CAN-catalyzed vinylogous povarov reactions: The first three-component synthesis of 2-functionalized tetrahydroquinolines from anilines, cinnamaldehyde and vinyl ethers

Article abstract of DOI:10.1055/s-2007-977432

The CAN-catalyzed reaction between anilines, cinnamaldehyde and vinyl ethers affords 2-styryl-1,2,3,4-tetrahydroquinolines. In the case of noncyclic vinyl ethers, these reactions are completely stereoselective and furnish exclusively the diastereomer with

Full text of DOI:10.1055/s-2007-977432

LETTER
1079
CAN-Catalyzed Vinylogous Povarov Reactions: The First Three-Component
Synthesis of 2-Functionalized Tetrahydroquinolines from Anilines,
Cinnamaldehyde and Vinyl Ethers
C
V
A
N
-CatalyzedV
e
inylogous
P
l
ovarov
l
R
eacti
a
ons isamy 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 7 February 2007
(a)
Abstract: The CAN-catalyzed reaction between anilines, cinnam-
aldehyde and vinyl ethers affords 2-styryl-1,2,3,4-tetrahydroquino-
lines. In the case of noncyclic vinyl ethers, these reactions are
completely stereoselective and furnish exclusively the diastereomer
with a cis relationship between the styryl and alkoxy groups.
D
D
Povarov reaction
N
Ar
N
H
Ar
Key words: cycloadditions, multicomponent reactions, stereo-
selective synthesis, Lewis acids, quinolines
D
D
(b)
type-I vinylogous
Povarov reaction
Besides exhibiting many interesting pharmacological
activities in themselves, tetrahydroquinoline systems are
1
N
Ar
N
Ar
H
a structural fragment of several bioactive natural products,
including the well-known hybrid anthraquinone–enedy-
ine antitumour drug dynemycin, the antiviral virant-
D
(c)
D
type-II vinylogous
Povarov reaction
2
3
mycin and the marine alkaloids discorhabdin and
4
5
martinelline. The imino-Diels–Alder reaction between
aniline-derived imines and electron-rich alkenes, normal-
ly vinyl ethers, is one of the most useful methods for the
N
Ar
N
Ar
H
Scheme 1
synthesis of 1,2,3,4-tetrahydroquinoline derivatives
6
(
Scheme 1, a). Although this reaction was first described
7
by Povarov in the 1960s, it lay relatively dormant until examples of this type of process have been reported, in-
the discovery of its efficient catalysis by lanthanide tri- volving two-component Lewis acid catalyzed reactions
8
flates, acting as Lewis acids. Following this develop- between N-Cbz-2-pyrroline derivative and cinnamalde-
ment, many groups have employed the Povarov reaction, hyde arylimines, in the course of efforts aimed at the total
1
1
in most cases using cyclic vinyl ethers as the dienophile synthesis of martinelline, or photochemical reactions of
9
12
component.
N-vinylpyrrolidinone and N-vinylcarbazole.
In spite of this interest, there has been surprisingly little In this context, we present here our studies on the first im-
activity on the development of vinylogous versions of the plementation of the type-II vinylogous Povarov reaction
Povarov reaction, although they would have the advan- for the case of vinyl ethers, including also the first exam-
tage of providing tetrahydroquinoline derivatives bearing ples of the use of noncyclic electron-rich alkene compo-
functionalization at C-2 or C-4 (see below). In order to nents in this reaction. The main potential drawback of our
achieve a better systematization of this field, we suggest approach was associated with the fact that cinnamalde-
that the two processes depicted in Scheme 1 (b and c) are hyde arylimines possess an exocyclic a,b-unsaturated
defined as type-I and type-II vinylogous Povarov reac- imine system (Scheme 1, c) that may act as a diene in in-
tions, respectively. The type-I reactions involve the use of verse electron-demand Diels–Alder reactions with elec-
butadiene derivatives bearing an electron-releasing sub- tron-rich dienophiles, leading to 1,4-dihydropyridines.13
stituent as the dienophile component of the imino-Diels– However, some nucleophilic 1,2-additions of ketene silyl
Alder process (Scheme 1, b), and to our knowledge they ketals and thioketals to a,b-unsaturated arylimines cata-
have been reported in the literature in only two cases.10 lyzed by Lewis acids, cation-exchange resins or
Alternatively (type-II reactions), the use of imines derived montmorillonite16 have been described. This was an en-
from anilines and cinnamaldehyde derivatives can be couraging, although remote, precedent because such an
envisaged (Scheme 1, c). To our knowledge, very few addition can be considered to be the first step of our pro-
posed transformation, as it is now generally accepted that
14
15
8
the Povarov reaction proceeds stepwise. If a similar
behavior were also found for the case of vinyl ethers, the
desired [4+2] cycloaddition involving the aromatic ring
SYNLETT 2007, No. 7, pp 1079–1082
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977432; Art ID: D03707ST
2
4.
0
4.
2
0
0
7
©
Georg Thieme Verlag Stuttgart · New York

1
080
V. Sridharan et al.
LETTER
The possibility of carrying out the reaction in a three-com-
ponent fashion, i.e. without isolation of the intermediate
imine, was attractive due to the increasing interest in mul-
O
R4
R3
R2
2
H
18
ticomponent reactions as a powerful tool for the creation
of several bonds in a single operation and hence for the
rapid generation of molecular complexity, besides having
additional advantages in terms of user and environmental
friendliness because of the step reduction and atom econ-
omy associated to their use. The use of CAN as a catalyst
is also relevant because of the current interest in the appli-
cation of this water-tolerant, nontoxic and inexpensive
reagent in carbon–carbon and carbon–heteroatom bond-
O
NH2
R1
3
1
CAN (5 mol%)
MeCN, r.t.
R4
O
R4
O
H
H
R3
R3
R2
+
H
19
H
forming reactions, specially when used in catalytic
R2
20
N
N
amounts.
H
H
H
H
R1
R1
As a further check of the generality of the vinylogous
Povarov process, we undertook its extension to the case of
noncyclic enol ethers 6 as alkene components, which has
received surprisingly little attention in previous studies of
endo-4
exo-5
Scheme 2
9
the standard Povarov reaction. As shown in Scheme 3
and Table 2, it is noteworthy that these reactions, although
lower yielding than those involving the use of cyclic vinyl
ethers, were completely diastereoselective and afforded
exclusively the endo diastereoisomer of tetrahydroquino-
lines 7, with a cis relationship between H-2 and H-4
could be expected to take place with preference to the
competing [4+2] cycloaddition of the exocyclic unsaturat-
ed system, which is normally carried out under thermal
conditions. In the event, this hypothesis turned out to be
correct and, as shown in Scheme 2 and Table 1, the de-
sired vinylogous reaction could be carried out efficiently
by mixing together anilines 1, cinnamaldehyde 3 and 2,3-
dihydrofuran 2 as a prototype cyclic ether in the presence
of cerium ammonium nitrate (CAN) as a catalyst, and led
to furoquinoline derivatives (compounds 4 and 5) bearing
several combinations of electron-releasing and electron-
(
Scheme 3 and Table 2). This configuration was estab-
lished through the study of two-dimensional NOESY
spectra, which showed the spatial proximity of the H-2
and H-4 protons. In the case of compound 7e, which re-
quired a higher concentration of CAN, we observed the
formation of a small amount of the corresponding aromat-
ic quinoline systems; there is some literature precedent for
the use of stoichiometric amounts of CAN in dehydroge-
1
7
withdrawing groups in good to excellent yields. How-
ever, these reactions almost lacked stereoselectivity, as
21
nation reactions in nitrogen heterocycles. Compounds 7
were accompanied by small amounts of the previously
described2 2-methyl-1,2,3,4-tetrahydroquinoline deriva-
tives 8, arising from the reaction between anilines 1 and
two equivalents of vinyl ethers 6.
expected from literature precedent on related standard
9
(
i.e. nonvinylic) Povarov reactions. The endo relative
0h
configuration of the (marginally) major product was de-
duced from NOESY experiments and from the low values
found for the coupling constants between H-3a and H-4;
for instance, J3a–4 was 3.5 Hz for compound 4a, while its
diastereoisomer 5a showed J3a–4 = 9.7 Hz. This conclu-
sion differs slightly from literature precedent in standard
The complete diastereoselection found in the vinylogous
processes involving open enol ethers can be attributed to
the fact that a cis arrangement between the alkoxy and
styryl groups leads to minimum interactions between
these bulky substituents and the axial protons in the chair-
like transition state of the cyclization step leading to the
tetrahydroquinoline system (Scheme 4).
9
Povarov reactions, where the exo product is normally
predominant.
Table 1 Vinylogous Povarov Reactions with a Cyclic Vinyl Ether
Compd
R1
H
R2
H
R3
H
R4
H
Time (h)
endo/exo
57:43
55:45
55:45
55:45
60:40
55:45
55:45
Yield (%)
4
4
4
4
4
4
4
,5a
,5b
,5c
,5d
,5e
,5f
2
83
80
79
70
70
75
85
H
H
Cl
Br
F
H
2
H
H
H
1.5
4
H
H
H
H
H
Me
H
H
4
H
Me
H
Me
H
4
,5g
Me
Me
6
Synlett 2007, No. 7, 1079–1082 © Thieme Stuttgart · New York

LETTER
CAN-Catalyzed Vinylogous Povarov Reactions
1081
Table 2 Diastereoselective Vinylogous Povarov Reactions with Noncyclic Vinyl Ethers
Compd
R1
H
R2
CAN (mol%)
Time (h)
Yield of 7 (%)
Yield of 8 (%)
7
7
7
7
a
b
c
Et
5
5
3
3
3
2
5
60
63
65
55
60a
6
5
H
n-Pr
n-Bu
n-Pr
Et
H
5
3
d
e
Cl
Me
5
13
3
7
15
a
Together with 15% of the corresponding aromatic quinoline.
OR2
In conclusion, the CAN-catalyzed reaction between
anilines, cinnamaldehyde and vinyl ethers affords 2-styr-
yl-1,2,3,4-tetrahydroquinolines. In the case of noncyclic
vinyl ethers, these reactions are stereoselective and fur-
nish exclusively the diastereomer with a cis relationship
between the styryl and alkoxy groups. The reaction
proceeds under very mild conditions, uses an inexpensive
and nontoxic catalyst, and has the additional advantage of
having water as the only side product.
6
R1
H
O
NH2
1
3
CAN
MeCN, r.t.
OR2
OR2
H
H
Acknowledgment
R1
R1
+
Financial support from MEC (grant CTQ2006-10930) and UCM-
CAM (Grupos de Investigación, grant 920234) is gratefully
acknowledged.
N
H
N
H
Me
H
H
7
8
Scheme 3
References and Notes
(
1) See, for instance: (a) Celing, R. W.; Leeson, P. D.; Moseley,
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Abstr. 2001, 134, 295752.
OR2
6
R1
Ce (IV)
1
+ 3
N
Ce (IV)
–
Ce (IV)
2
2
(2) (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.;
R O
R O
N
H
R1
N
H
R1
H
H
H
7
Shibukawa, N.; Kojima, Y.; Omura, S. J. Antibiot. 1981, 34,
1
408.
Scheme 4
(
3) Copp, B. R.; Fulton, K. F.; Perry, N. B.; Blunt, J. W.; Munro,
M. H. G. J. Org. Chem. 1994, 59, 8233.
Although the role of CAN in many reactions is due to its
ability to act as a one-electron donor and hence to generate
radical intermediates, in our case we have found that the
addition of large amounts of 1,1-diphenylethylene, a well-
known radical trap, does not significantly alter the course
of the reaction. Therefore, we propose that in this case
CAN acts as a Lewis acid, a behavior that has some
(4) For a review of the chemistry of the martinellines, see:
Nyerges, M. Heterocycles 2004, 63, 1685.
(5) For a general review of imino Diels–Alder reactions, see:
Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57,
6099.
(
6) For a review of synthetic approaches to 1,2,3,4-
tetrahydroquinolines, see: Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 48, 15031.
2
0h,22
precedent in the literature.
(7) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
8) Kobayashi, S.; Ishitani, H.; Nakagawa, S. Synthesis 1995,
195.
(
1
Synlett 2007, No. 7, 1079–1082 © Thieme Stuttgart · New York

1
082
V. Sridharan et al.
LETTER
(
9) For some representative examples of recent work in this
area, see: (a) Nagaiah, K.; Sreenu, D.; Srinivasa Rao, R.;
Vashishta, G.; Yadav, J. S. Tetrahedron Lett. 2006, 47,
MHz, CDCl ): d = 2.03–2.22 (m, 2 H), 2.73–2.84 (m, 1 H),
3
3.82–3.88 (m, 3 H), 4.19 (dd, J = 7.8, 3.5 Hz, 1 H), 5.13 (d,
J = 7.3 Hz, 1 H), 6.35 (dd, J = 15.8, 7.8 Hz, 1 H), 6.61–6.71
(m, 2 H), 6.85 (td, J = 7.5, 0.9 Hz, 1 H), 7.14 (td, J = 7.5, 0.9
4409. (b) Srinivas, K. V. N. S.; Das, W. Synlett 2004, 1715.
1
3
(
c) Yadav, J. S.; Reddy, B. V. S.; Reddy, J. S. S.; Srinivasa
Hz, 1 H), 7.27–7.47 (m, 6 H). C NMR (62.9 MHz, CDCl ):
3
Rao, S. Tetrahedron 2003, 59, 1599. (d) Kumar, R. S.;
Nagarajan, R.; Chitra, S.; Perumal, P. T. Tetrahedron 2001,
d = 26.1, 43.1, 56.2, 66.9, 75.9, 115.4, 119.4, 122.3, 126.9,
128.3, 129.0, 129.2, 130.2, 130.8, 131.8, 137.1, 144.7. Anal.
Calcd for C H NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
57, 3419. (e) Sundararajan, G.; Prabagaran, N.; Varghese, B.
1
9
19
Org. Lett. 2001, 3, 1973. (f) Crousse, B.; Bégué, J. P.;
Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009.
10) (a) Hermitage, S.; Howard, J. A. K.; Prichard, D. J. R. G.;
82.03; H, 6.65; N, 4.89.
Data for 5a: viscous oil. IR (neat): 3333.8, 3024.6, 2861.3,
1611.3, 1482.8, 1363.1, 1264.0, 1127.0, 1042.2 cm . H
–
1 1
(
Probert, M. R.; Whiting, A. Org. Biomol. Chem. 2004, 2,
NMR (250 MHz, CDCl ): d = 1.91–2.01 (m, 1 H), 2.20–2.35
3
2451. (b) Alves, M. J.; Azoia, N. A.; Gil-Fortes, A.
(m, 2 H), 3.48 (dd, J = 9.7, 8.9 Hz, 1 H), 3.84–3.94 (m, 1 H),
4.01–4.11 (m, 2 H), 4.64 (d, J = 4.8 Hz, 1 H), 6.24 (dd,
J = 15.8, 8.5 Hz, 1 H), 6.67–6.73 (m, 2 H), 6.84 (td, J = 7.4,
0.8 Hz, 1 H), 7.17 (td, J = 7.4, 0.8 Hz, 1 H), 7.28–7.49 (m, 6
Tetrahedron 2007, 63, 727.
(
11) (a) Hadden, M.; Nieuwenhuytzen, M.; Osborne, D.;
Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2001, 42,
1
3
6417. (b) Cia, C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002,
H). C NMR (62.9 MHz, CDCl ): d = 29.4, 41.9, 56.3, 65.7,
3
43, 9405. (c) Hadden, M.; Nieuwenhuyzen, M.; Osborne,
76.2, 115.4, 118.9, 120.6, 127.0, 128.5, 129.2, 129.5, 130.2,
131.7, 133.9, 136.8, 145.2. Anal. Calcd for C H NO: C,
D.; Stevenson, P. J.; Thompson, N.; Walker, A. D.
Tetrahedron 2006, 62, 3977.
1
9
19
82.28; H, 6.90; N, 5.05. Found: C, 81.97; H, 6.78; N, 4.89.
(18) For selected reviews and monographs on multicomponent
reactions, see: (a) Dömling, A.; Ugi, I. Angew. Chem. Int.
Ed. 2000, 39, 3168. (b) Bienaymé, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (c) Ugi, A.
Pure Appl. Chem. 2001, 73, 187. (d) Ugi, A. Molecules
2003, 8, 53. (e) Orru, R. V. A.; de Greef, M. Synthesis 2003,
1471. (f) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(g) Ramón, D. J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44,
1602. (h) Multicomponent Reactions; Zhu, J.; Bienaymé, H.,
Eds.; Wiley-VCH: Weinheim, 2005. (i) Dömling, A. Chem.
Rev. 2007, 107, 89. (j) for a symposium in print on this
topic, see: Marek, I., Ed. Tetrahedron 2005, 67, 11299
(19) Some reviews on CAN-promoted synthetic
(
(
12) Zhang, W.; Guo, Y.; Liu, Z.; Jin, X.; Yang, L.; Liu, Z.-L.
Tetrahedron 2005, 61, 1325.
13) (a) For a review, see ref. 5. For some [4+2] cycloadditions of
a,b-unsaturated imines leading to 1,4-dihydropyridines,
see: (b) Barluenga, J.; Tomás, M.; López-Pelegrín, J. A.;
Rubio, E. Tetrahedron Lett. 1997, 38, 3981. (c) Ishar, M. P.
S.; Kumar, K.; Kaur, S.; Kumar, S.; Girdhar, N. K.; Sachar,
S.; Markawa, A.; Kapoor, A. Org. Lett. 2001, 3, 2133.
14) (a) Shimizu, M.; Kurokawa, H.; Takahashi, A. Lett. Org.
Chem. 2004, 1, 353. (b) Akiyama, A.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
(
(
2
c) Shimizu, M.; Kamiya, M.; Hachiya, M. Chem. Lett.
003, 32, 606. (d) Shimizu, M.; Ogawaand, T.; Nishi, T.
Tetrahedron Lett. 2001, 42, 5463.
15) Shimizu, M.; Itohara, S.; Hase, E. Chem. Commun. 2001,
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Chem. Soc. Rev. 1997, 127. (b) Hwu, J. R.; King, K.-Y.
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(
(
(
2
318.
16) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett 1993,
41.
1
17) Representative Procedure
An equimolecular (3 mmol) mixture of aniline and
cinnamaldehyde was dissolved in MeCN (20 mL). To this
stirred solution, ethyl vinyl ether (4.5 mmol) and 5 mol% of
CAN were added, and stirring was continued for 3 h. After
completion of the reaction, as indicated by TLC (2 h reaction
(20) Some other CAN-catalyzed reactions have been described
very recently. For selected examples, see: (a) Zeng, X.-F.;
Ji, S.-J.; Wang, S. Y. Tetrahedron 2005, 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.
time), the mixture was poured into H O (20 mL) and
2
extracted with CH Cl (3 × 20 mL). The combined extracts
2
2
were dried over anhyd Na SO and evaporated, and the
2
4
residue was purified by silica gel column chromatography
using a PE–EtOAc mixture (96:4), to afford 60% of a
mixture of compounds 4a and 5a in 57:43 ratio, as
1
determined by H NMR analysis. Analytical samples of
compounds 4a and 5a were obtained through a second
column chromatography.
(21) Shanmugam, P.; Perumal, P. T. Tetrahedron 2006, 62, 9726.
(22) Markó, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-
M.; Quesnel, Y.; Vanherck, J.-C. Angew. Chem. Int. Ed.
1999, 12, 2653.
Data for 4a: viscous oil. IR (neat) 3327.2, 3024.0, 2875.2,
–
1 1
1
609.3, 1484.2, 1364.6, 1259.6, 1063.4 cm . H NMR (250
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