Regio- and stereo-selective aza-Diels-Alder reaction of ethyl glyoxylate 4-methoxyphenylimine with 1,3-dienes in the presence of?BF3·Et2O. Evidence for a non-concerted mechanism

Article abstract of DOI:10.1016/j.tet.2006.10.085

Cycloadditions of the glyoxylate imine 1 with 1-substituted and 1,4-disubstituted 1,3-dienes furnished tetrahydroquinoline compounds 4 and 5/15 with total regio- and stereo-control, except for one case where a mixture of isomers was formed. A stepwise mec

Full text of DOI:10.1016/j.tet.2006.10.085

Tetrahedron 63 (2007) 727–734
Regio- and stereo-selective aza-Diels–Alder reaction of ethyl
glyoxylate 4-methoxyphenylimine with 1,3-dienes in the presence
of BF $Et O. Evidence for a non-concerted mechanism
3
2
*
M. Jos ꢀe Alves, Nuno G. Azoia and A. Gil Fortes
Departamento de Qu ꢀı mica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Received 4 October 2006; revised 26 October 2006; accepted 29 October 2006
Available online 15 November 2006
Abstract—Cycloadditions of the glyoxylate imine 1 with 1-substituted and 1,4-disubstituted 1,3-dienes furnished tetrahydroquinoline com-
pounds 4 and 5/15 with total regio- and stereo-control, except for one case where a mixture of isomers was formed. A stepwise mechanism is
proposed in view of the stereochemistry of the products.
Ó 2006 Elsevier Ltd. All rights reserved.
3
1
. Introduction
tetrahydro derivatives. Cycloadditions of arylimines to
dienophiles including enolates,
4
–12
4,11
thioenolates, enami-
and cyclic dienes such as cyclopentadiene and
4
,7,13,14
Various tetrahydroquinolines are biologically active com-
pounds, several of them with pharmaceutical applications.
As an example they have been investigated for the treatment
of severe pain as an alternative to opiates.
nes,
cyclohexadiene
ture. However, cycloadditions of arylimines to open chain
1
4,9,11,15,16
are well documented in the litera-
2
17
dienes acting as dienophiles are less abundant. Scheme 1
gives a summary of the literature.
There are several methods for the synthesis of tetrahydroqui-
nolines, but the aza-Diels–Alder reaction of arylimines with
dienophiles, usually in the presence of a Lewis acid catalyst,
is one of the most powerful tools for obtaining 1,2,3,4-
Tetrahydroquinolines are formed by an ‘inverse electron
demand’ reaction. A competition with ‘normal electron de-
mand’ reaction occurs in the case where the diene possesses
Scheme 1.
Keywords: 2-Azadienes; Glyoxylate arylimines; Diels–Alder cycloaddition.
*
Corresponding author. E-mail: mja@quimica.uminho.pt
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.085

728
M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
1
7
a bulky group at C-2 and/or C-3. A substituent at position 1
of the diene, even a good electron releasing group, results
in the formation of the tetrahydroquinoline compound.
H
3
2
1
7,18
1 H
EtO C
2
N
This shows the major role played by the steric hindrance
of the approaching reagents in the selection of reaction type.
H
H
4
OMe
H
In this work 1-monosubstituted and 1,4-disubstituted dienes
were reacted with glyoxylate imine 1 with the aim of finding
the relative configuration of the stereocentres in the prod-
ucts. The comparison of the product stereochemistry with the
two types of diene, was expected to shed light on the mech-
anism of the reaction. We have found that in the case of
reaction with 1,4-disubstituted dienes the stereochemistry of
products is only possible on the basis of an ionic mechanism.
R1
1
4a R =OMe
1
t
4
b R =OSiMe Bu
2
J 2-Hax-3-Hax= 11.1 Hz
J 3-Hax-4-Hax= 11.1 Hz
J 2-Hax-3-Heq= 3.3 Hz
J 3-Heq-4-Hax= 5.4 Hz
J 2-Hax-3-Hax= 11.4 Hz
J 3-Hax-4-Hax= 10.8 Hz
J 2-Hax-3-Heq= 3.3 Hz
J 3-Heq-4-Hax= 5.4 Hz
Figure 1.
2
. Results and discussion
compound in a separate experiment starting from 4b, ethyl
glyoxylate and the diene 2b in the presence of BF $etherate.
3
In a typical procedure the imine 1 was first combined with
BF $ether at ꢀ78 C, in dry toluene, followed by addition
A complete conversion of 4b into the adduct 7b was ob-
served after 15 min. It is apparent that the hydrolysis of the
imine 1 to form ethyl glyoxylate was the origin of compound
ꢁ
of the diene 2 or 3 (1 equiv) after 5 min. BF $ether 0.1 equiv
3
3
was used in the cases of dienes 2 and 1 equiv with dienes 3a–
c, to accelerate the reaction. The reaction mixture was stirred
at room temperature from 15 min to several hours. A longer
period of time was needed with 3c (3 h, rt) and 3d (3 h,
7
mixing together aromatic imines with cyclopentadiene and
b. Cycloadducts of this type have been isolated before
19 1
trifluoroacetic acid in the presence of formaldehyde.
H
1
3
and C NMR spectra of compound 7b showed a highly sym-
metrical structure and its HRMS showed the correct mole-
cular ion. Compound 7b would be formed from 4b by
approach of the diene 2b by the less hindered face of the in-
termediate 8 (Fig. 2), probably by the same mechanism that
led to the synthesis of 4b from imine 1 and diene 2b.
ꢁ
rt+19 h, 5 C), to get the reaction to completion. Tetrahydro-
quinolines 4 (4a,b) (Scheme 2), 5 (5a,d) or an oxidation
product of 5b (6b) or 15 (15c) were obtained pure after
work-up (Schemes 4 and 7).
In the reaction of the imine 1 with the 1-monosubstituted
dienes 2a and 2b the regioselectivity shown in products 4
was expected due to primary electronic effects. The stereo-
Reaction of the imine 1 with the 1-trimethylsilyloxy-1,3-bu-
tadiene was reported before by Whiting, forming an open
1
selectivity of these reactions was determined by H NMR
17
chain aldehyde derivative 9 after hydrolysis. A simple
Mannich-process was proposed for the addition of the diene
to the activated iminium chelate. If a cycloaddition had oc-
spectroscopy. Adducts 4a and 4b show large axial–axial
coupling constants (10.8–11.4 Hz) between 2-H and one of
the 3-H (axial), and between 3-H and 4-H (Fig. 1). There are
also small coupling constants for interactions between 2-H
1
curred as a primary process to obtain 4b analog (R ¼TMS),
the formation of the aldehyde 9 would include an extremely
unlikely C–C cleavage. The isolated compound 4b was hy-
drolyzed in HCl–THF. A single compound was detected and
(
(
axial) and 3-H (equatorial) (3.3 Hz), and between 3-H
equatorial) and 4-H (axial) (5.4 Hz). These values are con-
sistent with the configuration shown in Figure 1.
Compounds 4a and 4b were obtained pure after flash chro-
matography, but the crude reaction mixtures showed no
other isomer by H NMR spectroscopy. The reaction of 1-
OTBS
1
MeO
acetoxy-1,3-butadiene reported by Whiting and co-workers
showed a 5:1 mixture of cis (major) and trans (minor) iso-
mers. When the reaction of the imine 1 with the diene 2b
was carried out using an old sample of the imine glyoxylate
N
CO Et
2
+
H
CO Et
2
8
1
(
a mixture of 4b together with compound 7b was formed
Scheme 2). Compound 7b was obtained as a single
Figure 2.
R1
R1
R1
OMe
1
MeO
R1
2
a, R =OMe
MeO
1
N
1
R = OTBS
2
b, R =OTBS
N
CO Et
2
EtO C
H
2
N
H
CO Et
2
(E)
1
CO Et
2
4
a, 44 %
b, 55 %
4
7b, 40 %
Scheme 2.

M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
729
CHO
CO Et
MeO
N
H
2
9
CHO
MeO
MeO
MeO
HCl-THF
4
b
N
H
CO Et
N
CO2Et
2
10
11
OR
MeO
OR
1
+
CO Et
N
2
N
CO Et
2
H
R= Menthyl
12
13
Scheme 3.
isolated, the aldehyde 10. Further exposition of 10 to acid
0.1 or 1 equiv of HCl) for 1 h at room temperature formed
neither the open chain aldehyde 9 nor the expected quinucli-
dine 11. The only product obtained was the quinoline 12
Nevertheless, an aliquot of the reaction mixture run after
5 min from the start of the reaction showed together with
reagents and incipient signals for 6b, signals for compound
5b. Protons H-2, H-3, and H-4 of 5b showed vicinal coupling
values comparable to those observed for H-2, H-3, and H-4
protons in compound 5a (Fig. 4). Inspection of the NMR
sample spectra over the time showed that consumption of
the reagents and conversion of 5b into 6b was complete
after 1 h.
(
(
Scheme 3). In the literature quinolines such as compounds
2 have been obtained in low yields from reactions of vinyl
enol ethers and arylimines or in good yields after acid
1
1
0
4
treatment of crude products. We therefore carried out the re-
action of vinyl menthyl ether with the imine 1 with the aim
of synthesizing compounds 13 and 12. The quinoline 12 was
observed during the course of the reaction and was isolated
in 60% yield together with compound 13 in only 4% yield,
contaminated with menthol. A CDCl solution of compound
3
1
3 showed its complete conversion into quinoline 12 and
menthol after 7 days at room temperature. A solid sample
of compound 13 also showed conversion of half of the mate-
rial into 12 after standing at room temperature for 7 days .
Reactions with symmetrical 1,4-disubstituted 1,3-dienes
3
2
a,b exhibited the same regioselectivity observed for dienes
a,b forming products with the vinyl group attached to the
position 4 (5a and 6b). The stereochemical outcome of the
cycloadditions (Scheme 4) was found to be different from
the mono-substituted dienes.
1
7
Compound 5a showed small coupling constants between
H-2 and H-3 (3.0 Hz), and between H-3 and H-4 (4.8 Hz).
Single X-ray crystallography showed the small dihedral
angle between those protons and confirmed the stereochem-
2
0
istry of products to be cis (Figs. 3 and 5).
Compound 5b could not be isolated; an oxidation process
producing 6b occurs immediately as 5b starts forming.
Figure 3. ORTEP view of the molecular structure of the 1,2,3,4-tetrahydro-
quinoline 5a.
R1
R1
OTBS
OTBS
CO2Et
R1
OMe
R1
MeO
MeO
1
3
a, R =Me
1
R =OTBS
N
3b, R1=OTBS
N
H
CO Et
N
2
EtO C
H
2
(E)
1
5a, 45 %
5b]
6b, 30 %
[
Scheme 4.

730
M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
H
H
EtO C
2
N
H
H
OMe
R1
R1
1
5
a R =Me
1
t
5
b R =OSiMe Bu
2
J 2-Hax-3-H = 3.0 Hz
eq
J 2-Hax-3-H = 4.2 Hz
eq
J 3-Heq-4-H = 4.8 Hz
ax
J 3-H -4-Hax= 3.9 Hz
eq
Figure 4.
The presence of compound 6b was confirmed by the
absence of NH absorption band (IR spectrum), disappear-
ance of the doublet at ca. d 4 ppm expected for H-2, a dou-
H
1
blet for H-3 due to coupling with H-4 ( H NMR spectrum)
and a signal at d 156.1 ppm assigned to C-2 ( C NMR
Figure 5. ORTEP view of the molecular structure of the 1,2,3,4-tetrahydro-
quinoline 15c.
1
3
C
spectrum). The coupling value for H-3/H-4 in 6b is the
same as the coupling of H-3/H-4 in the precursor structure
5
b (J¼3.9 Hz).
moiety rotates to give the less hindered configuration of
the product.
Considering the stereochemistry of compounds 5 a concerted
mechanism for their synthesis is not reasonable. Scheme 5
shows the two possible tetrahydroquinoline structures that
would result from the endo and the exo approach in the imino
Diels–Alder cycloaddition. None of the products were
formed.
Reaction of 1,4-diphenyl-1,3-butadiene with the imine 1
gave a tetrahydroquinoline (15c) showing a different stereo-
chemistry from compounds 5. Configurations are 2,3-trans-
2,4-cis. The different arrangements in turn of the tetrahedral
carbons are evidenced by the coupling constants between
H-2 and H-3 (8.7 Hz), and H-3 and H-4 (8.7 Hz). The struc-
ture of compound 15c was definitely confirmed by X-ray
analysis (Fig. 5).
Whiting and co-workers recently found some evidence for
a stepwise mechanism, rather than a Diels–Alder for the re-
actions of the arylimine 1 with dienes. We now have a stron-
ger evidence for such ionic mechanism. Scheme 6 shows the
less hindered approach of the diene to the activated imine
following the B €u rgi–Dunitz trajectory, with the major part
of the diene oriented away from the ethoxy carbonyl group.
This interaction would produce a cationic intermediate 14
that after rotation around C-3/C-4 would be attacked by
the aromatic ring and will produce the tetrahydroquinoline
The different relative configurations of C-2/C-3 demand
a different approach/mechanism from that observed for
compounds 5. Compound 15c could either be accessed by
an endo Diels–Alder or by the nucleophilic attack of the di-
ene terminal to the imine, with formation of the carbocation
16, as intermediate. In this case, the nucleophilic attack of
1
the diene would occur with the phenyl group (R ) approach-
ing the iminium nitrogen ion on the same hand side of the
5
(Scheme 6). Presumably the cation bearing the propenyl
Scheme 5.
R1
R1
MeO
H
H
H
MeO
R1
+
MeO
+
R1
R1
H
H
+
+
5
-N
CO Et
CO Et
2
N
2
N
F3B
CO Et
2
-
-
R1
BF3
BF3
14
Scheme 6.

M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
731
Ph
Ph
Ph
MeO
Ph
H
H
H
MeO
MeO
+
Ph
CO2Et
MeO
H
+
Ph
Ph
CO Et
3c
H
+
+
N
CO Et
CO2Et
N
2
N
N
H
F B -
-
3
2
-
Ph
BF3
BF3
16
15c
Scheme 7.
ethoxy carbonyl group, preferring the bulkier arrangement
of reagents. Scheme 7 shows this approach.
has an oxygen directly attached to the terminal positions,
shows that the approach of reagents would be like 18, the ox-
ygen atom preferring to drive away from the iminium ion.
An explanation for this is that a strong steric interaction
with the trimethylsilyl group would disfavor the approach
like 17. Another experiment was done with the diene 3d,
which combines a less bulky group at C-1 and C-4 with an
oxygen (R ¼OAc). H NMR of the crude product showed
a mixture of two diastereomers (3:1). The major isomer
(5d) was isolated in 22% yield, showing the stereochemistry
to be 2,3-trans-2,4-cis. The minor isomer was observed in
the crude, and in flash chromatography fractions, between
unidentified sub-products. The vicinal couplings of H-2/
H-3 and H-3/H-4 pairs are of the same magnitude
(J¼8.1 Hz), comparable to compound 15c. The major
isomer also showed the same coupling between H-2/H-3
and H-3/H-4 pairs, with a small coupling (J¼2.4 Hz) similar
to compound 5a.
Seeking for an explanation in literature for this bizarre result
we systematically found that dienophiles bearing aliphatic
groups, most frequently cyclic enes but also acyclic
2
1
21,22
gave mainly the 2,3-cis tetrahydroquinolines. On the other
side dienophiles attached to aromatic groups gave the 2,3-
trans isomers almost exclusively, unless a very strong bulky
1
1
2
3
2
4
interaction occurs. We believe that an electronically fa-
vored interaction of the iminium nitrogen with the approach-
ing aromatic group explains the preference depicted in the
formation of cation 16 (Scheme 7). Dihydropyrans and to
a less extent also dihydrofurans behave differently from their
carbodiene counterpart; they usually display a mixed stereo-
6
,8,10,25
chemistry around C-2/C-3.
A mixture of isomers is
usually formed, being the 2,3-trans isomer favored most of
the times, just like the case of the 1,4-diphenyl-1,3-butadi-
ene. Resembling the approach of reagents to form the inter-
mediate 16, intermediate 17 would be stabilized by the
oxygen atom in the proximity of the iminium ion, whereas
the alternative intermediate 18 having the carbocation placed
on the same side of the positive nitrogen atom would be less
stable from the electronic point of view (Fig. 6).
A steric/electronic balance seems to operate in the reaction of
the imine 1 with 3d, which led to the simultaneous formation
of diastereomers 5d (major) and 15d (minor) (Scheme 8).
In conclusion adducts are formed with total regio- and ste-
reo-control with 1-substituted and 1,4-disubstituted dienes.
Based on the stereochemistry of the products an ionic step-
wise mechanism is proposed for the reaction of 1,4-disubsti-
tuted dienes with the imine 1.
The missing rotation of the carbocation in the intermediate
16, around C3/C4 could be explained by the greater hin-
drance of the phenyl group compared to the groups occupy-
ing position 3 in compounds 5.
The stereochemistry of the tetrahydroquinoline resulting
from the reaction of the imine 1 with the diene 3b, which
3. Experimental section
3.1. General
H
1
H
H NMR spectra were recorded on a Varian Unity Plus 300
(300 MHz) spectrometer. Multiplicities are recorded as
broad peaks (br), singlets (s), doublets (d), triplets (t), dou-
blets of doublets (dd), doublets of doublets of doublets (ddd),
doublets of triplets (dt), triplets (t), quartets (q), and multi-
plets (m). J values are in Hertz and d in parts per million.
Infrared spectra were recorded on a Bomem MB 104 or
+
MeO
MeO
H
H
O
+
+
N
N
CO Et
CO Et
2
O
2
+
-
-
BF3
BF3
1
7
18
Figure 6.
H
H
OAc
H
EtO C
H
2
N
EtO2C
H
+
N
H
1
+
H
AcO
OMe
OMe
OAc
H
OAc 3d
OAc
OAc
5
d (major) J 2-Hax-3-H = 2.4 Hz
eq
15d (minor) J 2-Hax-3-H = 8.1 Hz
eq
J 3-Heq-4-Hax= 2.4 Hz
J 3-H -4-Hax= 8.1 Hz
eq
Scheme 8.

732
M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
on a Perkin–Elmer 1600 FT-IR spectrophotometer. Samples
were run as Nujol mulls, and oils as thin films. MS spectra
were recorded on a VG Autospec M. spectrometer. Micro-
analyses were performed in a LECO-CHNS-932 analyser.
Melting points (mp) were determined on a Gallenkamp
block and are uncorrected. Dry column flash chromato-
graphy was carried out using Kieselgel 60 and water pump
vacuum. Toluene was dried over sodium followed by distil-
3H), 1.76 (dt, J¼11.4, 12.9 Hz, 1H), 2.33 (ddd, J¼3.3, 5.4,
12.9 Hz, 1H), 3.42 (dt, J¼5.4, 10.8 Hz, 1H), 3.73 (s, 3H),
4.05 (dd, J¼3.3, 11.4 Hz, 1H), 4.15 (br s, 1H, NH)*, 4.25
(dq, J¼2.7, 7.2 Hz, 2H), 4.95 (dd, J¼9.9, 12.0 Hz, 1H),
6.44 (d, J¼12.0 Hz, 1H), 6.65 (dd, J¼2.7, 8.7 Hz, 1H),
1
3
6.73 (d, J¼2.7 Hz, 1H). * Disappears with D O shake.
C
2
NMR (75.5 MHz, CDCl ): d¼ꢀ5.3 (Me), ꢀ5.2 (Me), 14.1
3
t
(Me), 18.3 (C), 25.7 (Bu ), 33.8 (CH ), 36.5 (CH), 54.1
2
lation. Dichloromethane (DCM) was dried over CaH . Dry
2
(CH), 55.7 (OMe), 61.3 (OCH ), 113.6 (CH), 113.7 (CH),
2
flash chromatography was performed on silica gel 60
<
4
115.9 (CH), 125.3 (C), 136.9 (C), 142.4 (CH), 152.2 (C),
ꢀ
1
0.063 mm for column chromatography. Petroleum ether
0–60 C was distilled before use. The imine 1 was obtained
172.9 (CO). IR (Nujol) 3392, 1738, 1661, 1504 cm
Anal. Calcd for C H NO Si: C, 64.41; H, 8.49; N, 3.58.
.
ꢁ
from the reaction of ethyl glyoxylate (freshly distilled) and
2
1
33
4
Found: C, 63.96; H, 8.30; N, 3.68.
˚
p-anisidine in dry toluene, in the presence of 4 A molecular
sieves. Evaporation of the solvent gave an oil that was used
without further purification. 1,3-Dienes were used as pur-
chased with the exception of cyclopentadiene, which was
pyrolyzed and distilled prior to use.
3.1.1.3. Ethyl 6-methoxy-3-methyl-4-(prop-1-enyl)-
1,2,3,4-tetrahydroquinoline-2-carboxylate 5a. Compound
5a was obtained using the general procedure: Imine 1
(0.65 g, 3.14 mmol); BF $Et O (3.14 mmol); 2,4-hexadiene
3
2
(0.28 g, 3.45 mmol). Reaction time: 1 h. Dry flash column
chromatography [silica; ether–light petroleum, polarity gra-
3
4
.1.1. General procedure for the synthesis of compounds
and 5. Theimine1wasdissolvedindrytoluene(25 mL)and
dient] gave compound 5a; yield: (0.40 g, 1.40 mmol, 45%);
ꢁ
1
the solution refrigerated in an acetone/CO bath. BF $Et O
2
a white solid; mp 88–90 C (ether–light petroleum). H
3
2
(
1
0.1–1 equiv) was added dropwise and the diene (0.7–
.2 equiv) added within 5 min. The cold bath was removed
NMR (300 MHz, CDCl ): d¼0.77 (d, J¼6.9 Hz, 3H), 1.32
3
(t, J¼7.2 Hz, 3H), 1.81 (dd, J¼1.5, 6.6 Hz, 3H), 2.42 (m,
1H), 3.68 (dd, J¼4.8, 9.0 Hz, 1H), 3.74 (s, 3H), 4.18 (d,
J¼3.0 Hz, 1H), 4.27 (m, 2H), 5.50 (ddd, J¼1.8, 9.0,
15.0 Hz, 1H), 5.72 (dq, J¼6.6, 15.0 Hz, 1H), 6.57 (m, 1H),
after addition was complete and the solution was kept under
magnetic stirring for 15 min to several hours. The mixture
was then quenched with saturated aq NaHCO (100 mL)
3
1
3
and extracted with DCM (2ꢂ50 mL). The combined organic
6.65 (m, 2H). C NMR (75.5 MHz, CDCl ): d¼8.6 (Me),
3
solutions were dried over MgSO and evaporated.
4
14.2 (Me), 18.0 (Me), 34.0 (CH), 46.0 (CH), 55.7 (OMe),
5
(CH), 123.4 (C), 129.0 (CH), 131.2 (CH), 136.3 (C), 152.0
8.8 (CH), 61.2 (OCH ), 112.7 (CH), 114.9 (CH), 114.9
2
3
.1.1.1. Ethyl 6-methoxy-4-(2-methoxyvinyl)-1,2,3,4-
ꢀ
1
tetrahydroquinoline-2-carboxylate 4a. Compound 4a
was obtained using the general procedure: Imine 1 (1.05 g,
.00 mmol); BF $Et O (0.50 mmol); 1-methoxy-1,3-butadi-
3 2
ene (0.52 g, 6.38 mmol). Reaction time: 45 min. Dry flash
chromatography [silica; ether–light petroleum, polarity gra-
dient] gave compound 4a; yield: (0.64 g, 2.20 mmol, 44%);
(C), 172.4 (CO). IR (Nujol) 3387, 1741, 1725 cm . MS
+
+
(FAB): m/z (%)¼290 (17) [M+1] , 289 (55) [M] , 288 (10),
287 (23), 286 (100), 216 (25), 212 (27). Anal. Calcd for
C H NO : C, 70.56; H, 8.01; N, 4.84. Found: C, 70.13;
5
1
7
23
3
H, 7.99; N, 4.91.
ꢁ
1
a white solid; mp 88–90 C (ether–light petroleum). H
3.1.1.4. Ethyl 3-(tert-butyldimethylsilyloxy)-4-(2-(tert-
butyldimethylsilyloxy)vinyl)-6-methoxy-3,4-dihydroqui-
noline-2-carboxylate 6b. Compound 6b was obtained using
the general procedure: Imine 1 (0.14 g, 0.67 mmol);
BF $Et O (0.67 mmol); 1,4-di-tert-butyldimethylsilyl-
NMR (300 MHz, CDCl ): d¼1.32 (t, J¼7.2 Hz, 3H), 1.79
3
(
dt, J¼11.1, 12.9 Hz, 1H), 2.35 (ddd, J¼3.3, 5.4, 12.9 Hz,
1
4
4
H), 3.44 (dt, J¼5.4, 11.1 Hz, 1H), 3.57 (s, 3H), 3.73 (s, 3H),
.05 (dd, J¼3.3, 11.1 Hz, 1H), 4.24 (dq, J¼1.5, 7.2 Hz, 2H),
.68 (dd, J¼9.3, 12.6 Hz, 1H), 6.50 (d, J¼12.6 Hz, 1H), 6.57
3
2
oxy1,3-butadiene (0.21 g, 0.67 mmol. Reaction time: 1 h.
Dry flash column chromatography [silica; ether–light petro-
leum, polarity gradient] gave compound 6b as an oil; yield:
(
d, J¼8.4 Hz, 1H), 6.65 (dd, J¼2.7, 8.4 Hz, 1H), 6.75 (d,
1
3
J¼2.7 Hz, 1H). C NMR (75.5 MHz, CDCl ): d¼14.1
3
1
(
(
(
(
(
(
[
Me), 34.1 (CH ), 36.8 (CH), 54.1 (CH), 55.7 (OMe), 55.9
2
(0.10 g, 2.0 mmol, 30%). H NMR (300 MHz, CDCl3):
OMe), 61.2 (OCH ), 105.4 (CH), 113.2 (CH), 114.2
2
CH), 115.7 (CH), 125.4 (C), 137.0 (C), 149.0 (CH), 152.1
C), 172.8 (CO). IR (Nujol) 3392, 1733, 1648 cm . MS
d¼ꢀ0.02 (s, 3H), 0.10 (s, 3H), 0.21 (s, 6H), 0.72 (s, 9H),
0.97 (s, 9H), 1.43 (t, J¼7.2 Hz, 3H), 3.20 (dd, J¼3.9,
9.6 Hz, 1H), 3.84 (s, 3H), 4.43 (m, 2H), 4.65 (d, J¼3.9 Hz,
1H), 5.23 (dd, J¼9.6, 12.3 Hz, 1H), 6.45 (d, J¼12.3 Hz,
ꢀ
1
+
+
FAB): m/z (%)¼292 (28) [M+1] , 291 (100) [M] , 218
25), 186 (6), 160 (19). HRMS calcd for C H NO
4
1H), 6.82 (dd, J¼8.7 Hz, 1H), 6.87 (d, J¼3.0 Hz, 1H),
1
6
22
+
13
M+H] : 292.154883; found: 292.154513.
7.56 (d, J¼8.7 Hz, 1H). C NMR (75.5 MHz, CDCl ):
3
d¼ꢀ5.3 (Me), ꢀ5.1 (Me), ꢀ4.9 (Me), ꢀ4.6 (Me), 14.2
3
.1.1.2. Ethyl [2-(tert-butyldimethylsilyloxy)vinyl]-6-
(Me), 18.1 (C), 18.3 (C), 25.6 (Me), 25.7 (Me), 41.4 (CH),
55.3 (OMe), 62.0 (OCH ), 64.0 (CH), 106.6 (CH), 111.7
methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate 4b.
Compound 4b was obtained using the general procedure:
Imine 1 (1.00 g, 4.83 mmol); BF $Et O (0.48 mmol); 1-tert-
butyldimethylsilyloxy 1,3-butadiene (0.64 g, 3.49 mmol).
Reaction time: 15 min. Dry flash column chromatography
2
(CH), 113.4 (CH), 130.5 (CH), 133.1 (C), 136.4 (C), 144.1
(CH), 156.1 (C), 160.7 (C), 165.0 (C). IR (Nujol) 1732,
3
2
ꢀ1
1710, 1661, 1620, 1568 cm
.
HRMS calcd for
C H NO Si [M+H] : 520.291456; found: 520.291232.
+
2
7
46
5
2
[
pound 4b; yield: (0.75 g, 1.93 mmol, 55%); a white solid;
mp 59–60 C (light petroleum). H NMR (300 MHz,
silica; ether–light petroleum, polarity gradient] gave com-
3.1.1.5. Ethyl 6-methoxy-3-phenyl-4-styryl-1,2,3,4-tet-
rahydroquinoline-2-carboxylate 15c. Compound 15c was
obtained using the general procedure: Imine 1 (0.73 g,
ꢁ
1
CDCl ): d¼0.19 (s, 6H), 0.97 (s, 9H), 1.32 (t, J¼7.2 Hz,
3

M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
733
3
.50 mmol); BF $Et O (3.50 mmol); 1,4-diphenyl-1,3-buta-
3
J¼9.0, 12.6 Hz, 2H), 2.38 (dt, J¼5.7, 12.6 Hz, 2H), 3.35 (dt,
J¼4.8, 9.0 Hz, 2H), 3.70 (s, 3H), 4.04 (dd, J¼6.0, 8.1 Hz,
2H), 4.09–4.22 (m, 4H), 4.98 (dd, J¼9.0, 11.7 Hz, 2H), 6.31
2
diene (0.72 g, 3.50 mmol). Reaction time: 3 h. Dry flash col-
umn chromatography [silica; ether–light petroleum, polarity
gradient] gave compound 15c; yield: (0.59 g, 1.43 mmol,
1
3
(d, J¼11.7 Hz, 2H), 6.57 (s, 1H). C NMR (75.5 MHz,
ꢁ
1
4
1%), mp 57–60 C. H NMR (300 MHz, CDCl ): d¼0.89
CDCl ): d¼ꢀ5.24 (Me), 14.2 (Me), 18.3 (C), 25.7 (Me),
3
3
(
3
t, J¼7.2 Hz, 3H), 3.22 (t, J¼8.7 Hz, 1H), 3.73 (s, 3H),
.82–3.94 (m, 3H), 4.13, (d, J¼8.7 Hz, 1H), 4.20 (br s, 1H,
NH)*, 6.01 (dd, J¼8.7, 15.9 Hz, 1H), 6.18 (d, J¼15.9 Hz,
H), 6.75 (m, 3H), 7.25 (m, 10H). * Disappear with D O
34.5 (CH ), 34.9 (CH), 55.6 (OMe), 58.6 (CH), 60.8
2
(OCH ), 111.9 (CH), 113.3 (CH), 127.4 (C), 133.9 (C),
2
142.2 (CH), 151.2 (C), 173.2 (CO). IR (Nujol) 1740, 1661,
ꢀ
1472 cm . HRMS calcd for C H NO Si [M+H] :
35 58 7 2
1
+
1
2
1
3
shake. C NMR (75.5 MHz, CDCl ): d¼13.6 (Me), 42.2
660.375186; found: 660.374173.
3
(
(
(
(
(
1
OCH or CH), 48.1 (CH), 55.7 (OMe), 60.1 (CH), 60.9
CH or OCH ), 113.8 (CH), 114.7 (CH), 116.9 (CH), 124.5
C), 126.1 (CH), 126.8 (C), 127.1 (C), 128.2 (CH), 128.3
CH), 128.4 (CH), 131.3 (CH), 132.9 (CH), 136.4 (C), 137.1
C), 140.9 (C), 152.6 (C), 172.7 (CO). IR (Nujol) 3376,
2
3.1.1.8. Synthesis of ethyl 6-methoxy-4-(2-oxoethyl)-
1,2,3,4-tetrahydroquinoline-2-carboxylate 10. The tetra-
hydroquinoline 4b (1.0 g, 2.57 mmol) was dissolved in THF
(50 mL) and aq HCl 10% (10 mL) was added in an ice-water
bath. The solution was then stirred at room temperature for
2
ꢀ
1
731, 1599, 1505 cm . HRMS calcd for C H NO
3
2
7
28
+
[
MH] : 414.206919; found: 414.207913.
1 h. After addition of saturated aq NaHCO (100 mL) the
3
mixture was concentrated on the rotary evaporator and ex-
tracted with DCM (3ꢂ50 mL). The extracts were combined,
3
.1.1.6. Syntheses of ethyl 3-acetoxy-4-[(2-acetoxy)-
vinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline-2-carbox-
ylate 5d and 15d. Compounds 5d and 15d were obtained
using the general procedure: Imine 1 (0.31 g, 1.47 mmol);
BF $Et O (1.69 mmol); 1,4-diacetoxy1,3-butadiene (0.13 g;
dried over MgSO and concentrated to give a light yellow oil
4
identified as compound 10; yield (0.56 g, 2.0 mmol, 78%).
1
H NMR (300 MHz, CDCl ): d¼1.31 (t, J¼7.2 Hz, 3H),
3
1.75 (dt, J¼10.5, 12.6 Hz, 1H), 2.49 (ddd, J¼3.9, 5.4,
12.6 Hz, 1H), 2.69 (ddd, J¼2.1, 8.4, 17.7 Hz, 1H), 2.97
(ddd, J¼1.2, 4.5, 17.7 Hz, 1H), 3.53 (m, 1H), 3.73 (s, 3H),
4.03 (dd, J¼3.9, 10.5 Hz, 1H), 4.24 (q, J¼7.2 Hz, 2H), 6.59
(d, J¼8.7 Hz, 1H), 6.60 (d, J¼2.7 Hz, 1H), 6.67 (dd, J¼2.7,
3
2
ꢁ
0
.74 mmol). Reaction time: 3 h (rt)+19 h (5 C). Dry flash
column chromatography [silica; ether–light petroleum,
polarity gradient] gave compound 5d; yield: (0.06 g,
0
1
.16 mmol, 22%); a clear oil. H NMR (300 MHz, CDCl ):
3
1
3
d¼1.29 (t, J¼7.5 Hz, 3H), 1.96 (s, 3H), 2.11 (s, 3H), 3.62 (br
8.7 Hz, 1H), 9.88 (s, 1H). C NMR (75.5 MHz, CDCl ):
3
d, J¼6.6 Hz, H-4), 3.73 (s, 3H), 4.13 (d, J¼2.4 Hz, H-2),
d¼14.1 (Me), 30.4 (CH), 31.5 (CH ), 48.9 (CH ), 53.7 (CH),
2
2
4
.18–4.34 (m, 2H), 5.34 (t, J¼2.4 Hz, 1H, H-3), 5.55 (dd,
55.7 (OMe), 61.3 (OCH ), 112.5 (CH), 113.2 (CH),
2
J¼6.9, 12.0 Hz, 1H), 6.55 (d, J¼2.4 Hz, 1H), 6.64–6.78
116.1 (CH), 123.9 (C), 137.3 (C), 152.3 (C), 172.7 (CO),
1
3
ꢀ1
(
m, 2H), 7.01 (dd, J¼1.5, 12.0 Hz). C NMR (75.5 MHz,
CDCl ): d¼14.1 (Me), 20.6 (Me), 20.9 (Me), 40.6 (C-4),
201.3 (CHO). IR (Nujol) 3387, 1726, 1650, 1620 cm .
HRMS calcd for C H NO [M] : 277.131408; found:
277.131619.
+
3
15 19
4
5
3.2 (C-2), 55.6 (OMe), 61.8 (OCH ), 69.2 (C-3), 114.8
2
(
(
CH), 115.0 (CH), 115.3 (C-1), 116.8 (CH), 119.0 (C), 135.4
0
C), 139.3 (C-2 ), 152.6 (C), 167.7 (CO), 170.2 (CO), 170.5
3.1.1.9. Synthesis of ethyl 6-methoxyquinoline-2-car-
boxylate 12. Method 1. To a solution of the aldehyde 10
(0.26 g, 0.94 mmol) dissolved in dry acetonitrile (20 mL)
was added anilinium chloride (12.2 mg, 0.094 mmol). The
mixture was kept stirring at room temperature for 60 h.
Evaporation of the solvent gave an oil that was purified by
dry flash chromatography [silica; ether–pet ether, polarity
gradient]. Compound 12 was obtained as a solid (133 mg,
(
1
CO). IR (neat) 3395, 3083, 2979, 2935, 2855, 1742,
ꢀ
672 cm . HRMS calcd for C H NO [MH] : 378.1547;
19 24 7
1
+
found: 378.1540.
A minor isomer, compound 15d, was observed in the crude
and in fractions of the flash chromatography. Some signifi-
cant H NMR peaks are registered: H NMR (300 MHz,
1
1
ꢁ
1
CDCl ): d¼1.26 (t¼7.8 Hz, 3H), 1.99 (s, 3H), 2.08 (s, 3H),
0.58 mmol, 62%), mp (ether–pet ether) 128–129 C. H
3
3
4
1
.54 (t, J¼8.1 Hz, 1H, H-4), 4.00 (d, J¼8.1 Hz, 1H, H-2),
NMR (300 MHz, CDCl ): d¼1.47 (t, J¼7.2 Hz, 3H), 3.93
3
.19 (dq, J¼1.2, 7.5 Hz, 1H, OCH ), 5.21 (t, J¼8.1 Hz,
(s, 3H), 4.53 (q, J¼7.2 Hz, 2H), 7.07 (d, J¼2.7 Hz, 1H), 7.40
(dd, J¼2.7, 9.6 Hz, 1H), 8.13 (s, 2H), 8.18 (d, J¼9.6 Hz,
2
0
H, H-3), 7.06 (dd, J¼1.2, 12.6 Hz, 1H, H-2 ).
1
3
1
H). C NMR (75.5 MHz, CDCl ): d¼14.3 (Me), 55.6
3
3
.1.1.7. Synthesis of diethyl 1,7-bis((E)-2-(tert-butyldi-
(OMe), 62.0 (OCH ), 104.5, 121.4, 123.3, 130.7 (C), 132.2,
2
methylsilyloxy)vinyl)-9-methoxy-1,2,3,5,6,7-hexahydro-
pyrido[3,2,1-ij]quinoline-3,5-dicarboxylate 7b. The
adduct 4b (0.12 g, 0.30 mmol) was dissolved in dry toluene
135.5, 143.7 (C), 145.7 (C), 159.3 (C), 165.5 (CO). IR
(Nujol) 1729, 1621 cm . HRMS calcd for C H NO
3
[M+H] : 232.09728; found: 232.09748.
ꢀ1
1
3
14
+
(
10 mL) and ethyl glyoxylate (0.03 g, 0.30 mmol) was
ꢁ
.03 mmol) was added with a syringe and the diene 2b
added. After cooling to ꢀ78 C, BF $Et O (4.3 mg,
Method 2. The imine 1 (0.61 g, 2.96 mmol) was dissolved in
dry toluene (10 mL) and the solution was refrigerated in an
acetone/CO bath. BF $Et O (0.1 equiv, 0.30 mmol, 37 ml)
was added dropwise followed by (1S,2R,4R)-1-isopropyl-
4-methyl-(2-vinyloxy)cyclohexane (0.54 g, 2.96 mmol) in
toluene (10 mL). The cold bath was removed after addition
was complete and the solution was kept under magnetic stir-
ring for 30 min at room temperature. The mixture was
3
3
0
(
55 mg, 0.30 mmol) followed after 5 min. Stirring was
ꢁ
2
3
2
continued for 15 min at ꢀ78 C and 30 min after removal
of the refrigerating bath, then DCM (50 mL) was added. The
solution was washed with saturated NaHCO (50 mL) and
3
water (50 mL). The organic phase was dried over MgSO
and evaporated to give an oil, pure by H NMR (0.17 g,
0
4
1
1
.26 mmol, 85%). H NMR (300 MHz, CDCl ): d¼0.93
quenched with saturated aq NaHCO (20 mL) and extracted
3
with DCM (2ꢂ50 mL). The combined organic solutions
3
(
s, 18H), 1.15 (s, 12H), 1.25 (t, J¼7.2 Hz, 6H), 1.97 (dt,

734
M. J. Alves et al. / Tetrahedron 63 (2007) 727–734
were dried over MgSO and evaporated to give a yellow
4
oil. Flash chromatography (silica; pet ether–ether, 5.5:1)
gave a white solid (107 mg) that was a mixture of ethyl 4-
12. Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M.
J. Heterocycl. Chem. 1988, 25, 1831–1835.
13. Leeson, P. D.; Carling, R. W.; Moore, K. W.; Moseley, A. M.;
Smith, J. D.; Stevenson, G.; Chan, T.; Bakar, R.; Foster, A. C.;
Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Hoogsteen, K.
J. Med. Chem. 1992, 35, 1954–1968.
[
1
(1S,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)methoxy]-
,2,3,4-tetrahydroquinoline-2-carboxylate and menthol,
y
1
and a second fraction (ether) a white solid for which the H
NMR compared with the one described for compound 12 is
obtained in method 1.
14. Stevenson, G.; Leeson, P. D.; Rowley, M.; Sanderson, I.;
Stansfield, I. Bioorg. Med. Chem. Lett. 1992, 2, 371–374.
1
1
1
5. Nagarajam, R.; Perumal, P. T. Synth. Commun. 2001, 1733–
736.
6. Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P. J. Org. Chem.
988, 53, 2251–2258.
7. Hermitage, S.; Howard, J. A. K.; Prichard, D. J. R. G.; Probert,
M. R.; Whiting, A. Org. Biomol.Chem. 2004, 2, 2451–2460;
Hermitage, S.; Jay, D.; Whiting, A. Tetrahedron Lett. 2002,
1
Acknowledgements
1
We thank Dr. Thomas Gilchrist for reading the manuscript
and Funda c¸ ~a o Ci ^e ncia e Tecnologia for project funding
POCTI/32723/QUI/2000).
(
4
3, 9633–9636.
References and notes
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. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
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. U.S. Patent 0,087,926 A1, 2003.
19. Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855–
5858.
5
2
3
20. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 622654 (compound 15c) and 622655
(compound 5a). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk).
. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
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. Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969–3971.
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8
. Di Salvo, A.; Spanedda, M. V.; Our ꢀe vich, M.; Crousse, B.;
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1. Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995,
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1
1
3
1
y
1
Some peaks of H NMR (300 MHz, CDCl
3
) for compound 13: d¼2.53
(
1
ddd, J¼3.6, 5.1, 12.3 Hz, 1H, H-3), 3.76 (s, 3H), 4.07 (dd, J¼3.6,
0.8 Hz, 1H, H-2), 4.12 (br s, 1H, NH), 4.66 (dd, J¼5.4, 9.6 Hz, 1H,
H-4), 6.56 (d, J¼8.4 Hz, 1H), 6.69 (dd, J¼3.0, 8.4 Hz, 1H), 6.95 (1H,
d, J¼3.0 Hz, 1H).