New findings on the cerium(IV) ammonium nitrate catalyzed Povarov reaction: Stereoselective synthesis of 4-alkoxy-2-aryl-1,2,3,4-tetrahydroquinoline derivatives

Article abstract of DOI:10.1055/s-2008-1032126

Cerium(IV) ammonium nitrate catalyzes the three-component, imino Diels-Alder (Povarov) reaction between anilines, aromatic aldehydes, and acyclic vinyl ethers, giving cis-4-alkoxy-2-aryl-1,2,3,4-tetrahydroquinolines with almost complete diastereoselectivi

Full text of DOI:10.1055/s-2008-1032126

PAPER
1039
New Findings on the Cerium(IV) Ammonium Nitrate Catalyzed Povarov
Reaction: Stereoselective Synthesis of 4-Alkoxy-2-aryl-1,2,3,4-tetrahydro-
quinoline Derivatives
C
erium(IV
)
A
mmo
e
nium
N
itra
l
te Cata
l
lyzed P
a
ovarov Re
i
a
ction samy Sridharan, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
Received 18 October 2007; revised 2 January 2008
One of the most direct methods allowing the synthesis of
1,2,3,4-tetrahydroquinolines is the Povarov reaction, an
imino Diels–Alder reaction6 between aromatic imines and
electron-rich alkenes that are normally vinyl ethers. Al-
Abstract: Cerium(IV) ammonium nitrate catalyzes the three-com-
ponent, imino Diels–Alder (Povarov) reaction between anilines, ar-
omatic aldehydes, and acyclic vinyl ethers, giving cis-4-alkoxy-2-
aryl-1,2,3,4-tetrahydroquinolines with almost complete diastereo-
selectivity. The corresponding reaction starting from cyclic vinyl though this reaction was first described about 40 years
ago,7 it received relatively little attention until the discov-
ery of its efficient catalysis by lanthanide trifluoro-
ethers gave the two possible diastereomers, with the endo-com-
pound as the major product. This stereochemical outcome is ex-
plained through a stepwise mechanism for the imino Diels–Alder
methanesulfonates8 or chlorides9 acting as Lewis acids.
reaction, and this mechanism was subsequently proved by trapping
The high cost of these catalysts and their sensitivity to
the putative oxonium intermediate in the presence of ethanol.
moisture has prompted the study of the effects of a num-
Key words: cycloadditions, multicomponent reactions, stereose-
ber of alternative catalysts, including lithium tetra-
lective synthesis, Lewis acids, quinolines
fluoroborate,10 triphenylphosphonium perchlorate,11 po-
tassium hydrogen sulfate,12 iodine,13 and zirconium(IV)
chloride,14 on the Povarov reaction. In spite of the findings
Several bioactive natural products, including the well-
from these studies, there is still a need to identify catalysts
known marine alkaloids discorhabdin1 and martinelline2
for the Povarov reaction that are stable, easily handled, in-
and the antiviral agent virantmycin,3 contain a 1,2,3,4-tet-
expensive, and commercially available. Cerium(IV) de-
rahydroquinoline structural fragment. Many other, sim-
rivatives, and cerium(IV) ammonium nitrate (CAN) in
pler tetrahydroquinoline derivatives, including oxamni-
particular, meet these requirements. Although CAN is
quine, a schistosomicide, and L-689,560, a very potent
normally employed as a one-electron stoichiometric oxi-
NMDA antagonist (Figure 1), exhibit a variety of other
dant in processes such as oxidative demethylation, its use
relevant pharmacological properties.4 Tetrahydroquino-
in carbon–carbon and carbon–heteroatom bond-forming
lines are also useful starting materials for the preparation
reactions has attracted much attention over the last de-
of quinolines, which have a great pharmacological rele-
cade.15 These studies are still in their early stages and, as
vance as well.5
stated in a 2003 review on the subject,15c the current main
goal in this area is the development of the use of CAN as
HO
HO2C
Cl
a catalyst in organic synthesis.16
OMe
Although the reaction between in situ generated imines
and cyclic vinyl ethers using CAN as a catalyst has been
reported in a preliminary communication,17 an intriguing
discrepancy existed between the stereochemistry de-
scribed for the major product of this reaction and the re-
sults obtained for the Povarov reaction using other
catalysts.9–14 In addition, some key aspects of this trans-
formation have remained unexplored, including the possi-
bility of employing noncyclic vinyl ethers. Such ethers are
less reactive than their cyclic counterparts, but their use
would expand the scope of the reaction to include the syn-
thesis of nonfused tetrahydroquinoline systems. The con-
siderations summarized above prompted us to study these
aspects of the CAN-catalyzed Povarov reaction.
H
N
N
Me
H
O2N
N
H
Me
Me
Me
oxamniquine
Me
virantmycin
O
Cl HN
N
H
Cl
N
H
CO2H
L-689,560
Figure 1 Some bioactive natural products and drugs containing
Our first experiment re-examined the three-component re-
action between anilines, aromatic aldehydes, and cyclic
vinyl ethers in the presence of 5 mol% of CAN. As shown
in Scheme 1 and Table 1, in our hands the reaction gave
almost equimolar amounts of diastereomers 1 and 2, but
1,2,3,4-tetrahydroquinoline substructures
SYNTHESIS 2008, No. 7, pp 1039–1044
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032126; Art ID: T16207SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

1040
V. Sridharan et al.
PAPER
compounds 2 were the major products, in contrast with the cyclic counterparts. This prompted us to examine the in-
previous report. The use of a larger amount of catalyst (25 fluence of CAN on these reactions. Our results, summa-
mol%), as previously described,17 did not lead to appre- rized in Scheme 2 and Table 2, show that the reactions
ciable changes in the diastereomeric ratio.
proceed with almost complete diastereoselectivity to give
the cis-tetrahydroquinoline derivatives 3 in good yields as
the only isolated products.19
OHC
+
+
n
O
R1
NH2
R
OR3
OHC
+
+
CAN (5 mol%)
MeCN, r.t.
R2
NH2
CAN (5 mol%)
MeCN, r.t.
O
O
n
H
n
H
H
H
+
OR3
H
OR3
H
R1
N
N
R1
H
H
H
H
+
R
R
N
N
H
H
H
1
2
H
R2
R2
3
Scheme 1
4
Scheme 2
Table 1 Re-examination of the Stereochemical Outcome of Ceri-
um(IV) Ammonium Nitrate Catalyzed Povarov Reactions of Cyclic
Vinyl Ethers
Table 2 Diastereoselective Cerium(IV) Ammonium Nitrate Cata-
lyzed Povarov Reactions of Alkyl Vinyl Ethers
Products
1 and 2
R
n
Time
(min)
Yield
(%)
Ratio
(1/2)
Product R1
3
R2
R3
Time
(min) (3/4)
Ratio
Yield
(%) of 3
a
b
c
H
1
1
2
30
30
90
93
92
81
46:54
43:57
42:58
a
b
c
d
e
f
H
H
Et
45
45
45
60
60
45
45
60
60
60
92:8
97:3
95:5
95:5
97:3
96:4
96:4
95:5
97:3
96:4
72
70
67
70
74
70
76
74
77
71
Cl
H
F
H
Et
OMe
Me
H
H
Et
H
Et
The stereochemical assignment of compounds 1 and 2
was made using the coupling constants of the H-4a and H-
5 protons, and was confirmed by nuclear Overhauser ef-
fect spectroscopy experiments (e.g., see Figure 2 for com-
pounds 1c and 2c). The results are consistent with the
coupling constant values described by previous authors
that confirmed their assignment using X-ray diffraction.9
Me
H
Et
H
Bu
Bu
Bu
Bu
Bu
g
h
i
F
H
Me
H
H
Cl
H
2
2
1
1
O
3
3
O
j
Cl
Hc
Hc
4a
4a
4
4
Hb
Hb
NOESY
5
5
The cis diastereoselectivity can be explained by assuming
that the reaction takes place through the three-step mech-
anism summarized in Scheme 3. This involves the initial
formation of an imine from the starting aniline and alde-
hyde, followed by the addition of the vinyl ether to give
an oxonium derivative. Finally, this intermediate under-
goes intramolecular aromatic electrophilic substitution to
give the observed products. A cis arrangement between
the alkoxy and aryl groups leads to minimum interactions
between these bulky substituents and the axial protons in
the corresponding chair-like transition state of the cycliza-
tion step, which explains the observed preference for the
formation of the cis-tetrahydroquinoline derivatives 3.
N
H
N
H
Ha
Ha
1c
2c
Jab = 5.6 Hz
Jbc = 2.4 Hz
Jab = 10.6 Hz
Jbc = 2.8 Hz
Figure 2
Although Povarov reactions involving acyclic vinyl
ethers would provide ready access to nonfused 1,2,3,4-tet-
rahydroquinoline systems, which are of great chemical
and biological relevance,18 such reactions have received
very little attention in the literature, probably because of
the lower reactivity of these alkenes compared with their
Synthesis 2008, No. 7, 1039–1044 © Thieme Stuttgart · New York

PAPER
Cerium(IV) Ammonium Nitrate Catalyzed Povarov Reaction
1041
R
CHO
OHC
OEt
R1
R2
+
+
+
NH2
LA
NH2
CAN (5 mol%)
EtOH
R1
OR3
+OEt
N
R2
R
LA
N
H
R2
R3O
R2
N
N
R1
EtOH
LA
R3O
LA
R1
OEt
OEt
OEt
– LA
R3O
– LA
R
R
R2
R2
N
N
H
H
N
N
H
H
R1
R3O
R1
3
4
R = H
R = F
3a (25%)
3b (18%)
R = H
R = F
5a (44%)
5b (53%)
LA = Ce(NH4)2(NO3)6
Scheme 3
Scheme 4
To confirm this explanation, it was relevant to study
whether our imino Diels–Alder reaction took place in a
concerted or stepwise manner. Although the mechanism
of the Povarov reaction is normally accepted to be step-
wise,8 there is also evidence of concerted pathways in
some cases.20 For this reason, we wished to verify the gen-
eration of the putative intermediate oxonium species in
the above-mentioned stepwise mechanism. In agreement
with this hypothesis, when the reaction leading to com-
pounds 3a and 3b was carried out in ethanol as a nucleo-
philic solvent, the major products were not the
tetrahydroquinolines, but acetals 5 arising from a four-
component process involving the trapping of the oxonium
intermediate by a solvent molecule (Scheme 4). The ac-
companying tetrahydroquinoline derivatives 3a and 3b
stem from the cyclization of the oxonium intermediate
and not from the Lewis acid catalyzed cyclization of com-
pounds 5. This is shown by the fact that isolated acetal 5a
did not give 3a under our reaction conditions, but re-
mained unchanged instead.
OEt
+
N
catalyst
EtOH
OEt
OEt
OEt
+
N
H
N
H
5a
Scheme 5
Table 3 Povarov Reactions in Ethanol Using Five Alternative Cat-
alysts
Entry Catalyst
Quantity Time Yield (%) of the Yield (%)
(mol%) (h) Povarov product of 5a
1
2
3
4
5
I2
30
40
40
10
10
2
53
60
58
53
66
42
30
18
39
26
At this point, we considered it to be of interest to verify
experimentally the presence of the oxonium intermediate
for those cases where other catalysts have been shown to
be effective in promoting the Povarov reaction. To this
end, we examined the reaction between isolated N-ben-
zylideneaniline and ethyl vinyl ether in the presence of io-
dine, potassium hydrogen sulfate, triphenylphosphonium
perchlorate, and ytterbium and dysprosium trifluoro-
methanesulfonate21 in ethanol. As shown in Scheme 5 and
Table 3, compound 5a was isolated in all cases, confirm-
ing the presence of the oxonium species postulated as an
intermediate in Scheme 4.
KHSO4
Ph3P·HClO4
Yb(OTf)3
Dy(OTf)3
1
0.5
2
2
In conclusion, we have shown that CAN is an excellent
catalyst for the synthesis of cis-2,4-disubstituted deriva-
tives of the 1,2,3,4-tetrahydroquinoline system. A mecha-
nistic study involving the trapping of the intermediate
oxonium species has shown that the CAN-catalyzed reac-
tion proceeds in a stepwise manner. This study also ex-
Synthesis 2008, No. 7, 1039–1044 © Thieme Stuttgart · New York

1042
V. Sridharan et al.
PAPER
13C NMR (63 MHz, CDCl3): d = 16.2, 36.7, 52.1, 63.7, 73.2, 115.1,
117.2, 120.1, 127.4, 128.1, 129.0, 129.7, 131.4, 144.5, 145.2.
plains the observed diastereoselectivity relating to
minimum interactions between the substituents in the 2-
and 4-positions and the axial protons in the chair-like tran- Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C,
80.31; H, 7.28; N, 5.21.
sition state of the cyclization step.
( )-cis-4-Ethoxy-6-fluoro-2-phenyl-1,2,3,4-tetrahydroquino-
line (3b)
Yield: 379 mg (70%); viscous liquid.
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions
were monitored by TLC on aluminum plates coated with silica gel
with fluorescent indicator (SDS CCM221254). Separations by flash
chromatography were performed on silica gel (SDS 60 ACC 40–63
mm). Melting points were measured on a Reichert 723 hot stage mi-
croscope and are uncorrected. Infrared spectra were recorded on a
Perkin Elmer Paragon 1000 FT-IR spectrophotometer with all com-
pounds examined as thin films on NaCl disks. NMR spectra were
obtained on a Bruker Avance 250 spectrometer operating at 250 and
63 MHz for 1H and 13C NMR spectra, respectively (CAI de Reso-
nancia Magnética Nuclear, Universidad Complutense) with the sig-
nal of the residual non-deuterated solvent as an internal standard.
Elemental analyses were determined by the CAI de Microanálisis
Elemental, Universidad Complutense, using a Leco 932 CHNS
combustion microanalyzer.
IR (neat, NaCl): 3375.5, 3031.4, 2867.3, 1603.3, 1498.2, 1305.8,
1252.4, 1094.4 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.32 (t, J = 7.0 Hz, 3 H), 2.00–2.14
(m, 1 H), 2.46 (ddd, J = 12.1, 5.6, 2.3 Hz, 1 H), 3.58–3.79 (m, 2 H),
3.89 (br s, 1 H), 4.53 (dd, J = 11.8, 2.3 Hz, 1 H), 4.82 (dd, J = 10.7,
5.8 Hz, 1 H), 6.48 (dd, J = 8.7, 4.7 Hz, 1 H), 6.82 (td, J = 8.6, 2.9
Hz, 1 H), 7.19 (dd, J = 9.6, 2.9 Hz, 1 H), 7.33–7.50 (m, 5 H).
13C NMR (63 MHz, CDCl3): d = 16.1, 37.3, 56.5, 64.2, 74.3, 114.0
(d, J = 22.9 Hz), 115.2 (d, J = 1.3 Hz), 115.5 (d, J = 13.9 Hz), 124.4
(d, J = 6.4 Hz), 127.1, 128.4, 129.2, 141.2 (d, J = 1.8 Hz), 143.8,
156.5 (d, J = 235.0 Hz).
Anal. Calcd for C17H18FNO: C, 75.25; H, 6.69; N, 5.16. Found: C,
75.55; H, 6.62; N, 5.26.
4-Alkoxy-2-aryl-1,2,3,4-tetrahydroquinolines 3a–j; General
Procedure
( )-cis-4-Ethoxy-6-methoxy-2-phenyl-1,2,3,4-tetrahydroquino-
line (3c)
Yield: 379 mg (67%); viscous liquid.
To a stirred solution of the arylamine (2 mmol) and aromatic alde-
hyde (2 mmol) in MeCN (15 mL) were added the alkyl vinyl ether
(3 mmol) and CAN (55 mg, 0.1 mmol). The mixture was stirred at
r.t. for the corresponding time specified in Table 2. After comple-
tion of the reaction, as indicated by TLC, the mixture was extracted
with CH2Cl2 (2 × 20 mL), and the extracts were washed with H2O
and brine and then dried (anhyd Na2SO4). The solvent was removed
in vacuo to afford the crude product, which was purified by column
chromatography (silica gel, petroleum ether–EtOAc, 95:5). Small
amounts (3–8%) of the trans-products 4a–j were observed in the 1H
NMR spectra of the crude product mixtures (see Table 2); however,
in spite of repeated attempts, they could not be isolated in pure form
with the exception of compound 4a.
IR (neat, NaCl): 3361.3, 3028.9, 2971.0, 2864.4, 1602.1, 1503.3,
1330.6, 1252.2, 1096.3 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.32 (t, J = 7.0 Hz, 3 H), 2.03–2.18
(m, 1 H), 2.45 (ddd, J = 12.3, 5.9, 2.5 Hz, 1 H), 3.58–3.78 (m, 2 H),
3.82 (s, 3 H), 3.91 (br s, 1 H), 4.50 (dd, J = 11.7, 2.5 Hz, 1 H), 4.87
(dd, J = 10.6, 5.9 Hz, 1 H), 6.53 (d, J = 8.7 Hz, 1 H), 6.73 (dd, J =
8.7, 2.9 Hz, 1 H), 7.07 (d, J = 2.9 Hz, 1 H), 7.32–7.53 (m, 5 H).
13C NMR (63 MHz, CDCl3): d = 16.2, 37.6, 56.3, 56.7, 63.8, 74.6,
112.6, 115.3, 115.8, 124.1, 127.1, 128.2, 129.1, 139.3, 144.2, 152.8.
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.29; H, 7.38; N, 4.95.
( )-cis-4-Ethoxy-2-phenyl-1,2,3,4-tetrahydroquinoline (3a)
Yield: 364 mg (72%); viscous liquid.
( )-cis-4-Ethoxy-6-methyl-2-phenyl-1,2,3,4-tetrahydroquino-
line (3d)
Yield: 374 mg (70%); off-white solid; mp 96–97 °C.
IR (neat, NaCl): 3375.9, 3028.4, 2864.6, 1609.2, 1482.1, 1311.3,
1094.6 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.34 (t, J = 6.9 Hz, 3 H), 2.07–2.20
(m, 1 H), 2.48 (ddd, J = 12.3, 5.6, 2.6 Hz, 1 H), 3.57–3.79 (m, 2 H),
3.99 (br s, 1 H), 4.58 (dd, J = 11.6, 2.6 Hz, 1 H), 4.88 (dd, J = 10.5,
5.6 Hz, 1 H), 6.57 (dd, J = 8.0, 0.9 Hz, 1 H), 6.79 (td, J = 7.5, 1.0
Hz, 1 H), 7.11 (td, J = 7.5, 1.0 Hz, 1 H), 7.33–7.55 (m, 6 H).
13C NMR (63 MHz, CDCl3): d = 16.1, 37.5, 56.4, 63.9, 74.4, 114.5,
118.3, 123.0, 127.1, 127.7, 128.3, 128.7, 129.2, 144.1, 145.1.
IR (neat, NaCl): 3375.8, 2971.8, 2866.0, 1608.5, 1480.2, 1309.7,
1094.7 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.36 (t, J = 6.9 Hz, 3 H), 2.07–2.17
(m, 1 H), 2.33 (s, 3 H), 2.49 (ddd, J = 12.4, 5.8, 2.5 Hz, 1 H), 3.62–
3.79 (m, 2 H), 3.91 (br s, 1 H), 4.55 (dd, J = 11.5, 2.5 Hz, 1 H), 4.88
(dd, J = 10.4, 5.8 Hz, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.96 (dd, J =
8.1, 2.1 Hz, 1 H), 7.29–7.66 (m, 6 H).
13C NMR (63 MHz, CDCl3): d = 16.2, 21.6, 37.6, 56.1, 63.9, 74.5,
114.5, 118.2, 123.0, 127.0, 127.7, 128.7, 129.8, 137.9, 141.1, 145.2.
Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C,
80.42; H, 7.32; N, 5.64.
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
80.79; H, 7.77; N, 5.33.
( )-trans-4-Ethoxy-2-phenyl-1,2,3,4-tetrahydroquinoline (4a)
Yield: 25 mg (5%); viscous liquid.
( )-cis-4-Ethoxy-2-(4-tolyl)-1,2,3,4-tetrahydroquinoline (3e)
Yield: 395 mg (74%); off-white solid; mp 88–89 °C.
IR (neat, NaCl): 3387.9, 3029.1, 2972.1, 2864.9, 1610.2, 1488.4,
1316.0, 1264.0, 1081.8 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.31 (t, J = 7.0 Hz, 3 H), 1.93 (ddd,
J = 13.4, 12.4, 3.1 Hz, 1 H), 2.32 (dt, J = 13.6, 2.8 Hz, 1 H), 3.62–
3.75 (m, 2 H), 4.22 (br s, 1 H), 4.39 (t, J = 2.9 Hz, 1 H), 4.65 (dd,
J = 12.2, 2.8 Hz, 1 H), 6.63 (d, J = 8.1 Hz, 1 H), 6.74 (td, J = 7.5,
0.7 Hz, 1 H), 7.16 (td, J = 7.5, 1.2 Hz, 1 H), 7.23 (dd, J = 7.5, 1.2
Hz, 1 H), 7.35–7.54 (m, 5 H).
IR (neat, NaCl): 3363.7, 3021.6, 2971.7, 2859.4, 1618.5, 1504.5,
1301.5, 1157.9, 1096.5 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.30 (t, J = 7.0 Hz, 3 H), 2.02–2.16
(m, 1 H), 2.29 (s, 3 H), 2.45 (ddd, J = 12.2, 5.2, 2.2 Hz, 1 H), 3.57–
3.77 (m, 2 H), 3.87 (br s, 1 H), 4.52 (dd, J = 11.6, 2.2 Hz, 1 H), 4.83
(dd, J = 10.0, 5.2 Hz, 1 H), 6.49 (d, J = 8.2 Hz, 1 H), 6.91 (dd, J =
8.2, 1.6 Hz, 1 H), 7.25–7.49 (m, 6 H).
Synthesis 2008, No. 7, 1039–1044 © Thieme Stuttgart · New York

PAPER
Cerium(IV) Ammonium Nitrate Catalyzed Povarov Reaction
1043
13C NMR (63 MHz, CDCl3): d = 16.1, 21.1, 37.7, 56.5, 63.9, 74.5,
1H NMR (250 MHz, CDCl3): d = 1.02 (t, J = 7.3 Hz, 3 H), 1.43–1.54
114.7, 122.9, 127.1, 127.5, 128.1, 128.2, 129.1, 129.3, 142.7, 144.2.
(m, 2 H), 1.62–1.74 (m, 2 H), 2.01–2.14 (m, 1 H), 2.40–2.47 (m, 1
H), 3.52–3.72 (m, 2 H), 3.98 (br s, 1 H), 4.55 (dd, J = 11.3, 2.6 Hz,
1 H), 4.83 (dd, J = 10.3, 5.5 Hz, 1 H), 6.58 (dd, J = 8.0, 0.9 Hz, 1
H), 6.82 (td, J = 7.5, 0.9 Hz, 1 H), 7.13 (td, J = 7.5, 0.9 Hz, 1 H),
7.37–7.48 (m, 5 H).
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
81.00; H, 7.52; N, 5.45.
( )-cis-4-Butoxy-2-phenyl-1,2,3,4-tetrahydroquinoline (3f)
Yield: 393 mg (70%); viscous liquid.
13C NMR (63 MHz, CDCl3): d = 14.5, 19.9, 32.7, 37.5, 55.7, 68.6,
74.4, 114.7, 118.5, 123.1, 127.9, 128.5, 128.8, 129.3, 133.7, 142.8,
144.8.
IR (neat, NaCl): 3385.6, 3028.3, 2957.1, 2869.6, 1609.3, 1481.7,
1310.7, 1095.0 cm–1.
Anal. Calcd for C19H22ClNO: C, 72.25; H, 7.02; N, 4.43. Found: C,
72.23; H, 6.86; N, 4.53.
1H NMR (250 MHz, CDCl3): d = 1.00 (t, J = 7.2 Hz, 3 H), 1.45–1.57
(m, 2 H), 1.62–1.72 (m, 2 H), 2.04–2.13 (m, 1 H), 2.44–2.51 (m, 1
H), 3.52–3.75 (m, 2 H), 3.98 (br s, 1 H), 4.58 (dd, J = 11.7, 2.5 Hz,
1 H), 4.86 (dd, J = 10.6, 5.7 Hz, 1 H), 6.57 (dd, J = 8.1, 1.0 Hz, 1
H), 6.80 (td, J = 7.5, 1.0 Hz, 1 H), 7.11 (td, J = 7.5, 1.0 Hz, 1 H),
7.34–7.53 (m, 6 H).
( )-cis-4-Butoxy-6-chloro-2-phenyl-1,2,3,4-tetrahydroquino-
line (3j)
Yield: 447 mg (71%); viscous liquid.
IR (neat, NaCl): 3393.8, 3028.5, 2957.4, 2868.1, 1604.0, 1488.6,
1299.5, 1099.2 cm–1.
13C NMR (63 MHz, CDCl3): d = 14.5, 19.9, 32.7, 37.5, 56.4, 68.5,
74.5, 114.5, 118.2, 123.1, 127.1, 127.7, 128.3, 128.7, 129.2, 144.1,
145.0.
1H NMR (250 MHz, CDCl3): d = 0.98 (t, J = 7.2 Hz, 3 H), 1.42–1.61
(m, 2 H), 1.64–1.70 (m, 2 H), 1.96–2.10 (m, 1 H), 2.43–2.49 (m, 1
H), 3.50–3.73 (m, 2 H), 3.99 (br s, 1 H), 4.54 (dd, J = 11.7, 2.5 Hz,
1 H), 4.75 (dd, J = 10.7, 5.6 Hz, 1 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.02
(dd, J = 8.5, 2.4 Hz, 1 H), 7.35–7.48 (m, 6 H).
13C NMR (63 MHz, CDCl3): d = 14.4, 19.9, 32.7, 37.1, 56.3, 68.9,
74.2, 115.6, 122.8, 124.6, 127.0, 127.3, 127.4, 128.4, 128.5, 143.4,
143.7.
Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C,
81.39; H, 7.98; N, 5.18.
( )-cis-4-Butoxy-6-fluoro-2-phenyl-1,2,3,4-tetrahydroquino-
line (3g)
Yield: 455 mg (76%); viscous liquid.
IR (neat, NaCl): 3381.9, 3031.0, 2957.9, 2868.8, 1604.0, 1498.2,
1330.4, 1253.1, 1147.6, 1093.8 cm–1.
Anal. Calcd for C19H22ClNO: C, 72.25; H, 7.02; N, 4.43. Found: C,
72.30; H, 7.12; N, 4.35.
1H NMR (250 MHz, CDCl3): d = 0.99 (t, J = 6.9 Hz, 3 H), 1.41–1.62
(m, 2 H), 1.65–1.74 (m, 2 H), 2.02–2.12 (m, 1 H), 2.43–2.51 (m, 1
H), 3.50–3.75 (m, 2 H), 3.98 (br s, 1 H), 4.53 (dd, J = 11.8, 2.3 Hz,
1 H), 4.80 (dd, J = 10.4, 5.4 Hz, 1 H), 6.48 (dd, J = 8.7, 4.7 Hz, 1
H), 6.81 (td, J = 8.7, 2.9 Hz, 1 H), 7.18 (dd, J = 9.6, 2.5 Hz, 1 H),
7.33–7.50 (m, 5 H).
13C NMR (63 MHz, CDCl3): d = 14.4, 19.9, 32.7, 37.3, 56.5, 68.7,
74.4, 114.0 (d, J = 22.9 Hz), 115.2 (d, J = 1.7 Hz), 115.4 (d, J = 13.7
Hz), 124.5 (d, J = 6.4 Hz), 127.1, 128.4, 129.2, 141.2 (d, J = 1.8 Hz),
143.9, 156.5 (d, J = 234.9 Hz).
Cerium(IV) Ammonium Nitrate Catalyzed, Four-Component
Reaction between Arylamines, Benzaldehyde, and Ethyl Vinyl
Ether in Ethanol; General Procedure
To a stirred solution of the aniline (2 mmol) and benzaldehyde (212
mg, 2 mmol) in EtOH (15 mL) were added ethyl vinyl ether (216
mg, 3 mmol) and CAN (55 mg, 0.1 mmol). The mixture was stirred
at r.t. for 1 h. After completion of the reaction, as indicated by TLC,
the mixture was extracted with CH2Cl2 (2 × 20 mL), and the extracts
were washed with H2O and brine and then dried (anhyd Na2SO4).
The solvent was removed in vacuo to afford the crude product,
which was purified by column chromatography (silica gel, petro-
leum ether–EtOAc, 95:5) to give compounds 3a and 3b together
with 5a and 5b, respectively.
Anal. Calcd for C19H22FNO: C, 76.22; H, 7.41; N, 4.68. Found: C,
76.24; H, 7.36; N, 4.88.
( )-cis-4-Butoxy-6-methyl-2-phenyl-1,2,3,4-tetrahydroquino-
line (3h)
Yield: 437 mg (74%); viscous liquid.
( )-N-(3,3-Diethoxy-1-phenylpropyl)aniline (5a)
Yield: 263 mg (44%); viscous oil.
IR (neat, NaCl): 3365.8, 3025.8, 2956.5, 2864.8, 1619.0, 1505.0,
1454.0, 1301.9, 1157.9, 1096.0 cm–1.
IR (neat, NaCl): 3388.5, 3024.6, 2974.4, 2872.0, 1602.4, 1507.9,
1317.7, 1120.2, 1058.9 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.29–1.37 (m, 6 H), 2.19–2.24 (m,
2 H), 3.54–3.82 (m, 4 H), 4.59 (t, J = 6.6 Hz, 1 H), 4.65 (t, J = 5.3
Hz, 1 H), 5.10 (br s, 1 H), 6.58 (dd, J = 8.5, 0.9 Hz, 2 H), 6.72 (tt,
J = 7.4, 0.9 Hz, 1 H), 7.17 (t, J = 7.4 Hz, 2 H), 7.28–7.49 (m, 5 H).
1H NMR (250 MHz, CDCl3): d = 1.04 (t, J = 7.2 Hz, 3 H), 1.46–1.59
(m, 2 H), 1.67–1.76 (m, 2 H), 2.05–2.19 (m, 1 H), 2.35 (s, 3 H),
2.45–2.53 (m, 1 H), 3.55–3.77 (m, 2 H), 3.89 (br s, 1 H), 4.55 (dd,
J = 11.7, 2.4 Hz, 1 H), 4.86 (dd, J = 10.5, 5.7 Hz, 1 H), 6.52 (d, J =
8.0 Hz, 1 H), 6.95 (dd, J = 8.0, 1.5 Hz, 1 H), 7.31 (d, J = 1.5 Hz, 1
H), 7.38–7.55 (m, 5 H).
13C NMR (63 MHz, CDCl3): d = 14.5, 19.9, 21.2, 32.8, 37.8, 56.6,
68.5, 74.7, 114.8, 123.1, 127.1, 127.5, 128.1, 128.2, 129.2, 129.4,
142.8, 144.3.
13C NMR (63 MHz, CDCl3): d = 15.9, 42.8, 56.1, 61.6, 62.4, 101.9,
113.8, 117.5, 126.7, 127.5, 129.2, 129.6, 144.2, 148.0.
Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C,
76.44; H, 8.45; N, 4.82.
Anal. Calcd for C20H25NO: C, 81.31; H, 8.53; N, 4.74. Found: C,
81.30; H, 8.36; N, 4.92.
( )-N-(3,3-Diethoxy-1-phenylpropyl)-4-fluoroaniline (5b)
Yield: 336 mg (53%); viscous oil.
( )-cis-4-Butoxy-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquino-
line (3i)
Yield: 487 mg (77%); viscous liquid.
IR (neat, NaCl): 3386.0, 2974.8, 2880.1, 1613.6, 1510.7, 1452.3,
1221.6, 1120.2, 1058.0 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.22–1.33 (m, 6 H), 2.14–2.20 (m,
2 H), 3.52–3.79 (m, 4 H), 4.49 (t, J = 7.2 Hz, 1 H), 4.62 (t, J = 5.4
Hz, 1 H), 4.98 (br s, 1 H), 6.46 (dd, J = 8.9, 4.4 Hz, 2 H), 6.84 (t, J =
8.7 Hz, 2 H), 7.29–7.45 (m, 5 H).
IR (neat, NaCl): 3383.8, 2956.8, 2868.0, 1609.1, 1483.3, 1310.2,
1089.1, 1013.7 cm–1.
Synthesis 2008, No. 7, 1039–1044 © Thieme Stuttgart · New York

1044
V. Sridharan et al.
PAPER
13C NMR (63 MHz, CDCl3): d = 15.9, 42.7, 56.6, 61.7, 62.4, 101.9,
114.5 (d, J = 7.3 Hz), 115.9 (d, J = 22.2 Hz), 126.7, 127.5, 129.2,
144.1, 144.4 (d, J = 1.7 Hz), 156.0 (d, J = 234.4 Hz).
(15) For some reviews on CAN-promoted synthetic
transformations, see: (a) Nair, V.; Matthew, J.; Prabhakaran,
J. Chem. Soc. Rev. 1997, 127. (b) Hwu, J. R.; King, K.-Y.
Curr. Sci. 2001, 81, 1043. (c) Nair, V.; Panicker, S. B.; Nair,
L. G.; George, T. G.; Augustine, A. Synlett 2003, 156.
(d) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc.
Chem. Res. 2004, 37, 21. (e) Dhakshinamoorty, A. Synlett
2005, 3014. (f) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107,
1862.
Anal. Calcd for C19H24FNO2: C, 71.90; H, 7.62; N, 4.41. Found: C,
72.16; H, 7.65; N, 4.64.
Acknowledgment
Financial support from MEC (grant CTQ2006-10930) and UCM-
CAM (Grupos de Investigación, grant 920234) is gratefully ack-
nowledged.
(16) For selected examples of CAN-catalyzed reactions, see:
(a) Zeng, X.-F.; Ji, S.-J.; Wang, S. Y. Tetrahedron 2005, 61,
10235. (b) Wang, S. Y.; Ji, S.-J. Tetrahedron 2006, 62,
1527. (c) Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006,
47, 3589. (d) Nair, V.; Mohanan, K.; Suja, T. D.; Suresh, E.
Tetrahedron Lett. 2006, 47, 705. (e) Varala, R.; Enugala,
R.; Nuvula, S.; Adapa, S. R. Synlett 2006, 1009. (f) Varala,
R.; Sreelatha, N.; Adapa, S. R. Synlett 2006, 1549. (g) Ko,
S.; Yao, C. F. Tetrahedron 2006, 62, 7293. (h) Sridharan,
V.; Avendaño, C.; Menéndez, J. C. Tetrahedron 2007, 63,
673. (i) Sridharan, V.; Avendaño, C.; Menéndez, J. C.
Synlett 2007, 881. (j) Sridharan, V.; Avendaño, C.;
Menéndez, J. C. Tetrahedron 2007, 63, 4407. (k)Sridharan,
V.; Avendaño, C.; Menéndez, J. C. Synlett 2007, 1079.
(17) Ravindranath, N.; Ramesh, C.; Reddy, M. R.; Das, B. Chem.
Lett. 2003, 32, 222.
References
(1) Copp, B. R.; Fulton, K. F.; Perry, N. B.; Blunt, J. W.; Munro,
M. H. G. J. Org. Chem. 1994, 59, 8233.
(2) For a review of the chemistry of martinellines, see: Nyerges,
M. Heterocycles 2004, 63, 1685.
(3) (a) Omura, S.; Nakagawa, A.; Hashimoto, H.; Oiwa, R.;
Iwai, Y.; Hirano, A.; Shibukawa, N.; Kojima, Y. J. Antibiot.
1980, 33, 1395. (b) Nakagawa, A.; Iwai, Y.; Hashimoto, H.;
Miyazaki, N.; Oiwa, R.; Takahashi, Y.; Hirano, A.;
Shibukawa, N.; Kojima, Y.; Omura, S. J. Antibiot. 1981, 34,
1408.
(18) For a review of the synthesis of tetrahydroquinolines and
their applications, see: (a) Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 52, 15031. For selected,
more recent examples, see: (b) Wallace, O. B.; Lauwers, K.
S.; Jones, S. A.; Dodge, J. A. Bioorg. Med. Chem. Lett. 2003,
13, 1907. (c) Di Fabio, R.; Tranquillini, E.; Bertani, B.;
Alvaro, G.; Micheli, F.; Sabbatini, F.; Pizzi, M. D.;
Pentassuglia, G.; Pasquarello, A.; Messeri, T.; Donati, D.;
Ratti, E.; Arban, R.; Dal Forno, G.; Reggiani, A.; Barnaby,
R. Bioorg. Med. Chem. Lett. 2003, 13, 3863. (d) Asolkar,
R. N.; Schröder, D.; Heckmann, R.; Lang, S.; Wagner-
Döbler, I.; Laatsch, H. J. Antibiot. 2004, 57, 17.
(4) For representative examples, see: (a) Celing, R. W.; Leeson,
P. D.; Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood,
S.; Kemp, J. A.; Marshall, G. R. J. Med. Chem. 1992, 35,
1942. (b) Carling, R. W.; Leeson, P. D.; Moseley, A. M.;
Smith, J. D.; Saywell, K.; Trickelbank, M. D.; Kemp, J. A.;
Marshall, G. R.; Foster, A. C.; Grimwood, S. Bioorg. Med.
Chem. Lett. 1993, 3, 65. (c) Paris, D.; Cottin, M.;
Demonchaux, P.; Augert, G.; Dupassieux, P.; Lenoir, P.;
Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669.
(d) Hanada, K.; Furuya, K.; Inoguchi, K.; Miyakawa, M.;
Nagata, N. WO 0127086, 2001; Chem. Abstr. 2001, 134,
295752.
(e) Lombardo, L. J.; Camuso, A.; Clark, J.; Fager, K.; Gullo-
Brown, J.; Hunt, J. T.; Inigo, I.; Kan, D.; Koplowitz, B.; Lee,
F.; McGlynchey, K.; Qian, L. J.; Ricca, C.; Rowniak, G.;
Traeger, S.; Tokarski, J.; Williams, D. K.; Wu, L. I.; Zhao,
Y. F.; Manne, V.; Bhide, R. S. Bioorg. Med. Chem. Lett.
2005, 15, 1895. (f) Nallan, L.; Bauer, K. D.; Bendale, P.;
Rivas, K.; Yokoyama, K.; Horney, C. P.; Pendyala, P. R.;
Floyd, D.; Lombardo, L. J.; Williams, D. K.; Hamilton, A.;
Sebti, S.; Windsor, W. T.; Weber, P. C.; Buckner, F. S.;
Chakrabarti, D.; Gelb, M. H.; Van Voorhis, W. C. J. Med.
Chem. 2005, 48, 3704.
(5) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605.
(b) Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996, 245.
(6) For a general review of imino Diels–Alder reactions, see:
Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57,
6099.
(7) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(8) Kobayashi, S.; Ishitani, H.; Nakagawa, S. Synthesis 1995,
1195.
(9) Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64,
6462.
(10) Yadav, J. S.; Subba Reddy, B. V.; Rheddy Madhuri, C.;
Sabitha, G. Synthesis 2001, 1065.
(11) Nagarajan, R.; Chitra, S.; Perumal, P. T. Tetrahedron 2001,
57, 3419.
(19) For a preliminary communication of a CAN-catalyzed
vinylogous Povarov reaction involving a,b-unsaturated
aldehydes, see ref. 16k.
(20) (a) Beifuss, U.; Ledderhose, S.; Ondrus, V. ARKIVOC 2005,
(v), 147. (b) Stevenson, P. J.; Nieuwenhuyzen, M.; Osborne,
D. ARKIVOC 2007, (ix), 129.
(21) Verification of the presence of an iminium intermediate by
carrying out the reaction in the presence of nucleophiles has
been possible for some Lewis acid catalyzed Povarov
reactions involving the use of ytterbium trifluoromethane-
sulfonate as catalyst (see ref. 8). For a recent synthetic
application of the four-component reaction, see: Jiménez,
O.; de la Rosa, G.; Lavilla, R. Angew. Chem. Int. Ed. 2005,
44, 6521.
(12) Kumar, R. S.; Nagarajan, R.; Perumal, P. T. Synthesis 2004,
949.
(13) Das, B.; Reddy, M. R.; Reddy, V. S.; Ramu, R. Chem. Lett.
2004, 33, 1526.
(14) Xia, M.; Lu, Y.-D. Synlett 2005, 2357.
Synthesis 2008, No. 7, 1039–1044 © Thieme Stuttgart · New York