Uncatalysed Domino Reaction in Hexafluoroisopropanol: A Simple Protocol for the Synthesis of Tetrahydroquinoline Derivatives

Article abstract of DOI:10.1055/s-2003-41074

A range of tetrahydroquinolines were synthesised in excellent yields through a domino reaction performed in hexafluoropropanol, starting from anilines and enol ethers and in the absence of Lewis acid catalysis. This solvent was shown to promote the nucleophilic addition of anilines to enol ethers as well as the aza-Diels-Alder reaction.

Full text of DOI:10.1055/s-2003-41074

PAPER
2231
Uncatalysed Domino Reaction in Hexafluoroisopropanol: A Simple Protocol
for the Synthesis of Tetrahydroquinoline Derivatives
U
ncatalysedDomi
n
no
R
eaction
d
inHexafluor
r
oisoprop
e
anol a Di Salvo, Maria Vittoria Spanedda, Michèle Ourévitch, Benoit Crousse, Danièle Bonnet-Delpon*
BioCIS, Centre d’Etudes Pharmaceutiques, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France
Fax +33(1)46835740; E-mail: daniele.bonnet-delpon@cep.u-psud.fr
Received 4 June 2003; revised 3 July 2003
This article is dedicated to Dr Jean-Pierre Bégué for hi 65th birthday.
OR
OR
Abstract: A range of tetrahydroquinolines were synthesised in ex-
NH2
N
cellent yields through a domino reaction performed in hexafluoro-
propanol, starting from anilines and enol ethers and in the absence
of Lewis acid catalysis. This solvent was shown to promote the nu-
cleophilic addition of anilines to enol ethers as well as the aza-Di-
els–Alder reaction.
OR
LA
+
N
H
X
X
X
Scheme 1
Key words: Diels–Alder reactions, domino reactions, cycloaddi-
tion, nucleophilic additions, 1,1,1,3,3,3-hexafluoro-2-propanol
δ+
OR
HN
OR
OR
LA
aniline
The synthesis of tetrahydroquinoline derivatives is the ob-
ject of continuous interest because of the pharmaceutical
importance of this class of compounds.1 A powerful and
frequently exploited route for the synthesis of these com-
pounds is the aza-Diels–Alder reaction of N-arylimines.2
According to the literature this reaction requires the pres-
ence of a catalyst, such as a classical Lewis acid
(BF3·Et2O, TiCl4, AlCl3, InCl3, etc.) or a lanthanide trif-
late [Yb(OTf)3, Sc(OTf)3].3 Due to the presence of the
relatively basic nitrogen in both the reagent and the prod-
uct, it is often necessary to use one equivalent of the Lewis
acid.
δ−
LA
X
OR
OR
N
N
X
H
X
Scheme 2
In 1964, Povarov and Michailov published a modification
of the procedure in which the imine was formed in situ
from a substituted aniline and an enol ether and subse-
quently underwent an aza-Diels–Alder cycloaddition with
a second molecule of the enol ether, to afford the corre-
sponding tetrahydroquinoline (Scheme 1).4 The reaction
was performed in benzene and was promoted by
BF3·Et2O. More recently other investigations about the
scope of this reaction showed that it can be performed ei-
ther with InCl3 in water or CH3CN,5,6 with Sc(OTf)3 in the
ionic liquid bmimPF6,7 or also with Dy(OTf)3 in CH3CN.8
This one-pot procedure is the sole published method for
the preparation of this class of 4-alkoxy tetrahydroquino-
lines. In fact, there are to date no reports of cycloadditions
between the corresponding imines and enol ethers, proba-
bly due to the instability of the intermediate aldimine that
can not be isolated.
properties of these solvents, notably their high hydrogen
bond donor abilities [for hexafluoroisopropanol (HFIP)
= 1.96, for trifluoroethanol (TFE) = 1.51]10 were ex-
ploited to carry out the reaction in the absence of catalysis.
Thus, hexafluoroisopropanol (HFIP) was tested as solvent
for the one-pot formation of tetrahydroquinolines from ar-
omatic amines and alkyl enol ethers, hoping that this rela-
tively acidic alcohol (pKa = 9.3) could promote the
formation of imines from enol ethers, which probably oc-
curs through the generation of an oxonium salt (Scheme
2). This article reports the results of this study.
In a preliminary experiment the reaction between 1 mmol
of aniline (1a) and three equivalents of the ethyl vinyl
ether (2) was conducted in 1 mL of HFIP at room temper-
ature (Scheme 3). The reaction (monitored by GC) was
complete within 20 minutes, and the tetrahydroquinoline
4a was retrieved in an excellent 96% overall yield after
distillation of the solvent and column chromatography on
silica gel (Table 1, entry 1). In a similar experiment con-
ducted in trifluoroethanol at reflux temperature the con-
version was only 20% after one day. The scope of the
reaction in HFIP was then investigated. Table 1 lists the
outcome of the reactions between aniline (1a) and a range
of enol ethers.
Recently we have described a simple and efficient proce-
dure for the aza-Diels–Alder reaction of N-benzylidene
aniline and alkyl enol ethers in fluorinated alcohols.9 The
SYNTHESIS 2003, No. 14, pp 2231–2235
0
2.
1
0
.
2
0
0
3
Advanced online publication: 24.09.2003
DOI: 10.1055/s-2003-41074; Art ID: Z07803SS.pdf
© Georg Thieme Verlag Stuttgart · New York

2232
A. Di Salvo et al.
PAPER
X
OR
OR
X
X
OR
HFIP
+
+
Y
N
H
N
H
NH2
Y
Y
X=Y=H 1a
R=Et 2
R=Et, X=Y=H 4a
R=Et, X=Y=H 5a
X=CH3O, Y=H 1b
X=NO2, Y=H 1c
X=CH3, Y=H 1d
X=Cl, Y=H 1e
X=H, Y=CH3O 1f
R=n-Bu 3
R=n-Bu, X=Y=H 6a
R=Et, X=CH3O, Y=H 4b
R=Et, X=NO2, Y=H 4c
R=Et, X=CH3, Y=H 4d
R=Et, X=Cl, Y=H 4e
R=Et, X=H, Y=CH3O 4f
R=n-Bu, X=Y=H 7a
R=Et, X=CH3O, Y=H 5b
R=Et, X=NO2, Y=H 5c
R=Et, X=CH3, Y=H 5d
R=Et, X=Cl, Y=H 5e
R=Et, X=H, Y=CH3O 5f
X
O
O
n
n
n
X
X
HFIP
+
+
n
n
O
OH
OH
N
H
N
H
NH2
X=H 1a
X=CH3O 1b
X=NO2 1c
n=1 8
n=2 9
X=H, n=1 10a
X=H, n=1 11a
X=CH3O, n=1 10b
X=NO2, n=1 10c
X=H, n=2 12a
X=CH3O, n=1 11b
X=NO2, n=1 11c
X=H, n=2 13a
Scheme 3
In both cases, with the acyclic ethers 2 and 3 and with the trans-isomer is higher when bulkier enol ethers are em-
cyclic ethers 8 and 9, the cycloadducts were obtained in ployed. So enol ether 3 affords more trans product than 2,
good yields in reasonable reaction times. As expected, the and 9 more than 8.
acyclic ethoxyethylene (2) proved to be the most reactive
ether, affording the best yield in the shortest reaction time,
Table 1 Reactions of Aniline with Enol Ethers in HFIPa
whereas the reaction with 3,4-dihydro-2H-pyran (9) re-
quired one day and afforded a lower yield.
En- Enol ether
try
Products
4a + 5a
Reaction T
Yield cis/trans
time
(°C)
(%)b
With all the ethers used, except 2, the reaction yielded a
mixture of the stereoisomers 4 and 5, which were not sep-
arated. The isomers were identified by comparison with
literature data if available.5,6,8 Otherwise, for tetrahydro-
quinolines 4a,b,d–f, 5b,d–f, 6d, and 7a NMR studies
(COSY, HSQC, HMBC, NOESY) were carried out to as-
sign the stereochemistry. The cis-isomer is the prevalent
in all of the cases studied. In the cycloaddition step of the
reaction the cis products are the outcome of the favourite
endo transition states, assuming that the imine is in the
favoured E configuration (Scheme 4).11 The amount of
OEt
1
20 min r.t.
96
68
94
100/0
86/14
72/28
2
OBu
2
6a + 7a
5 h
2 h
r.t.
r.t.
3
3
10a + 11a
O
8
4
12a + 13a
1 d
1 h
r.t.
r.t.
84
67/33
O
Y
OR
N
H
N
9
X
OMe
5
0c
X
N
H
RO
exo
14
OR
Y
a Reaction conditions: aniline (1 mmol), enol ether (3 equiv), HFIP (1
trans
mL).
b Isolated yields.
Y
OR
c Yielded 1-(isopropylidene)phenylamine (15) quantitatively.
H
N
N
X
It must be remarked that, following the reaction, the for-
mation of the intermediate imine could not be detected by
GC analysis. Moreover, even when enol ether 2 was react-
ed with an excess of aniline the only product recovered
was cycloadduct 4a. This indicates that the rate limiting
X
N
H
RO
OR
Y
endo
cis
Scheme 4
Synthesis 2003, No. 14, 2231–2235 © Thieme Stuttgart · New York

PAPER
Uncatalysed Domino Reaction in Hexafluoroisopropanol
2233
step is the formation of the imine through an oxonium cat- covered from a complex crude mixture. The outcome of
ion or an intermediate with a cationic character (Scheme the reaction with 4-chloroaniline (1e) confirms that deac-
2). The formation of this cationic species and the subse- tivating substituents on the aniline decrease the efficiency,
quent elimination of a molecule of alcohol is promoted by even though in this case an excellent yield could be ob-
the acidity of HFIP. Once formed the imine reacts in a fast tained increasing the concentration of the reagents. The
step with the enol ether, confirming the efficiency of HFIP effect of the electronic nature of the substituent on the re-
in promoting Diels–Alder cycloadditions.9
action rate had already been noted when the reaction was
carried out in water with InCl3 by Li and coworkers.7 Even
in the reactions with deactivated aniline 1e it was not pos-
sible to detect the formation of the intermediate imine by
GC.
In one case though, with enol ether 14, the reaction did not
afford any cycloaddition products, and after only 1 hour 1-
(isopropylidene)phenylamine (15) was obtained in quan-
titative yield (Scheme 5). Even after prolonged reaction
time and refluxing overnight the imine remained un-
changed. Moreover, when three equivalents of the more
reactive ether 2 were added to imine 15, formed in situ, it
was not possible to detect the formation of the corre-
sponding tetrahydroquinoline. The failure to afford the
desired product in this case can therefore be attributed to
the steric hindrance and hence the low reactivity of imine
15 in the aza-Diels–Alder reaction.
Table 2 Comparison Between Published Methods for the One-pot
Synthesis of Tetrahydroquinolines
Entry Aniline Enol
ether
Products
Method
Yield cis/trans
(%)
HFIP
(1 d/r.t.)
1
12a + 13a
84
67/33
O
NH2
9
NH2
1a
OMe
1.
2.
H2O
+
N
2a
3b
4c
1a
1a
1a
9
9
9
12a + 13a InCl3
(3 d/r.t.)
90
90
87
68/32
95/5
95/5
14
15
CH3CN
12a + 13a InCl3
Scheme 5 Reaction conditions: 1. aniline (1 mmol), 2-methoxy-
prop-1-ene (14, 3 equiv), HFIP (1 mL), 3 d at r.t. then 1 d at reflux; 2.
ethoxyethylene (2, 3 equiv), 3 d at r.t.
(4 h/r.t.)
bmimPF6
12a + 13a Sc(OTf)3
(4 h/r.t.)
This first set of reactions proved the ability of HFIP to
promote the formation of imines from enol ethers and
anilines and, in agreement with previously reported re-
sults, [4+2] cycloadditions, and showed that efficient re-
actions can be performed in this solvent without catalysis.
A comparison with literature data for reactions with pyran
9 shows that in terms of endo/exo selectivity in the cy-
cloaddition step the behaviour of HFIP is very similar to
that of water but the reaction is faster. On the other hand,
the procedures in the ionic liquid bmimPF6 or in CH3CN
are more selective towards the cis-product and have short-
er reaction times (Table 2).5–7
a Ref. 7.
b Ref. 6.
c Ref. 5.
Table 3 Reactions of Substituted Anilines with Enol
Ethersa
En- Aniline
try
Enol Products Reac-
T
Yield cis
ether
tion
(°C) (%)b /trans
time
In the next step of the study different substituted anilines
were reacted with an acyclic and a cyclic enol ether (2 and
8, respectively) in order to investigate the effect of the
substitution in the aromatic ring on the reaction. In this
case the reactions were conducted at a lower concentra-
tion (0.33 M in aniline) in order to slow down the reaction
rate and make the comparison easier. The results are re-
ported in Table 3. The efficiency of the reaction is easily
related to the electronic properties of the substituted
anilines and, as expected, electron-donating substituents
like methoxy or methyl groups give the best results
whereas the electron-withdrawing nitro group is ineffi-
cient and even after one day at reflux the conversion was
not complete and only traces of the product could be re-
OEt
1
4a + 5a
7 h
r.t.
79
97
100/0
83/17
NH2
2
2
1a
OMe
2
4b + 5b 1.5 h r.t.
NH2
1b
Synthesis 2003, No. 14, 2231–2235 © Thieme Stuttgart · New York

2234
A. Di Salvo et al.
PAPER
Table 3 Reactions of Substituted Anilines with Enol
confirming the ability of HFIP to promote the aza-Diels–
Alder cycloaddition, we show that enol ethers can under-
go nucleophilic addition of anilines in this medium.
Ethersa (continued)
En- Aniline
try
Enol Products Reac-
T
Yield cis
ether
tion
(°C) (%)b /trans
The scope of the reaction was investigated and it was
shown that this method can be used to synthesise a range
of tetrahydroquinolines in excellent yields starting from
cyclic and acyclic enol ethers and a range of anilines. The
evidence shows that the electronic properties of the
aniline influence the efficiency of the nucleophilic addi-
tion step whereas the use of a hindered enol ether hampers
the cycloaddition step of the procedure.
time
3
2
4f + 5f
2 h
r.t.
r.t.
93
80
92/8
MeO
NH2
1f
Me
This new procedure permits to avoid the use of a catalyst,
to work without taking any particular precautions to re-
move moisture, and to recover the products without work-
up.
4
2
2
2
4d + 5d 3 h
65/35
NH2
1d
NO2
1H NMR and 13C NMR spectra were recorded on either a 200 MHz
or a 400 MHz multinuclear Bruker spectrometer. COSY, NOESY,
HSQC and HMBC experiments were performed on a 400 MHz
multinuclear Bruker spectrometer. Chemical shifts ( ) are given in
ppm relative to TMS. Coupling constants are given in Hz. Elemen-
tal analyses were performed by the Service de Microanalyses of the
Centre d’Etudes Pharmaceutiques, Châtenay-Malabry. GC analyses
were performed using a SE 30 capillary column (12 m). All starting
materials are commercially available. HFIP was provided by Cen-
tral Glass Co. Ltd.
r.t. +
5
4c + 5c
7 d
traces
refluxc
NH2
1c
Cl
6
4e + 5e
1 d
r.t.
r.t.
r.t.
65d
77/23
74/26
80/20
NH2
cis-4-Ethoxy-2-methyl-1,2,3,4-tetrahydroquinoline (4a); Typi-
cal Procedure
1e
Aniline (1a, 0.09 mL, 1 mmol) and ethoxyethylene (2, 0.3 ml, 3
mmol) were stirred in HFIP (1 mL) at r.t. The reaction was moni-
tored by GC. After 20 min the solvent was distilled and the residue
was purified by column chromatography on silica gel (EtOAc–
Et2O, 1:9) to afford 0.183 g (96% yield) of 4a as a pale yellow oil.
7
10a + 11a 1 h
10b + 11b 1 h
60
O
NH2
8
1a
IR (neat): 3383, 2970, 2868, 1731, 1609, 1095, 748 cm–1.
OMe
1H NMR (400 MHz, CDCl3): = 1.25 (d, 3 H, J = 6.3 Hz, H-2 ),
1.28 (t, 3 H, J = 7.0 Hz, 2-CH3), 1.67 (q, 1 H, J = 11.0 Hz, H-3ax),
2.24 (ddd, 1 H, J = 12.2, 5.7, 2.5 Hz, H-3eq), 3.53 (qdd, 1 H,
J = 11.0, 6.3, 2.5 Hz, H-2), 3.58 (qd, 1 H, J = 8.0, 7.0 Hz, H-1 ),
3.65 (br s, 1 H, H-1), 3.71 (qd, 1 H, J = 8.0, 7.0 Hz, H-1 ), 4.67 (dd,
1 H, J = 5.8, 10.5 Hz, H-4), 6.46 (d, 1 H, J = 7.7 Hz, ArH), 6.69 (t,
1 H, J = 7.7 Hz, ArH), 7.0 (t, 1 H, J = 7.0 Hz, ArH), 7.34 (d, 1 H,
J = 7.7 Hz, ArH).
8
8
8
81
NH2
1b
NO2
13C NMR (100 MHz, CDCl3): = 16.0, 22.5, 37.0, 47.0, 64.0, 74.0,
114.0, 117.6, 123.0, 127.7, 128.3, 145.0.
9
10c + 11c 2 d
reflux traces
NH2
Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C,
75.45; H, 9.04; N, 7.35.
1c
a Reaction conditions: aniline (1 mmol), enol ether (3 equiv), HFIP
4-Ethoxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroquinolines
(4b and 5b)
Pale yellow oil.
IR (neat): 3367, 2926, 1501 cm–1.
1H NMR (200 MHz, CDCl3): = 1.11–1.30 (m, 3 H/trans, 3 H/cis,
2-CH3), 1.64 (q, 1 H, J = 12.2 Hz, H-3ax/cis), 1.89–2.10 (m, 1 H, H-
3/trans), 2.22 (ddd, 1 H, J = 12.2, 5.7, 2.5 Hz, H-3eq/cis), 3.36–3.72
(m, 3 H/trans, 3 H/cis, H-1 , H-2), 3.74 (s, 3 H, OCH3/cis), 3.92 (s,
3 H, OCH3/trans), 4.41–4.53 (m, 1 H, H-4/trans), 4.67 (dd, 1 H,
J = 12.2, 5.7 Hz, H-4/cis), 6.62–7.89 (m, 3 H/trans, 3 H/cis, ArH).
(3 mL).
b Isolated yields.
c 6 d at r.t. + 1 d at reflux.
d The same reaction in 1 mL of HFIP afforded 98% yield with the
same cis/trans ratio.
The cis/trans ratio does not show a strong dependence on
the electronic properties of the substituents in the aniline
ring.
13C NMR (50 MHz, CDCl3): = 14.2, 15.6, 22.4, 35.5, 36.2, 42.4,
46.6, 55.7, 63.1, 73.0, 73.8, 112.3, 114.7, 115.2, 115.6, 115.8,
123.8, 138.8, 152.2.
In conclusion we describe a simple protocol for the forma-
tion of tetrahydroquinolines in HFIP from anilines and
enol ethers in the absence of Lewis acid catalysis. Besides
Synthesis 2003, No. 14, 2231–2235 © Thieme Stuttgart · New York

PAPER
Uncatalysed Domino Reaction in Hexafluoroisopropanol
2235
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.53. Found: C,
70.43; H, 8.67; N, 6.31.
1H NMR (200 MHz, CDCl3): = 0.90–1.86 (m, 11 H/cis, 12 H/
trans, H-2 , H-3 , H-4 , 2-CH3, H-3ax/cis, H-3/trans), 2.33 (ddd, 1 H,
J = 12.2, 5.8, 2.6 Hz, H-3eq/cis), 3.50–3.84 (m, 3 H, H-1 , H-2), 4.36
(m, 1 H, H-4/trans), 4.73 (dd, 1 H, J = 10.4, 5.8 Hz, H-4/cis), 6.49–
7.50 (m, 4 H, ArH).
4-Ethoxy-2,6-dimethyl-1,2,3,4-tetrahydroquinoline (4d and 5d)
Pale yellow oil.
IR (neat): 3368, 2969, 1505, 1095 cm–1.
13C NMR (50 MHz, CDCl3): = 13.9, 19.4, 22.1, 22.5, 32.1, 32.3,
35.4, 35.9, 42.1, 46.2, 67.6, 67.8, 73.1, 73.8, 113.8, 114.4, 116.4,
117.3, 119.9, 122.6, 127.3, 128.0, 128.9, 130.9, 144.5, 144.9.
1H NMR (200 MHz, CDCl3): = 1.18–1.28 (m, 6 H/trans, 6 H/cis,
H-2 , 2-CH3), 1.73 (q, 1 H/cis, J = 12.2 Hz, H-3ax/cis), 2.01–2.39
(m, 4 H/cis, 5 H/trans, 6-CH3, H-3eq/cis, H-3/trans), 3.42–3.77 (m,
3 H/trans, 3 H/cis, H-1 , H-2), 4.22–4.41 (m, 1 H, H-4/trans), 4.64
(dd, 1 H, J = 12.2, 5.0 Hz, H-4/cis), 6.37–7.18 (m, 3 H/trans, 3 H/
cis, ArH).
13C NMR (50 MHz, CDCl3): = 14.6, 15.6, 17.4, 20.5, 22.5, 23.8,
35.6, 36.2, 42.2, 46.4, 63.3, 73.0, 73.8, 114.2, 114.6, 122.6, 126.6,
127.6, 128.7, 129.7, 131.2, 142.2.
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C,
70.44; H, 8.79; N, 6.32.
Acknowledgement
We thank Central Glass Co. Ltd. for kindly providing HFIP. We
also thank the European Contract of Research Training Network
(‘Fluorous Phase’ HPRN CT 2000-00002) for studentships to AD
and MVS.
Anal. Calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C,
75.75; H, 9.67; N, 6.57.
6-Chloro-4-ethoxy-2-methyl-1,2,3,4-tetrahydroquinolines (4e
and 5e)
References
Pale yellow oil.
IR (neat): 3383, 2971, 2868, 1489, 1101 cm–1.
(1) (a) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211. (b) Faber, K.;
Stueckler, H.; Kappe, T. Heterocyl. Chem. 1984, 21, 1177.
(c) Johnson, J. V.; Rauckman, S.; Baccanari, P. D.; Roth, B.
J. Med. Chem. 1989, 32, 1942.
(2) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis, Chaps. 2 and 9;
Academic: San Diego, 1987. (b) Weinreb, S. M.
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 401–449.
(c) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57,
6099.
1H NMR (200 MHz, CDCl3): = 1.15–1.27 (m, 3 H/cis, 3 H/trans,
2-CH3), 1.60 (q, 1 H, J = 12.1 Hz, H-3ax/cis), 2.03–2.12 (m, 2 H, H-
3/trans), 2.22 (ddd, 1 H, J = 12.1, 5.9, 2.7 Hz, H-3eq/cis), 3.50–3.75
(m, 3 H/cis, 3 H/trans, H-1 , H-2), 4.23–4.42 (m, 1 H, H-4/trans),
4.58 (dd, 1 H, J = 10.7, 5.9 Hz, H-4/cis), 6.45–7.35 (m, 3 H/trans, 3
H/cis, ArH).
13C NMR (50 MHz, CDCl3): = 15.5, 21.9, 22.3, 29.6, 35.0, 35.6,
40.8, 42.1, 46.2, 63.3, 63.3, 72.5, 73.3, 114.8, 115.5, 121.9, 124.0,
126.9, 127.8, 128.3, 128.8, 130.3, 142.9.
(3) (a) Cabral, J.; Laszlo, P. Tetrahedron Lett. 1989, 30, 7237.
(b) Worth, D. F.; Perricone, S. C.; Elsager, E. F. J.
Heterocycl. Chem. 1970, 7, 1353. (c) Povarov, L. C. Russ.
Chem. Rev. 1967, 36, 656. (d) Crousse, B.; Bégué, J. P.;
Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009.
(e) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org.
Lett. 2001, 3, 1973. (f) Babu, G.; Perumal, P. T.
Tetrahedron Lett. 1998, 38, 3225. (g) Babu, G.; Perumal, P.
T. Tetrahedron Lett. 1997, 37, 5025. (h) Kobayashi, S.;
Ishitani, H.; Nagayama, S. Synthesis 1995, 1195.
(i) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W.
Chem. Rev. 2002, 102, 2227. (j) Yadav, J. S.; Reddy, B. V.
S.; Reddy, J. S. S.; Srinivasa Rao, R. Tetrahedron 2003, 59,
1599.
Anal. Calcd for C12H16ClNO: C, 63.86; H, 7.14; N, 6.21. Found: C,
63.72; H, 7.30; N, 6.09.
cis-4-Ethoxy-8-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline
(4f)
Yellow oil.
IR (neat): 3405, 3058, 1246, 1112, 1079, 1064 cm–1.
1H NMR (200 MHz, CDCl3): = 1.13–1.23 (m, 6 H, H-2 , 2-CH3),
1.62 (q, 1 H, J = 11.1 Hz, H-3ax), 2.13 (ddd, 1 H, J = 12.2, 5.7, 2.3
Hz, H-3eq), 3.32–3.67 (m, 3 H, H-2, H-1'), 3.72 (s, 3 H, CH3O), 4.61
(dd, 1 H, J = 10.3, 5.7 Hz, H-4), 6.55 (d, 2 H, J = 4.5 Hz, ArH), 6.91
(t, 1 H, J = 4.5 Hz, ArH).
13C NMR (50 MHz, CDCl3): = 15.6, 22.4, 35.9, 46.0, 55.3, 63.1,
73.7, 108.4, 116.2, 119.3, 122.5, 134.5, 145.7.
(4) Povarov, L. C.; Michailov , B. M. Izv. Akad. Nauk. SSSR,
Ser. Khim. 1964, 12, 2221.
(5) Yadav, J. S.; Reddy, B. V. S.; Uma Gayathri, K.; Prasad, A.
R. Synthesis 2002, 17, 2537.
Anal. Calcd for C14H21NO2: C, 76.67; H, 9.65; N, 6.39. Found: C,
76.48; H, 9.75; N, 6.29.
(6) Yadav, J. S.; Reddy, B. V. S.; Srinivasa Rao, R.; Kiran
Kumar, S.; Kunwar, A. C. Tetrahedron 2002, 58, 7891.
(7) Zhang, J.; Li, C. J. Org. Chem. 2002, 67, 3969.
(8) Batey, R. A.; Powell, D. A.; Acton, A.; Lough, A. J.
Tetrahedron Lett. 2001, 42, 7935.
(9) Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-
Delpon, D.; Bégué, J. P. Tetrahedron Lett. 2003, 44, 217.
(10) (a) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F. J.
Chem. Soc., Chem. Commun. 1996, 2105. (b) Richard, J. P.
Tetrahedron 1995, 51, 1535. (c) Schaal, H.; Haber, T.;
Suhm, M. A. J. Phys. Chem. A 2000, 104, 265.
(11) (a) Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P. J. Org.
Chem. 1988, 53, 2251. (b) Borrione, E.; Prato, M.;
Scorrano, G.; Stivanello, M.; Lucchini, V.; Valle, G. J.
Chem. Soc., Perkin Trans. 1 1989, 2245.
trans-4-Ethoxy-8-methoxy-2-methyl-1,2,3,4-tetrahydroquino-
line (5f)
1H NMR (200 MHz, CDCl3): = 0.78–1.60 (m, 8 H, H-2 , 2-CH3,
H-3), 3.58–3.75 (m, 3 H, H-1 , H-2), 3.90 (s, 3 H, CH3O), 4.39 (t, 1
H, J = 2.4 Hz, H-4), 6.61–6.90 (m, 3 H, ArH).
13C NMR (50 MHz, CDCl3): = 15.5, 22.1, 35.5, 41.7, 55.3, 63.1,
72.6, 109.0, 115.1, 119.7, 122.9, 134.9, 146.1.
4-Butoxy-2-methyl-1,2,3,4-tetrahydroquinolines (6a and 7a)
Yellow oil.
IR (neat): 3382, 3053, 1270, 1256, 1129, 1091 cm–1.
Synthesis 2003, No. 14, 2231–2235 © Thieme Stuttgart · New York