group at C-4 into C3-
functionalized
quinolines
by
simple
reflux
in
o-
scope
that
includes
4-alkyl-2-aryl-
and
2-acyl-1,2,3,4-
dichlorobenzene.[7] We now extend the scope of this thermal
reaction and also describe an alternative one-pot process
comprising an initial dehydrogenation, followed by C4 to C3
rearrangement and a second dehydrogenation. This domino
reaction takes place at room temperature in the presence of
DDQ and can be performed on the Povarov products with no
functional group exchange, allowing the synthesis of C3-
functionalized quinolines from very simple starting materials in
two steps. Furthermore, we report a DFT computational study of
the mechanism of both reactions and an initial exploration of the
synthetic applicability of the 2,3-difunctionalized quinolines thus
generated.
tetrahydroquinolines. We also report
a
computational and
experimental study of the mechanism of both reactions, which
supports an unusual intramolecular aza-ene pathway. The ready
availability by this method of 2,3-difunctionalized quinolines allowed
the simple preparation of fused heterocyclic systems derived from
the pyrrolo[3,4-b]quinoline framework, using both reductive and non-
reductive domino processes.
Quinoline is one of the most relevant and widely studied
heterocyclic systems. It can be regarded as
a privileged
structure in drug discovery[1,2] and is also widespread in nature.[3]
Furthermore, quinoline derivatives are important synthetic
intermediates en route to natural products and other targets.[4]
The classic synthetic approaches to this ring system go back to
the end of the 19th century and include the Skraup, Doebner-
von Miller, Friedländer, Pfitzinger and Combes reactions,[5]
although a large number of more recent methods has also been
Results and Discussion
The thermal protocol for the synthesis of 3-functionalized
quinolines is summarized in Scheme 1. The starting materials
for our study were obtained by an InCl3-catalyzed aza-
vinylogous Povarov reaction between aromatic imines and α,β-
unsaturated dimethylhydrazones, which acted as the dienophiles
of this imino Diels-Alder-like process.[8] The tetrahydroquinolines
1 thus obtained were hydrolyzed to the corresponding aldehydes
2 by exposure to Cu(II) chloride at room temperature[9] or by
acidic hydrolysis, in both cases using THF-water as the reaction
medium. From these aldehydes, compounds 3a-p were
prepared under standard Wadsworth-Emmons, Henry or
Knoevenagel conditions. In order to increase the structural
variation at C-4, we also prepared the hydroxymethyl derivatives
3q by DIBAL reduction of 3a and 5 by sodium borohydride
reduction of 2r.
[a]
Mr. J. Clerigué, Dr. G. Bianchini, Dr. P. Ribelles, Prof. M. T. Ramos,
Prof. J. C. Menéndez
Departamento de Química en Ciencias Farmacéuticas, Unidad de
Química Orgánica y Farmacéutica
Universidad Complutense
Address: Plaza de Ramón y Cajal, s.n., 28040 Madrid, Spain
E-mail: josecm@ucm.es
homepage: https://www.ucm.es/bioheterociclos/
Prof. T. Tejero
[b]
[c]
Instituto de Síntesis Química
y Catálisis Homogénea (ISQCH),
Universidad de Zaragoza, CSIC, 50009 Zaragoza, Spain
Prof. P. Merino
We next established that heating compounds 3 in refluxing 1,2-
dichlorobenzene afforded good to excellent yields of the
quinoline derivatives 4, where the functional group at C-4 has
undergone an unusual migration to C-3, allowing the
concomitant aromatization of the nitrogenated ring. As shown in
Table 1, this method provides a broad range of polysubstituted
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI),
Universidad de Zaragoza, 50009 Zaragoza, Spain
e-mail: pmerino@unizar.es
homepage: http://www.bioorganica.es
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
R5
R4
R5
R5
R4
R4
Z
H3C
vi
R6
R7
iii, iv
or v
R6
R7
O
R6
R7
OH
H3CO
N-NMe2
R2
(from 3a)
i or ii
Y
N
H
R2
R2
N
H
C6H5
N
H
2
N
H
H
H
R8
H
H
R8
R8
3
3q
1
vii
viii
R5 R4
(from 2r)
viii
H3C
OH
H3CO
R6
R7
Z
viii
Y
N
H
N
R2
H
R8
Br
4
5
Scheme 1. Synthesis of 3-functionalized quinolines under thermal conditions. Reagents and conditions: i. CuCl2, THF-H2O, rt; ii. THF-5M HCl (3:1), rt (for
compounds 2f,g,i). iii. (EtO)2P(O)CH2CO2Et, NaH, benzene, reflux, 5-6 h (compounds 3a-k); (EtO)2P(O)CH2COCH3 or (EtO)2P(O)CH2CN, DBU, LiCl, Et2O-MeCN,
rt, 24 h (compounds 3l and 3m, respectively); iv. CH3NO2, NH4OAc, 120 °C, 24 h (compound 3n); v. NC-CH2-CN or NC-CH2-CO2Et, NH4OAc, AcOH, Dean-Stark,
benzene, reflux, 24 h (compounds 3o or 3p, respectively); vi. 3a, DIBAL (4 eq), THF, - 20 °C to rt, 1 h, then rt, 2 h; vii. NaBH4, MeOH-Cl2CH2, rt; viii. o-
Dichlorobenzene, reflux, 18-24 h.
Table 1. Scope and yields of the synthesis of 3-functionalized quinolines under thermal conditions.[a,b]
Entry
1
Cmpd.
R2
Y
Z
R4
R5
H
R6
R7
H
R8
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
% 4
81
76
78
96
63[d]
0
a
b
c
d
e
f
C6H5
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COCH3
CN
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
OMe
OMe
OMe
Me
2
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
C6H5
H
H
H
3
H
H
H
4
H
H
H
5
H
H
OMe
H
H
6
H
Me
OMe
H
Me
OMe
H
7
g
h
i
4-MeC6H4
C6H5
H
H
0
8
H
Me
79
88
95
89
94
93[e]
94
90
98
63
9
C6H5
H
H
NMe2
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
10
11
12
13
14
15
16
17
j
C6H5
H
H
H
k
l
2-Furyl
C6H5
H
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
m
n
o
p
q
C6H5
H
H
H
C6H5
H
NO2
H
H
C6H5
CN
CN
H
CN
H
H
C6H5
CO2Et
CH2OH
H
H
C6H5
H
H
[a] The letters a,b,c, etc. reflect substituent combinations and are maintained throughout the article. [b] Compounds 4a, 4b, 4d, 4e, 4h, 4j and 4l-o were described
in our preliminary communication.[7] [c] Compounds 3l-q come from aldehyde 2a. [d] Together with 34% of compound 5 (see below). [e] As a 60/40 mixture of E and
Z diastereomers.
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
CO2Et
O
R4
R4
N
R6
DDQ (2 eq),
toluene, rt, 1 h
Z
R6
Me
Me
Z
+
N
H
R2
R2
H
R8
N
R2
R8
7
1 (Z = NNMe2)
3 (Z = CH-CO2Et)
4 (Z = CH-CO2Et)
6 (Z = NNMe2)
Scheme 2. DDQ-promoted synthesis of 3-functionalized quinolines at room temperature.
Table 2. Scope and yields of the synthesis of 3-functionalized quinolines under oxidative conditions.
Entry
1
Cmpd.
4a
R2
Z
R4
R6
R8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
% 4 or 6
21
% 7
46
42
38
55
0
C6H5
CH-CO2Et
CH-CO2Et
CH-CO2Et
CH-CO2Et
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
N-NMe2
Me
Me
Me
Me
Me
Me
Me
Me
Et
OMe
OMe
Me
2
4c
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
23
3
4d
4e
25
4
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
25
5
6a
C6H5
51
6
6c
4-MeOC6H4
4-ClC6H4
50
0
7
6e
57
0
8
6r
2-BrC6H4
53
0
9
6s
3-MeC6H4
3-ClC6H4
44
0
10
11
12
13
14
15
16
17
18
6t
Me
Me
Me
Me
Et
73
0
6u
6v
C6H5CO
75
0
4-MeOC6H4CO
4-MeC6H4 CO
C6H5 CO
73
0
6w
6x
60
0
40
0
6y
4-FC6H4 CO
4-FC6H4CO
3-BrC6H4 CO
3,4-Cl2C6H4 CO
Me
Me
Me
Me
59
0
6z
OMe
OMe
OMe
53
0
6aa
6ab
48
0
46
0
quinolines having a vinylogous electron-withdrawing functional
group attached to the quinoline C-3 position and a variety of
substituents at C-2, C-4, C-6 and C-8. The rearrangement step
usually proceeded in good to excellent yields, but the reaction
failed to afford C-5 substituted quinolines (entries 6 and 7),
probably due to repulsive interactions of the R5 substituent in the
transition state. Interestingly, the reaction also worked well for
the case of 3q (Z = hydroxymethyl), which was not obvious
bearing in mind that all previous examples required an electron-
withdrawing substituent at the end of the migrating group,
although it failed for the hydroxymethyl derivative 5 and for the
starting hydrazones 1.
We next investigated an alternative approach to the
rearrangement reaction that involved treating the starting
materials 1 and 3 with an oxidant, in the hope to accelerate the
dehydrogenation reaction that was believed to initiate the whole
process (see the mechanistic study below). In the event, when
selected compounds 3 were exposed to DDQ in toluene solution
at room temperature we observed the desired rearranged
compounds 4, but the major reaction products were quinolin-3-
ones 7, arising from N1-C2 dehydrogenation accompanied by
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
oxidation at C3 (Scheme 2, Table 2, entries 1-4). On the other
of C3-functionalized quinolines from very simple starting
materials in two steps, including the construction oft he
heterocyclic ring. Furthermore, the new rearrangement also
allowed the synthesis of 2-acylquinolines functionalized at C-3,
which was not possible by the thermal protocol because of
chemoselectivity issues during the transformation of the
dimethylhydrazono group.
hand, the starting hydrazones
1 proved to be excellent
substrates for the room temperature DDQ-promoted
dehydrogenation/ rearrangement/ dehydrogenation domino
process, and no interference from C-3 oxidation was found, as
shown by the very efficient preparation of the 3-
(dimethylhydrazonomethyl)quinolines 6 (Scheme 2 and Table 2).
The reactions leading to 4-ethylquinolines proceed in lower yield
(entries 11 and 14 of Table 2), which may be attributed to
increased steric compression in the transition state (see below).
This new method is complementary to the thermal one in that it
allows the rearrangement of the dimethylhydrazono group,
which was not possible under thermal conditions. Therefore, it
has the advantage of not requiring any functional group
exchange at the Povarov products, thus allowing the synthesis
A
computational and experimental mechanistic study was
undertaken to rationalize the results summarized above. In our
preliminary communication, we proposed the thermal
rearrangement to be initiated by the formation of
cyclopropa[1,2-c]quinoline intermediate IN0a via
a
the
dehydrogenation of the starting compound S00a (using 3c as a
representative example) to the dihydroquinoline S01a, followed
CO2Me
TS02a
H
O
O
(42.3)
Me
MeO
OR
OR
Me
Me
N
MeO
MeO
OMe
N
N
H
H
OMe
OMe
S01a
IN0a
Me
MeO
CO2Me
H
Ar
N
CO2Me
TS01a
Me
(8.4)
CO2Me
MeO
Cl
Cl
O
MeO2C
MeO
N
H
Me
MeO
H
O
CN
OMe
CN
OMe
N
S00a
(0.0)
N
CO2Me
TS04a
(-11.3)
OMe
Me
MeO
TS01Da
(-8.0)
TS03a
(-15.5)
H2
N
CO2Me
IN02a
CO2Me
OMe
Me
(-21.8)
MeO
Me
Me
MeO
MeO
CO2Me
N
H
N
N
OMe
S01a
(-26.3)
OMe
IN01a
(-27.8)
P01a
(-32.5)
OMe
Me
CO2Me
CO2Me
Me
MeO
S02a
(-31.5)
MeO
H
CO2Me
N
IN03a
(-36.4)
N
Me
CO2Me
Me
OMe
MeO
OMe
IN04a
(-39.3)
MeO
CO2Me
Me
N
H
OMe
N
MeO
OMe
N
F02a
(-68.0)
OMe
Me
MeO
CO2Me
OMe
F01a
(-69.7)
N
Scheme 3. Computational study of the rearrangement pathways starting from compounds 3
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
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Under the high-temperature reaction conditions used in our
thermal experiments, this intermediate can overcome the large
energy barrier corresponding to TS02a, the rate-limiting step, in
which the α,β-unsaturated ester P01a is formed by concomitant
H-transfer and cyclopropane ring-opening.
A final thermal
dehydrogenation of P01a leads to the observed product F01a
(red pathway in Scheme 3). Regarding the case where Z =
CH2OH, a similar situation to that of the ester (TS02a) is found,
the corresponding TS02b being also the rate-limiting step with a
barrier of 46.4 kcal/mol (for details, see the SI file). The
optimized geometries of both transition structures are shown in
Figure 1, and their similarity is evident. The transition structure
corresponding to the ester (TS02a) shows a slightly higher
asyncronicity than that of the hydroxymethyl moeity (TS02b),
although in both cases the H-transfer and cyclopropane opening
can be considered concerted processes. The starting enamine
S01a can conceivably arise from isomerization of the more
stable imine S02a, and this was verified experimentally by
Figure 1. Transition structures for TS02a and TS02b.
by attack of its enamine moiety to the Michael acceptor.[7]
However, calculation has shown that IN0a is not a stationary
point and it reverts to S01a when optimized (box in Scheme 3).
As an alternative mechanism, we now propose that an
alternative, uncharged cyclopropane intermediate is generated
from S01a by an intramolecular aza-ene reaction via the
transition state TS01a. While aza-ene reactions, although
relatively rare, are known in the literature,[10] to our knowledge
this is the first intramolecular example of such a transformation.
Me
MeO
N
NMe2
H
Ar
NMe2
N
N
NMe2
TS01c
(5.6)
H
Me
N
Me
MeO
MeO
NMe2
Cl
N
N
Cl
O
N
H
Me
MeO
OMe
OMe
H
S00c
(0.0)
O
CN
TS02c not located
NMe2
Me
NH
CN
N
MeO
OMe
TS01Dc
(-9.6)
N
DEAD END
OMe
NMe2
N
IN01c
(-15.7)
NMe2
Me
N
Me
N
MeO
N
NMe2
MeO
H
Me
MeO
IN02c
N
H
(-21.7)
IN03c
(-23.0)
OMe
S01c
(-24.1)
N
OMe
Me
N
OMe
MeO
NMe2
N
S02c
(-32.0)
P01c
(-31.2)
NMe2
N
Me
NMe2
N
OMe
MeO
Me
H
N
MeO
IN04c
(-41.6)
OMe
N
NMe2
N
OMe
MeO
Me
N
Me
N
NMe2
OMe
MeO
N
F02c (-68.5)
F01c (-68.8)
OMe
Scheme 4. Computational study of the rearrangement pathways starting from hydrazones 1
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
application of the usual thermal rearrangement protocol to the 1-
D derivative of compound 1a, an experiment that showed no
incorporation of deuterium into 4a and therefore agrees with the
initial formation of S02a followed by its isomerization to S01a.
Regarding the mechanism of the DDQ-promoted reactions, we
first needed to discriminate between a proton-transfer or an
electron-transfer mechanism.[11] We discarded the latter
possibility by verifying that the reaction leading to 6w could be
performed with no loss in yield in the presence of a large excess
of TEMPO, a well-known radical trap. Considering therefore a
cationic mechanism, our calculations show that the presence of
DDQ allows the reaction to be performed at room temperature
(blue pathway in Scheme 3) because it facilitates the initial
dehydrogenation.
The DDQ-promoted process is proposed to have as an
intermediate the carbocation IN02a, formed through TS01Da
(Figure 2). From this point, two pathways are possible, the most
favorable one being that leading to the observed product F01a
via TS03a and the carbocation IN03a, while the formation of the
alternative regioisomer F02a would take place through the less
stable transition state TS04a and intermediate IN04a. In this
pathway, the formation of IN02a is the rate-limiting step.
Figure 2. Transition structures for TS01Da and TS01Dc.
considered
a dead end. This prediction has experimental
support, since we verified experimentally that several
hydrazones 1 did not undergo rearrangement reactions at high
temperatures. Regarding the DDQ-promoted pathway, the
optimization of the starting C-3 carbocation led to the cyclic form
IN02c due to the presence of the hydrazino moiety. Intermediate
IN02c is formed through TS01Dc (Figure 2), the rate-limiting
step for this pathway as in the previous cases. Actually, IN02c is
a valence tautomer of the carbocation equivalent to IN02a.
Therefore, methyl migration leading to IN04c and then F02c is
not favorable.[12] Instead, the most stable tertiary carbocation
IN03c is formed, leading to the observed final product F01c (for
full details, see the SI file).
A similar study was undertaken for the reactions starting from
hydrazones 1, using compound 1c (S00c) as a representative
example (Scheme 4). In this case, the transition structure
corresponding to the thermal pathway (equivalent to the former
TS02a) could not be located and thus intermediate IN01c was
In order to provide experimental evidence for these mechanisms,
we have isolated two of the proposed intermediates and verified
that they give the rearrangement reaction (Scheme 5). Thus,
treatment of compound 1c (S00c) with a single equivalent of
CH3
H3C
N(CH3)2
H3C
N(CH3)2
DDQ (1 eq)
toluene, rt, 16h
DDQ (1 eq)
toluene, rt, 16h
H3CO
N
N(CH3)2
OCH3
H3CO
N
H3CO
N
(66%)
(75%)
N
N
N
H
OCH3
8 (S02c)
OCH3
6c
1c (S00c)
HCl 5M : THF
(1:3)
O
O
P
EtO
EtO
CH3
H3C
OEt
CO2Et
H3C
H3CO
H3CO
H3CO
O
NaH, benzene, reflux
4c
N
(72%)
N
N
OCH3
10 (30%)
OCH3
OCH3
9 (68%)
S02a
CO2Et
O
NH2-NH2.H2O,
ethyleneglycol,
MW, 400W, 30 s
Me
MeO
Me
N
O
N
H2N
MeO
OH
OEt
R
H2N
7a,c
Me
O
MeO
R
N
11a R = H (98%)
11c R = OMe (96%)
R
Scheme 5. Some experimental evidence for the proposed mechanism and a synthetic application of compounds 7
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
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DDQ in toluene at room temperature afforded 8, which is
identical to the proposed intermediate S02c. This compound,
when treated with a second equivalent of DDQ under the usual
DDQ-promoted rearrangement conditions afforded the expected
quinoline derivative 6c.
in the Supporting Information), we concluded that the best
combination of catalyst and solvent corresponded to the use of
InCl3 in MeOH. This reaction was initially carried out from
purified quinoline 6b, but we later found that
a one-pot
procedure starting from tetrahydroquinolines 1, without isolation
of 6, was also possible. Indeed, the one-pot protocol could be
carried out in shorter reaction times and required only a change
of solvent (toluene to methanol). Using the optimal one-pot
conditions, we briefly studied the transformation of compounds 1
into C1-oxidized pyrrolo[3,4-b]quinolin-1-ones 13, as shown in
Scheme 6 and Table 3.
On the other hand, the availability of 8 allowed us to also study
experimentally the mechanism of the thermal rearrangement.
The acid hydrolysis of its hydrazone group afforded the
corresponding aldehyde 9, together with the deformylated
quinoline derivative 10, probably arising from acid-promoted loss
of hydrogen cyanide and dimethylamine from 8. A subsequent
Wadsworth-Emmons olefination of compound 9 with ethyl 2-
(diethoxyphosphoryl)acetate afforded directly the rearranged
product 4c, presumably through the intermediacy of S02a, which
was not stable under the harsh reaction conditions. In parallel
with these studies, we also attempted the isolation of S02a by
Wolff-Kishner reduction of the C-3 carbonyl group in compounds
7. To this end, we treated 7a and 7c with hydrazine hydrate in
ethyleneglycol under microwave irradiation.[13] However, instead
of the expected carbonyl reduction we observed the formation of
compounds 11a and 11c in almost quantitative yields by loss of
the α,β-unsaturated ester unit via an hydrazine addition-
elimination reaction where the 3-hydroxyquinoline anion acts as
a leaving group. Thus, this reaction provides access to 3-
hydroxyquinoline derivatives, which are key structural elements
R4
NMe2
Ar
N
O
MeO
N
H
1
H
NaCNBH3,
HCl-MeOH,
pH 5; rt, 1 h
[Z = H2]
R4
R4
N
Z
MeO
NMe2
MeO
N
N-NMe2
Ar
N
[Z = O]
Ar
O
6
InCl3 (10%),
MeOH, rt, 3 h
(without isolation of 6)
12 Z = H2
13 Z = O
in
a variety of bioactive compounds, including P-selectin
antagonists[14] and natural depsipeptides[15] such as SW-163E,
sandramycin, and thiocoraline. This framework is not always
easy to synthesize, in particular when also bearing a 2-aryl
substituent.[16]
Scheme 6. Two approaches to the one-pot domino synthesis of pyrrolo[3,4-
b]quinolines, compounds 12 and 13
The ready availability of functionalized quinoline derivatives by
our rearrangement-based method stimulated us to perform a
brief investigation of their potential as synthetic intermediates.
Indeed, quinoline derivatives carrying acyl and hydrazonomethyl
groups at C-2 and C-3, respectively, are ideally functionalized to
act as substrates of simple transformations leading to more
complex fused heterocycles.
In this context, we first demonstrated the reductive cyclization in
excellent yields of compounds 6 (R2 = CO-Ar) to pyrrolo[3,4-
b]quinolines 12 by treatment with sodium cyanoborohydride
under mildly acidic conditions. This transformation presumably
proceeded via a reductive domino process comprising the initial
chemoselective reduction of the hydrazone group, followed by
cyclocondensation of the resulting hydrazine with the carbonyl at
C-2 and a final reduction of the hydrazinium intermediate thus
generated. The pyrrolo[3,4-b]quinoline framework is present as
Table 3. Results of the synthesis of pyrrolo[3,4-b]quinolines 12 and 13
Entry
Cmpd.
Z
Ar
R4
Yield, %
1
2
3
4
5
6
7
8
12w
12x
H2
H2
H2
H2
O
4-MeC6H4
C6H5
Me
Et
91
88
85
99
46
35
36
34
12aa
12ab
13w
13x
3-BrC6H4
3,4-Cl2C6H3
4-MeC6H4
C6H5
Me
Me
Me
Et
O
13aa
13ab
O
3-BrC6H4
3,4-Cl2C6H3
Me
Me
a
structural fragment of polycyclic alkaloids such as
O
camptothecin and luotonin and their bioactive analogues,[17] and
some derivatives of the parent system itself have shown
interesting pharmacological properties.[18]
A mechanism that explains the formation of the oxidized
compounds 13 is proposed in Scheme 7. An initial 5-exo-trig
cyclization by attack of the hydrazine nitrogen onto the Lewis
acid-activated carbonyl to give intermediate I would be followed
by a second annelation onto the iminium cation to furnish a
bridged intermediate II, which would finally be transformed into
the final products 13 via a Lewis acid-catalyzed Meinwald
rearrangement.
Interestingly, we found that a similar transformation could be
carried out under non-reducing conditions. Thus, during our prior
work on the synthesis of certain compounds 6 (R2 = COAr) we
had observed the isolation of small amounts of pyrrolo[3,4-
b]quinolin-1-ones 13 if the crude reaction products were
maintained for a long time in a chromatographic silica gel
column. After optimization of this transformation (see Table S1
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10.1002/ejoc.201900986
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Melting points were determined using a Stuart Scientific apparatus,
SMP3 Model, and are uncorrected. Infrared spectra were recorded with
an Agilent Cary630 FTIR spectrophotometer with a diamond accessory
for solid and liquid samples. NMR spectroscopic data were recorded
using a Bruker Avance 250 spectrometer operating at 250 MHz for 1H
NMR and 63 MHz for 13C NMR (CAI de Resonancia Magnética Nuclear,
Universidad Complutense); chemical shifts are given in ppm and
coupling constants in Hertz. Elemental analyses were determined by the
CAI de Microanálisis Elemental, Universidad Complutense, using a Leco
932 combustion microanalyzer. The synthesis of starting materials 1 and
the details of the computational studies are described in the Supporting
Information. Relative configurations have been indicated with the R*, S*
convention, according to IUPAC rules.[19]
6
InCl3
R4
R4
N
MeO
MeO
N-NMe2
R2
N-NMe2
InCl3
N
O
R2
O
InCl3
I
- InCl3
O
R4
O
R4
MeO
[InCl3]
MeO
H
N-NMe2
R2
N
General method for the synthesis of 1,2,3,4-tetrahydroquinoline-4-
carbaldehydes 2
N
R2
NMe2
N
13
II
Method A: To a solution of CuCl2·2 H2O (1.1 eq) in water (10 mL) was
added a solution of hydrazones 1 (1.0 eq) in THF (15 mL) and the whole
was stirred at room temperature until no starting material was detected
by TLC. Then the reaction mixture was quenched with aqueous 3N
NH4OH, diluted with ethyl acetate (15 mL), and washed with brine (10
mL). The aqueous layer was extracted with CH2Cl2 (2 x 20 mL), and the
combined organic layers were dried over Na2SO4. Removal of the solvent
and column chromatography on silica gel eluting with petroleum
ether:ethyl acetate (9:1) gave aldehydes 2. Method B: To a solution of 1
in THF (15 mL), 5N HCl (5 mL) was added dropwise with stirring, and the
mixture was vigorously stirred at room temperature until TLC detected no
starting material. Isolation and purification of aldehydes were as
described in method A.
Scheme 7. Mechanistic proposal to explain the formation of pyrrolo[3,4-
b]quinolin-1-ones 13
Conclusions
4-Alkyl-1,2,3,4-tetrahydroquinolines bearing aryl or aroyl
substituents at C-2 and vinylogous electron-withdrawing groups
(–CH=CH-Z) at C-4 can be rearranged into polysubstituted, C3-
functionalized quinolines by two alternative protocols, namely
their simple reflux in o-dichlorobenzene or their treatment with
DDQ in toluene at room temperature. DFT calculations correctly
predict both the requirement of high temperature for the reaction
in the absence of DDQ in the cases of ester and hydroxymethyl
moieties and lack of reactivity of hydrazino derivatives under
these thermal conditions. The smooth reactivity promoted by
DDQ is also well predicted, with the formation of an initial C-3
carbocation being the rate-limiting step, and the mechanistic
proposal was supported by the isolation of some of the proposed
intermediates. According to these studies, the work described
here constitutes the first example of a rearrangement process
initiated by an intramolecular aza-ene reaction. The ready
preparation of 2,3-difunctionalized quinolines by this method
was exploited for the construction of two types of derivatives of
the synthetically and biologically relevant pyrrolo[3,4-b]quinoline
framework by application of reductive and non-reductive domino
(±)-(2S*,4S*)-6-Methoxy-2-(4-methoxyphenyl)-4‐methyl‐1,2,3,4‐
tetrahydroquinoline‐4-carbaldehyde (2c): Obtained by method A.
Yellow solid (0.650 g, 90% yield), mp: 122-124 oC. 1H NMR (250 MHz,
CDCl3) δ: 9.41 (s, 1H); 7.40 (d, J = 8.6 Hz, 2H); 6.95 (d, J = 8.6 Hz, 2H);
6.77 (dd, J = 8.7, 2.7 Hz, 1H); 6.63 (d, J = 8.6 Hz, 1H); 6.44 (d, J = 2.5
Hz, 1H); 4.37 (dd, J = 11.2, 1.5 Hz, 1H); 3.98 (br s, 1H); 3.85 (s, 3H);
3.76 (s, 3H), 2.20 (t, J =12.5 Hz, 1H); 1.72 (dd, J = 13.2, 1.8 Hz, 1H);
1.56 (s, 3H). 13C NMR (63 MHz, CDCl3) δ: 201.4; 159.3; 152.3; 139.3;
135.0; 127.8; 120.9; 116.4; 115.1; 114.0; 113.7; 55.7; 55.3; 51.7; 50.1;
38.6; 24.6. IR (neat, NaCl): 3362.1, 2935.1, 2834.0, 1719.1. Elemental
analysis: Calc. for C19H21NO3 (M = 311.37): C, 73.29; H, 6.80; N, 4.50.
Found: C, 72.90; H, 6.58; N, 4.40.
(±)-(2S*,4S*)-6-dimethylamino-4-methyl-2-phenyl-1,2,3,4-
tetrahydroquinoline-4-carbaldehyde (2i): Obtained by method B. Pale
orange viscous liquid (0.505 g, 74% yield). 1H-NMR (CDCl3, 250 MHz) δ:
9.43 (s, 1H); 7.53-7.33 (m, 5H); 6.75 (dd, J = 8.7, 2.5 Hz, 1H); 6.66 (d,
J = 8.6 Hz, 1H); 6.34 (d, J = 2.3 Hz, 1H); 4.43 (d, J = 10.3 Hz, 1H); 3.82
(br s, 1H); 2.85 (s, 6H); 2.24 (t, J = 12.6 Hz, 1H); 1.74 (dd, J = 13.0, 2.3
Hz, 1H); 1.60 (s, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 201.7; 144.3; 143.1;
137.2; 128,6; 127.8; 126.7; 120.8; 116.5; 115.6; 114.4; 52.4; 50.1; 41.9;
38.8; 24.5. IR (neat, NaCl): 3362.0, 2932.8, 2833.7, 1721.1. Elemental
analysis: Calc. for C19H22N2O (M = 294.39): C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.19; H, 7.37; N, 9.20.
processes, including the first example of
a
one-pot
transformation of 1,2,3,4-tetrahydroquinolines into pyrrolo[3,4-
b]quinolines, including an unusual 1,3-oxygen shift.
Experimental Section
General experimental information
(±)-(2S*,4S*)-2-(Furan-2-yl)-6-methoxy-4-methyl-1,2,3,4-
All reagents (Aldrich, Fischer, Alpha Aesar) and solvents (Scharlau,
Fischer) were of commercial quality and were used as received.
Reactions were monitored by thin layer chromatography on aluminium
plates coated with silica gel and fluorescent indicator (Macherey-Nagel
Xtra SIL G/UV254). Separations by flash chromatography were
performed by manual columns on silica gel (Scharlau 40–60 µm, 230–
400 mesh ASTM) or using a Teledyne Isco Combiflash instrument.
tetrahydroquinoline-4-carbaldehyde (2k): Obtained by method A.
Orange viscous liquid (0.656 g, 86% yield).1H-NMR (CDCl3, 250 MHz) δ:
9.39 (s, 1H); 7.43 (dd, J = 1.8, 0.7 Hz, 1H); 6.76 (dd, J = 8.7, 2.7 Hz, 1H);
6.65 (d, J = 8.7 Hz, 1H); 6.45 (d, J = 2.7 Hz, 1H); 6.39 (dd, J = 3.2, 1.8
Hz, 1H); 6.31 (d, J = 3.3 Hz, 1H); 4.53 (dd, J = 10.9, 2.4 Hz, 1H); 4.14 (br
s, 1H); 3.74 (s, 3H); 2.38 (t, J = 13.0 Hz, 1H); 1.93 (dd, J = 13.0, 2.5 Hz,
1H); 1.52 (s, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 201.2; 155.3; 152.5;
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142.0; 138.2; 121.3; 116.7; 115.0; 113.5; 110.2; 105.7; 55.6; 49.2; 46.1;
34.9; 24.4. IR (neat, NaCl): 3342.3, 2930.6, 2832.3, 1720.8. Elemental
analysis: Calc. for C16H17NO3 (M = 271.31): C, 70.83; H, 6.32; N, 5.16.
Found: C, 71.13; H, 6.30; N, 5.55.
96-98oC. 1H-NMR (CDCl3, 250 MHz) δ: 7.41 (s, 1H); 7.06 (d, J = 15.9 Hz,
1H); 6.70 (dd, J = 8.8, 2.8 Hz, 1H); 6.59 (d, J = 8.8 Hz, 1H); 6.56 (d, J =
2.6 Hz, 1H); 6.37 (dd, J = 2.9, 1.5 Hz, 1H); 6.27 (d, J = 3.2 Hz, 1H); 5.98
(d, J = 15.9 Hz, 1H); 4.59 (dd, J = 11.7, 2.4 Hz, 1H); 4.23 (q, J = 7.1 Hz,
2H); 3.75 (s, 3H); 2.21 (t, J = 13.0 Hz, 1H); 1.96 (dd, J = 12.7, 2.1 Hz,
1H); 1.54 (s, 3H); 1.32 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ:
166.8; 156.0; 155.9; 152.2; 141.8; 137.1; 126.8; 119.4; 116.1; 114.3;
113.6; 110.2; 105.4; 60.3; 55.7; 46.6; 40.4; 39.6; 28.1; 14.2. IR (neat,
NaCl): 3346.8, 1714.8. Elemental analysis: Calc. for C20H23NO4 (M =
341.40): C, 70.36; H, 6.79; N, 4.10. Found: C, 70.42; H, 6.72; N, 4.35
(±)-(2S*,4S*)-2-(2-Bromophenyl)-6-methoxy-4-methyl-1,2,3,4-
tetrahydroquinoline-4-carbaldehyde (2r): Obtained by method A.
Yellow solid (0.760 g, 91%), mp: 138-140 oC. 1H NMR (250 MHz, CDCl3)
δ: 9.40 (s, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 (dd, J = 8.0, 1.1 Hz,
1H), 7.45 – 7.36 (m, 1H), 7.25 – 7.16 (m, 1H), 6.79 (dd, J = 8.7, 2.7 Hz,
1H), 6.69 (d, J = 8.7 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 4.85 (d, J = 9.0 Hz,
1H), 3.76 (s, 3H), 2.08 – 1.88 (m, 2H), 1.63 (s, 3H). 13C NMR (63 MHz,
CDCl3) δ: 201.7, 153.0, 141.9, 139.7, 133.4, 129.6, 128.5, 128.2, 123.4,
121.9, 117.4, 115.6, 114.1, 56.2, 51.7, 50.7, 37.2, 24.6. IR (neat, NaCl):
3358.6, 2928.1, 2832.5, 1710.2. Elemental analysis: Calc. for C16H17NO3
(M = 271.31): C, 60.01; H, 5.04; N, 3.89. Found: C, 59.83; H, 4.93; N,
3.89.
Synthesis of ethyl (2S*,4R*,Z)-2-cyano-3-(6-methoxy-4-methyl-2-
phenyl-1,2,3,4-tetrahydroquinolin-4-yl)acrylate 3p
A mixture of aldehyde 2a (0.400 g, 1.42 mmol, 1 eq), ammonium acetate
(0.109 g 1.42 mmol, 1 eq), ethyl cyanoacetate (0.321 g, 2.84 mmol, 2 eq),
and glacial acetic acid (1 mL) in benzene (20 mL) was refluxed with a
Dean-Stark trap for 24 h. After cooling, the reaction mixture was washed
with water (1 x 10 mL), and with saturated NaHCO3 solution (1 x 10 mL).
The organic layer was dried over anhydrous Na2SO4 and concentrated to
yield a residue which was purified by column chromatography on silica
gel eluting with a mixture of petroleum ether:ethyl acetate (12:1, v/v),
obtaining 0.433 g (78%) of 3p as a yellow solid, mp: 128-129 oC. 1H-
NMR (CDCl3, 250 MHz) δ: 7.83 (s, 1H); 7.50-7.30 (m, 5H); 6.75 (dd, J =
8.7, 2.7 Hz, 1H); 6.61 (d, J = 8.7 Hz, 1H); 6.55 (d, J = 2.7 Hz, 1H); 4.48
(dd, J = 10.4, 3.3 Hz, 1H); 4.33 (q, J = 7.1 Hz, 2H); 3.77 (s, 3H); 2.17 (t, J
= 13.0 Hz, 1H); 2.08 (dd, J = 13.1, 3.4 Hz, 1H); 1.91 (s, 3H); 1.37 (t, J =
7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 170.2; 161.9; 152.3; 142.8;
138.0; 128.7; 127.9; 126.7; 126.2; 116.0; 114.3; 114.2; 113.6; 107.4;
62.7; 55.9; 52.7; 43.9; 41.8; 29.3; 14.0. IR (neat, NaCl): 3375.4, 2228.6,
1727.0. Elemental analysis: Calc. for C23H24N2O3 (M = 376.45): C, 73.38;
H, 6.43; N, 7.44. Found: C, 73.76; H, 6.65; N, 7.26.
General method for the synthesis of ethyl 3-(1,2,3,4-
tetrahydroquinolin-4-yl)-acrylate derivatives 3
Sodium hydride (60% dispersion in mineral oil) (3.1 eq) was washed with
dry petroleum ether (3 x 3 mL) and suspended in dry benzene (10 mL)
under argon. To this stirred mixture at room temperature was added via
syringe a solution of triethyl phosphonoacetate (1.2 eq) in dry benzene
(2.5 mL). After
5 minutes, the corresponding tetrahydroquinoline-4-
carbaldehyde derivative 2 in dry benzene (10 mL) was also added via
cannula, and the resulting mixture was refluxed for 5-6 h. After cooling,
the reaction was quenched by the slow addition of water and diluted with
dichloromethane (20 mL). The organic layer was washed with brine (2 x
10 mL), dried over anhydrous Na2SO4, and evaporated, and the oily
residue was purified by column chromatography on silica gel eluting with
mixtures of petroleum ether:ethyl acetate (12:1 to 6:1).
Synthesis of (±)-(2S*,4R*,E)-3-(6-methoxy-4-methyl-2-phenyl-1,2,3,4-
tetrahydroquinolin-4-yl)-2-propen-1-ol 3q
(±)-Ethyl(2S*,4R*,E)-3-[6-methoxy-2-(4-methoxyphenyl)-4-methyl-
1,2,3,4-tetrahydroquinolin-4-yl]acrylate (3c): Yellow solid (0.643 g,
81%), mp: 97-98 oC. 1H-NMR (CDCl3, 250 MHz) δ: 7.37 (d, J = 8.6 Hz,
2H); 7.08 (d, J = 15.8 Hz, 1H); 6.92 (d, J = 8.7 Hz, 2H); 6.70 (dd, J = 8.6,
2.8 Hz, 1H); 6.57 (d, J = 2.2 Hz, 1H); 6.55 (d, J = 8.4 Hz, 1H); 6.00 (d, J
= 15.8 Hz, 1H); 4.43 (dd, J = 11.6, 2.4 Hz, 1H); 4.22 (q, J = 7.1 Hz, 2H);
3.84 (s, 3H); 3.75 (s, 3H); 2.06 (t, J = 12.9 Hz, 1H); 1.76 (dd, J = 13.1,
2.5 Hz, 1H); 1.57 (s, 3H); 1.32 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63
MHz) δ: 166.8; 159.1; 156.4; 151.9; 138.2; 135.6; 127.8; 126.6; 119.2;
115.6; 114.4; 113.9; 113.6; 60.3; 55.8; 55.3; 52.4; 44.5; 40.2; 28.3; 14.2.
IR (neat, NaCl): 3360.4, 1713.1. Elemental analysis: Calc. for C23H27NO4
(M = 381.46): C, 72.42; H, 7.13; N, 3.67. Found: C, 72.22; H, 6.96; N,
3.75.
To a solution of 3a (0.360 g, 1.02 mmol, 1 eq) in dry THF (20 mL)
maintained at -20 °C under argon, a solution of DIBAL (1.0 M solution in
THF, 4.08 mL, 4.08 mmol, 4 eq) was added during a period of 5 min.
Stirring was continued while the reaction reached room temperature, and
then two additional hours. Then, MeOH (10 mL) was added to destroy
the excess of hydride and stirring was continued for 30 min. A saturated
solution of NH4Cl (20 mL) was added to the reaction mixture, and the
resulting emulsion was filtered through celite to remove the white solid
formed. The filtrate was extracted with Cl2CH2 (2 × 20 mL), the organic
layer dried over Na2SO4, and concentrated. The crude product was
purified by column chromatography on silica gel eluting with a mixture of
petroleum ether:ethyl acetate (3:1, v/v) to afford 0.294 g (93%) of 3q as a
yellow oil. 1H-NMR (CDCl3, 250 MHz) δ: 7.50-7.30 (m, 5H); 6.89-6.82 (m,
2H); 6.72-6.63 (m, 2H); 6.55 (dd, J = 7.2, 1.7 Hz, 1H); 4.50 (dd, J = 11.6,
2.6 Hz, 1H); 4.25-4.17 (m, 2H); 3.76 (s, 3H); 2.03 (t, J = 12.9 Hz, 1H);
1.79 (dd, J = 13.2, 2.7 Hz, 1H); 1.54 (s, 3H). 13C-NMR (CDCl3, 63 MHz)
δ: 151.8; 144.0; 141.4; 138.1; 128.6; 128.5; 127.5; 126.7; 126.7; 115.3;
114.5; 112.8; 63.8; 55.8; 53.3; 45.5; 39.3; 28.7. IR (neat, NaCl): 3363.7.
Elemental analysis: Calc. for C20H23NO2 (M = 309.40): C, 77.64; H, 7.49;
N, 4.53. Found: C, 77.49; H, 7.23; N, 4.32.
(±)-Ethyl(2S*,4R*,E)-3-(6-dimethylamino-4-methyl-2-phenyl-1,2,3,4-
tetrahydroquinolin-4-yl)acrylate (3i): Red viscous liquid (0.372 g, 83%).
1H-NMR (CDCl3, 250 MHz) δ: 7.50-7.30 (m, 5H); 7.13 (d, J = 15.8 Hz,
1H); 6.69 (dd, J = 8.6, 2.6 Hz, 1H); 6.58 (d, J = 8.6 Hz, 1H); 6.51 (d, J =
2.2 Hz, 1H); 6.02 (d, J = 15.8 Hz, 1H); 4.48 (d, J = 10.2 Hz, 1H); 4.22 (q,
J = 7.1 Hz, 2H); 2.83 (s, 6H); 2.10 (t, J = 12.8 Hz, 1H); 1.79 (dd, J = 13.1,
2.4 Hz, 1H); 1.61 (s, 3H); 1.32 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63
MHz) δ: 166.8; 156.8; 143.9; 143.7; 136.5; 128.5; 127.6; 126.7; 126.3;
118.9; 115.7; 115.2; 115.1; 60.2; 53.0; 44.8; 42.3; 40.3; 28.3; 14.1. IR
(neat, NaCl): 3361.5, 1713.7. Elemental analysis: Calc. for C23H28N2O2
(M = 364.22): C, 75.79; H, 7.74; N, 7.69. Found: C, 75.56; H, 7.63; N,
7.57.
General method for the synthesis of 3-vinylquinoline derivatives 4
A solution of the corresponding compound 3 (0.7-0.8 mmol) in o-
dichlorobenzene (5 mL) was refluxed until no starting material was
detected by TLC. The reaction mixture was allowed to reach room
temperature, then concentrated, and the oily residue was purified by
(±)-Ethyl(2S*,4R*,E)-3-[2-(2-furyl)-6-methoxy-4-methyl-1,2,3,4-
tetrahydroquinolin-4-yl]acrylate (3k): White solid (0.558 g, 74%), mp:
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
column chromatography eluting with petroleum ether:ethyl acetate (6:1)
to give compounds 4.
A solution of 2r (0.180 g, 0.5 mmol) and NaBH4 (0.095 g, 2.5 mmol) in 5
mL of a 1:1 MeOH/CH2Cl2 mixture was stirred at room temperature for 2
h, until no starting material was detected by TLC. Then, solvent was
evaporated under reduced pressure and the reaction mixture was diluted
with ethyl acetate (10 mL) and neutralized with 0.5 N HCl (10 mL). The
aqueous layer was extracted with ethyl acetate (2 x 10 mL), and the
organic layer was filtered to remove any precipitate formed. The filtrate
was dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give 5 as a yellowish oil in quantitative yield, used in
the next reaction without further purification. 1H NMR (250 MHz, MeOD)
δ: 7.72 (dd, J = 7.8, 1.7 Hz, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.37 (td, J
= 7.5, 1.0 Hz, 1H), 7.16 (td, J = 7.6, 1.7 Hz, 1H), 6.84 – 6.77 (m, 1H),
6.67 – 6.61 (m, 2H), 4.75 (dd, J = 11.0, 2.8 Hz, 1H), 3.73 (s, 3H), 3.65 (d,
J = 2.0 Hz, 2H), 1.97 – 1.75 (m, 2H), 1.39 (s, 3H). 13C NMR (63 MHz,
MeOD) δ: 154.5, 145.4, 142.1, 134.6, 130.6, 130.2, 130.0, 129.8, 124.7,
118.5, 114.9, 114.1, 72.4, 57.0, 54.5, 43.0, 40.9, 29.0.
Ethyl
(E)-3-[6-methoxy-2-(4-methoxyphenyl)-4-methylquinolin-3-
yl]acrylate (4c): Yellow solid (0.247 g, 78%), mp: 119-122 oC. 1H-NMR
(CDCl3, 250 MHz) δ: 8.06 (d, J = 9.1 Hz, 1H); 7.86 (d, J = 16.3 Hz, 1H);
7.54 (d, J = 8.7 Hz, 2H); 7.41 (dd, J = 9.1, 2.7 Hz, 1H); 7.28 (d, J = 2.7
Hz, 1H); 6.99 (d, J = 8.7 Hz, 2H); 6.00 (d, J = 16.3 Hz, 1H); 4.27 (q, J =
7.1 Hz, 2H); 4.01 (s, 3H); 3.89 (s, 3H); 2.78 (s, 3H); 1.34 (t, J = 7.1 Hz,
3H). 13C-NMR (CDCl3, 63 MHz) δ: 166.1; 159.7; 157.8; 155.6; 143.2;
142.8; 141.2; 133.0; 131.5; 131.2; 127.6; 127.1; 125.9; 121.9; 113.6;
102.5; 60.6; 55.4; 55.3; 16.1; 14.2. IR (neat, NaCl): 1713.9, 1620.3.
Elemental analysis: Calc. for C23H23NO4 (M = 377.43): C, 73.19; H, 6.14;
N, 3.71. Found: C, 73.10; H, 6.14; N, 3.63.
Ethyl
(E)-3-(6-dimethylamino-4-methyl-2-phenylquinolin-3-
yl)acrylate (4i): Orange solid (0.241 g, 88%), mp: 145-147 oC. 1H-NMR
(CDCl3, 250 MHz) δ: 8.05 (d, J = 9.2 Hz, 1H); 7.85 (d, J = 16.2 Hz, 1H);
7.58 (m, 2H); 7.51-7.36 (m, 4H); 6.94 (d, J = 2.7 Hz, 1H); 5.95 (d, J =
16.2 Hz, 1H); 4.25 (q, J = 7.1 Hz, 2H); 3.16 (s, 6H); 2.75 (s, 3H); 1.32 (t,
J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 166.2; 154.1; 148.7; 143.4;
140.8; 140.6; 140.3; 130.7; 129.8; 128.1; 128.0; 127.9; 126.9; 125.7;
119.4; 101.6; 60.5; 40.7; 16.2; 14.2. IR (neat, NaCl): 1713.5, 1618.0.
Elemental analysis: Calc. for C23H24N2O2 (M = 360.45): C, 76.64; H, 6.71;
N, 7.77. Found: C, 76.49; H, 6.59; N, 7.67.
General method for the synthesis of 2-aryl/2-acyl-3-[(2,2-
dimethylhydrazono)methyl]quinolines 6
To a stirred solution of 2-aryl- or 2-acyltetrahydroquinolines 1 (1 mmol) in
toluene (10 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (2 eq,
2 mmol) slowly. The solution was stirred at room
temperature until the starting material disappeared as confirmed by TLC
(1 h). The solvent was evaporated under reduced pressure. The solid
residue was purified by flash column chromatography, eluting with an 8:2
(v/v) mixture of petroleum ether:ethyl acetate, to give compounds 6.
Ethyl (E)-3-[2-(2-furyl)-6-methoxy-4-methylquinolin-3-yl]acrylate (4k):
Dark orange solid (0.210 g, 89%), mp: 119-121 oC. 1H-NMR (CDCl3, 250
MHz) δ: 8.12 (d, J = 9.1 Hz, 1H); 8.08 (d, J = 16.3 Hz, 1H); 7.67 (dd, J =
1.7, 0.6 Hz, 1H); 7.42 (dd, J = 9.2, 2.7 Hz, 1H); 7.26 (d, J = 2.7 Hz, 1H);
6.89 (dd, J = 3.4, 0.6 Hz, 1H); 6.57 (dd, J = 3.4, 1.7 Hz, 1H); 6.12 (d, J =
16.3 Hz, 1H); 4.36 (q, J = 7.1 Hz, 2H); 4.00 (s, 3H); 2.75 (s, 3H); 1.41 (t,
J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 166.1; 158.1; 152.3; 144.8;
143.8; 142.9; 142.7; 140.8; 131.6; 127.6; 126.2; 122.1; 113.5; 111.6;
102.5; 60.8; 55.5; 16.3; 14.3. IR (neat, NaCl): 1715.1, 1621.1. Elemental
analysis: Calc. for C20H19NO4 (M = 337.37): C, 71.20; H, 5.68; N, 4.15.
Found: C, 70.92; H, 5.37; N, 3.91.
3-[(2,2-Dimethylhydrazono)methyl]-6-methoxy-4-methyl-2-
phenylquinoline (6a): Pale yellow solid (0.163 g, 51%), mp: 119-121oC.
1H NMR (250 MHz, CDCl3) δ: 8.06 (d, J = 9.0 Hz, 1H), 7.65 – 7.58 (m,
2H), 7.50 – 7.32 (m, 5H), 7.24 (s, 1H), 4.01 (s, 3H), 2.90 (s, 6H), 2.87 (s,
3H). 13C NMR (63 MHz, CDCl3) δ: 158.2, 157.3, 142.7, 141.6, 141.4,
133.5, 131.9, 130.3, 129.2, 128.4, 127.7, 121.5, 103.1, 56.0, 43.2, 16.4.
IR (neat, NaCl): 1616.4. Elemental analysis: Calc. for C20H21N3O (M=
319.40): C, 75.21; H, 6.63; N, 13.16. Found: C, 74.81; H, 6.50; N, 12.84.
3-[(2,2-Dimethylhydrazono)methyl]-6-methoxy-2-(4-methoxyphenyl)-
4-methylquinoline (6c): Yellow viscous liquid (0.175 g, 50%). 1H-NMR
(CDCl3, 250 MHz) δ: 8.02 (d, J = 9.1 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.40 (s,
1H), 7.35 (dd, J = 9.1, 2.7 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.94 – 6.85
(m, 2H), 4.01 (s, 3H), 3.87 (s, 3H), 2.77 (s, 6H), 2.75 (s, 3H). 13C-NMR
(CDCl3, 63 MHz) δ: 159.7, 157.9, 156.3, 134.7, 134.2, 133.2, 131.4,
131.1, 128.8, 127.5, 121.4, 113.5, 102.9, 55.7, 55.5, 43.0, 16.2. IR (neat,
NaCl): 1620.5. Elemental analysis: Calc. for C21H23N3O2 (M = 349.43): C,
72.18; H, 6.63; N, 12.03. Found: C, 71.93; H, 6.85; N, 11.88.
Ethyl
(Z)-2-cyano-3-(6-methoxy-4-methyl-2-phenylquinolin-3-
yl)acrylate (4p): Yellow solid (0.288 g, 98%), mp: 167-168 oC. 1H-NMR
(CDCl3, 250 MHz) δ: 8.48 (s, 1H); 8.14 (d, J = 9.1 Hz, 1H); 7.62-7.42 (m,
6H); 7.32 (d, J = 2.6 Hz, 1H); 4.38 (q, J = 7.1 Hz, 2H); 4.03 (s, 3H); 2.79
(s, 3H); 1.40 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 160.9;
158.3; 156.5; 154.6; 143.5; 142.3; 139.8; 131.7; 129.6; 128.9; 128.4;
127.3; 124.5; 123.2; 114.1; 111.9; 102.5; 62.8; 55.6; 17.1; 14.0. IR (neat,
NaCl): 2242.7, 1730.1, 1621.6. Elemental analysis: Calc. for C23H20N2O3
(M = 372.42): C, 74.18; H, 5.41; N, 7.52. Found: C, 73.81; H, 5.45; N,
7.61.
2-(4-Chlorophenyl)-3-[(2,2-dimethylhydrazono)methyl]-6-methoxy-4-
methylquinoline (6e): Yellow solid (0.202 g, 57%), mp: 140-142 °C. 1H-
NMR (CDCl3, 250 MHz) δ: 8.04 (d, J = 9.1 Hz, 1H); 7.52 (d, J = 6.2 Hz,
2H); 7.40-7.36 (m, 3H); 7.30 (d, J = 2.7 Hz, 1H); 7.15 (s, 1H); 3.98 (s,
3H); 2.89 (s, 6H); 2.83 (s, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 158.3, 155.0,
142.4, 141.4, 138.8, 134.5, 131.4, 131.2, 130.7, 129.1, 128.4, 127.6,
121.9, 102.8, 55.7, 42.8, 16.3. IR (neat, NaCl): 1618.7. Elemental
analysis: Calc. for C20H20ClN3O (M = 353.85): C, 67.89; H, 5.70; N, 11.88.
Found: C, 67.67; H, 5.99; N, 11.60.
(E)-3-(6-Methoxy-4-methyl-2-phenylquinolin-3-yl)-2-propen-1-ol (4q):
Pale yellow solid (0.112 g, 63%), mp: 161-163 oC. 1H-NMR (CDCl3, 250
MHz) δ: 8.07 (d, J = 9.1 Hz, 1H); 7.57 (m, 2H); 7.48-7.34 (m, 4H); 7.27 (d,
J = 2.7 Hz); 6.65 (d, J = 16.2 Hz, 1H); 5.73 (dt, J = 16.2, 5.5 Hz, 1H);
4.21 (dd, J = 5.5, 1.6 Hz, 2H); 4.00 (s, 3H); 2.73 (s, 3H). 13C-NMR (CDCl3,
63 MHz) δ: 157.8; 156.4; 142.1; 141.3; 140.4; 136.4; 131.4; 129.8; 129.2;
128.0; 127.9; 127.8; 121.8; 102.3; 63.5; 55.5; 16.0. IR (neat, NaCl):
3208.2, 1621.0. Elemental analysis: Calc. for C20H19NO2 (M = 305.37): C,
78.66; H, 6.27; N, 4.59. Found: C, 78.33; H, 6.08; N, 4.35.
2-(2-Bromophenyl)-3-[(2,2-dimethylhydrazono)methyl]-6-methoxy-4-
methylquinoline (6r): Dark yellow oil (0.211 g, 53%). 1H NMR (250 MHz,
CDCl3) δ: 8.05 (d, J = 8.9 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.45 – 7.24 (m,
5H), 7.17 (s, 1H), 4.01 (s, 3H), 2.87 (s, 3H), 2.76 (s, 6H). 13C NMR (63
MHz, CDCl3) δ: 158.4, 156.7, 142.9, 142.3, 140.7, 132.7, 131.9, 131.7,
130.9, 129.7, 129.5, 128.0, 127.8, 122.9, 121.5, 102.9, 56.0, 42.9, 16.2.
Synthesis of (±)-((2S*,4S*)-[2-(2-bromophenyl)-6-methoxy-4-methyl-
1,2,3,4-tetrahydroquinolin-4-yl]methanol 5
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
IR (neat, NaCl): 1618.0. Elemental analysis: Calc. for C20H20BrN3O (M=
398.30): C, 60.31; H, 5.06; N, 10.55. Found: C, 60.23; H, 5.18; N, 10.18.
NaCl): 1671.1, 1615.9. Elemental analysis: Calc. for C22H23N3O2 (M =
361.44): C, 73.11; H, 6.41; N, 11.63. Found: C, 72.89; H, 6.54; N, 11.30.
3-[(2,2-Dimethylhydrazono)methyl]-4-ethyl-6-methoxy-2-(m-
tolyl)quinoline (6s): Yellow solid (0.152 g, 44%), mp: 89-90 oC. 1H NMR
(250 MHz, CDCl3) δ: 8.10 – 8.03 (m, 1H), 7.47 (s, 1H), 7.42 – 7.32 (m,
4H), 7.25 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 4.01 (s, 3H), 3.34 (q, J = 7.4
Hz, 2H), 2.89 (s, 6H), 2.43 (s, 3H), 1.46 (t, J = 7.4 Hz, 3H). 13C NMR (63
MHz, CDCl3) δ: 158.1, 157.7, 147.1, 143.2, 141.5, 138.1, 133.4, 132.1,
130.9, 129.1, 128.2, 128.1, 127.5, 127.0, 121.3, 102.9, 56.0, 43.1, 23.0,
21.9, 15.4. IR (neat, NaCl): 1601.9. Elemental analysis: Calc. for
C23H26N3O (M=347.45): C, 76.05; H, 7.25; N, 12.09. Found: C, 75.97; H,
7.08; N, 12.36.
3-[(2,2-Dimethylhydrazono)methyl]-2-(4-fluorobenzoyl)-4,6,8-
trimethylquinoline (6y): Orange solid (0.214 g, 59%), mp: 149-152 °C.
1H-NMR (CDCl3, 250 MHz) δ: 7.91-7.85 (m, 2H); 7.72 (s, 1H); 7.35 (s,
1H); 7.22 (s, 1H); 7.10-7.03 (m, 2H); 2.91 (s, 6H); 2.71 (s, 6H); 2.45 (s,
3H). 13C-NMR (CDCl3, 63 MHz) δ: 194.0, 165.6 (d, J = 254.4 Hz), 155.2,
146.8, 142.8, 139.9, 135.0, 133.8, 133.6 (d, J = 2.9 Hz), 132.6 (d, J = 9.3
Hz), 127.9, 127.5, 127.0, 125.9, 115.3 (d, J = 22.0 Hz), 42.1, 26.2, 21.3,
19.9. IR (neat, NaCl): 1689.4, 1595.3. Elemental analysis: Calc. for
C22H22FN3O (M = 363.44): C, 72.71; H, 6.10; N, 11.56. Found: C, 72.77;
H, 5.91; N, 11.65.
2-(3-Chlorophenyl)-3-[(2,2-dimethylhydrazono)methyl]-6-methoxy-4-
methylquinoline (6t): Yellow solid (0.258 g, 73%), mp: 74-76 oC. 1H
NMR (250 MHz, CDCl3) δ: 8.04 (d, J = 9.1 Hz, 1H), 7.67 – 7.62 (m, 1H),
7.52 – 7.47 (m, 1H), 7.41 – 7.36 (m, 3H), 7.32 (d, J = 2.7 Hz, 1H), 7.21 (s,
1H), 4.01 (s, 3H), 2.92 (s, 6H), 2.85 (s, 3H). 13C NMR (63 MHz, CDCl3) δ:
158.4, 155.6, 143.4, 142.7, 141.6, 134.3, 132.3, 131.9, 130.5, 129.6,
129.3, 128.6, 128.4, 127.6, 121.8, 103.0, 56.0, 43.1, 16.4. IR (neat,
NaCl): 1615.7. Elemental analysis: Calc. for C20H20ClN3O (M= 353.84):
C, 67.89; H, 5.70; N, 11.88. Found: C, 67.56; H, 5.84; N, 11.54.
3-[(2,2-Dimethylhydrazono)methyl]-2-(4-fluorobenzoyl)-6-methoxy-4-
methylquinoline (6z): Yellow solid (0.193 g, 53%), mp: 151-154 °C. 1H-
NMR (CDCl3, 250 MHz) δ: 7.97 (d, J = 9.1 Hz, 1H); 7.95-7.84 (m, 2H);
7.38 (s, 1H); 7.33 (dd, J = 9.1, 2.7 Hz, 1H); 7.27 (d, J = 2.7 Hz, 1H); 7.13-
7.03 (m, 2H); 3.98 (s, 3H); 2.74 (s, 6H); 2.73 (s, 3H). 13C-NMR (CDCl3,
63 MHz) δ: 194.3, 165.5 (d, J = 254.0 Hz), 158.7, 153.9, 141.2, 138.8,
133.9 (d, J = 2.5 Hz), 132.6 (d, J = 9.4 Hz), 131.9, 129.1, 127.0, 125.2,
121.2, 115.4 (d, J = 22.0 Hz), 102.2, 55.7, 42.1, 14.6. IR (neat, NaCl):
1673.9, 1600.0. Elemental analysis: Calc. for C21H20FN3O2 (M = 365.41):
C, 69.03; H, 5.52; N, 11.50. Found: C, 68.83; H, 5.34; N, 11.23.
2-Benzoyl-3-[(2,2-Dimethylhydrazono)methyl]-6-methoxy-4-
methylquinoline (6u): Yellow solid (0.260 g, 75%), mp: 180-182 °C. 1H-
NMR (CDCl3, 250 MHz) δ: 7.87 (d, J = 9.1, 1H); 7.76 (d, J = 8.3 Hz, 2H);
7.40 (m, 1H); 7.32-7.26 (m, 3H); 7.21 (dd, J = 9.1, 2.7 Hz, 1H); 7.16 (d,
J = 2.7 Hz, 1H); 3.87 (s, 3H); 2.61 (s, 9H). 13C-NMR (CDCl3, 63 MHz) δ:
195.8, 158.6, 154.3, 141.3, 138.7, 137.3, 132.6, 131.9, 130.0, 129.0,
128.3, 127.0, 125.2, 121.1, 102.2, 55.7, 42.0, 14.5. IR (neat, NaCl):
1712.8, 1676.7. Elemental analysis: Calc. for C21H21N3O2 (M = 347.42):
C, 72.60; H, 6.09; N, 12.10. Found: C, 72.25; H, 6.13; N, 11.95.
2-(3-Bromobenzoyl)-3-[(2,2-dimethylhydrazono)methyl]-6-methoxy-
4-methylquinoline (6aa): Orange solid (0.204 g, 48%), mp: 166-167 °C.
1H NMR (250 MHz, CDCl3) δ: 8.04-7.97 (m, 2H), 7.80 (dt, J = 7.8, 1.3 Hz,
1H), 7.65 (m, 1H), 7.39-7.27 (m, 4H), 4.01 (s, 3H), 2.77 (s, 6H), 2.74 (s,
3H). 13C NMR (63 MHz, CDCl3) δ: 194.5, 159.0, 153.7, 141.5, 139.6,
139.0, 135.6, 133.0, 132.2, 130.2, 129.4, 128.8, 127.3, 125.2, 122.8,
121.5, 102.4, 56.0, 42.4, 14.8. IR (neat, NaCl): 1673.1, 1615.9.
Elemental analysis: Calc. for C21H20BrN3O2 (M = 426.31): C, 59.17; H,
4.73; N, 9.86. Found: C, 59.18, H, 5.07; N, 9.54.
3-[(2,2-Dimethylhydrazono)methyl]-6-methoxy-2-(4-
methoxybenzoyl)-4-methylquinoline (6v): Yellow solid (0.265 g, 73%),
mp: 173-174 °C. 1H-NMR (CDCl3, 250 MHz) δ: 7.98 (d, J = 9.0 Hz, 1H);
7.87-7.78 (m, 2H); 7.37 (s, 1H); 7.32 (dd, J = 9.1, 2.7 Hz, 1H); 7.26 (d, J
= 2.7 Hz, 1H); 6.94-6.77 (m, 2H); 3.97 (s, 3H); 3.84 (s, 3H); 2.74 (s, 6H);
2.72 (s, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 195.7, 163.3, 158.6, 154.4,
141.0, 139.1, 132.3, 131.7, 130.4, 129.1, 127.1, 125.6, 121.1, 113.5,
102.2, 55.7, 55.6, 42.1, 14.7. IR (neat, NaCl): 1743.8, 1649.3. Elemental
analysis: Calc. for C22H23N3O3 (M = 377.44): C, 70.01; H, 6.14; N, 11.13.
Found: C, 69.86; H, 6.07; N, 10.96.
2-(3,4-Dichlorobenzoyl)-3-[(2,2-dimethylhydrazono)methyl]-6-
methoxy-4-methylquinoline (6ab): Yellow solid (0.191 g, 46%), mp:
237-239 °C. 1H NMR (250 MHz, CDCl3) δ: 8.01-7.95 (m, 2H), 7.73 (dd, J
= 8.3, 2.0 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.39 (br s, 1H), 7.36 (dd, J =
9.1, 2.7 Hz, 1H), 7.30 – 7.28 (m, 1H), 4.01 (s, 3H), 2.79 (s, 6H), 2.74 (s,
3H). 13C NMR (63 MHz, CDCl3) δ: 193.7, 159.1, 153.3, 141.5, 139.1,
137.6, 137.1, 133.1, 132.2, 132.0, 130.8, 129.4, 129.2, 127.3, 125.1,
121.6, 102.4, 56.0, 42.4, 14.8. IR (neat, NaCl): 1674.8, 1616.6.
Elemental analysis: Calc. for C21H19Cl2N3O2 (M = 416.30): C, 60.59; H,
4.60; N, 10.09. Found: C, 60.28, H, 4.62; N, 9.81.
3-[(2,2-Dimethylhydrazono)methyl]-6-methoxy-2-(4-methylbenzoyl)-
4-methylquinoline (6w): Pale yellow solid (0.217 g, 60%), mp: 196-
198 °C. 1H NMR (250 MHz, CDCl3) δ: 8.00 (d, J = 9.1 Hz, 1H), 7.78 (d, J
= 8.1 Hz, 2H), 7.40 (s, 1H), 7.34 (dd, J = 9.0, 2.7 Hz, 1H), 7.30 (s, 1H),
7.22 (d, J = 8.0 Hz, 2H), 4.00 (s, 3H), 2.76 (s, 6H), 2.75 (s, 3H), 2.42 (s,
3H). 13C NMR (63 MHz, CDCl3) δ: 196.0, 158.8, 154.8, 143.6, 141.5,
139.0, 135.1, 132.2, 130.4, 129.3, 127.3, 125.8, 121.3, 102.5, 56.0, 42.4,
22.2, 14.9. IR (neat, NaCl): 1668.9, 1604.7. Elemental analysis: Calc. for
C22H23N3O2 (M = 361.44): C, 73.11; H, 6.41; N, 11.63. Found: C, 72.91;
H, 6.20, N, 11.28.
General method for the synthesis of ethyl 3-(2-aryl-3-oxo-3,4-
dihydroquinolin-4-yl)acrylates 7
To a solution of the corresponding tetrahydroquinoline 3 (1.2-1.6 mmol)
in toluene (5 mL) an equimolar amount of DDQ was added, and the
mixture was stirred at room temperature for an hour. Then, the reaction
was washed with water (1 x 2 mL), with brine (1 x 2 mL) and the aqueous
layer was extracted with dichloromethane (3 x 10 mL). The combined
organic layers were dried over anhydrous Na2SO4, and concentrated.
Column chromatography of the residue on silica gel, eluting with
petroleum ether:ethyl acetate (19:1), allowed the isolation of compounds
7.
2-Benzoyl-3-[(2,2-dimethylhydrazono)methyl]-4-ethyl-6-
methoxyquinoline (6x): Orange solid (0.144 g, 40%), mp: 134-136 °C.
1H NMR (250 MHz, CDCl3) δ: 8.02 (m, 1H), 7.92 – 7.86 (m, 2H), 7.53 (m,
1H), 7.46 – 7.37 (m, 3H), 7.37 – 7.32 (m, 2H), 4.00 (s, 3H), 3.22 (q, J =
7.6 Hz, 2H), 2.74 (s, 6H), 1.40 (t, J = 7.6 Hz, 3H). 13C NMR (63 MHz,
CDCl3) δ: 196.1, 158.9, 154.8, 144.6, 141.9, 137.6, 132.8, 132.3, 130.2,
128.5, 128.22 126.4, 124.9, 121.2, 102.2, 56.0, 42.3, 21.8, 14.5. IR (neat,
(±)-Ethyl 3-(6-methoxy-4-methyl-3-oxo-2-phenyl-3,4-dihydroquinolin-
4-yl)acrylate (7a): Yellow viscous liquid (0.276 g, 46%). 1H-NMR (CDCl3,
250 MHz) δ: 8.05-7.94 (m, 2H); 7.66 (d, J = 8.6 Hz, 1H); 7.54-7.42 (m,
3H); 6.97 (dd, J = 8.6, 2.4 Hz, 1H); 6.95 (d, J = 15.6 Hz, 1H); 6.78 (d, J =
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
2.7 Hz, 1H); 5.83 (d, J = 15.7 Hz, 1H); 4.18 (q, J = 7.1 Hz, 2H); 3.90 (s,
3H); 1.74 (s, 3H); 1.28 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ:
195.5; 165.5; 160.5; 154.5; 146.7; 136.7; 134.7; 134.3; 132.3; 130.5;
128.7; 128.3; 123.6; 113.4; 112.9; 60.7; 55.6; 53.6; 21.1; 14.1. IR (neat,
NaCl): 1718.7, 1609.2. Elemental analysis: Calc. for C22H21NO4 (M =
363.41): C, 72.71; H, 5.82; N, 3.85. Found: C, 72.32; H, 6.19; N, 4.20.
To a solution of compound 8 in THF (15 mL), 5M HCl (5 mL) was added
dropwise and the mixture was vigorously stirred at room temperature for
5 hours. The reaction mixture was quenched with 3M aqueous NH4OH.
The aqueous layer was extracted with CH2Cl2 (3 x 20 mL) and the
combined organic layers were dried over Na2SO4. The solvent was
removed under vacuum and the obtained residue was purified by flash
chromatography on silica gel eluting with petroleum ether :ethyl acetate,
giving the aldehyde 9 as a yellow oil in 68% yield, and the deformylated
derivative 10, as a white solid (mp: 109-111 °C) in 30% yield.
(±)-Ethyl
3-[6-methoxy-2-(4-methoxyphenyl)-4-methyl-3-oxo-3,4-
dihydroquinolin-4-yl]acrylate (7c): Pale yellow viscous liquid (0.195 g,
42%). 1H-NMR (CDCl3, 300 MHz) δ: 8.01 (dd, J = 7.0, 2.0 Hz, 2H); 7.62
(d, J = 8.6 Hz, 1H); 7.02-6.88 (m, 4H); 6.76 (d, J = 2.7 Hz, 1H); 5.82 (d, J
= 15.7 Hz, 1H); 4.18 (q, J = 7.1 Hz, 2H); 3.88 (s, 3H); 1.71 (s, 3H); 1.28 (t,
J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 75 MHz) δ: 196.2; 165.5; 161.6; 160.0;
153.9; 146.8; 136.4; 134.9; 131.8; 130.4; 126.8; 123.5; 113.7; 113.2;
112.9; 60.7; 55.6; 55.3; 53.6; 20.9; 14.1. IR (neat, NaCl): 1719.1, 1605.3.
Elemental analysis: Calc. for C23H23NO5 (M = 393.43): C, 70.21; H, 5.89;
N, 3.56. Found: C, 69.92; H, 5.84; N, 3.79.
(±)-6-methoxy-2-(4-methoxyphenyl)-4-methyl-3,4-dihydroquinoline-4-
carbaldehyde (9): 1H-NMR (CDCl3, 250 MHz) δ: 9.48 (s, 1H); 7.99 (d, J
= 8.9 Hz, 2H); 7.47 (d, J = 8.6 Hz, 1H); 6.96 (d, J = 8.9 Hz, 2H); 6.91 (dd,
J = 8.6, 2.8 Hz); 6.77 (d, J = 2.7 Hz); 3.86 (s, 3H); 3.84 (s, 3H); 3.22 (d, J
= 16.4, 1H); 2.60 (d, J = 16.4 Hz, 1H); 1.41 (s, 3H). 13C-NMR (CDCl3, 63
MHz) δ: 199.9; 161.9; 161.7; 159.1; 138.9; 131.8; 129.5; 128.8; 127.8;
114.2; 113.4; 112.0; 55.9; 55.8; 48.4; 31.7; 20.1.
(±)-Ethyl
3-[2-(4-methoxyphenyl)-4,6-dimethyl-3-oxo-3,4-
6-Methoxy-2-(4-methoxyphenyl)-4-methylquinoline (10): 1H-NMR
(CDCl3, 250 MHz) δ: 8.13-8.02 (m, 3H); 7.65 (s, 1H); 7.36 (dd, J = 9.2,
2.8 Hz, 1H); 7.19 (d, J = 2.7 Hz, 1H); 7.08-6.98 (m, 2H); 3.96 (s, 3H);
3.88 (s, 3H); 2.71 (s, 3H).
dihydroquinolin-4-yl]acrylate (7d): Yellow viscous liquid (0.156 g, 38%).
1H-NMR (CDCl3, 250 MHz) δ: 7.92 (d, J = 8.3 Hz, 2H); 7.70 (d, J = 8.7 Hz,
1H); 7.34-7.23 (m, 2H); 7.00-6.90 (m, 2H); 6.78 (d, J = 2.6 Hz, 1H); 5.82
(d, J = 15.7 Hz, 1H); 4.19 (q, J = 7.1 Hz, 2H); 3.89 (s, 3H); 2.43 (s, 3H);
1.73 (s, 3H); 1.28 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 195.8;
165.5; 160.2; 154.5; 146.8; 140.9; 136.6; 134.8; 132.1; 131.5; 129.0;
128.6; 123.5; 113.3; 112.9; 60.7; 55.6; 53.6; 21.4; 20.9; 14.1. IR (neat,
NaCl): 1719.6, 1608.7. Elemental analysis: Calc. for C23H23NO4 (M =
377.43): C, 73.19; H, 6.14; N, 3.71. Found: C, 72.96; H, 6.30; N, 3.93.
General method for the synthesis of 3-hydroxyquinolines 11
A mixture of the corresponding compound 7a or 7c (1 eq), 55 %
hydrazine (0.25 eq) and ethylene glycol (1 mL) was stirred in a beaker to
get a uniform mixture. The beaker was covered with a watch glass and
irradiated in a conventional microwave oven at 400 W for 30-40 seconds.
Then, the mixture was allowed to cool to room temperature and extracted
with ethyl ether (3 x 15 mL). The combined organic layers were dried
over anhydrous Na2SO4, and concentrated. The residue was purified by
column chromatography eluting with petroleum ether:ethyl acetate (14:1)
to give compounds 11a or 11c.
(±)-Ethyl
3-[2-(4-chlorophenyl)-6-methoxy-4-methyl-3-oxo-3,4-
dihydroquinolin-4-yl]acrylate (7e): Yellow solid (0.282 g, 55%), mp:
121-122 oC. 1H-NMR (CDCl3, 250 MHz) δ: 7.99 (d, 2H); 7.65 (d, J = 8.6
Hz, 1H); 7.43 (d, J = 8.7 Hz, 2H); 6.96 (dd, J = 8.7, 2.7 Hz, 1H); 6.92 (d, J
= 15.7 Hz, 1H); 6.78 (d, J = 2.7 Hz, 1H); 5.81 (d, J = 15.7 Hz, 1H); 4.18
(q, J = 7.1 Hz, 2H); 3.90 (s, 3H); 1.73 (s, 3H); 1.28 (t, J = 7.1 Hz, 3H).
13C-NMR (CDCl3, 63 MHz) δ: 195.5; 165.5; 160.5; 154.5; 146.7; 136.7;
134.7; 134.3; 132.3; 130.5; 128.7; 128.3; 123.6; 113.4; 112.9; 60.7; 55.6;
53.6; 21.1; 14.1. IR (neat, NaCl): 1718.6, 1608.3. Elemental analysis:
Calc. for C22H20ClNO4 (M = 397.85): C, 66.42; H, 5.07; N, 3.52. Found: C,
66.72; H, 5.04; N, 3.49.
3-Hydroxy-6-methoxy-4-methyl-2-phenylquinoline (11a): Pale orange
solid (0.034 g, 98%), mp: 170-171 oC. 1H-NMR (CDCl3, 300 MHz) δ: 8.00
(d, J = 9.1 Hz, 1H); 7.75 (d, J = 8.1 Hz, 2H); 7.60-7.45 (m, 3H); 7.25 (dd,
J = 9.1, 2.6 Hz, 1H); 7.13 (d, J = 2.3 Hz, 1H); 3.99 (s, 3H); 2.59 (s, 3H).
13C-NMR (CDCl3, 75 MHz) δ: 10.7 (CH3); 55.4 (OCH3); 101.3 (C-5);
118.9 (C-7); 124.8 (C-4); 128.8 (C-3´ and C-5´); 129.1 (C-4´); 129.3 (C-2´
and C-6´); 130.0 (C-4a); 131.3 (C-8); 136.8 (C-1´); 139.1 (C-8a); 145.1
(C-2); 147.1 (C-3); 158.0; 147.1; 145.1; 139.1; 136.8; 131.3; 130.0;
129.3; 129.1; 128.8; 124.8; 118.9; 101.3; 55.4; 10.7. IR (neat, NaCl):
3234.6, 2926.8, 1621.1. Elemental analysis: Calc. for C17H15NO2 (M =
265.31): C, 76.96; H, 5.70; N, 5.28. Found: C, 76.61; H, 5.96; N, 5.57.
Synthesis of 4-[(2,2-dimethylhydrazono)methyl]-6-methoxy-2-(4-
methoxyphenyl)-4-methyl-3,4-dihydroquinoline 8
To a solution of the tetrahydroquinoline 1c (0.6 mmol) in toluene (5 mL)
an equimolar amount of DDQ was added, and the mixture was stirred at
room temperature for 16 hours. Then, the reaction was washed with
water (2 mL), with brine (2 mL) and the aqueous layer was extracted with
dichloromethane (3 x 10 mL). The combined organic layers were dried
over anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash chromatography on silica gel
eluting with petroleum ether :ethyl acetate, and compound 8 was isolated
as a yellow viscous liquid, in 66% yield. 1H-NMR (CDCl3, 250 MHz) δ:
8.05 (d, J = 8.9 Hz, 2H); 7.46 (d, J = 8.4 Hz, 1H); 6.98 (d, J = 8.9 Hz, 2H);
6.91 (d, J = 2.5 Hz, 1H); 6.86 (dd, J = 8.4, 2.5 Hz); 6.50 (s, 1H); 3.87 (s,
3H); 3.86 (s, 3H); 3.22 (d, J = 16.0, 1H); 2.66 (s, 6H); 2.57 (d, J = 16.1 Hz,
1H); 1.46 (s, 3H). 13C-NMR (CDCl3, 63 MHz) δ: 163.9; 161.5; 158.7;
139.5; 138.6; 135.0; 132.6; 129.0; 128.9; 114.0; 111.9; 111.3; 55.8; 55.7;
43.4; 39.7; 35.9; 24.4.
3-Hydroxy-6-methoxy-2-(4-methoxyphenyl)-4-methylquinoline (11c):
Orange viscous liquid (0.019 g, 92%). 1H-NMR (CDCl3, 500 MHz) δ: 8.02
(d, J = 9.3 Hz, 1H); 7.71 (d, J = 8.7 Hz, 2H); 7.25 (dd, J = 9.1, 2.7 Hz,
1H); 7.13 (d, J = 2.6 Hz, 1H); 7.06 (d, J = 8.7 Hz, 2H); 3.99 (s, 3H); 3.88
(s, 3H); 2.60 (s, 3H). 13C-NMR (CDCl3, 125 MHz) δ: 160.3; 157.9; 146.8;
145.2; 142.3; 130.9; 130.2; 129.8; 118.9; 114.7; 101.3; 55.4; 55.3; 10.8.
IR (neat, NaCl): 3229.8, 2932.9, 1620.3. Elemental analysis: Calc. for
C18H17NO3 (M = 295.33): C, 73.20; H, 5.80; N, 4.74. Found: C, 73.06; H,
5.66; N, 4.57.
General method for the synthesis of pyrrolo[3,4-b]quinolines 12
To a stirred solution of the corresponding quinoline 6 (1 eq, 0.5 mmol) in
methanol (3 mL) at room temperature, was added dropwise a HCl/MeOH
solution (pH 3) to adjust the pH of the mixture at 4-5. Then, NaCNBH3
was added in a portion (1 eq), stirring was continued for 10 minutes, and
Synthesis of intermediates 9 and 10
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
pH was readjusted again to 4-5. This process was repeated until 4.5 eq
of NaCNBH3 were employed and pH set to 5. Then, solvent was
evaporated and the residue was dissolved in CH2Cl2 (5 mL), washed with
water (1 x 5 mL) and brine (1 x 5 mL). The aqueous layer was extracted
with CH2Cl2 (2 x 5 mL) and the combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. The resulting residue
was purified by a column chromatography in silica gel, eluting with
hexane:ethyl acetate (8:2).
eq, 0.05 mmol) was added and the mixture was stirred at room
temperature for 3 h. Water (15 mL) was added to the mixture and the
aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined
organic phases were dried over anhydrous Na2SO4 and evaporated to
dryness under low pressure. The residue was purified by silica gel flash
chromatography, eluting with hexane:ethyl acetate (85:15 to 80:20).
2-Dimethylamino-7-methoxy-9-methyl-3-(p-tolyl)-2,3-dihydro-1H-
pyrrolo[3,4-b]quinolin-1-one (13w): Brown solid (0.083 g, 46%), mp:
198-199 °C. 1H NMR (250 MHz, CDCl3) δ: 7.95 (d, J = 9.1 Hz, 1H), 7.39
(dd, J = 9.1, 2.8 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.17 (s, 4H), 5.51 (s,
1H), 3.97 (s, 3H), 3.14 (s, 3H), 2.90 (s, 6H), 2.35 (s, 3H). 13C NMR (63
MHz, CDCl3) δ: 167.6, 160.4, 158.2, 145.6, 144.1, 138.6, 134.4, 131.7,
129.8, 129.5, 128.8, 123.4, 120.8, 102.9, 65.8, 55.9, 44.6, 21.6, 12.5. IR
(neat, NaCl): 1687.5, 1620.4. Elemental analysis: Calc. for C22H23N3O2
(M = 361.45): C, 73.11; H, 6.41; N, 11.63. Found: C, 72.87; H, 6.17; N,
11.25.
2-Dimethylamino-7-methoxy-9-methyl-3-(p-tolyl)-2,3-dihydro-1H-
pyrrolo[3,4-b]quinoline (12w): Dark orange solid (0.063 g, 91%), mp:
146-148 °C. 1H NMR (250 MHz, CDCl3) δ: 7.90 (d, J = 9.1 Hz, 1H), 7.44
(d, J = 8.1 Hz, 2H), 7.26 (dd, J = 9.2, 2.8 Hz, 1H), 7.23 – 7.17 (m, 3H),
5.35 (s, 1H), 4.52 (d, J = 13.2 Hz, 1H), 4.31 (d, J = 13.3 Hz, 1H), 3.95 (s,
3H), 2.60 (s, 3H), 2.54 (s, 6H), 2.37 (s, 3H). 13C NMR (63 MHz, CDCl3) δ:
161.2, 157.6, 144.3, 139.5, 137.3, 136.2, 131.9, 129.5, 129.4, 129.0,
128.7, 120.3, 102.3, 68.5, 55.9, 46.5, 41.2, 21.7, 15.5. IR (neat, NaCl):
1619.6. Elemental analysis: Calc. for C22H25N3O (M = 347.45): C, 76.05;
H, 7.25; N, 12.09. Found: C, 75.67; H, 6.95; N, 11.79.
2-Dimethylamino-9-ethyl-7-methoxy-3-phenyl-2,3-dihydro-1H-
pyrrolo[3,4-b]quinolin-1-one (13x): Pale orange solid (0.063 g, 35%),
mp: 145-146 °C. 1H NMR (250 MHz, CDCl3) δ: 8.01 – 7.94 (m, 1H), 7.44
– 7.34 (m, 5H), 7.32 – 7.27 (m, 2H), 5.53 (s, 1H), 3.99 (s, 3H), 3.81 –
3.63 (m, 2H), 2.90 (s, 6H), 1.47 (t, J = 7.6 Hz, 3H). 13C NMR (63 MHz,
CDCl3) δ: 167.2, 160.5, 158.3, 150.3, 146.2, 137.5, 131.9, 129.1, 128.9,
128.9, 128.4, 123.4, 120.0, 102.9, 66.2, 56.0, 44.6, 19.7, 15.4. IR (neat,
NaCl): 1685.7, 1602.3. Elemental analysis: Calc. for C22H23N3O2 (M =
361.45): C, 73.11; H, 6.41; N, 11.63. Found: C, 72.85; H, 6.45; N, 11.28.
2-Dimethylamino-9-ethyl-7-methoxy-3-phenyl-2,3-dihydro-1H-
pyrrolo[3,4-b]quinoline (12x): Brown solid (0.061 g, 88%), mp: 120-
122 °C. 1H NMR (250 MHz, CDCl3) δ: 7.91 (m, 1H), 7.59 – 7.53 (m, 2H),
7.44 – 7.36 (m, 2H), 7.35 – 7.31 (m, 1H), 7.28 – 7.24 (m, 2H), 5.39 (s,
1H), 4.52 (d, J = 13.4 Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 3.96 (s, 3H),
3.03 (q, J = 7.7 Hz, 2H), 2.54 (s, 6H), 1.38 (t, J = 7.6 Hz, 3H). 13C NMR
(63 MHz, CDCl3) δ: 161.3, 157.7, 144.9, 142.6, 142.1, 132.0, 129.1,
128.7, 128.7, 127.8, 127.6, 120.2, 102.3, 68.7, 55.9, 46.2, 41.3, 23.2,
14.1. IR (neat, NaCl): 1619.5. Elemental analysis: Calc. for C22H25N3O
(M = 347.45): C, 76.05; H, 7.25; N, 12.09. Found: C, 75.88; H, 6.99; N,
11.98.
3-(3-Bromophenyl)-2-dimethylamino-7-methoxy-9-methyl-2,3-
dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (13aa): Orange solid (0.077 g,
36%), mp: 167-169 °C. 1H NMR (250 MHz, CDCl3) δ: 7.97 (d, J = 9.2 Hz,
1H), 7.51 – 7.40 (m, 3H), 7.37 (d, J = 2.7 Hz, 1H), 7.26 – 7.21 (m, 2H),
5.47 (s, 1H), 4.00 (s, 3H), 3.15 (s, 3H), 2.91 (s, 6H). 13C NMR (63 MHz,
CDCl3) δ: 167.7, 159.6, 158.4, 145.7, 144.6, 139.9, 132.1, 132.0, 131.7,
130.7, 129.7, 127.7, 123.8, 123.1, 120.7, 103.00, 65.6, 56.0, 44.7, 12.6.
2-Dimethylamino-3-(3-bromophenyl)-7-methoxy-9-methyl-2,3-
dihydro-1H-pyrrolo[3,4-b]quinoline (12aa): Dark red oil (0.070 g, 85%).
1H NMR (250 MHz, CDCl3) δ: 7.89 (d, J = 9.2 Hz, 1H), 7.71 (t, J = 1.7 Hz,
1H), 7.51 (d, J = 7.6 Hz, 1H), 7.43 (m, 1H), 7.31 – 7.23 (m, 2H), 7.19 (d,
J = 2.7 Hz, 1H), 5.33 (s, 1H), 4.51 (d, J = 13.2 Hz, 1H), 4.35 (d, J = 13.2
Hz, 1H), 3.96 (s, 3H), 2.61 (s, 3H), 2.55 (s, 6H). 13C NMR (63 MHz,
CDCl3) δ: 160.1, 157.8, 145.0, 144.3, 136.6, 131.9, 131.8, 130.9, 130.3,
129.2, 128.8, 127.8, 122.9, 120.6, 102.3, 68.6, 55.9, 45.6, 41.2, 15.6. IR
(neat, NaCl): 1619.8. Elemental analysis: Calc. for C21H22BrN3O (M =
412.32): C, 61.17; H, 5.38; N, 10.19. Found: C, 60.85; H, 5.14; N, 9.84.
IR (neat, NaCl):
1684.5, 1617.2. Elemental analysis: Calc. for
C21H20BrN3O2 (M = 426.31): C, 59.17; H, 4.73; N, 9.86. Found: C, 58.88;
H, 4.65; N, 9.53.
3-(3,4-Dichlorophenyl)-2-dimethylamino-7-methoxy-9-methyl-2,3-
dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (13ab): Yellowish solid (0.071
g, 34%), mp: 87-89 °C. 1H NMR (250 MHz, CDCl3) δ: 7.96 (d, J = 9.2 Hz,
1H), 7.46 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 2.1 Hz,
1H), 7.36 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 5.46 (s, 1H),
4.00 (s, 3H), 3.14 (s, 3H), 2.92 (s, 6H). 13C NMR (63 MHz, CDCl3) δ:
167.7, 159.2, 158.5, 145.7, 144.8, 137.9, 133.2, 133.1, 131.7, 131.1,
131.1, 129.8, 128.2, 123.9, 120.6, 103.0, 65.1, 56.03, 44.7, 12.6. IR (neat,
NaCl): 1688.1, 1619.4. Elemental analysis: Calc. for C21H19Cl2N3O2 (M =
416.30): C, 60.59; H, 4.60; N, 10.09. Found: C, 60.24; H, 4.67; N, 9.76.
2-Dimethylamino-3-(3,4-dichlorophenyl)-7-methoxy-9-methyl-2,3-
dihydro-1H-pyrrolo[3,4-b]quinoline (12ab): Dark green paste (0.080 g,
99%). 1H NMR (250 MHz, CDCl3) δ: 7.88 (d, J = 9.2 Hz, 1H), 7.67 (d, J =
1.6 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.31 – 7.26 (m, 1H), 7.19 (d, J = 2.7 Hz,
1H), 5.29 (s, 1H), 4.49 (d, J = 13.1 Hz, 1H), 4.34 (d, J = 13.1 Hz, 1H),
3.96 (s, 3H), 2.61 (s, 3H), 2.55 (s, 6H). 13C NMR (63 MHz, CDCl3) δ:
159.6, 157.9, 144.2, 142.9, 136.8, 132.7, 131.7, 131.6, 130.9, 130.7,
129.0, 128.8, 128.5, 120.7, 102.3, 68.4, 55.9, 44.9, 41.1, 15.6. IR (neat,
NaCl): 1620.1. Elemental analysis: Calc. for C21H21Cl2N3O (M = 402.32):
C, 62.69; H, 5.26; N, 10.44. Found: C, 62.37; H, 5.21; N, 10.05.
Acknowledgements
We gratefully acknowledge financial support from MINECO
(grants CTQ2015-68630-R and CTQ-RTI2018-097662-B-I00, to
JCM, and CTQ2016-76155-R, to PM) and Universidad
Complutense (Ph. D. contract to JC). The authors also
acknowledge with thanks the use of resources from the
supercomputers “Memento” and “Cierzo” and technical expertise
and assistance provided by BIFI-ZCAM (Universidad de
Zaragoza, Spain).
General method for the synthesis of pyrrolo[3,4-b]quinolin-1-ones
13
To a stirred solution of 2-acyltetrahydroquinolines 1 (1 eq, 0.5 mmol) in
toluene (10 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (2 eq,
1 mmol) slowly. The solution was stirred at room
temperature until the starting material was converted to compound 6, as
confirmed by TLC (1 h). Then, toluene was evaporated under reduced
pressure and the residue was redissolved in methanol (5 mL). InCl3 (0.1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900986
European Journal of Organic Chemistry
FULL PAPER
[9]
T. Mino, S. Fukui, M. Yamashita, J. Org. Chem. 1997, 62, 734-735.
Keywords: tetrahydroquinolines • quinolines • hydrazones •
[10] a) J.-H. Zhang, M.-X. Wang, Z.-T. Huang, Tetrahedron Lett. 1998, 39,
9237-9240. b) L. Zu, H. Xie, H. Li, J. Wang, X. Yu, W. Wang. Chem.
Eur. J. 2008, 14, 6333-6335. c) W. Tan, B.-X. Du, X. Li, X. Zhu, F. Shi,
S.-J. Tu, J. Org. Chem. 2014, 79, 4635-4643.
rearrangement reactions • domino reactions
[1]
a) K. Kaur, M. Jain, R. P.; Reddy, R. Jain, Eur. J. Med. Chem. 2010, 45,
3245-3264. b) S. Bongarzone, M. L. Bolognesi, Expert Opin. Drug
Discov. 2011, 6, 251-268. c) V. R. Solomon, H. Lee, Curr. Med. Chem.
2011, 18, 1488-1508. d) P. Y. Chung, Z. X. Bian, H. Y. Pun, D. Chan, A.
S. Chan, C.H. Chui, J. C. Tang, K. H. Lam, Future Med. Chem. 2015, 7,
947-967. e) O. Afzal, S. Kumar, M. R. Haider, M. R. Ali, R. Kumar, M.
Jaggi, S. Bawa, Eur. J. Med. Chem. 2015, 97, 871-910. f) S. Jain, V.
Chandra, P. K. Jain, K. Pathak, D. Pathak, A. Vaidya, Arab. J. Chem.,
in press, DOI:10.1016/j.arabjc.2016.10.009.
[11] See, for instance: L. Zhai, R. Shukla, S. H. Wadumethrige, R. Rathore,
J. Org. Chem. 2010, 75, 4748-4760.
[12] Indeed, attempts of optimizing the equivalent to IN02a with the
hydrazino moiety in the form of a secondary carbocation only led to the
relative minimum IN02c. For this reason, although IN04c is located as a
relative minimum, the migration of the methyl group from a non-stable
(as stationery point) intermediate cannot be considered. Attempts to
migrate the methyl group from IN02c to IN024c also failed.
[2]
a) A. Encinas-López, in Privileged Scaffolds in Medicinal Chemistry.
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10.1002/ejoc.201900986
European Journal of Organic Chemistry
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José Clerigué, Giulia Bianchini, Pascual
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Highly substituted and functionalized quinolines were obtained by thermal or DDQ-
induced C4 to C3 migration of functionalized vinyl substituents in racemic 4,4-
disubstituted 1,2,3,4-tetrahydroquinolines.
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