CAN-catalyzed three-component reaction between anilines and alkyl vinyl ethers: stereoselective synthesis of 2-methyl-1,2,3,4-tetrahydroquinolines and studies on their aromatization

Article abstract of DOI:10.1016/j.tet.2006.11.002

The CAN-catalyzed reaction between anilines and vinyl ethers at room temperature provides a convenient and efficient access to?4-alkoxy-2-methyl-1,2,3,4-tetrahydroquinolines. This reaction is stereoselective, favouring a cis arrangement for the alkoxy and methyl groups, and involves a three-component process that leaves a molecule of alcohol as the only side product. 2-Methylquinoline derivatives were efficiently prepared from 4-alkoxy-2-methyl-1,2,3,4-tetrahydroquinolines by Pd-C-promoted dehydrogenation.

Full text of DOI:10.1016/j.tet.2006.11.002

Tetrahedron 63 (2007) 673–681
CAN-catalyzed three-component reaction between anilines and
alkyl vinyl ethers: stereoselective synthesis of 2-methyl-1,2,3,4-
tetrahydroquinolines and studies on their aromatization
*
ꢀ
Vellaisamy Sridharan, Carmen Avendan˜o and J. Carlos Menendez
´
Departamento de Quꢀımica Orgaꢀnica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 9 October 2006; revised 30 October 2006; accepted 1 November 2006
Available online 28 November 2006
Abstract—The CAN-catalyzed reaction between anilines and vinyl ethers at room temperature provides a convenient and efficient access
to 4-alkoxy-2-methyl-1,2,3,4-tetrahydroquinolines. This reaction is stereoselective, favouring a cis arrangement for the alkoxy and methyl
groups, and involves a three-component process that leaves a molecule of alcohol as the only side product. 2-Methylquinoline derivatives
were efficiently prepared from 4-alkoxy-2-methyl-1,2,3,4-tetrahydroquinolines by Pd–C-promoted dehydrogenation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
spite of this progress, the development of new methods for
quinoline synthesis continues to be a very active research
area.
2-Methylquinolines are important synthetic intermediates,
and have been employed as starting materials for the prepa-
ration of many types of biologically active heterocyclic
compounds. Some relevant examples include the use of
8-hydroxy-2-methylquinoline as an intermediate in a synthe-
sis of lavendamycin methyl ester,1 a member of the strepto-
nigrin family of antitumour alkaloids,2 and the preparation
of styrylquinolines, some of which are HIV integrase
inhibitors,3,4 by condensation of 2-methylquinolines with
aromatic aldehydes. Additionally, 2-methylquinolines also
have interesting biological properties, including chemother-
apeutic5 (antibacterial, antimalarial and antitumour) and
antiplatelet6 activities. The synthesis of 2-methylquinoline
derivatives7,8 has usually relied on the traditional Doebner–
Within this context, we envisioned that a three-component
reaction starting from anilines and non-cyclic vinyl ethers,
which can be considered as acetaldehyde enol ethers, would
allow access to 2-methyl-1,2,3,4-tetrahydro-quinolines,
which would in turn be precursors to 2-methylquinolines
(Scheme 1). Such an approach has the advantage of proceed-
inginonlytwosteps, whilesimultaneouslyallowingthestudy
oftheintermediatetetrahydroquinolines, which areimportant
in themselves due to the broad range of biological properties
of this class of compounds in the agrochemical and phar-
maceutical fields.14 To name just one example, 2-methyl-5-
hydroxy-1,2,3,4-tetrahydroquinoline is a potent analgesic.15
von Miller,7–9 Combes,7,8 Conrad–Limpach–Knorr,7,8
10
Friedlander, Niementowski7,8 and Pfitzinger7,8 syntheses.
€
OR1
Although they have the advantage of their simplicity, these
methods also have considerable drawbacks such as low
yields and the use of harsh reaction conditions and highly
acidic reaction media, although in some cases improvements
of the classical reactions have been reported.9,10 More recent
methods for quinoline synthesis that can be applied to the
preparation of 2-methyl derivatives include treatment of
N-arylimines with a benzotriazole-derived Vilsmeier-type
reagent,11 heterocyclization of 2-aminobenzonitriles with
ketenes12 and dimethyltitanocene methylenation of N-(alk-
oxycarbonyl)amides derived from 2-allylanilines followed
by ring-closing metathesis of the resulting enamides.13 In
R
R
N
CH3
OR1
N
H
CH3
OR1
OR1
R
R
N
CH3
NH2
Scheme 1.
The three-component reaction between anilines16 and cyclic
vinyl ethers, like tetrahydropyran and dihydrofuran, has
been previously reported using a variety of catalysts that
* Corresponding author. Tel.: +34 91 3941840; fax: +34 91 3941822;
e-mail: josecm@farm.ucm.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.002

674
V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
include Dy(OTf)3,17 indium trichloride,18 iodine,19 a cation
exchange resin,20 Montmorillonite clay21 and Sc(OTf)3 in
ionic liquids.22 On the other hand, the related reaction with
non-cyclic ethers is almost unknown, and to our knowledge
it has been reported only once, in a procedure that involves
the use of the very expensive hexafluoropropanol as the re-
action medium.23 Indeed, with this exception, C-2 aliphatic
substituted tetrahydroquinolines were previously inaccessi-
ble using the Povarov reaction, because of the instability of
the intermediate aliphatic N-arylaldimine. We report here
that catalysis by cerium ammonium nitrate (CAN) allows
to carry out the proposed synthesis of 2-methyltetrahydro-
quinolines under very mild conditions.24 The reaction uses a
non-toxic catalyst, proceeds with maximum atom economy
and its only side product is one molecule of R3OH. It is
relevant to note that, although cerium is the most common
lanthanide, the use of its salts as Lewis acids has received
relatively little attention, and most of this work has focused
on Ce(III) species.25 However, Ce(IV) compounds have
good qualities such as their low toxicities and their stability
in water. Although Ce(IV) derivatives are normally
employed as one-electron oxidants, the use of the commer-
cially available, inexpensive and easily handled CAN in
C–C bond forming reactions has recently attracted much
attention,26 although these studies are still in their early
stages. One of the main goals to be achieved in this area is
the development of reactions that allow the use of catalytic
amounts of CAN.26c We also report here our studies on
the aromatization of 2-methyl-1,2,3,4-tetrahydroquinoline
derivatives.
2 (trans), in good to excellent yields, and typically with
about 9/1 cis/trans diastereoselectivity. An increase in the
amount of CAN to 15 mol % led to decreased reaction times
(e.g., 1 h for 1, 2h and 2 h for 1, 2i) without significantly
affecting the yields or the cis/trans ratios (entries 9 and
11). The stereochemistry of compounds 1 and 2 was deter-
mined by study of their 1H NMR spectra. The major isomer
obtained in the reaction between aniline and ethyl vinyl ether
(compound 1a) shows large coupling constants between H-4
and H-3ax (10.5 Hz) and H-2 and H-3ax (12.2 Hz), which are
consistent with a trans-diaxial relationship between these
protons and hence with a cis relationship between the ethoxy
and methyl groups. In agreement with this assignment, the
H-4eq proton of the minor product 2a appears as a triplet
with J¼2.9 Hz.
Hax
Hax
Heq
3
EtO
3
4
4
Heq
Heq
CH3
CH3
N
H
N
H
1
2
1
2
EtO
R
Hax
Hax
Hax
1a
2a
Regarding the mechanism of the reaction, radical intermedi-
ates could be in principle expected due to the strong oxidant
properties of CAN. However, an experiment involving the
addition of large amounts of 1,1-diphenylethylene, a well-
known radical trap, proved that this assumption was wrong,
since the reaction was not altered, and therefore CAN must
be assumed to act as a Lewis acid. Literature contains at least
one previous case where CAN was shown to remain in the
Ce(IV) oxidation state by cyclic voltammetry measure-
ments, and hence to behave as a Lewis acid.27 We propose
for our CAN-catalyzed transformation the domino mecha-
nism28 summarized in Scheme 3, that comprises five
individual steps. Thus, the CAN-catalyzed condensation
between the starting aniline and one molecule of the alkyl
vinyl ether, which can be regarded as an enol ether derived
from acetaldehyde, affords imine 3, which then undergoes
2. Results and discussion
As shown in Scheme 2 and Table 1, treatment of aniline
derivatives with vinyl ethers in the presence of 5 mol %
CAN in acetonitrile at room temperature led to the corre-
sponding 2-methyl-1,2,3,4-tetrahydroquinolines 1 (cis) and
OR3
OR3
R2
OR3
CH2
R2
R2
CAN (5 mol %)
CH3CN, rt
+
+
NH2
N
H
CH3
N
H
CH3
R1
R1
R1
1
2
Scheme 2.
Table 1. CAN-catalyzed synthesis of 2-methyl-1,2,3,4-tetrahydroquinolines
Entry
Compound
R1
R2
R3
Reaction time
CAN, mol %
Yield, %
1/2 ratioa
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
h
i
H
H
H
OCH3
OCH3
OCH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
OCH3
OCH3
Cl
CH2CH3
nPr
1 h
1 h
1 h
45 min
45 min
45 min
1 h
3 h
1 h
5
5
5
5
5
5
5
5
15
5
75
73
76
80
88
90
64
70
72
71
75
74
89/11b
91/9
91/9
nBu
CH2CH3
90/10b
91/9
93/7
nPr
nBu
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
93/7
87/13
87/13
85/15b
85/15
80/20b
9
10
11
12
4 h
2 h
45 min
i
j
15
5
The cis/trans ratios were calculated from the 1H NMR spectra of the crude reaction products.
The minor trans product was isolated and characterized in these cases.
a
b

V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
675
- R3OH
CeIV
OR3
Ce(IV)
R
- Ce (IV)
OR3
CH3
R
+
NH2
R
N
3
CH3
N
H
CH2
OR3
N
CH2
R3O
- Ce (IV)
CH3
CH3
R
N
N
H
H
CH3
R
3O
5
R
R
4a
Ce(IV)
R3O
CH3
N
H
CH3
N
H
R
R3O
R
2
1
Scheme 3.
a CAN-catalyzed imino Diels–Alder reaction with a second
molecule of alkyl vinyl ether, now acting as an electron-rich
dienophile, to give the observed tetrahydroquinolines. The
imino Diels–Alder reaction (also known as the Povarov reac-
tion) is known to proceed in a stepwise manner, as proved by
the trapping of the intermediate oxonium species when the
reaction is carried out in the presence of nucleophiles,29
and therefore generation of intermediates 4 and 5 is
expected. The final cyclization step should take place
through a chair-like transition state, explaining the prefer-
ence for an equatorial arrangement of the alkoxy substituent,
and hence the cis stereochemistry observed for the major
products, and would be followed by deprotonation to give
compounds 1 and 2. Previous explanations for the stereo-
selectivity of Povarov-like reactions that have assumed
a concerted mechanism23 can now be discarded.
under acidic conditions, since 2-phenyl-30 and 2-tri-
fluoromethyl-1,2,3,4-tetrahydroquinolines31,32 are known
to aromatize efficiently by treatment with aqueous HCl.
However, in our case the typical literature conditions (2 M
HCl–CH3CN, rt) led to mixtures of the desired aromatic
compounds 6 and alcohols 7 and 8 (Scheme 4). The forma-
tion of the latter compound is probably due to its stabiliza-
tion by intramolecular hydrogen bonding between the NH
and the axial OH group, arising from the addition of water
to a benzylic cation generated by elimination of ethanol from
1 in the acidic reaction medium. Reflux conditions, rather
surprisingly, allowed the isolation of dihydroquinoline 9,
which can be considered to be an intermediate of the process
since it can generate equimolecular mixtures of the quino-
line 6a and the tetrahydroquinoline derivative 10 through
dismutation involving a Brønsted acid-catalyzed hydrogen
transfer process (Scheme 5). The last transformation can
be considered as closely related to the recently described
reduction of quinolines by Hantzsch dihydropyridines in
the presence of Brønsted acids.33
With an efficient synthesis of 1-methyl-1,2,3,4-tetrahydro-
quinolines in hand, we next examined their transformation
into 2-methylquinolines. We first studied their behaviour
OH
OH
R
R
R
+
+
N
H
CH3
N
CH3
N
H
CH3
6
7
8
Starting
Overall yield
(%)
2M HCl
CH3CN, rt
R
Time (h)
6 : 7 : 8
compound
1a
1a
1i
H
H
OCH3
8
14
16
95
96
86
15 : 30 : 55
29 : 27 : 44
7 : 32 : 61
OCH2CH3
R
N
H
CH3
1
2M HCl
CH3CN,
reflux
+
+
(R = H)
N
H
CH3
N
CH3
N
H
CH3
6a
9
10
Starting
Overall yield
(%)
Time (h)
6a : 9 : 10
compound
1a
0.5
2
96
95
20 : 60 : 20
40 : 20 : 40
1a
Scheme 4.

676
V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
H+
a non-toxic and inexpensive catalyst, with an alcohol mole-
1a
8
9
+
7
H+
cule as the only side product. The efficient aromatization of
the 4-alkoxy-2-methyltetrahydroquinoline derivatives thus
obtained to 2-methylquinolines in the presence of Pd–C
was also demonstrated.
- H2O
Dismutation
10
6a +
CH3
N
H
H
O
8
3. Experimental
3.1. General
Scheme 5.
All reagents were of commercial quality (Aldrich, Fluka,
SDS, Probus) and were used as received. Solvents (from
SDS) were dried and purified using standard techniques.
Reactions were monitored by thin layer chromatography,
on aluminium plates coated with silica gel with fluorescent
indicator (SDS CCM221254). Separations by flash chroma-
tography were performed on silica gel (SDS 60 ACC, 40–
63 mm particle size). Melting points were measured with
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 exam-
ined as films on a NaCl disk. NMR spectra were obtained
on a Bruker Avance instrument (250 MHz for 1H,
62.9 MHz for 13C), maintained by the Servicio de RMN,
Universidad Complutense, with CDCl3 as solvent. Combus-
tion elemental analyses were determined by the Servicio de
In view of these results, alternative methods for the aromati-
zation of compounds 1 were investigated. The most reliable
one was dehydrogenation in the presence of palladium,
which, to our knowledge, had not been previously applied
to the transformation of 4-alkoxy-1,2,3,4-tetrahydroquino-
lines into 4-unsubstituted quinoline derivatives. As shown
in Scheme 6 and Table 2, refluxing compounds 1 in the pres-
ence of Pd–C resulted in their efficient transformation into
the 4-unsubstituted 2-methylquinoline derivatives 6 where
ethanol elimination has taken place concomitantly with
dehydrogenation. These compounds were accompanied in
some instances by small amounts of the 4-ethoxy-2-methyl-
quinolines 11. Aromatization of the chloro derivative 1j led
to a mixture of 6j and 6a, the latter compound being gener-
ated from hydrogenolysis of the C–Cl bond in 6j by the
hydrogen liberated in the aromatization process.
ꢀ
Microanalisis Elemental, Universidad Complutense, using
a Leco 932 CHNS microanalyzer.
R2
3.2. General procedure for the synthesis of
tetrahydroisoquinolines
N
CH3
OCH2CH3
R1
Pd/C,
reflux
R2
6
+
To a stirred solution of the starting aniline (3 mmol) and
alkyl vinyl ether (7.5 mmol) in acetonitrile (15 mL) was
added CAN (5 mol %). Stirring was continued for the time
period specified in Table 1. After completion of the reaction,
as indicated by TLC, the mixture was extracted with di-
chloromethane (2ꢀ20 mL), dried (anhydrous Na2SO4) and
evaporated. The ratio of cis/trans isomers was calculated
from the crude 1H NMR spectra and the mixture was sepa-
rated by silica gel column chromatography eluting with a
petroleum ether–ethyl acetate (96/4, v/v) mixture. Charac-
terization data are given below.
N
H
CH3
OCH2CH3
R1
R2
1
N
CH3
R1
11
Scheme 6.
In conclusion, we have shown that addition of CAN allows
the efficient and stereoselective preparation of 2-methyl-
1,2,3,4-tetrahydroquinolines in a three-component protocol
starting from anilines and vinyl ethers. This user-friendly
new method proceeds under very mild conditions, using
3.2.1. ( )-cis-4-Ethoxy-2-methyl-1,2,3,4-tetrahydroqui-
noline (1a).23 Viscous oil. IR (neat) 3374.1, 2970.3,
2925.8, 1609.0, 1487.6, 1310.7, 1095.2 cmꢁ1 1H NMR
.
Table 2. Aromatization of 1-alkoxy-1,2,3,4-tetrahydroquinolines 1 in the
presence of Pd–C
(CDCl3, 250 MHz) d 1.26–1.35 (m, 6H), 1.70 (q, J¼
12.2 Hz, 1H), 2.27 (ddd, J¼12.2, 5.7, 2.6 Hz, 1H), 3.52–
3.78 (m, 4H), 4.70 (dd, J¼10.5, 5.7 Hz, 1H), 6.50 (dd,
J¼8.0, 1.0 Hz, 1H), 6.72 (td, J¼7.5, 1.1 Hz, 1H), 7.05 (td,
J¼7.5, 1.0 Hz, 1H), 7.38 (d, J¼7.6 Hz, 1H). 13C NMR
(CDCl3, 62.9 MHz) d 16.1, 23.0, 36.5, 46.8, 63.8, 74.1,
114.3, 117.9, 123.0, 127.7, 128.5, 145.0. Anal. Calcd for
C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.46;
H, 8.87; N, 7.68.
Starting R1
compd
R2
Solvent
Time Overall
(h)
6/11
yield (%) ratioa
1a
1d
1g
1h
1i
H
H
H
Toluene
Toluene
Toluene
Toluene
5
5
4
5
5
93
85
82
92
96
85
95
81/19
OCH3
CH3
H
H
H
100/0
100/0
88/12
74/26
62/23b
H
CH3
OCH3 Toluene
OCH3 Methanol 18
Cl Toluene
1i
1j
c
—
H
4
3.2.2. ( )-trans-4-Ethoxy-2-methyl-1,2,3,4-tetrahydro-
quinoline (2a). Viscous oil. IR (neat) 3382.1, 2968.3,
This ratio was calculated from the 1H NMR spectra of the crude reaction
products.
These products were accompanied by 15% of trans-1-methoxy-4-methyl-
1,2,3,4-tetrahydroquinoline (compound 12).
An inseparable mixture of 6j and 6a was isolated in 60/40 ratio.
a
2918.4, 1610.9, 1493.2, 1316.7, 1158.0, 1077.6 cmꢁ1
.
b
c
1H NMR (CDCl3, 250 MHz) d 1.22–1.29 (m, 6H), 1.51
(ddd, J¼13.5, 12.1, 3.1 Hz, 1H), 2.13 (dt, J¼13.5,

V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
677
2.7 Hz, 1H), 3.57–3.68 (m, 3H), 3.93 (br s, 1H), 4.33 (t,
J¼2.9 Hz, 1H), 6.56 (dd, J¼8.0, 0.7 Hz, 1H), 6.67 (td,
J¼7.4, 1.0 Hz, 1H), 7.06–7.16 (m, 2H). 13C NMR (CDCl3,
62.9 MHz) d 16.1, 22.7, 35.9, 42.6, 63.5, 73.3, 114.9,
116.8, 120.2, 129.5, 131.5, 145.4. Anal. Calcd for
C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 76.05;
H, 8.60; N, 7.97.
2959.7, 2874.0, 2840.2, 1588.9, 1494.8, 1331.7, 1247.9,
1084.1 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.03 (t,
.
J¼7.5 Hz, 3H), 1.33 (d, J¼6.3 Hz, 3H), 1.67–1.81 (m,
3H), 2.28 (ddd, J¼12.2, 5.7, 2.6 Hz, 1H), 3.44–3.70 (m,
3H), 3.86 (s, 3H), 4.17 (br s, 1H), 4.74 (dd, J¼10.5,
5.7 Hz, 1H), 6.68–6.73 (m, 2H), 7.03–7.06 (m, 1H).
13C NMR (CDCl3, 62.9 MHz) d 11.3, 22.9, 23.9, 36.3,
46.5, 55.8, 70.2, 74.3, 108.8, 116.8, 119.8, 123.2, 134.9,
146.2. Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N,
5.95. Found: C, 71.65; H, 8.70; N, 6.28.
3.2.3. ( )-cis-4-Propoxy-2-methyl-1,2,3,4-tetrahydroqui-
noline (1b). Viscous oil. IR (neat) 3384.5, 2960.6, 2922.7,
2871.9, 1609.0, 1487.5, 1310.5, 1090.8 cmꢁ1 1H NMR
.
(CDCl3, 250 MHz) d 1.05 (t, J¼7.5 Hz, 3H), 1.30 (d, J¼
6.3 Hz, 3H), 1.64–1.78 (m, 3H), 2.29 (ddd, J¼12.2, 5.7,
2.6 Hz, 1H), 3.46–3.73 (m, 4H), 4.70 (dd, J¼10.5, 5.7 Hz,
1H), 6.51 (dd, J¼8.0, 1.1 Hz, 1H), 6.73 (td, J¼8.0, 1.0 Hz,
1H), 7.06 (td, J¼8.0, 1.0 Hz, 1H), 7.41 (dd, J¼8.0,
1.1 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz) d 11.3, 23.0,
23.9, 36.4, 46.8, 70.3, 74.3, 114.3, 117.9, 123.1, 127.8,
128.5, 145.0. Anal. Calcd for C13H19NO: C, 76.06; H,
9.33; N, 6.82. Found: C, 76.48; H, 8.93; N, 7.61.
3.2.8. ( )-cis-4-Butoxy-8-methoxy-2-methyl-1,2,3,4-tet-
rahydroquinoline (1f). Viscous oil. IR (neat) 3410.5,
2957.4, 2929.2, 2868.0, 1588.8, 1494.6, 1331.6, 1248.1,
1086.3 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 0.98 (t,
.
J¼7.2 Hz, 3H), 1.32 (d, J¼6.3 Hz, 3H), 1.41–1.56 (m,
2H), 1.62–1.80 (m, 3H), 2.27 (ddd, J¼12.2, 5.7, 2.6 Hz,
1H), 3.48–3.59 (m, 2H), 3.64–3.73 (m, 1H), 3.86 (s, 3H),
4.16 (br s, 1H), 4.73 (dd, J¼10.5, 5.7 Hz, 1H), 6.68–6.70
(m, 2H), 7.03–7.07 (m, 1H). 13C NMR (CDCl3, 62.9 MHz)
d 14.4, 19.9, 22.9, 32.8, 36.3, 46.5, 55.8, 68.2, 74.3, 108.8,
116.8, 119.8, 123.2, 134.9, 146.2. Anal. Calcd for
C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C, 72.50;
H, 9.28; N, 5.82.
3.2.4. ( )-cis-4-Butoxy-2-methyl-1,2,3,4-tetrahydroqui-
noline (1c). Viscous oil. IR (neat) 3375.9, 2957.7, 2929.2,
2868.5, 1609.5, 1487.4, 1310.2, 1093.2 cmꢁ1 1H NMR
.
(CDCl3, 250 MHz) d 0.99 (t, J¼7.2 Hz, 3H), 1.28 (d,
J¼6.3 Hz, 3H), 1.44–1.57 (m, 2H), 1.62–1.76 (m, 3H),
2.28 (ddd, J¼12.2, 5.8, 2.6 Hz, 1H), 3.49–3.60 (m, 2H),
3.66–3.75 (m, 2H), 4.68 (dd, J¼10.4, 5.8 Hz, 1H), 6.50
(dd, J¼8.0, 1.0 Hz, 1H), 6.73 (td, J¼8.0, 1.0 Hz, 1H),
7.05 (td, J¼8.0, 1.0 Hz, 1H), 7.39 (dd, J¼8.0, 1.0 Hz).
13C NMR (CDCl3, 62.9 MHz) d 14.4, 19.9, 23.0, 32.8,
36.4, 46.7, 68.3, 74.3, 114.3, 117.9, 123.1, 127.7, 128.5,
145.0. Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N,
6.39. Found: C, 76.78; H, 9.33; N, 6.73.
3.2.9. ( )-cis-4-Ethoxy-2,8-dimethyl-1,2,3,4-tetrahydro-
quinoline (1g).34 Viscous oil. IR (neat) 3408.7, 2969.2,
2925.0, 2856.9, 1601.1, 1493.8, 1474.2, 1335.0,
1119.4 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.30–1.36
.
(m, 6H), 1.66–1.79 (m, 1H), 2.13 (s, 3H), 2.28 (ddd,
J¼12.2, 5.7, 2.6 Hz, 1H), 3.50 (br s, 1H), 3.55–3.78 (m,
3H), 4.75 (dd, J¼10.5, 5.7 Hz, 1H), 6.69 (t, J¼7.9 Hz,
1H), 6.98 (dd, J¼7.9, 1.5 Hz, 1H), 7.31 (dd, J¼7.9,
1.5 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz) d 16.1, 17.8,
23.2, 36.2, 46.7, 63.6, 74.3, 117.2, 121.1, 122.5, 125.5,
129.5, 143.0. Anal. Calcd for C13H19NO: C, 76.06; H,
9.33; N, 6.82. Found: C, 75.76; H, 9.21; N, 6.87.
3.2.5. ( )-cis-4-Ethoxy-8-methoxy-2-methyl-1,2,3,4-tet-
rahydroquinoline (1d).23 Viscous oil. IR (neat) 3411.0,
2969.2, 2926.6, 2837.9, 1588.0, 1494.5, 1457.1, 1330.3,
1248.0, 1167.8, 1089.5 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d 1.28–1.34 (m, 6H), 1.74 (q, J¼12.2 Hz, 1H), 2.27 (ddd,
J¼12.2, 5.7, 2.4 Hz, 1H), 3.31–3.80 (m, 3H), 3.87 (s, 3H),
4.15 (br s, 1H), 4.75 (dd, J¼10.4, 5.7 Hz, 1H), 6.67–6.70
(m, 2H), 7.03–7.06 (m, 1H). 13C NMR (CDCl3, 62.9 MHz)
d 16.2, 23.0, 36.4, 46.5, 55.8, 63.6, 74.2, 108.8, 116.8,
119.7, 123.0, 135.0, 146.2. Anal. Calcd for C13H19NO2: C,
70.56; H, 8.65; N, 6.33. Found: C, 70.98; H, 8.70; N, 6.74.
3.2.10. ( )-cis-4-Ethoxy-2,6-dimethyl-1,2,3,4-tetrahydro-
quinoline (1h). Viscous oil. IR (neat) 3371.3, 2969.4,
2918.2, 2856.4, 1617.9, 1506.0, 1338.8, 1300.5, 1172.1,
1097.0 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.28 (d,
.
J¼6.3 Hz, 3H), 1.34 (d, J¼7.0 Hz, 3H), 1.61–1.75 (m,
1H), 2.24–2.31 (m, 4H), 3.47–3.79 (m, 4H), 4.68 (dd,
J¼10.4, 5.9 Hz, 1H), 6.44 (d, J¼8.1 Hz, 1H), 6.86 (dd,
J¼8.1, 1.5 Hz, 1H), 7.20 (d, J¼1.5 Hz, 1H). 13C NMR
(CDCl3, 62.9 MHz) d 16.2, 21.0, 23.0, 36.7, 46.9, 63.8,
74.2, 114.6, 123.1, 127.3, 128.1, 129.2, 142.7. Anal. Calcd
for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C,
76.36; H, 9.15; N, 7.32.
3.2.6. ( )-trans-4-Ethoxy-8-methoxy-2-methyl-1,2,3,4-
tetrahydroquinoline (2d).23 Viscous oil. IR (neat) 3415.5,
2966.7, 2934.0, 2860.1, 1612.6, 1587.1, 1501.0, 1458.3,
1
1332.7, 1246.8, 1169.7, 1077.6 cmꢁ1. H NMR (CDCl3,
250 MHz) d 1.26 (t, J¼7.0 Hz, 3H), 1.33 (d, J¼6.3 Hz,
3H), 1.53 (ddd, J¼13.5, 12.2, 3.2 Hz, 1H), 2.14 (dt,
J¼13.5, 2.3 Hz, 1H), 3.57–3.69 (m, 3H), 3.87 (s, 3H), 4.36
(t, J¼2.8 Hz, 1H), 4.39 (br s, 1H), 6.64 (t, J¼7.7 Hz, 1H),
6.73 (dd, J¼7.9, 1.5 Hz, 1H), 6.83 (dd, J¼7.5, 1.5 Hz,
1H). 13C NMR (CDCl3, 62.9 MHz) d 16.1, 22.7, 35.9,
42.2, 55.8, 63.6, 73.2, 109.4, 115.7, 120.2, 123.4, 135.4,
146.6. Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N,
6.33. Found: C, 70.84; H, 8.32; N, 6.66.
3.2.11. ( )-cis-4-Ethoxy-6-methoxy-2-methyl-1,2,3,4-tet-
rahydroquinoline (1i).34 Viscous oil. IR (neat) 3364.2,
2969.3, 2869.3, 1500.8, 1339.4, 1267.5, 1231.9, 1154.5,
1095.0 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.26 (d,
.
J¼6.3 Hz, 3H), 1.32 (t, J¼7.0 Hz, 3H), 1.60–1.74 (m, 1H),
7.26 (ddd, J¼12.2, 5.9, 2.3 Hz, 1H), 3.44–3.77 (m, 4H),
3.79 (s, 3H), 4.70 (dd, J¼10.6, 5.9 Hz, 1H), 6.48 (d,
J¼8.7 Hz, 1H), 6.67 (dd, J¼8.7, 2.9 Hz, 1H), 6.99 (d,
J¼2.9 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz) d 16.2,
23.0, 36.6, 47.1, 56.2, 63.6, 74.3, 112.6, 115.2, 115.8,
124.3, 139.2, 152.7. Anal. Calcd for C13H19NO2: C, 70.56;
H, 8.65; N, 6.33. Found: C, 70.18; H, 8.37; N, 6.54.
3.2.7. ( )-cis-8-Methoxy-2-methyl-4-propoxy-1,2,3,4-tet-
rahydroquinoline (1e). Viscous oil. IR (neat) 3411.3,

678
V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
3.2.12. ( )-trans-4-Ethoxy-6-methoxy-2-methyl-1,2,3,4-
tetrahydroquinoline (2i).34 IR (neat) 3375.6, 2967.6,
2927.1, 2862.1, 1503.6, 1346.9, 1254.0, 1156.2, 1077.5,
20.9, 36.6, 39.3, 40.3, 45.0, 64.4, 65.6, 112.6, 113.2,
115.9, 116.3, 120.9, 123.2, 125.5, 127.0, 127.9, 128.9,
142.9, 143.4.
1040.1 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.24–1.29
.
(m, 6H), 1.49 (ddd, J¼13.6, 12.0, 3.3 Hz, 1H), 2.12 (dt,
J¼13.6, 2.5 Hz, 1H), 3.52–3.71 (m, 3H), 3.77 (s, 3H), 4.29
(t, J¼2.8 Hz, 1H), 6.53 (d, J¼9.4 Hz, 1H), 6.72–6.76 (m,
2H). 13C NMR (CDCl3, 62.9 MHz) d 16.1, 22.7, 35.9,
42.9, 56.3, 63.8, 73.5, 116.1, 116.2, 116.3, 121.4, 139.7,
151.8. Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N,
6.33. Found: C, 70.85; H, 8.30; N, 6.72.
3.3.2. ( )-6-Methoxy-2-methyl-1,2,3,4-tetrahydroquino-
lin-4-ol cis–trans mixture (7i and 8i). H NMR (CDCl3,
1
250 MHz) d 1.22 (d, J¼6.4 Hz, 3H, 7i), 1.25 (d, J¼6.3 Hz,
3H, 8i), 1.49–1.62 (m, 2H, 7i and 8i), 1.99 (dt, J¼13.6,
2.6 Hz, 1H, 8i), 2.22 (ddd, J¼12.1, 5.9, 2.3 Hz, 1H, 7i),
3.43–3.52 (m, 2H, 7i and 8i), 3.75 (s, 6H, 7i and 8i), 4.68
(t, J¼2.9 Hz, 8i), 4.88 (dd, J¼10.6, 5.9 Hz, 1H, 7i), 6.46
(d, J¼8.6 Hz, 1H, 7i), 6.53 (d, J¼8.7 Hz, 1H, 8i), 6.68
(dd, J¼8.6, 2.9 Hz, 1H, 7i), 6.74 (dd, J¼8.7, 2.9 Hz, 1H,
8i), 6.80 (d, J¼2.9 Hz, 1H, 8i), 7.01 (d, J¼2.9 Hz, 1H, 7i).
13C NMR (CDCl3, 62.9 MHz) d 22.4, 22.8, 38.9, 41.4,
42.5, 47.2, 56.2, 56.3, 66.4, 67.6, 112.2, 115.1, 115.6,
115.9, 116.4, 116.7, 123.7, 126.4, 138.8, 139.4, 152.3,
152.8. Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82;
N, 7.25. Found: C, 68.65; H, 7.53; N, 7.38.
3.2.13. ( )-cis-6-Chloro-4-ethoxy-2-methyl-1,2,3,4-tetra-
hydroquinoline (1j).34 IR (neat) 3397.2, 2971.5, 2927.1,
2869.1, 1604.0, 1488.8, 1339.3, 1229.4, 1251.8,
1101.9 cmꢁ1 1H NMR (CDCl3, 250 MHz) d 1.26 (d,
.
J¼6.3 Hz, 3H), 1.32 (t, J¼7.0 Hz, 3H), 1.56–1.69 (m, 1H),
2.27 (ddd, J¼12.2, 5.7, 2.6 Hz, 1H), 3.50–3.82 (m, 4H),
4.60 (dd, J¼10.6, 5.7 Hz, 1H), 6.40 (d, J¼8.5 Hz, 1H),
6.97 (dd, J¼8.5, 2.5 Hz, 1H), 7.33 (d, J¼2.5 Hz, 1H). 13C
NMR (CDCl3, 62.9 MHz) d 16.1, 22.8, 36.1, 46.7, 64.2,
73.8, 115.3, 122.4, 124.5, 127.4, 128.4, 143.4. Anal. Calcd
for C12H16ClNO: C, 63.85; H, 7.14; N, 6.21. Found: C,
63.06; H, 6.92; N, 6.41.
3.3.3. 2-Methyl-1,2-dihydroquinoline (9). Viscous liquid.
IR (neat) 3386.6, 3052.3, 2923.0, 2844.2, 1603.5, 1498.2,
1
1310.6, 1153.3, 1122.1, 1039.0 cmꢁ1. H NMR (CDCl3,
250 MHz) d 1.34 (d, J¼6.5 Hz, 3H), 3.73 (br s, 1H), 4.43–
4.47 (m, 1H), 5.58 (dd, J¼9.8, 3.6 Hz, 1H), 6.33 (dd,
J¼9.8, 1.5 Hz, 1H), 6.43 (d, J¼7.9 Hz, 1H), 6.63
(td, J¼7.4, 1.1 Hz, 1H), 6.89 (dd, J¼7.4, 1.4 Hz, 1H), 7.00
(td, J¼7.7, 1.4 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz)
d 24.7, 48.7, 113.0, 117.9, 120.8, 125.6, 127.1, 127.5,
129.1, 144.3. Anal. Calcd for C10H11N: C, 82.72; H, 7.64;
N, 9.65. Found: C, 82.60; H, 7.59; N, 9.63.
3.2.14. ( )-trans-6-Chloro-4-ethoxy-2-methyl-1,2,3,4-tet-
rahydroquinoline (2j).34 IR (neat) 3403.9, 2970.0, 2919.9,
2867.4, 1608.0, 1492.1, 1348.0, 1309.6, 1268.3, 1160.0,
1077.6 cmꢁ1. 1H NMR (CDCl3, 250 MHz) d 1.23–1.29 (m,
6H), 1.46 (ddd, J¼13.6, 12.0, 3.2 Hz, 1H), 2.11 (dt,
J¼13.6, 2.6 Hz, 1H), 3.56–3.67 (m, 3H), 3.95 (br s, 1H),
4.27 (t, J¼2.9 Hz, 1H), 6.47 (d, J¼8.6 Hz, 1H), 7.03 (dd,
J¼8.6, 2.4 Hz, 1H), 7.11 (d, J¼2.4 Hz, 1H). 13C NMR
(CDCl3, 62.9 MHz) d 16.0, 22.5, 35.5, 42.6, 63.8, 73.0,
116.0, 121.1, 121.6, 129.3, 130.8, 144.0. Anal. Calcd for
C12H16ClNO: C, 63.85; H, 7.14; N, 6.21. Found: C, 64.08;
H, 7.01; N, 6.38.
3.3.4. 2-Methyl-1,2,3,4-tetrahydroquinoline (10). Viscous
liquid. IR (neat) 3394.6, 3050.5, 2961.5, 2844.2, 1608.1,
1489.4, 1309.6, 1257.5, 1153.5, 1124.5, 1039.8 cmꢁ1
.
1H NMR (CDCl3, 250 MHz) d 1.26 (d, J¼6.3 Hz, 3H),
1.56–1.72 (m, 1H), 1.93–2.03 (m, 1H), 2.72–2.96 (m, 2H),
3.38–3.51 (m, 1H), 3.74 (br s, 1H), 6.51 (dd, J¼8.5,
1.2 Hz, 1H), 6.66 (td, J¼7.4, 1.2 Hz, 1H), 6.99–7.05 (m,
2H). 13C NMR (CDCl3, 62.9 MHz) d 23.0, 27.0, 30.5,
47.6, 114.6, 117.6, 121.7, 127.1, 129.7, 145.0. Anal. Calcd
for C10H13N: C, 81.59; H, 8.90; N, 9.51. Found: C, 81.14;
H, 8.60; N, 9.24.
3.3. Reaction of tetrahydroquinolines 1 with 2 M HCl
To a solution of tetrahydroquinoline 1 (400 mg) in aceto-
nitrile (20 mL) was added 2 M hydrochloric acid (6 mL).
The mixture was stirred at room temperature or heated under
reflux. After the time period specified in Scheme 4, the reac-
tion was quenched by saturated NaHCO3 solution, extracted
with CH2Cl2, dried (anhydrous Na2SO4) and evaporated.
Pure products were separated through silica gel column
chromatography using a petroleum ether–ethyl acetate
mixture (97/3, v/v) as the eluant. Compounds 7 and 8 were
obtained as inseparable mixtures. Characterization data are
given below.
3.4. General procedure for the synthesis of 2-methyl-
quinolines by aromatization of compounds 1
A mixture of 200 mg of the suitable tetrahydroquinoline 1
and 200 mg of 10% Pd on activated carbon (Pd–C) in
10 mL of toluene (or methanol) was refluxed for the time
period specified in Table 2. The progress of the reaction
was monitored by TLC. After completion, the mixture was
filtered through Celite and the solvent was evaporated under
reduced pressure. 2-Methylquinoline derivatives 6 and 11
were separated through silica column using a mixture of
petroleum ether and ethyl acetate as eluent (80/20, v/v).
Characterization data for these compounds are given below.
3.3.1. ( )-2-Methyl-1,2,3,4-tetrahydroquinolin-4-ol cis–
trans mixture (7a and 8a). H NMR (CDCl3, 250 MHz)
1
d 1.25 (d, J¼6.5 Hz, 3H, 7a), 1.28 (d, J¼7.1 Hz, 3H, 8a),
1.55–1.68 (m, 2H, 7a and 8a), 2.03 (dt, J¼13.6, 2.6 Hz,
1H, 8a), 2.25 (ddd, J¼12.1, 5.9, 2.3 Hz, 1H, 7a), 3.52–
3.61 (m, 2H, 7a and 8a), 3.90 (br s, 2H, 7a and 8a), 4.74
(t, J¼2.9 Hz, 1H, 8a), 4.92 (dd, J¼10.6, 5.9 Hz, 1H, 7a),
6.51 (dd, J¼7.8, 0.9 Hz, 1H, 7a), 6.56 (dd, J¼7.8, 0.5 Hz,
1H, 8a), 6.67–6.77 (m, 2H, 7a and 8a), 7.03–7.14 (m, 2H,
7a and 8a), 7.22 (d, J¼7.8, 0.5 Hz, 1H, 8a), 7.41 (d,
J¼7.8 Hz, 1H, 7a). 13C NMR (CDCl3, 62.9 MHz) d 20.6,
3.4.1. 2-Methylquinoline (6a).9c Viscous liquid. IR (neat)
3051.6, 2958.5, 2917.8, 1601.7, 1559.9, 1507.0, 1423.4,
1
1373.6, 1312.0 cmꢁ1. H NMR (CDCl3, 250 MHz) d 2.75
(s, 3H), 7.26 (d, J¼8.5 Hz, 1H), 7.47 (td, J¼8.0, 1.0 Hz,
1H), 7.68 (td, J¼8.0, 1.0 Hz, 1H), 7.76 (d, J¼8.0 Hz, 1H),

V. Sridharan et al. / Tetrahedron 63 (2007) 673–681
679
8.00–8.06 (m, 2H). 13C NMR (CDCl3, 62.9 MHz) d 25.8,
122.4, 126.1, 126.9, 127.9, 129.0, 129.8, 136.6, 148.2,
159.4. Anal. Calcd for C10H9N: C, 83.88; H, 6.34; N, 9.78.
Found: C, 83.24; H, 6.54; N, 9.71.
156.7, 157.5. Anal. Calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09. Found: C, 75.99; H, 6.45; N, 8.03.
3.4.8. 4-Ethoxy-6-methoxy-2-methylquinoline (11i). Mp
61–62 ꢂC. IR (neat) 2981.8, 2936.8, 2838.4, 1598.0, 1504.3,
3.4.2. 4-Ethoxy-2-methylquinoline (11a).35 Viscous liquid.
IR (neat) 3063.4, 2980.9, 2929.5, 1594.3, 1566.5, 1509.0,
1483.6, 1384.8, 1267.1, 1223.7, 1096.4, 1032.6 cmꢁ1
.
1H NMR (CDCl3, 250 MHz) d 1.58 (t, J¼7.0 Hz, 3H), 2.67
(s, 3H), 3.94 (s, 3H), 4.25 (q, J¼7.0 Hz, 2H), 6.60 (s, 1H),
7.31 (dd, J¼9.1, 2.9 Hz, 1H), 7.43 (d, J¼2.9 Hz, 1H), 7.86
(d, J¼9.1 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz) d 15.0,
26.0, 55.9, 64.3, 100.3, 101.7, 120.8, 122.2, 129.9, 145.0,
157.1, 157.8, 161.1. Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96; N, 6.45. Found: C, 71.74; H, 6.72; N, 6.50.
1
1423.5, 1381.0, 1345.7, 1233.6 cmꢁ1. H NMR (CDCl3,
250 MHz) d 1.57 (t, J¼7.0 Hz, 3H), 2.70 (s, 3H), 4.23 (q,
J¼7.0 Hz, 2H), 6.60 (s, 1H), 7.44 (td, J¼8.4, 1.5 Hz, 1H),
7.66 (td, J¼8.4, 1.5 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 8.18
(dd, J¼8.4, 1.5 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz)
d 14.9, 26.4, 64.4, 101.5, 120.3, 122.1, 125.1, 128.4,
130.1, 149.2, 160.5, 162.0. Anal. Calcd for C12H13NO: C,
76.98; H, 7.00; N, 7.48. Found: C, 76.62; H, 7.03; N, 7.51.
3.4.9. ( )-trans-4,6-Dimethoxy-2-methyl-1,2,3,4-tetra-
hydroquinoline (12). Viscous oil. IR (neat) 3375.2,
2961.1, 2862.3, 2822.5, 1504.4, 1447.5, 1347.4, 1254.6,
1156.6, 1077.5, 1040.3 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d 1.25 (d, J¼6.3 Hz, 3H), 1.50 (ddd, J¼13.7, 12.2, 3.3 Hz,
1H), 2.14 (dt, J¼13.7, 2.6 Hz, 1H), 3.48 (s, 3H), 3.50–3.57
(m, 1H), 3.78 (s, 3H), 4.18 (t, J¼2.8 Hz, 1H), 6.54 (d,
J¼9.4 Hz, 1H), 6.73–6.79 (m, 2H). 13C NMR (CDCl3,
62.9 MHz) d 22.7, 35.4, 42.8, 56.3, 56.4, 75.4, 116.1,
116.2, 116.6, 120.8, 139.6, 151.7. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.83;
H, 7.98; N, 7.06.
3.4.3. 2-Methyl-8-methoxyquinoline (6d).9c Mp 124–
125 ꢂC. IR (neat) 2999.8, 2952.3, 2836.4, 1603.4, 1565.7,
1466.3, 1427.8, 1331.0, 1261.9, 1238.3, 1110.9 cmꢁ1
.
1H NMR (CDCl3, 250 MHz) d 2.78 (s, 3H), 4.06 (s, 3H),
7.00 (dd, J¼8.4, 1.5 Hz, 1H), 7.25–7.37 (m, 3H), 7.98 (dd,
J¼8.4, 1.5 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz) d 26.1,
56.4, 107.9, 119.8, 123.0, 126.1, 127.9, 136.5, 140.0,
155.1, 158.5. Anal. Calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.04; H, 6.29; N, 8.26.
3.4.4. 2,8-Dimethylquinoline (6g).36 Viscous liquid. IR
(neat) 3043.8, 2921.0, 2850.6, 1602.0, 1500.2, 1425.3,
1311.3, 1266.6, 1136.2 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d 2.83 (s, 3H), 2.89 (s, 3H), 7.31 (d, J¼8.4 Hz, 1H), 7.42
(t, J¼7.7 Hz, 1H), 7.59 (d, J¼7.7 Hz, 1H), 7.66 (d,
J¼7.7 Hz, 1H), 8.04 (d, J¼8.4 Hz, 1H). 13C NMR (CDCl3,
62.9 MHz) d 18.5, 26.2, 122.1, 125.7, 126.0, 126.8, 129.9,
136.7, 136.9, 147.4, 158.3. Anal. Calcd for C11H11N: C,
84.04; H, 7.05; N, 8.91. Found: C, 83.78; H, 7.38; N, 8.83.
Acknowledgements
We thank MEC (grant CTQ2006-10930) and UCM-CAM
ꢀ
(Grupos de Investigacion, grant 920234) for financial
support.
References and notes
3.4.5. 2,6-Dimethylquinoline (6h).37 Mp 72–73 ꢂC. IR
(neat) 3055.0, 2917.0, 2858.6, 1601.4, 1496.1, 1372.9,
1221.5, 1119.3, 1034.5 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d 2.49 (s, 3H), 2.71 (s, 3H), 7.20 (d, J¼8.4 Hz, 1H), 7.47–
7.50 (m, 2H), 7.89–7.93 (m, 2H). 13C NMR (CDCl3,
62.9 MHz) d 20.1, 23.9, 120.6, 125.0, 125.1, 126.8, 130.3,
134.0, 134.2, 145.0, 156.6. Anal. Calcd for C11H11N: C,
84.04; H, 7.05; N, 8.91. Found: C, 83.86; H, 7.06; N, 8.99.
1. (a) Behforouz, M.; Gu, Z.; Cai, W.; Horn, M. A.; Ahmadian, M.
J. Org. Chem. 1993, 58, 7089; (b) Behforouz, M.; Merriman, R.
L. U.S. Patent 5,646,150, July 8, 1994.
2. (a) For a recent review of synthetic work in the total synthesis
of streptonigrin and related alkaloids, see: Bringmann, G.;
Reichert, Y.; Kane, V. V. Tetrahedron 2004, 60, 3539; (b) For
an overview of the structural determination of alkaloids
containing quinolinequinone and isoquinolinequinone moie-
ties, including the streptonigrins and lavendamycins, see:
3.4.6. 4-Ethoxy-2,6-dimethylquinoline (11h). Mp 79–
80 ꢂC. IR (neat) 3055.0, 2980.2, 2919.3, 1593.9, 1569.5,
ꢀ
Avendan˜o, C.; Menendez, J. C. Structural Analysis of Cyclic
Systems; Iriepa, I., Ed.; Research Signpost: Trivandrum,
1443.4, 1385.6, 1345.2, 1231.3, 1180.5, 1113.3 cmꢁ1
.
1H NMR (CDCl3, 250 MHz) d 1.58 (t, J¼7.0 Hz, 3H),
2.53 (s, 3H), 2.68 (s, 3H), 4.24 (q, J¼7.0 Hz, 2H), 6.59 (s,
1H), 7.50 (dd, J¼8.6, 2.0 Hz, 1H), 7.85 (d, J¼8.6 Hz, 1H),
7.94 (d, J¼2.0 Hz, 1H). 13C NMR (CDCl3, 62.9 MHz)
d 15.0, 22.0, 26.3, 64.3, 101.4, 120.1, 121.0, 128.2, 132.2,
134.8, 147.7, 159.5, 161.5. Anal. Calcd for C13H15NO: C,
77.58; H, 7.51; N, 6.96. Found: C, 77.30; H, 7.35; N, 6.99.
India, 2005; Chapter 2.
3. (a) Normand-Bayle, M.; Benard, C.; Zouhiri, F.; Mouscadet,
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Benard, C.; Zouhiri, F.; Normand-Bayle, M.; Canet, M.;
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Thomas, C.-M.; Bonnenfant, S.; Le Bret, M.; d’Angelo, J.
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IR (neat) 3053.5, 2942.0, 2830.4, 1625.3, 1603.6, 1499.9,
1
1375.4, 1234.1, 1161.0, 1031.3 cmꢁ1. H NMR (CDCl3,
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7.91–7.94 (m, 2H). 13C NMR (CDCl3, 62.9 MHz) d 25.4,
55.9, 105.6, 122.3, 122.7, 127.7, 130.4, 135.5, 144.2,
€
Polanski, J.; Zouhiri, F.; Jeanson, L.; Desmaele, D.;
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