Diastereoselective, multicomponent access to trans-2-aryl-4-arylamino-1,2, 3,4-tetrahydroquinolines via an AA′BC sequential four-component reaction and their application to 2-arylquinoline synthesis

Article abstract of DOI:10.1039/c2ob26754c

The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA′BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude product from the MCR with FeCl₃ in methanol.

Full text of DOI:10.1039/c2ob26754c

Organic &
Biomolecular
Chemistry
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Volume 11 | Number 4 | 28 January 2013 | Pages 525–688
ISSN 1477-0520
PAPER
J. Carlos Menéndez et al.
Diastereoselective, multicomponent access to trans-2-aryl-4-arylamino-1,2,3,4-
tetrahydroquinolines via an AA’BC sequential four-component reaction and their
application to 2-arylquinoline synthesis

Organic &
Biomolecular
Chemistry
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PAPER
Diastereoselective, multicomponent access to trans-
2-aryl-4-arylamino-1,2,3,4-tetrahydroquinolines via an
AA’BC sequential four-component reaction and their
application to 2-arylquinoline synthesis†
Cite this: Org. Biomol. Chem., 2013, 11,
569
Pascual Ribelles, Vellaisamy Sridharan, Mercedes Villacampa, Mª Teresa Ramos and
J. Carlos Menéndez*
The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes
leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA’BC sequential multicomponent trans-
formation related to the Povarov reaction that was also extended to the use of a second aniline as the
C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding
intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed
adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude
product from the MCR with FeCl3 in methanol.
Received 6th September 2012,
Accepted 3rd October 2012
DOI: 10.1039/c2ob26754c
www.rsc.org/obc
Introduction
Heterocycles are the most important single class of com-
pounds in the pharmaceutical and agrochemical industries,
and comprise around 60% of all drug substances in thera-
peutic use. The tetrahydroquinoline ring system, in particular,
is a very common structural motif and is found in a large
number of bioactive natural products and pharmacologically
relevant compounds. Owing to the significance of these
scaffolds in drug discovery and medicinal chemistry, the devel-
opment of new methodologies for the synthesis of tetrahydro-
quinoline derivatives continues to be a very active field of
research.1,2
Among the many bioactive 1,2,3,4-tetrahydroquinolines,
compounds bearing a nitrogen substituent at C-4 are particu-
larly important. Fig. 1 summarizes the structures of a few
representative examples, including torcetrapib 1,3 a potent
inhibitor of cholesteryl ester transfer protein (CETP) that was
studied clinically for the treatment of hypercholesterolemia,
although it was later withdrawn due to an unexpected high
mortality in Phase III clinical studies, and has served as the
stimulus to the preparation of other families of analogues.4
Other pharmacologically relevant compounds belonging to
Fig. 1 Some bioactive tetrahydroquinolines with a C-4 nitrogen substituent.
this group include cis-2-methyl-4-aminotetrahydroquinolines
2, which have been characterized as antagonists of the CRTH2
receptor, a chemoattractant receptor-homologous molecule
expressed on Th2 lymphocytes.5 As exemplified by compounds
in Fig. 1, most available biological data for 2,4-disubstituted-
1,2,3,4-tetrahydroquinolines correspond to those with a cis
relative configuration, probably due to difficulties in preparing
their trans analogues. Furthermore, in spite of advances in
synthetic methodology, some types of substitution in
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@farm.ucm.es;
Fax: +34 91 3941822; Tel: +34 91 3941840
†Electronic supplementary information (ESI) available: Spectra of all com-
pounds. CCDC 894715. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob26754c
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tetrahydroquinolines (e.g. at C-5) remain relatively unaccessi-
ble. In this context, we describe here a Povarov-type reaction
that leads to trans-2-aryl-4-arylamino-1,2,3,4-tetrahydro-
quinolines with additional substitution at the C-5 and other
positions of the benzene ring, together with two synthetic
applications of these compounds.
The formal [4 + 2] cycloaddition reaction between aromatic
imines and electron-rich alkenes to give 1,2,3,4-tetrahydro-
quinolines was developed in the 1960s and is known as the
Povarov reaction.6 It can also be performed in a three-
component fashion and received relatively little attention until
the discovery of its efficient catalysis by lanthanide triflates,7
which prompted its widespread use in the synthesis of tetra-
hydroquinolines and related fused systems.8 While alkyl ethers
are the most commonly employed dienophiles, reactions with
N-vinylamides are also quite common, and allow the synthesis
of compounds bearing nitrogen substituents at C-4. The
reactions using acyclic dienophiles, which provide access to
non-fused 1,2,3,4-tetrahydroquinoline systems, have received
relatively little attention in the literature, probably because of
the lower reactivity of these compounds when compared with
their cyclic counterparts. Regarding the stereochemical
outcome of the Povarov reaction, the use of cyclic dienophiles
tends to give mixtures of the two diastereomers arising from
the exo- and endo-approaches.9 Reactions starting from acyclic
dienophiles are normally accepted to give cis-2,4-disubstituted
tetrahydroquinolines as the major or only products,10 although
one example of the opposite diastereoselection has been
described for an organocatalyzed version of the reaction
carried out under reaction conditions rather different than the
usual ones and involving the presence of a chiral thiourea cata-
lyst able to interact with the reactants via hydrogen bonding.11
Scheme 1 AA’BB’ multicomponent reaction leading to trans-4-arylamino-2-
methyl-1,2,3,4-tetrahydroquinolines.
Results and discussion
The reaction between anilines and vinyl ethers in the presence
of cerium(IV) ammonium nitrate provides ready access to cis-
2-methyl-4-alkoxy-1,2,3,4-tetrahydroquinolines.12 While striv-
ing to extend the scope of this transformation, we have discov-
ered that the use of 3,5-dimethylaniline as the starting
material caused the reaction to deviate to a different course,
affording the trans-2-methyl-4-arylamino-1,2,3,4-tetrahydro-
quinoline derivative 5 in a fully diastereoselective fashion
(Scheme 1). This transformation can be considered as one of
the few examples of reactions taking place via an AA′BB′ multi-
component mechanism, since the final product contains two
units of each of two components, all of which have different
chemical roles in the process and hence react in a chemodiffer-
entiated fashion. The ABB′-type multicomponent reactions and
related transformations have attracted much attention because
of their ability to generate molecular diversity and complexity
from a very reduced number of starting materials.13
Scheme 2 Three- and four-component access to trans-2-aryl-4-(3,5-dimethyl-
phenylamino)-1,2,3,4-tetrahydroquinolines.
to this end we examined the three-component reaction
between isolated aromatic imines 6, 3,5-dimethylaniline and
ethyl vinyl ether, which afforded compounds 7 in excellent
yields. An AA′BC four-component sequential protocol with no
isolation of the imine was then examined, involving mixing
equimolecular amounts of 3,5-dimethylaniline and the alde-
hyde, together with the catalyst, for about 1 min, followed by
addition of ethyl vinyl ether and a second molecule of the
aniline. This modified method gave very similar results to the
three-component one (Scheme 2 and Table 1).
In view of the interest in this unexpected transformation,
we sought to broaden its scope. We first decided to explore the
possibility of introducing an aromatic substituent at C-2, and
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Table 1 Structures and yields of compounds 7a–ea
Entry
Compound
R
Yield (%) (3-CR)
Yield (%) (4-CR)
1
2
3
4
5
7a
7b
7c
7d
7e
H
85
86
89
88
87
83
86
87
87
87
Me
OMe
Cl
Br
a Isolated yields after chromatography.
Fig. 2 NMR evidence for the assignment of a trans stereochemistry to com-
pounds 7 and 8.
Scheme 3 Four-component reaction leading to trans-2-aryl-4-(arylamino)-
1,2,3,4-tetrahydroquinolines containing two different aniline fragments.
Table 2 Synthesis of trans-2-aryl-4-(arylamino)-1,2,3,4-tetrahydroquinolines
8a–c
Fig. 3 X-Ray diffraction structure of compound 7b.
Entry
Compound
R3
R4
Yielda (%)
1
2
3
8a
8b
8c
H
H
Cl
Cl
Br
Cl
87
88
72
assignment of the trans structure with an axial 4-arylamino
group was based on the coupling constants of the H-2 proton;
for instance, in compound 7a this signal is observed as a
doublet of doublets with J values of 12.9 and 2.3 Hz, which are
compatible only with an axial arrangement for H-2. For com-
parison purposes, the J23 values of two previously reported
related compounds are given in Fig. 2. Furthermore, a NOESY
experiment proved the spatial proximity of the H-2 and Ar–NH
protons, which can only be explained by a trans structure with
an axial anilino substituent. Finally, the structure of com-
pounds 7 was definitively confirmed by an X-ray diffraction
study of 7b, which is shown in Fig. 3.14
Regarding the mechanism of the reaction, there were
several points that needed to be established. In the first place,
due to the fact that Ce(IV) species normally act as one-electron
oxidants,15 our transformation might be expected to take place
via a radical mechanism. However, this possibility was dis-
carded by a control experiment carried out in the presence of a
large amount of 1,1-diphenylethylene, a well-known radical
a Isolated yields after chromatography.
In view of the almost instantaneous formation of the inter-
mediate imine, we reasoned that it should be feasible to
broaden the scope of our method by devising a modified
four-component reaction involving two different anilines. Thus,
in situ generation of the imine derived from 3,5-dimethylaniline
as described above, followed by immediate addition of a
second aniline and ethyl vinyl ether, afforded compounds 8 in
good to excellent yields, without any trace of products derived
from a transimination reaction (Scheme 3 and Table 2).
As previously mentioned, the generation of a trans-2,4-dis-
ubstituted 1,2,3,4-tetrahydroquinoline is unusual in Povarov
chemistry, which almost always gives cis derivatives. For this
reason, it was important to establish unambiguously the rela-
tive configuration of compounds 5, 7, and 8. Our initial
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trap, which showed no decrease in yield for the reaction example of this type of intermediate from 3,5-dimethylaniline
leading to 7a. This suggests that in this case CAN is acting as a because 7 or 8 were obtained instead, compound 9 was avail-
Lewis acid catalyst, a behaviour that has been established in able to us from our previous work on CAN-catalyzed Povarov
recent years on a firm basis.16 Secondly, the unusual prefer- reactions,17 and we found that its treatment with p-toluidine
ence for the trans stereochemistry had to be explained. A first under our usual conditions did not lead to a 4-anilino deriva-
mechanistic possibility that could account for this result tive, but only to recovered starting materials (Scheme 4).
would be a pathway comprising a normal Povarov reaction
With this result in mind, we propose the mechanism sum-
leading to a trans-4-ethoxy-2-aryl-1,2,3,4-tetrahydroquinoline marized in Scheme 5 to explain our results. Oxonium inter-
and a subsequent nucleophilic displacement of the alkoxy mediate A, from addition of vinyl ether to the imine generated
group by a second molecule of aniline, with inversion of the from the starting aniline and aldehyde, cannot undergo the
configuration at C-4. While we were unable to prepare an usual Friedel–Crafts-like cyclization leading to the normal
Povarov product B owing to steric compression between the
alkoxy substituent and the C-3 methyl. This allows the attack
of a second molecule of aniline to A, giving iminium species
C1, which has the same problems as A to cyclize to a cis-tetra-
hydroquinoline D. However, in this case a conformational
change to C2 is possible, in spite of an unfavorable interaction
with the “axial” C-2 proton, owing to its stabilization by for-
mation of an intramolecular hydrogen bond, which was con-
firmed by an ab initio study of C2 at the HF 6-31G* level.
Furthermore, the trans final products are more stable accord-
ing to computational studies; for instance, 7a was found to be
5.25 kcal mol−1 more stable than its cis isomer at the B3LYP/
6-31G* level. While this is not the usual behaviour for Povarov
reactions, which normally have similar stabilities for the two
possible diastereomeric final products,10f in our case the
Scheme 4 Experiment that discarded a normal Povarov mechanism followed unstabilizing effect of the interaction between the C-5 methyl
by displacement of the 4-alkoxy group by a molecule of toluidine.
and the equatorial C-4 substituent in the cis compound has to
Scheme 5 Mechanistic proposal explaining the formation and trans stereochemistry of compounds 7 and 8.
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be considered. As a precedent, we will cite the reaction of methanol, which gave virtually the same yield and was experi-
N-vinylpyrrolidone with a 3,5-disubstituted aromatic imine to mentally more convenient while having the additional advan-
give a 1 : 1 mixture of the cis and trans Povarov products and tage of involving the use of milder conditions and a much
this mixture could be epimerized to the trans product, cheaper reagent (entry 3). We then set out to extend the scope
showing that the latter is thermodynamically more stable.18
of the method by completing the examples summarized in
While the preparation of compounds 7 and 8 was interest- entries 4–10 of Table 3, which show that the reaction consist-
ing in itself, we also planned to investigate their application as ently proceeded in good to excellent yields. It will be noted
synthetic intermediates, prompted by the presence of a good that the step leading to the intermediate tetrahydroquinoline
leaving group at C-4. Due to the pharmacological importance could be carried out either by the three-component or the
of 2-arylquinolines,19 we started this study by examining their four-component protocols previously described. Interestingly,
aromatization with concomitant elimination of the 4-anilino our method allows the preparation of quinolines bearing a
group, using the crude of the reaction leading to compound 7a substituent at C-5, which cannot be easily done with many of
as the model substrate (Scheme 6 and Table 3). We compared the known methods. It can be regarded as complementary to
several methods, the first of which was based on the treatment Povarov reactions involving alkynes as dienophiles, which
of the crude 7a with hydrochloric acid, which gave 65% of 10a cannot be readily adapted to the preparation of quinolines
in our first experiment but turned out to be not general (entry bearing only a C-2 substituent at the heterocyclic ring.20 Fur-
1). The traditional dehydrogenation with Pd–C in refluxing thermore, our protocol provides compounds with substitution
toluene gave 10a in 89% yield (entry 2), but we selected as our patterns (e.g. 2,5-disubstitution) that are not readily accessible
method of choice the reaction with iron trichloride in by other methods.
In an effort to extend the application of this strategy to the
generation of structurally more complex quinoline systems, we
also studied a reaction involving a dialdehyde. Thus, treatment
of imine 11 (prepared by a standard method from 3,5-dimethyl-
aniline and m-phthalaldehyde) with 2 equiv. of 3,5-dimethyl-
aniline and 2 equiv. of ethyl vinyl ether under our usual
conditions afforded a mixture of partially aromatized products
that was taken directly to the FeCl3 oxidation to yield com-
pound 12 in 77% yield (Scheme 7). This reaction presumably
proceeded via the formation of bis-tetrahydroquinoline A as an
intermediate, followed by aromatization of one of the tetra-
hydroquinoline rings by elimination of the corresponding aryl-
amino unit to give a dihydroquinoline, followed by Fe3+-
induced oxidation. In the other ring, the arylamino group is
displaced by a molecule of methanol with retention of trans
relative configuration with respect to the aryl substituent at
C-2, as judged by the coupling constants between H-3 and H-4
(J3(ax)–4 3.0 Hz, J3(eq)–4 2.3 Hz). This indicates an
Scheme 6 Synthesis of 2-arylquinolines from anilines, aromatic aldehydes and
vinyl ethers.
=
=
SN1 mechanism in which a Lewis acid-generated intermediate
cation is diastereoselectively attacked by a molecule of metha-
nol from the bottom face to avoid a repulsive interaction of the
C-4 hydrogen with the C5-methyl substituent in the transition
state. The reason for the different behaviour of both rings can
be explained by the almost planar structure of 2-phenylquino-
lines in comparison to biphenyls;21 this creates a steric hin-
drance for the formation of a double bond in the third ring,
which would bring the new vinylic proton approximately to the
same plane.
In order to provide experimental support to the mechanistic
proposal, we studied the reaction between compound 7b and
methanol under our reaction conditions, and found that it
afforded the corresponding trans-4-alkoxy derivative 13 in 98%
yield (Scheme 8). Again, the trans arrangement for the substi-
Table 3 Scope and yields of the synthesis of 2-arylquinolines 10
Entry Compound R1
R2
Ar
Method Yielda (%)
1
2
3
4
5
6
7
8
10a
10a
10a
10b
10c
10d
10e
10f
H
H
H
Me
H
H
H
H
Me C6H5
Me C6H5
Me C6H5
B
B
B
A
A
A
A
A
65b
89c
87d
62
95
92
83
86
75
H
4-ClC6H4
Me 4-MeC6H4
Me 4-MeOC6H4
Me 4-ClC6H4
Me 4-BrC6H4
9
10g
H
Me
B
10
10h
H
Me
B
90
tuents was proved by the J34 values (J3(ax)–4 = 3.1 Hz, J3(eq)–4
=
a Isolated yields after chromatography. b Conditions for the
aromatization step: aqueous HCl–CH2Cl2, rt, 3 h. c Conditions for
the aromatization step: Pd–C, toluene, reflux, 6 h. d Conditions for the
aromatization step: FeCl3, MeOH, rt, 3 h.
2.6 Hz). In contrast to its more complex analogue 12 and in
line with our explanation for the stability of the latter, com-
pound 13 showed a considerable tendency to aromatize to 10c.
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related to the Povarov reaction, and it was also extended to the
use of a second aniline as the C-4 substituent. The final pro-
ducts showed an unusual trans relative configuration for the
C-2 and C-4 substituents, which was explained by stabilization
of the corresponding intermediate by intramolecular hydrogen
bonding. The presence of the 4-anilino substituent allowed us
to develop a method for the synthesis of not readily accessible
4-unsubstituted 2-arylquinolines, by treatment of the crude
product from the MCR with FeCl3 in methanol.
Experimental section
General experimental information
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reac-
tions were monitored by thin layer chromatography, on alu-
minium plates coated with silica gel with a fluorescent
indicator (SDS CCM221254). Separations by flash chromato-
graphy were performed on silica gel (SDS 60 ACC 40–63 μm) or
neutral alumina (Merck S22). Melting points were measured
on a Reichert 723 hot stage microscope, and are uncorrected.
Infrared spectra were recorded on a Perkin Elmer Paragon
1000 FT-IR spectrophotometer, with all compounds examined
as KBr pellets or as thin films on NaCl disks. NMR spectra
were obtained on a Bruker Avance 250 spectrometer operating
at 250 MHz for 1H and 63 MHz for 13C (CAI de Resonancia
Magnética Nuclear, Universidad Complutense). Elemental ana-
lyses were determined by the CAI de Microanálisis Elemental,
Universidad Complutense, using a Leco 932 CHNS combustion
microanalyzer.
Scheme 7 Synthesis of compound 12.
( )-(2R*,4R*)-4-(3,5-Dimethylphenylamino)-2,5,7-trimethyl-
1,2,3,4-tetrahydroquinoline (5). To a stirred solution of 3,5-
dimethylaniline (363 mg, 3 mmol) and ethyl vinyl ether
(540 mg, 7.5 mmol) in acetonitrile (15 mL) was added CAN
(164.4 mg, 10 mol%). The reaction was stirred at room temp-
erature for 2 h. After completion of the reaction, as indicated by
TLC, water (20 mL) was added and the mixture was extracted
with dichloromethane (3 × 20 mL). The combined organic
layers were dried (anhydrous Na2SO4), and evaporated. The
residue was purified by silica gel column chromatography
eluting with a petroleum ether–ethyl acetate (96 : 4, v/v) mixture,
Scheme 8 An experiment proving the SN1 displacement of the 3,5-dimethyl-
phenylamino substituent by methanol, with retention of the C-4 configuration.
1
yielding 353 mg (80%) of 5. H-NMR (CDCl3, 250 MHz) δ: 1.25
(d, 3H, J = 6.2 Hz, C2-CH3), 1.49 (td, 1H, J = 12.8 and 3.7 Hz,
H-3ax); 2.25 (m, 1H, H-3eq); 2.25 (s, 3H, CH3); 2.28 (s, 3H, CH3);
2.32 (s, 6H, 2 CH3); 3.43–3.51 (m, 1H, H-2); 3.75 (br s, 1H, NH);
3.85 (br s, 1H, NH); 4.57 (br s, 1H, H-4); 6.31 (s, 1H, H-4′); 6.33
(s, 2H, H-2′ and H-6′); 6.43 (s, 1H, H-8); 6.45 (s, 1H, H-6).
13C-NMR (CDCl3, 63 MHz) δ: 19.1, 21.6, 22.1, 22.6, 36.0, 42.4,
46.6, 110.6, 113.3, 117.3, 119.4, 121.0, 138.6, 139.3, 139.6, 145.5,
147.1. Analysis: Calculated for C20H26N2 (M = 294.43): C, 81.59;
H, 8.90; N, 9.51. Found: C, 81.34; H, 8.75; N, 9.32.
The preparation of 13 could be carried out with equal
efficiency in the presence of indium trichloride, underscoring
the fact that CAN behaves as a Lewis acid under our reaction
conditions.
Conclusions
In conclusion, we have developed an efficient method for the
synthesis of trans-2-aryl-4-arylamino-tetrahydroquinolines
from 3,5-disubstituted anilines, vinyl ethers and aromatic alde-
hydes. This one-pot reaction can be considered as an AA′BC
Synthesis of compounds 7 and 8. General procedures
(a) Three-component method. A mixture of 3,5-dimethyl-
chemodivergent, sequential multicomponent transformation aniline (1 equiv.) and the suitable aromatic aldehyde (1 equiv.)
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was stirred vigorously with a glass rod for 5 min and then it and H-5′); 7.88 (d, J = 8.4 Hz, 2H, H-2′ and H-6′); 8.46 (s, 1H,
was kept at room temperature overnight in an open beaker CHvN). 13C-NMR (CDCl3, 63 MHz) δ: 21.1 (2 CH3); 118.5 (C-2
placed in a fume cupboard to afford imines 6, which were and C-6); 127.7 (C-4); 128.8 (C-3′ and C-5′); 129.7 (C-2′ and
characterized spectroscopically and used without further puri- C-6′); 134.6 (C-1′); 136.9 (C-4′); 138.5 (C-3 and C-5); 151.4 (C-1);
fication (see below their spectral data). To a stirred solution of 158.0 (CHvN).
the suitable imine (3 mmol) and CAN (10%) in acetonitrile
3,5-Dimethyl-N-(4-bromobenzylidene)aniline
(6e). Yield:
1H-NMR
(10 mL) was added dropwise a solution of 3,5-dimethylaniline 100%, as a yellow solid. IR (NaCl) ν: 1627 cm−1
.
¯
(1 equiv.) and ethyl vinyl ether (1 equiv.) in acetonitrile. The (CDCl3, 250 MHz) δ: 2.40 (s, 6H, 2 CH3); 6.89 (s, 2H, H-2 and
reaction mixture was stirred at room temperature for 3 h and H-6); 6.94 (s, 1H, H-4); 7.64 (d, J = 8.5 Hz, 2H, H-3′ and H-5′);
upon completion, as judged by TLC, it was diluted with water 7.80 (d, J = 8.5 Hz, 2H, H-2′ and H-6′); 8.43 (s, 1H, CHvN).
(20 mL) and extracted with dichloromethane (3 × 20 mL). In 13C-NMR (CDCl3, 63 MHz) δ: 21.2 (2 CH3); 118.5 (C-2 and C-6);
some cases where an emulsion was formed, the dichloro- 125.6 (C-4′); 127.8 (C-4); 130.0 (C-3′ and C-5′); 131.8 (C-2′ and
methane extracts were shaken with brine (10 mL). The com- C-6′); 135.1 (C-1′); 138.7 (C-3 and C-5); 151.5 (C-1); 158.3
bined organic layers were dried over anhydrous Na2SO4 and (CHvN).
filtered, the solvent was evaporated under reduced pressure
and the residue was purified by chromatography on neutral dimethyl-1,2,3,4-tetrahydroquinoline (7a). White solid, mp
alumina, eluting with a 98 : 2 petroleum ether–ethyl acetate 125–126 °C. IR (NaCl) ν: 3390, 1599 cm−1 1H-NMR (CDCl3,
250 MHz) δ: 1.90 (td, J = 12.9, 3.6 Hz, 1H, H-3ax); 2.27 (s, 3H,
( )-(2S*,4R*)-4-(3,5-Dimethylphenylamino)-2-phenyl-5,7-
.
¯
mixture.
(b) Four-component method. To a stirred solution of 3,5- CH3); 2.29 (s, 9H, 3 CH3); 2.41 (dt, J = 12.9, 4.5, 2.3 Hz, 1H,
dimethylaniline (3 mmol), the suitable aromatic aldehyde H-3eq); 3.84 (br s, 1H, NH); 4.14 (br s, 1H, NH-1); 4.46 (dd, J =
(1 equiv.) and CAN (10 mol%) in acetonitrile (10 mL) was 12.9, 2.3 Hz, 1H, H-2); 4.60 (br s, 1H, H-4); 6.35 (s, 3H, H-2″,
added dropwise a mixture of 1 equiv. of 3,5-dimethylaniline H-6″ and H-8); 6.43 (s, 1H, H-4″); 6.50 (s, 1H, H-6); 7.33–7.48
(preparation of 7) or another aniline (preparation of 8) and (m, 5H, Ph). 13C-NMR (CDCl3, 63 MHz) δ: 19.1 (CH3); 21.6
ethyl vinyl ether (1 equiv.) in acetonitrile (5 mL). Workup and (CH3); 22.1 (2 CH3); 37.5 (C-3); 46.9 (C-4); 52.1 (C-2); 110.6
purification were carried out as in the three-component (C-2″ and C-6″); 113.5 (C-8); 117.1 (C-4a); 119.6 (C-4″); 121.3
protocol.
3,5-Dimethyl-N-benzylideneaniline (6a). Yield: 100%, as a 138.8 (C-7); 139.3 (C-5); 139.5 (C-3″ and C-5″); 144.3 (C-1′);
pale brown viscous liquid. IR (NaCl) ν: 1628 cm−1 1H-NMR 145.3 (C-8a); 147.1 (C-1″). Analysis: Calculated for C25H28N2
(C-6); 127.5 (C-2′ and C-6′); 128.1 (C-4″); 129.0 (C-3′ and C-5′);
.
¯
(CDCl3, 250 MHz) δ: 2.44 (s, 6H, 2 CH3); 6.95 (s, 2H, H-2 and (M = 356.23): C, 84.23; H, 7.92; N, 7.86. Found: C, 84.01; H,
H-6); 6.97 (s, 1H, H-4); 7.51–7.58 (m, 3H, H-3′, H-4′ and H-5′); 7.80; N, 7.92.
7.95–8.05 (m, 2H, H-2′ and H-6′); 8.53 (s, 1H, CHvN).
13C-NMR (CDCl3, 63 MHz) δ: 21.0 (2 CH3); 118.4 (C-2 and C-6); 5,7-dimethyl-1,2,3,4-tetrahydroquinoline (7b). White solid, mp
127.4 (C-4); 128.4 and 128.5 (C-3′,5′ and C-2,6′); 130.9 (C-4′); 129–130 °C. IR (NaCl) ν: 3392, 1599 cm−1 1H-NMR (CDCl3,
250 MHz) δ: 1.87 (td, J = 12.5, 3.6 Hz, 1H, H-3ax); 2.25 (s, 3H,
(6b). Yield: CH3); 2.28 (s, 9H, 3 CH3); 2.35–2.41 (m, 1H, H-3eq); 2.38 (s, 3H,
100% as a pale red viscous liquid. IR (NaCl) ν: 1627 cm−1
CH3); 3.81 (d, J = 4.8 Hz, 1H, NH); 4.11 (br s, 1H, NH); 4.42
( )-(2S*,4R*)-4-(3,5-Dimethylphenylamino)-2-(4-methylphenyl)-
.
¯
136.0 (C-1′); 138.4 (C-3 and C-5); 151.6 (C-1); 159.7 (CHvN).
3,5-Dimethyl-N-(4-methylbenzylidene)aniline
.
¯
1H-NMR (CDCl3, 250 MHz) δ: 2.45 (s, 6H, 2 CH3); 2.50 (s, 3H, (dd, J = 12.5, 2.1 Hz, 1H, H-2); 4.59 (br s, 1H, H-4); 6.33 (s, 3H,
CH3); 6.94 (s, 2H, H-2 and H-6); 6.96 (s, 1H, H-4); 7.36 (d, J = H-2″, H-6″ and H-8); 6.41 (br s, 1H, H-4″); 6.48 (br s, 1H, H-6);
7.9 Hz, 2H, H-3′ and H-5′); 7.88 (d, J = 8.0 Hz, 2H, H-2′ and 7.19 (d, J = 8.0 Hz, 2H, H-3′ and H-5′); 7.34 (d, J = 8.0 Hz, 2H,
H-6′); 8.49 (s, 1H, CHvN). 13C-NMR (CDCl3, 63 MHz) δ: 21.0 H-2′ and H-6′). 13C-NMR (CDCl3, 63 MHz) δ: 19.1 (CH3); 21.5
(2 CH3); 21.2 (CH3); 118.4 (C-2 and C-6); 127.2 (C-4); 128.4 (C-2′ (CH3); 21.6 (CH3); 22.1 (2 CH3); 37.5 (C-3); 46.9 (C-4); 51.8
and C-6′); 129.1 (C-3′ and C-5′); 133.5 (C-1′); 138.2 (C-3 and (C-2); 110.6 (C-2″ and C-6″); 113.5 (C-8); 117.0 (C-4a); 119.5
C-5); 141.2 (C-4′); 151.9 (C-1); 159.4 (CHvN).
(C-4″); 121.2 (C-6); 127.3 (C-2′ and C-6′); 129.7 (C-3′ and C-5′);
3,5-Dimethyl-N-(4-methoxybenzylidene)aniline (6c). Yield: 137.8 (C-4′); 138.8 (C-7); 139.3 (C-5); 139.5 (C-3″ and C-5″);
100% as a pale red viscous liquid. IR (NaCl) ν: 1627 cm−1
.
141.3 (C-1′); 145.3 (C-8a); 147.1 (C-1″). Analysis: Calculated for
¯
1H-NMR (CDCl3, 250 MHz) δ: 2.41 (s, 6H, 2 CH3); 3.91 (s, 3H, C26H30N2 (M = 370.24): C, 84.28; H, 8.16; N, 6.76. Found: C,
OCH3); 6.90 (s, 2H, H-2 and H-6); 6.92 (s, 1H, H-4); 7.03 (d, J = 84.09; H, 7.98; N, 6.67.
8.8 Hz, 2H, H-3′ and H-5′); 7.90 (d, J = 8.8 Hz, 2H, H-2′ and
( )-(2S*,4R*)-4-(3,5-Dimethylphenylamino)-2-(4-methoxyphenyl)-
H-6′); 8.43 (s, 1H, CHvN). 13C-NMR (CDCl3, 63 MHz) δ: 21.0 (2 5,7-dimethyl-1,2,3,4-tetrahydroquinoline (7c). White solid. IR
CH3); 55.0 (OCH3); 113.8 (C-3′ and C-5′); 118.4 (C-2 and C-6); (NaCl) ν: 3391, 1599 cm−1. H-NMR (CDCl3, 250 MHz) δ: 1.86
1
¯
127.0 (C-4); 128.9 (C-1′); 130.1 (C-2′ and C-6′); 138.3 (C-3 and (td, J = 12.5, 3.6 Hz, 1H, H-3ax); 2.25 (s, 3H, CH3); 2.28 (s, 9H,
C-5); 152.0 (C-1); 159.0 (CHvN); 161.8 (C-4′).
3,5-Dimethyl-N-(4-chlorobenzylidene)aniline
3 CH3); 2.31–2.41 (m, 1H, H-3eq); 3.81 (d, J = 6.0 Hz, 1H, NH);
(6d). Yield: 3.84 (s, 3H, OCH3); 4.09 (br s, 1H, NH); 4.40 (dd, J = 11.9, 1.9
100% as a pale red viscous liquid. IR (NaCl) ν: 1627 cm−1
.
Hz, 1H, H-2); 4.59 (br s, 1H, H-4); 6.33 (s, 3H, H-2″, H-6″ and
¯
1H-NMR (CDCl3, 250 MHz) δ: 2.42 (s, 6H, 2 CH3); 6.91 (s, 2H, H-8); 6.41 (s, 1H, H-4″); 6.48 (s, 1H, H-6); 6.91 (d, J = 8.7 Hz,
H-2 and H-6); 6.96 (s, 1H, H-4); 7.49 (d, J = 8.4 Hz, 2H, H-3′ 2H, H-3′ and H-5′); 7.37 (d, J = 8.6 Hz, 2H, H-2′ and H-6′).
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13C-NMR (CDCl3, 63 MHz) δ: 19.1 (CH3); 21.6 (CH3); 22.1
( )-(2S*,4R*)-4-(4-Bromophenylamino)-2-phenyl-5,7-dimethyl-
(2 CH3); 37.4 (C-3); 46.9 (C-4); 51.4 (C-2); 55.8 (OCH3); 110.6 1,2,3,4-tetrahydroquinoline (8b). White solid, mp 119–120 °C.
(C-2″ and C-6″); 113.5 (C-8); 114.3 (C-3′ and C-5′); 117.0 (C-4a); IR (NaCl) ν: 3407, 1590 cm−1 1H-NMR (CDCl3, 250 MHz) δ:
.
¯
119.7 (C-4″); 121.2 (C-6); 128.5 (C-2′ and C-6′); 136.4 (C-1′); 1.90 (td, J = 12.5, 3.5 Hz, 1H, H-3ax); 2.23 (s, 3H, CH3); 2.27 (s,
138.8 (C-7); 139.3 (C-5); 139.5 (C-3″ and C-5″); 145.3 (C-8a); 3H, CH3); 2.33–2.38 (m, 1H, H-3eq); 3.96 (br s, 1H, NH); 4.17
147.1 (C-1″); 159.5 (C-4′). Analysis: Calculated for C26H30N2O (br s, 1H, NH-1); 4.45 (dd, J = 12.1, 2.3 Hz, 1H, H-2); 4.56 (br s,
(M = 386.24): C, 80.79; H, 7.82; N, 7.25. Found: C, 80.50; H, 1H, H-4); 6.35 (s, 1H, H-8); 6.48 (s, 1H, H-6); 6.60 (d, J = 7.9 Hz,
7.64; N, 7.25.
2H, H-2″ and H-6″); 7.30–7.46 (m, 7H, H-3″, H-5″ and Ph).
( )-(2S*,4R*)-4-(3,5-Dimethylphenylamino)-2-(4-chlorophenyl)- 13C-NMR (CDCl3, 63 MHz) δ: 18.9 (CH3); 21.5 (CH3); 37.1 (C-3);
5,7-dimethyl-1,2,3,4-tetrahydroquinoline (7d). White solid, mp 47.1 (C-4); 52.0 (C-2); 108.9 (C-4″); 113.5 (C-8); 114.2 (C-2″ and
137–138 °C. IR (NaCl) ν: 3390 (NH), 1598 cm−1 1H-NMR C-6″); 116.4 (C-4a); 121.3 (C-6); 127.3 (C-2′ and C-6′); 128.1
.
¯
(CDCl3, 250 MHz) δ: 1.84 (td, J = 12.5, 3.5 Hz, 1H, H-3ax); 2.25 (C-4′); 129.0 (C-3′ and C-5′); 132.5 (C-3″ and C-5″); 139.1 (C-5
(s, 3H, CH3); 2.29 (s, 9H, 3 CH3); 2.31–2.41 (m, 1H, H-3eq); 3.79 and C-7); 143.9 (C-1′); 145.2 (C-8a); 145.9 (C-1″). Analysis:
(d, J = 5.3 Hz, 1H, NH); 4.08 (br s, 1H, NH-1); 4.44 (dd, J = 12.0, Calculated for C23H23BrN2 (M = 407.35): C, 67.82; H, 5.69; N,
2.1 Hz, 1H, H-2); 4.59 (br s, 1H, H-4); 6.33 (s, 2H, H-2″ and 6.88. Found: C, 67.45; H, 5.53; N 7.25.
H-6″); 6.36 (s, 1H, H-8); 6.43 (s, 1H, H-4″); 6.50 (s, 1H, H-6);
7.30–7.43 (m, 4H, H-2′, H-3′, H-5′ and H-6′). 13C-NMR (CDCl3, dimethyl-1,2,3,4-tetrahydroquinoline (8c). White solid, mp
63 MHz) δ: 19.1 (CH3); 21.6 (CH3); 22.0 (2 CH3); 37.6 (C-3); 46.8 145–146 °C. IR (NaCl) ν: 3404, 1589 cm−1 1H-NMR (CDCl3,
( )-(2S*,4R*)-4-(3,5-Dichlorophenylamino)-2-phenyl-5,7-
.
¯
(C-4); 51.6 (C-2); 110.5 (C-2″ and C-6″); 113.6 (C-8); 117.1 250 MHz) δ: 1.91 (td, J = 12.8, 3.6 Hz, 1H, H-3ax); 2.22 (s, 3H,
(C-4a); 119.7 (C-4″); 121.5 (C-6); 128.8 (C-3′ and C-5′); 129.1 CH3); 2.27 (s, 3H, CH3); 2.27–2.33 (m, 1H, H-3eq); 4.08 (d, J =
(C-2′ and C-6′); 133.6 (C-4′); 138.8 (C-7); 139.3 (C-5); 139.6 (C-3″ 6.0 Hz, 1H, NH); 4.16 (br s, 1H, NH-1); 4.38 (dd, J = 12.0,
and C-5″); 142.8 (C-1′); 145.0 (C-8a); 147.0 (C-1″). Analysis: 2.1 Hz, 1H, H-2); 4.53 (br s, 1H, H-4); 6.35 (s, 1H, H-8); 6.49 (s,
Calculated for C25H27ClN2 (M = 390.19): C, 76.80; H, 6.96; N, 1H, H-6); 6.53 (d, J = 1.7 Hz, 2H, H-2″ and H-6″); 6.70 (t, J =
7.17. Found: C, 76.35; H, 6.78; N, 7.30.
1.7 Hz, 1H, H-4″); 7.33–7.46 (m, 5H, Ph). 13C-NMR (CDCl3,
( )-(2S*,4R*)-4-(3,5-Dimethylphenylamino)-2-(4-bromophenyl)- 63 MHz) δ: 18.9 (CH3); 21.6 (CH3); 36.9 (C-3); 46.9 (C-4); 52.1
5,7-dimethyl-1,2,3,4-tetrahydroquinoline (7e). White solid, mp (C-2); 110.8 (C-2″ and C-6″); 113.6 (C-8); 115.7 (C-4a); 117.4
130–131 °C. IR (NaCl) ν: 3389.6 (NH), 1598.6 cm−1 1H-NMR (C-4″); 121.4 (C-6); 127.3 (C-2′ and C-6′); 128.3 (C-4′); 129.1 (C-3′
.
¯
(CDCl3, 250 MHz) δ: 1.84 (td, J = 12.5, 3.5 Hz, 1H, H-3ax); 2.25 and C-5′); 136.1 (C-3″ and C-5″); 139.1 (C-7); 139.4 (C-5); 143.7
(s, 3H, CH3); 2.29 (s, 9H, 3 CH3); 2.31–2.41 (m, 1H, H-3eq); 3.79 (C-1′); 145.2 (C-8a); 148.3 (C-1″). Analysis: Calculated for
(d, J = 4.9 Hz, 1H, NH); 4.08 (br s, 1H, NH); 4.43 (dd, J = 11.8, C23H22Cl2N2 (M = 397.34): C, 69.52; H, 5.58; N, 7.05. Found: C,
1.6 Hz, 1H, H-2); 4.58 (br s, 1H, H-4); 6.33 (s, 2H, H-2″ and 69.83; H, 5.79; N, 6.97.
H-6″); 6.36 (s, 1H, H-8); 6.43 (s, 1H, H-4″); 6.50 (s, 1H, H-6);
Synthesis of 2-arylquinolines 10. General procedure. To a
7.33 (d, J = 8.4 Hz, 2H, H-2′ and H-6′); 7.50 (d, J = 8.4 Hz, 2H, stirred solution of the suitable aniline (3 mmol), the suitable
H-3′ and H-5′). 13C-NMR (CDCl3, 63 MHz) δ: 19.1 (CH3); 21.6 aromatic aldehyde (1 equiv.) and CAN (10 mol%) in aceto-
(CH3); 22.1 (2 CH3); 37.6 (C-3); 46.8 (C-4); 51.6 (C-2); 110.6 nitrile (10 mL) was added dropwise a mixture of the same or a
(C-2″ and C-6″); 113.6 (C-8); 117.1 (C-4a); 119.7 (C-4″); 121.6 different aniline (1 equiv.) and ethyl vinyl ether (1 equiv.) in
(C-6); 121.7 (C-4′) 129.2 (C-2′ and C-6′); 132.1 (C-3′ and C-5′); acetonitrile (5 mL). The reaction mixture was stirred at room
138.9 (C-7); 139.3 (C-5); 139.6 (C-3″ and C-5″); 143.4 (C-1′); temperature for 3 h and upon completion, as judged by TLC, it
145.0 (C-8a); 147.0 (C-1″). Analysis: Calculated for C25H27BrN2 was diluted with water (20 mL) and extracted with dichloro-
(M = 434.14): C, 68.96; H, 6.25; N, 6.43. Found: C, 68.68; H, methane (3 × 20 mL). In some cases where an emulsion was
6.12; N, 6.61.
formed, the dichloromethane extracts were shaken with brine
( )-(2S*,4R*)-4-(4-Chlorophenylamino)-2-phenyl-5,7-dimethyl- (10 mL). The combined organic layers were dried over anhy-
1,2,3,4-tetrahydroquinoline (8a). White solid, mp 114–115 °C. drous Na2SO4 and filtered, and the solvent was evaporated
IR (NaCl) ν: 3395, 1598 cm−1 1H-NMR (CDCl3, 250 MHz) δ: under reduced pressure. The residue was dissolved in metha-
.
¯
1.89 (td, J = 12.8, 3.6 Hz, 1H, H-3ax); 2.22 (s, 3H, CH3); 2.28 (s, nol (30 mL), and FeCl3·6H2O (2.5 equiv.) was added. The solu-
3H, CH3); 2.29–2.36 (m, 1H, H-3eq); 3.95 (br s, 1H, NH); 4.13 tion was stirred at room temperature for 3 h and evaporated to
(br s, 1H, NH-1); 4.43 (dd, J = 12.1, 2.3 Hz, 1H, H-2); 4.55 (br s, dryness. The residue was taken up with water (20 mL) and
1H, H-4); 6.36 (s, 1H, H-8); 6.49 (s, 1H, H-6); 6.62 (d, J = 8.8 Hz, extracted with dichloromethane (3 × 20 mL). The combined
2H, H-2″ and H-6″); 7.17 (d, J = 8.8 Hz, 2H, H-3″ and H-5″); organic layers were dried over anhydrous Na2SO4 and evapor-
7.32–7.46 (m, 5H, Ph). 13C-NMR (CDCl3, 63 MHz) δ: 18.9 (CH3); ated, and the residue was purified by chromatography on silica
21.5 (CH3); 37.2 (C-3); 47.2 (C-4); 52.0 (C-2); 113.5 (C-8); 113.7 gel, eluting with a 97 : 3 petroleum ether–ethyl acetate mixture.
(C-2″ and C-6″); 116.5 (C-4a); 121.3 (C-6); 122.0 (C-4″); 127.3
2-Phenyl-5,7-dimethylquinoline (10a). White solid, mp
1H-NMR (CDCl3,
(C-2′ and C-6′); 128.1 (C-4′); 129.0 (C-3′ and C-5′); 129.7 (C-3″ 89–90 °C. IR (NaCl) ν: 1619, 1598 cm−1
.
¯
and C-5″); 139.0 (C-7); 139.1 (C-5); 143.9 (C-1′); 145.2 (C-8a); 250 MHz) δ: 2.57 (s, 3H, CH3); 2.70 (s, 3H, CH3); 7.23 (s, 1H,
145.5 (C-1″). Analysis: Calculated for C23H23ClN2 (M = 362.15): H-6); 7.45–7.63 (m, 3H, H-3′, H-4′ and H-5′); 7.85 (d, J = 8.7 Hz,
C, 76.12; H, 6.39; N, 7.72. Found: C, 75.85; H, 6.26; N, 7.89.
1H, H-3); 7.86 (s, 1H, H-8); 8.18 (dd, J = 8.4, 1.6 Hz, 2H, H-2′
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and H-6′); 8.35 (d, J = 8.7 Hz, 1H, H-4). 13C-NMR (CDCl3, (CDCl3, 250 MHz) δ: 2.57 (s, 3H, CH3); 2.71 (s, 3H, CH3); 7.25
63 MHz) δ: 18.5 (CH3); 21.8 (CH3); 117.6 (C-3); 124.5 (C-4a); (s, 1H, H-6); 7.68 (dd, J = 6.8, 2.0 Hz, 2H, H-3′ and H-5′); 7.82
126.9 (C-6); 127.4 (C-3′ and C-5′); 128.7 (C-2′ and C-6′); 129.1 (d, J = 8.8 Hz, 1H, H-3); 7.84 (s, 1H, H-8); 8.08 (dd, J = 6.8, 2.0
(C-4′ and C-8); 132.9 (C-4); 133.9 (C-5); 139.4 and 139.7 (C-1′ Hz, 2H, H-2′ and H-6′); 8.38 (d, J = 8.7 Hz, 1H, H-4). 13C-NMR
and C-7); 148.8 (C-8a); 156.7 (C-2). Analysis: Calculated for (CDCl3, 63 MHz) δ: 18.5 (CH3); 21.8 (CH3); 117.2 (C-3); 123.7
C17H15N2 (M = 233.31): C, 87.52; H, 6.48; N, 6.00. Found: C, (C-4′); 124.6 (C-4a); 126.8 (C-6); 128.9 (C-2′ and C-6′); 129.4
87.22; H, 6.59; N, 5.97.
2-(4-Chlorophenyl)-5,8-dimethylquinoline (10b). Pale yellow 139.8 (C-7); 148.7 (C-8a); 155.4 (C-2). Analysis: Calculated for
viscous oil. IR (NaCl) ν: 1602, 1563 cm−1 1H-NMR (CDCl3, C17H14BrN (M = 312.20): C, 65.40; H, 4.52; N, 4.49. Found: C,
250 MHz) δ: 2.70 (s, 3H, CH3); 2.89 (s, 3H, CH3); 7.28 (d, J = 63.77; H, 4.47; N, 4.35.
(C-8); 131.9 (C-3′ and C-5′); 133.2 (C-4); 133.9 (C-5); 138.5 (C-1′);
.
¯
7.6 Hz, 1H, H-6); 7.45–7.57 (m, 3H, H-7, H-3′ and H-5′); 7.91 (d,
2-(2-Furyl)-5,7-dimethylquinoline (10g). Pale yellow oil. IR
1
J = 8.8 Hz, 1H, H-3); 8.25 (d, J = 8.5 Hz, 2H, H-2′ and H-6′); 8.39 (NaCl) ν: 1619, 1598 cm−1. H-NMR (CDCl3, 250 MHz) δ: 2.54
¯
(d, J = 8.8 Hz, 1H, H-4). 13C-NMR (CDCl3, 63 MHz) δ: 17.8 (CH3); (s, 3H, CH3); 2.67 (s, 3H, CH3); 6.58–6.63 (m, 1H, H-4′); 7.19 (s,
18.4 (CH3); 117.1 (C-3); 126.4 (C-4a); 126.6 (C-6); 128.5 (C-2′ and 1H, H-6); 7.23 (d, J = 3.4 Hz, 1H, H-3′); 7.65 (s, 1H, H-5′); 7.79
C-6′); 128.8 (C-3′ and C-5′); 129.4 (C-7); 131.9 (C-5); 133.5 (C-4); (d, J = 8.9 Hz, 1H, H-3); 7.81 (s, 1H, H-8); 8.28 (d, J = 8.3 Hz,
135.2 (C-4′); 135.4 (C-8); 138.1 (C-1′); 147.2 (C-8a); 153.5 (C-2). 1H, H-4). 13C-NMR (CDCl3, 63 MHz) δ: 18.4 (CH3); 21.7 (CH3);
Analysis: Calculated for C17H14ClN (M = 267.75): C, 76.26; H, 109.6 (C-4′); 112.0 (C-3′); 116.0 (C-3); 124.4 (C-4a); 126.5 (C-6);
5.27; N, 5.23. Found: C, 75.94; H, 5.15; N, 5.37.
129.0 (C-8); 132.7 (C-4); 133.8 (C-5); 139.6 (C-7); 143.8 (C-5′);
2-(4-Methylphenyl)-5,7-dimethylquinoline (10c). Pale yellow 148.4 and 148.5 (C-2′ and C-8a); 153.7 (C-2). Analysis: Calcu-
1
solid, mp 101–102 °C. IR (NaCl) ν: 1621, 1598 cm−1. H-NMR lated for C15H13NO (M = 223.27): C, 80.69; H, 5.87; N, 6.27.
¯
(CDCl3, 250 MHz) δ: 2.47 (s, 3H, CH3); 2.56 (s, 3H, CH3); 2.70 Found: C, 75.33; H, 5.68; N, 6.01.
(s, 3H, CH3); 7.22 (s, 1H, H-6); 7.36 (d, J = 8.3 Hz, 2H, H-3′ and
2-(2-Thienyl)-5,7-dimethylquinoline (10h). White solid, mp,
1H-NMR (CDCl3,
H-5′); 7.84 (s, 1H, H-8); 7.85 (d, J = 8.7 Hz, 1H, H-3); 8.10 (d, J = 96–97 °C. IR (NaCl) ν: 1619, 1597 cm−1
.
¯
8.2 Hz, 2H, H-2′ and H-6′); 8.34 (d, J = 8.8 Hz, 1H, H-4). 250 MHz) δ: 2.51 (s, 3H, CH3); 2.63 (s, 3H, CH3); 7.10–7.20 (m,
13C-NMR (CDCl3, 63 MHz) δ: 18.5 (CH3); 21.3 (CH3); 21.8 2H, H-6 and H-4′); 7.45 (d, J = 6.3 Hz, 1H, H-3′); 7.72 (m, 3H,
(CH3); 117.5 (C-3); 124.4 (C-4a); 126.8 (C-6); 127.3 (C-3′ and H-3, H-8 and H-5′); 8.22 (d, J = 11.0 Hz, 1H, H-4). 13C-NMR
C-5′); 128.9 (C-8); 129.5 (C-2′ and C-6′); 132.9 (C-4); 133.9 (C-5); (CDCl3, 63 MHz) δ: 18.4 (CH3); 21.7 (CH3); 116.3 (C-3); 124.5
136.8 (C-4′); 139.2 (C-1′); 139.4 (C-7); 148.7 (C-8a); 156.7 (C-2). (C-4a); 125.5 (C-5′); 126.5 (C-6); 127.9 and 128.2 (C-3′ and C-4′);
Analysis: Calculated for C18H17N (M = 247.33): C, 87.41; H, 129.0 (C-8); 132.8 (C-4); 133.9 (C-5); 139.6 (C-7); 145.5 (C-2′);
6.93; N, 5.66. Found: C, 87.12; H, 6.97; N, 5.58.
148.6 (C-8a); 151.7 (C-2). Analysis: Calculated for C15H13NS
2-(4-Methoxyphenyl)-5,7-dimethylquinoline (10d). Pale yellow (M = 239.34): C, 75.28; H, 5.47; N, 5.85; S, 13.40. Found: C,
1
solid, mp 118–119 °C. IR (NaCl) ν: 1620, 1599 cm−1. H-NMR 74.99; H, 5.48; N, 6.01; S, 13.33.
¯
(CDCl3, 250 MHz) δ: 2.56 (s, 3H, CH3); 2.69 (s, 3H, CH3); 3.92
2-[3-[(2R*,4S*)-4-Methoxy-5,7-dimethyl-1,2,3,4-tetrahydro-
(s, 3H, OCH3); 7.08 (dd, J = 6.8, 2.1 Hz, 2H, H-3′ and H-5′); 7.21 quinolin-2-yl]phenyl]-5,7-dimethylquinoline (12). A mixture of
(s, 1H, H-6); 7.81 (d, J = 8.7 Hz, 1H, H-3); 7.83 (s, 1H, H-8); 8.17 3,5-dimethylaniline (2.42 g, 20 mmol) and isophthalaldehyde
(dd, J = 6.8, 2.0 Hz, 2H, H-2′ and H-6′); 8.32 (d, J = 8.8 Hz, H-4). (1.34 g, 10 mmol) was stirred vigorously with a glass rod for
13C-NMR (CDCl3, 63 MHz) δ: 18.5 (CH3); 21.8 (CH3); 55.3 5 min and then it was kept overnight at room temperature over
(OCH3); 114.1 (C-3′ and C-5′); 117.2 (C-3); 124.2 (C-4a); 126.7 filter paper to afford the corresponding imine 11 as a pale
(C-6); 128.7 (C-2′ and C-6′); 128.8 (C-8); 132.3 (C-1′); 132.8 (C-4); brown solid (3.40 g, 100%), which was used for the next step
1
133.8 (C-5); 139.3 (C-7); 148.7 (C-8a); 156.3 (C-2); 160.6 (C-4′). without further purification. IR (NaCl) ν: 1628 cm−1. H-NMR
¯
Analysis: Calculated for C18H17NO (M = 263.33): C, 82.10; H, (CDCl3, 250 MHz) δ: 2.40 (s, 12H, 4 CH3); 6.89 (s, 4H, H-2′ and
6.51; N, 5.32. Found: C, 81.84; H, 6.60; N, 5.28.
H-6′); 6.95 (s, 2H, H-4′); 7.61 (t, J = 7.6 Hz, 1H, H-5); 8.06 (dd,
2-(4-Chlorophenyl)-5,7-dimethylquinoline (10e). Pale yellow J = 7.7, 1.6 Hz, 2H, H-4 and H-6); 8.41 (s, 1H, H-2); 8.70 (s, 2H,
1
solid, mp 133–134 °C. IR (NaCl) ν: 1620, 1597 cm−1. H-NMR 2 CHvN). 13C-NMR (CDCl3, 63 MHz) δ: 21.3 (4 CH3); 118.6
¯
(CDCl3, 250 MHz) δ: 2.57 (s, 3H, CH3); 2.71 (s, 3H, CH3); 7.25 (C-2′ and C-6′); 127.8 (C-4′); 129.2 and 129.3 (C-2 and C-5);
(s, 1H, H-6); 7.52 (dd, J = 6.7, 1.8 Hz, 2H, H-3′ and H-5′); 7.82 130.9 (C-4 and C-6); 136.8 (C-1 and C-3); 138.8 (C-3′ and C-5′);
(d, J = 8.7 Hz, 1H, H-3); 7.84 (s, 1H, H-8); 8.15 (dd, J = 6.7, 151.7 (C-1′); 154.2 (2 CHvN).
1.8 Hz, 2H, H-2′ and H-6′); 8.37 (d, J = 8.8 Hz, 1H, H-4).
To a stirred solution of the imine 11 (1.02 g, 3 mmol) and
13C-NMR (CDCl3, 63 MHz) δ: 18.5 (CH3); 21.8 (CH3); 117.2 CAN (10 mol%) in acetonitrile (10 mL) was added dropwise a
(C-3); 124.6 (C-4a); 126.8 (C-6); 128.7 (C-2′ and C-6′); 128.9 (C-3′ mixture of 3,5-dimethylaniline (726 mg, 6 mmol) and ethyl
and C-5′); 129.3 (C-8); 133.2 (C-4); 133.9 (C-5); 135. 3 (C-4′); vinyl ether (450 mg, 6 mmol) in acetonitrile (5 mL). The reac-
138.1 (C-1′); 139.7 (C-7); 148.8 (C-8a); 155.4 (C-2). Analysis: tion mixture was stirred at room temperature for 3 h. Then, it
Calculated for C17H14ClN (M = 267.75): C, 76.26; H, 5.27; N, was diluted with water (20 mL) and extracted with dichloro-
5.23. Found: C, 75.95; H, 5.26; N, 5.16.
methane (3 × 20 mL). The combined dichloromethane extracts
2-(4-Bromophenyl)-5,7-dimethylquinoline (10f). Pale yellow were shaken with brine (1 × 10 mL), dried over anhydrous
1
solid, mp 116–117 °C. IR (NaCl) ν: 1619, 1598 cm−1. H-NMR Na2SO4 and evaporated under reduced pressure. The residue
¯
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was dissolved in methanol (30 mL), and FeCl3·6H2O (2.03 g,
7.5 mmol) was added. The solution was stirred at room temp-
erature for 3 h and then evaporated to dryness. The residue
was taken up with water (20 mL) and extracted with dichloro-
methane (3 × 20 mL). The combined organic layers were dried
over anhydrous Na2SO4 and evaporated, and the residue was
purified by chromatography on silica gel, eluting with a pet-
roleum ether–ethyl acetate (95 : 5, v/v) mixture, yielding
Notes and references
1 For reviews, see: (a) A. R. Katritzky, S. Rachwal and
B. Rachwal, Tetrahedron, 1996, 52, 15031; (b) V. Sridharan,
P. Suryavanshi and J. C. Menéndez, Chem. Rev., 2011, 111,
7157.
2 For reviews on related topics that contain information on
tetrahydroquinolines, see: (a) V. Kouznetsov, A. Palma,
C. Ewert and A. Varlamov, J. Heterocycl. Chem., 1998, 35,
761; (b) A. Mitchinson and A. Nadin, J. Chem. Soc., Perkin
Trans. 1, 1999, 2553; (c) A. Mitchinson and A. Nadin,
J. Chem. Soc., Perkin Trans. 1, 2000, 2862.
976 mg (77%) of 12 as a pale orange solid, mp 133 °C. IR
1
(NaCl) ν: 3390; 1619, 1599 cm−1. H-NMR (CDCl3, 250 MHz) δ:
¯
1.89 (td, J = 13.8, 3.0 Hz, 1H, H-3″ax); 2.24 (s, 3H, CH3); 2.35 (s,
3H, CH3); 2.47 (dt, J = 13.8, 2.3 Hz, 1H, H-3″eq); 2.57 (s, 3H,
CH3); 2.71 (s, 3H, CH3); 3.53 (s, 3H, OCH3); 4.21 (br s, 1H,
NH); 4.38 (t, J = 2.5 Hz, 1H, H-4″); 4.60 (dd, J = 11.5, 1.5 Hz,
1H, H-2″); 6.35 (s, 1H, H-8″); 6.47 (s, 1H, H-6″); 7.25 (s, 1H,
H-6); 7.53–7.63 (m, 2H, H-4′ and H-5′); 7.86 (s, 1H, H-8); 7.88
(d, J = 8.7 Hz, 1H, H-3); 8.10 (dt, J = 6.9, 1.8 Hz, 1H, H-6′); 8.31
(s, 1H, H-2′); 8.38 (d, J = 9.0 Hz, 1H, H-4). 13C-NMR (CDCl3,
63 MHz) δ: 18.5 (CH3); 18.6 (CH3); 21.1 (CH3); 21.8 (CH3); 34.9
(C-3″); 51.4 (C-2″); 55.4 (OCH3); 71.7 (C-4″); 113.2 (C-8″); 116.0
(C-4a″); 117.8 (C-3); 120.9 (C-6″); 124.6 (C-4a); 126.2 (C-6′);
126.8 (C-6); 127.8 (C-4′); 128.3 (C-5′); 129.1 (C-8); 129.2 (C-2′);
133.1 (C-4); 133.9 (C-5); 138.7 (C-5″, C-7″ and C-1′); 144.6 (C-7);
144.8 (C-1′); 148.7 (C-8a″); 149.3 (C-8a); 156.5 (C-2). Analysis:
Calculated for C29H30N2O2 (M = 422.56): C, 82.43; H, 7.16; N,
6.63. Found: C, 82.31; H, 7.18; N, 6.58.
3 (a) J. A. Sikorski, J. Med. Chem., 2006, 49, 1;
(b) M. DePasquale, G. Cadelina, D. Knight, W. Loging,
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4 (a) T. A. Rano, E. Sieber-McMaster, P. D. Pelton, M. Yang,
K. T. Demarest and G.-H. Kuo, Bioorg. Med. Chem. Lett.,
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K. T. Demarest, A. C. Gibbs, W. V. Murray, B. P. Damiano
and M. A. Connelly, J. Med. Chem., 2009, 52, 1768;
(c) A. Escribano, A. I. Mateo, E. M. Martín de la Nava,
D. R. Mayhugh, S. L. Cockerham, T. P. Beyer, R. J. Schmidt,
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( )-(2S*,4R*)-4-Methoxy-2-(4-methylphenyl)quinoline (13). A
solution of compound 7b (386.3 mg, 1 mmol) and CAN or
InCl3 (10 mol%) in MeOH (5 mL) was stirred at room temp-
erature until no starting material was detected by TLC (5 h)
and then it was diluted with water (10 mL) and extracted with
dichloromethane (3 × 10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and evaporated, and the
residue was purified by chromatography on silica gel, eluting
with a petroleum ether–ethyl acetate (99 : 1, v/v) mixture, yield-
5 J. Liu, Y. Wang, Y. Sun, D. Marshall, S. Miao, G. Tonn,
P. Anders, J. Tocker, H. L. Tang and J. Medina, Bioorg. Med.
Chem. Lett., 2009, 19, 6840.
6 L. S. Povarov, Russ. Chem. Rev., 1967, 36, 656.
7 S. Kobayashi, H. Ishitani and S. Nakagawa, Synthesis, 1995,
1195.
8 For reviews, see: (a) V. A. Glushkov and A. G. Tolstikov,
Russ. Chem. Rev., 2008, 77, 137; (b) V. V. Kouznetsov, Tetra-
hedron, 2009, 65, 2721; (c) D. Bello, R. Ramón and
R. Lavilla, Curr. Org. Chem., 2010, 14, 332.
9 For a representative example of Povarov reactions involving
nitrogen-substituted cyclic dienophiles, see: R. A. Batey and
D. A. Powell, Chem. Commun., 2001, 2362.
ing 292 mg (98%) of 13 as a yellow viscous liquid. IR (NaCl) ν:
¯
3392; 1600 cm−1
.
1H-NMR (CDCl3, 250 MHz) δ: 1.78 (td, J =
13.1, 3.1 Hz, 1H, H-3ax); 2.21–2.27 (m, 1H, H-3eq); 2.23 (s, 3H,
CH3); 2.34 (s, 3H, CH3); 2.40 (s, 3H, CH3); 3.50 (s, 3H, OCH3);
4.06 (br s, 1H, NH); 4.35 (t, J = 2.6 Hz, 1H, H-4); 4.42 (dd, J = 10 For representative examples of reactions involving N-vinyl-
12.4, 2.4 Hz, 1H, H-2); 6.30 (s, 1H, H-8); 6.46 (s, 1H, H-6); 7.22
(d, J = 7.8 Hz, 2H, H-3′ and H-5′); 7.39 (d, J = 8.0 Hz, 2H, H-2′
and H-6′). 13C-NMR (CDCl3, 63 MHz) δ: 18.5 (CH3); 21.0 (CH3);
21.1 (CH3); 34.8 (C-3); 50.9 (C-2); 55.2 (OCH3); 71.7 (C-4); 113.2
(C-8); 116.0 (C-4a); 120.8 (C-6); 126.8 (C-2′ and C-6′); 129.2 (C-3′
and C-5′); 137.3 (C-4′); 138.6 and 138.7 (C-5 and C-7); 140.9
(C-1′); 144.9 (C-8a). Calculated for C19H23NO2 (M = 297.39): C,
76.73; H, 7.80; N, 4.71. Found: C, 76.34; H, 7.49; N, 4.65.
amides and leading to cis-2,4-disubstituted products, see:
(a) G. Stevenson, P. Leeson, M. Rowley, I. Sanderson and
I. Stansfield, Bioorg. Med. Chem. Lett., 1992, 2, 371;
(b) B. Crousse, J. Bégué and D. Bonnet-Delpon, J. Org. Chem.,
2000, 65, 5009; (c) S. Talukdar, C.-T. Chen and J.-M. Fang,
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Chem., 2004, 1, 37; (f) D. B. Damon, R. W. Dugger,
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Acknowledgements
11 H. Xu, S. J. Zuend, M. G. Woll, Y. Tao and E. N. Jacobsen,
Science, 2010, 327, 986.
Financial support from MICINN (grant CTQ2009-12320-BQU),
MINECO (grant CTQ2012-33272) and UCM (Grupos de Investi- 12 V. Sridharan, C. Avendaño and J. C. Menéndez, Tetrahedron,
gación, grant GR35/10-A-920234) is gratefully acknowledged.
2007, 63, 673.
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Paper
13 For a review, see: D. Tejedor and F. García-Tellado, Chem. 19 For representative examples, see: (a) G. Manfroni, B. Gatto,
Soc. Rev., 2007, 36, 484.
O. Tabarrini, S. Sabatini, V. Cecchetti, G. Giaretta,
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14 Crystallographic data (excluding structure factors) for com-
pound 7b have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication under the
reference CCDC 894715.
15 For a review of the synthetic applications of CAN, with
emphasis on those that employ stoichiometric amounts of
the reagent, see: V. Nair and A. Deepthi, Chem. Rev., 2007, 20 For representative examples, see: (a) S. Kikuchi, M. Iwai
107, 1862.
and S.-i. Fukuzawa, Synlett, 2007, 2639; (b) F. Xiao, Y. Chen,
Y. Liu and J. Wang, Tetrahedron, 2008, 64, 2755;
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C. Madaan, Tetrahedron Lett., 2009, 50, 6861; (e) M. Zhu,
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16 For a review of the use of CAN as a catalyst in organic syn-
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17 V. Sridharan, C. Avendaño and J. C. Menéndez, Synthesis,
2008, 1039.
18 P. Leeson, R. W. Carling, K. W. Moore, A. M. Moseley,
J. D. Smith, G. Stevenson, T. Chan, R. Baker, A. C. Foster, 21 See, for instance: W.-W. Li, Y. Bing, M.-Q. Zha, T.-H. Li and
S. Grimwood, J. A. Kemp, G. R. Marshall and K. Hoogsteen,
X. Li, Acta Crystallogr., Sect. E Struct. Rep. Online, 2011, 67,
J. Med. Chem., 1992, 35, 1954.
m1464.
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