Auto-tandem catalysis in the synthesis of substituted quinolines from aldimines and electron-rich olefins: Cascade Povarov-hydrogen-transfer reaction

Article abstract of DOI:10.1021/jo8009243

(Chemical Equation Presented) We demonstrated a catalytic cascade inverse electron demand hetero-Diels-Alder reaction (Povarov reaction) and hydrogen-transfer process. The reaction of electron-rich olefins and excess amount of imines in the presence of ac

Full text of DOI:10.1021/jo8009243

Auto-Tandem Catalysis in the Synthesis of Substituted Quinolines
from Aldimines and Electron-Rich Olefins: Cascade
Povarov-Hydrogen-Transfer Reaction
Naoya Shindoh,† Hidetoshi Tokuyama,‡ Yoshiji Takemoto,*,† and Kiyosei Takasu*,†
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan, and Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aobayama, Sendai 980-8578, Japan
kay-t@pharm.kyoto-u.ac.jp
ReceiVed May 6, 2008
We demonstrated a catalytic cascade inverse electron demand hetero-Diels-Alder reaction (Povarov reaction)
and hydrogen-transfer process. The reaction of electron-rich olefins and excess amount of imines in the presence
of acid catalysts under appropriate conditions affords substituted quinolines in a single operation. In the cascade
process, the catalysts, such as Tf2NH, TfOH, and Lewis acids, catalyze two mechanistically distinct reactions
(auto-tandem catalysis). We also describe the synthetic utility of the prepared quinolines.
Introduction
ment of several efficient methods for the synthesis of quinolines
from anilines and acetylenes.4 Moreover, the cycloaddition
followed by oxidation approach has also been shown to afford
a quinoline nucleus. For example, the hetero-Diels-Alder
reaction of imines, derived from anilines and aryl aldehydes,
with dienophiles gives 1,2,3,4-tetrahydroquinolines.5,6 The cy-
cloaddition favors the inverse electron demand Diels-Alder
reaction mode. Thus, electron-rich olefins, such as vinyl ethers
and enamines, can promote the reaction (Povarov reaction); on
the contrary, electron-withdrawing olefins show much less
reactivity. The cycloaddition can be activated in the presence
of an acid catalyst, such as BF3 ·Et2O, SnCl4, lanthanide triflates,
and p-toluenesulfonic acid. The obtained tetrahydroquinolines
could be transformed into quinolines by treatment with oxidants.
The quinoline nucleus is a common heterocyclic ring found
in a broad range of natural and unnatural compounds. A number
of them are reported to have biologically activities,1 including
antimalarial, antimicrobial, antifungal, and antineoplastic, as well
as inhibitory effects on HIV integrase. Owing to their medicinal
importance, great attention has been paid to the synthesis of
substituted quinoline compounds.2 Classical methods, such as
the Skraup reaction, Combes quinoline synthesis, Friedla¨nder
synthesis, and Doebner-Miller reaction, are widely recognized
for the preparation of quinolines from anilines.3 Recent progress
in transition-metal-catalyzed reactions has led to the develop-
† Kyoto University.
‡ Tohoku University.
(1) (a) Ward, S. A.; Bray, P. G.; Mungthin, M.; Hawley, S. R. Ann. Trop.
Med. Parasit. 1995, 89, 121–124. (b) Musiol, R.; Jampilek, J.; Kralova, K.;
Richardson, D. R.; Kalinowski, D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka,
A.; Polanski, J. Bioorg. Med. Chem. 2007, 15, 1280–1288. (c) Michael, J. P.
Nat. Prod. Rep. 2007, 24, 223–246.
(2) Kouznetsov, V. V.; Méndez, L. V.; Gómez, C. M. M. Curr. Org. Chem.
2005, 9, 141–161.
(4) (a) Zhang, X.; Campo, M. A.; Larock, R. C. Org. Lett. 2005, 7, 763–
766. (b) Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675–2678. (c) Gabriele,
B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72,
6873–6877. (d) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109–
1112.
(5) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656–670.
(6) For a review of tetrahydroquinoline synthesis, see: Katritzky, A. R.;
Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031–15070.
(3) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl. Compd. 2006,
42, 701–718.
10.1021/jo8009243 CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7451–7456 7451

Shindoh et al.
SCHEME 1
FIGURE 1. auto-tandem catalysis in the synthesis of quinoline.
In recent years, cascade, multicomponent, and one-pot
reactions have been significantly focused on as powerful and
useful synthetic tools in drug discovery and process chemistry.7
These reactions, if the catalytic variants are possible, would give
a number of opportunities to improve chemical transformations,
such as improvement of atom-economy, reducing of the number
of operations, and saving reagents, energy, time, and labor.
Therefore, the development of classes of cascade, multicom-
ponent, and one-pot reactions would have a significant impact
on the field. As a related chemistry, auto-tandem catalysis has
also received great interest for synthetic efficiency.8-10 The term
“auto-tandem catalysis” is defined as one catalyst which
promotes two or more mechanistically distinct reactions in a
cascade reaction process. We recently reported the auto-tandem
catalysis of EtAlCl2 and triflic imide (Tf2NH) in a cascade
cycloaddition.11 The catalysts independently activate two dif-
ferent cycloadditions, such as Diels-Alder reaction and [2 +
2] cycloaddition, in the cascade process.11a The reaction enables
high-throughput synthesis of structurally complex compounds
from simple and readily available substrates. We envisaged that
the discovery of new auto-tandem catalysis reactions, which
activate Povarov reaction and successive oxidative aromatiza-
tion, would provide a new method to give substituted quinolines
from readily available substrates in a single operation. In a recent
paper, we have reported the auto-tandem catalysis of Tf2NH in
the synthesis of substituted quinolines in which Tf2NH catalyzes
Povarov reaction giving 1,2,3,4-tetrahydroquinolines and then
the oxidation of the cycloadducts to yield quinolines.12 Herein,
we report a detailed account of auto-tandem catalysis in the
reaction of arylaldimines and electron-rich olefins, such as
allylsilanes and styrenes. In addition, the one-pot synthesis of
quinolines by a catalytic Povarov reaction followed by DDQ-
oxidation is reported below.
was treated with allyltriisopropylsilane (2a, 1.0 equiv) in the
presence of Tf2NH (10 mol%) in CH2Cl2 (DCM) at 60 °C using
a sealed tube for 24 h. Tetrahydroquinoline 3aa was obtained
in 51% yield as a mixture of two diastereomers (trans/cis )
53: 47) together with quinoline 4aa (12% yield), which resulted
from the oxidation of 3aa (Scheme 1). At the same time,
production of amine 5a was observed. We supposed that
hydrogen-transfer between the obtained tetrahydroquinoline 3aa
and imine 1a would take place in this reaction. We have
examined the details of the oxidation process of the isolated
3aa (mixture of diastereomers). Oxidation of 3aa did not take
place under an oxygen atmosphere at 60 °C, either in the
presence or absence of catalyst. On the other hand, 64%
conversion of 3aa into 4aa was observed at 60 °C for 12 h in
the presence of 2 equiv of imine 1a and Tf2NH (15 mol%).
However, in the absence of catalyst, no hydrogen-transfer
occurred at all. These results suggest imine 1a acts as an oxidant
and Tf2NH activates hydrogen-transfer to imine 1a from 3aa
in the formation of 4aa. In other words, Tf2NH acts as an auto-
tandem catalysis activating two mechanistically distinct reactions
in the cascade Povarov-hydrogen-transfer reaction (Figure 1).
We found two new catalytic aspects of Tf2NH. To the best of
our knowledge, Tf2NH is the first example of a catalyst for
Povarov reaction of aryl aldimines with allylsilanes. Second,
tetrahydroquinoline 3 can be oxidized into 4 by the assistance
of imine as an oxidant in the presence of catalytic amounts of
Tf2NH.
We were intrigued that the reaction with an excess amount
of imine would improve the chemical yield of quinoline. When
the reaction of 2a (1.0 equiv) with 3 equiv of 1a in the presence
of Tf2NH (10 mol %) was carried out at 60 °C for 12 h, the
chemical yield of 4aa increased to 31%. On the other hand,
production of 3aa decreased to 48% and its trans/cis ratio was
changed to 74:26 (Table 1, entry 1). Optimization of the reaction
conditions, such as reaction temperature, reaction time, and
solvent, were examined. At ambient temperature, allylsilane 2a
was completely consumed within 1.5 h to give 3aa (59%, trans/
cis ) 55: 45; as an inseparable mixture of diastereomers), but
quinoline 4aa was produced in less than 11% yield (entry 2).
On the contrary, the reaction at more than 80 °C resulted in the
formation of unidentified byproduct (entry 3). When the reaction
time was prolonged to 6 days at 60 °C, trans-3aa as a single
diastereomer and 4aa were obtained in 36% and 48% yields,
respectively (entry 4). The stereochemistry of both diastereomers
Results and Discussion
Cascade Povarov-Hydrogen-Transfer by Acid Catalyst
(Auto-tandem Catalysis). Benzylideneaniline 1a (1.0 equiv)
(7) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
(8) Definition of “auto-tandem catalysis”: Fogg, D. E.; dos Santos, E. N.
Coord. Chem. ReV. 2004, 248, 2365–2379.
(9) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005,
105, 1001–1020.
(10) For recent representative examples for auto-tandem catalysis, see: (a)
Field, L. D.; Messerle, B. A.; Wren, S. L. Organometallics 2003, 22, 4393–
4395. (b) Du, H.; Zhang, X.; Wang, Z.; Ding, K. Tetrahedron 2005, 61, 9465–
9477. (c) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006,
441, 861–863. (d) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 11770–11771.
(11) (a) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004, 126,
1352–1353. (b) Takasu, K.; Nagao, S.; Ihara, M. AdV. Synth. Catal. 2006, 348,
2376–2380. (c) Takasu, K.; Inanaga, K.; Ihara, M. Tetrahedron Lett. 2008, 49,
4220–4222. (d) Takasu, K. Synth. Org. Chem., Jpn. 2008, 66, 554–563.
(12) Apartofthisworkwaspublishedasapreliminarycommunication:Shindoh,
N.; Tokuyama, H.; Takasu, K. Tetrahedron Lett. 2007, 48, 4749–4753.
1
of 3aa was assigned by the coupling constants of H NMR.
The yielding of 3aa with only the trans isomer indicates that
the kinetic resolution of the two diastereomers of 3aa proceeds
in the hydrogen-transfer process and that the reaction rate of
cis-3aa is much faster than that of trans-3aa. In fact, no reaction
7452 J. Org. Chem. Vol. 73, No. 19, 2008

Cascade PoVaroV-Hydrogen-Transfer Reaction
TABLE 1. Reaction of Aldimine 1a and Allylsilane 2a in the
Presence of Tf2NHa
of imine 1 affects the reactivity of Povarov reaction. Thus, the
electron-rich aromatic ring of the aniline portion shows poor
reactivity (entries 1 and 8). However, introduction of an electron-
withdrawing substituent on the benzilidene moiety can restore
the chemical yield (entries 9 and 10). Thus, the reaction of imine
1h, which was prepared from electron-donating p-anisidine and
electron-withdrawing p-nitrobenzaldehyde, in toluene afforded
quinoline 4ha in 47% yield (entry 10). When allyltrimethylsilane
(2b) was employed, a Hosomi-Sakurai-type adduct 6a was
obtained in 26% yield along with tetrahydroquinoline 3ab (22%
yield) and desilylated quinoline 7a (9% yield), which would
be converted from 4ab by means of protodesilylation (entry
11). In contrast, allyl-tert-butyldimethylsilane (2c), bearing a
sterically demanding silyl group, suppressed both the formation
of 6a and the desilylation into 7a, thereby furnishing the
heterocyclic compounds 3ac and 4ac (entry 12). Reaction with
styrenes 2d and 2e, instead of allylsilanes, also furnishes
quinolines 4ad and 4ae, respectively, in the presence of Tf2NH
(entries 13 and 14). When reaction of N-vinyl-2-pyrroridone
(2f) as an electron-rich olefin was carried out under the same
conditions, cis-tetrahydroquinoline 3af and quinoline 7b were
obtained in 27% and 54% yields, respectively (entry 15). No
desired quinoline 4af was formed. In this case, ꢀ-elimination
of 3af giving 7b and 2-pyrroridone would be preferable to the
hydrogen-transfer reaction leading to 4af. Production of only
the cis diastereomer of 3af can be reasonably explained: because
both substituents of cis-3af at C(2) and C(4) atoms would
exclusively orient at the equatorial position, conformation of
an appropriate transition state for ꢀ-elimination would be
unfavorable.
We next examined the cascade Povarov-hydrogen-transfer
reaction using various acidic catalysts (Table 3). Lewis acids
also act as a catalyst for the cascade reaction to give quinolines
4aa in moderate yield (entries 1-4). Akiyama and his co-
workers reported the Povarov reaction of equimolar amounts
of aldimines and allylsilanes in the presence of a stoichiometric
amount of SnCl4 at 0 °C to give tetrahydroquinolines in excellent
yield, but without information as to the production of quino-
lines.13 We have assessed that the result is reproducible under
the reported conditions.
However, quinoline 4aa was obtained in 38% yield under
our tested conditions (10 mol% SnCl4, 60 °C; entry 3).
Hydrochloric acid and camphorsulfonic acid (CSA) are inactive
in the Povarov reaction under the tested conditions (entries 5
and 6), whereas triflic acid (TfOH) functions in auto-tandem
catalysis in the cascade reaction (entries 7 and 8). Although
there are several studies on the Povarov reaction of imines with
electron-rich olefins to give tetrahydroquinolines, to the best of
our knowledge, very limited examples have been reported to
furnish quinolines by cascade Povarov-oxidation reaction under
similar conditions.14,15
% yieldb
entry
solvent
T (°C)
time (h)
3aa (trans/cis)c
4aa
1
2
DCM
DCM
DCM
DCM
60
rt
24
12
24
144
24
24
60
240
24
48 (74:26)
59 (55:45)
47 (71:29)
36 (100:0)
49 (76:24)
32 (71:29)
56 (28:72)
25 (88:12)
60 (59:41)
31
11
31
48
37
44
8
3
80
60
60
60
0
4d
5
DCE
6
toluene
toluene
toluene
CH3CN
7
8e
9
0 to 60
60
69
3f
a Reaction conditions: 1a (3.0 equiv), 2a (1.0 equiv), Tf2NH (10 mol
%). b Isolated yields. All chemical yields are calculated on the basis of
2a. c The diastereomeric ratios were determined by 1H NMR. d Tf2NH
(15 mol%) was used. e Reaction was carried out at 0 °C for 120 h and
then at 60 °C for 120 h. f Homoallylamine 6a was obtained in 11%
yield.
occurred when the isolated trans-3aa was exposed under similar
reaction conditions (with 2.0 equiv of 1a in the presence of 10
mol % of Tf2NH in DCM). Next, solvent effects were examined.
Production of 4aa slightly increased in 1,2-dichloroethane
(DCE) and toluene (entries 5 and 6). Careful study taught us
the following solvent effects. First, the rate of Povarov reaction
of 1a with 2a in DCE is faster than that in toluene; in contrast,
the oxidation of 3aa proceeds more smoothly in toluene than
that in DCE. Second, the reaction temperature does not have
an affect on diastereoselectivity in Povarov reaction occurring
in DCE or DCM; however, in toluene, the cis selectivity
increases at low temperature. When the reaction was carried
out at 0 °C in toluene, 3aa was obtained in 56% with 72:28
selectivity (cis/trans) along with 4aa in 8% for 60 h (entry 7).
These findings suggest that the chemical yield could be
improved by controlling the reaction temperature. Thus, after
the completion of Povarov reaction at 0 °C for 6 days to furnish
cis-3aa as a major diastereomer, the reaction temperature was
raised to 60 °C giving quinoline 4aa in 69% yield (entry 8).
When the reaction was carried out in polar solvents, such as
THF, CH3CN, and AcOEt, homoallylamine 6a was obtained in
11% yield (CH3CN) along with 3aa and 4aa (entry 9). The
formation of homoallylamine indicates that Povarov reaction
under the tested conditions proceeds in a stepwise manner rather
than as a concerted cycloaddition. In a polar solvent, the
zwitterionic intermediate given by the Hosomi-Sakurai-type
addition of allylsilanes to imines would be stabilized and would
result in the formation of olefin by the elimination of the
neighboring silyl group.
One-Pot Synthesis of Quinolines Using DDQ. Both trans-
and cis-3aa could be oxidized into 4aa by treatment with 2,3-
dichloro-5,6-dicyano-p-benzoquinone (DDQ) in DCE at ambient
Next,thescopeofauto-tandemcatalysisincascadePovarov-hy-
drogen-transfer reaction was investigated under the standard
conditions in hand. The results are summarized in Table 2. With
allyltriisopropylsilane 2a, reaction of benzylideneimine 1b-h
gave quinolines 4ba-ha in low to moderate yield (19-47%
yield) along with tetrahydroquinoline 3ba-ha (10-68% yield),
in which the trans diastereomer was enriched. The Povarov
reaction (the first step in the cascade reaction) promoted all in
good yield, except for 1b and 1g, as can be seen in the total
yields in Table 2. The electronic nature of the aromatic rings
(13) Akiyama, T.; Suzuki, M.; Kagoshima, H. Heterocycles 2000, 52, 529–
532.
(14) After publication of our preliminary communication (ref 12), Mahajan
and his co-workers reported an interesting synthetic study using Povarov-
hydrogen-transfer reaction in the presence of Lewis acids; see: Bhargave, G.;
Mohan, C.; Mahajan, M. P. Tetrahedron 2008, 64, 3017–3024.
(15) Hydrogen-transfer between 1,2-dihydroquinolines and imines has been
reported by several groups; see: (a) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi,
G.; Ruggieri, F. J. Org. Chem. 1992, 57, 1842–1848. (b) Tanaka, S.; Yasuda,
M.; Baba, A. J. Org. Chem. 2006, 71, 800–803. (c) Kobayashi, S.; Ishitani, H.;
Nagayama, S. Chem. Lett. 1995, 423–424.
J. Org. Chem. Vol. 73, No. 19, 2008 7453

Shindoh et al.
TABLE 2. Scope of the Cascade Povarov-Hydrogen-Transfer Reaction in Auto-Tandem Catalysisa
products
% yieldb
entry
1 (R1, R2)
1b (H, H)
1c (p-NO2, H)
1d (p-Cl, H)
2 (R3)
solvent
3
4
3 (trans/cis)c
4
totald
1
2
3
4
5
6
7
8
2a (CH2TIPS)
DCE
DCE
DCE
toluene
DCE
toluene
DCE
DCE
DCE
toluene
DCE
DCE
DCE
DCE
DCE
3ba
3ca
3da
3da
3ea
3ea
3fa
3ga
3ha
3ha
3ab
3ac
3ad
3ae
3af
4ba
4ca
4da
4da
4ea
4ea
4fa
4ga
4ha
4ha
4ab
4ac
4ad
4ae
4af
19 (71:29)
68 (70:30)e
29 (79:21)
16 (84:16)
30 (78:22)
15 (79:21)
47 (60:40)
10 (88:12)
35 (69:31)
27 (62:38)
22 (75:25)e
48 (63:37)
32 (75:15)
0 (-)
29
48
87e
65
55
69
56
66
41
68
74
22e,f
77
82
64
27h
2a
2a
2a
2a
2a
2a
2a
2a
19e
36
39
39
41
19
31
33
47
0
29
50
64
0
1d
1e (p-Br, H)
1e
1f (o-Br, H)
1g (p-MeO, H)
1h (p-MeO, p-NO2)
1h
1a (p-CF3, H)
1a
1a
1a
1a
9
10
11
12
13
14g
15
2a
2b (CH2TMS)
2c (CH2TBS)
2d (p-MeOC6H4)
2e (p-BrC6H4)
2f (pyrrolidone)
27 (0:100)
a Reaction conditions: 1 (3.0 equiv), 2 (1.0 equiv), Tf2NH (10 mol %), 60 °C, 24 h. b Isolated yields. All chemical yields are calculated based on 2.
c The diastereomeric ratios were determined by 1H NMR. d Sum of the %yields of 3 and 4. e The yield has ∼10% error owing to contamination of
inseparable impurities. f In the reaction, homoallylamine 6a and quinoline 7a were obtained in 22 and 9% yield, respectively. g Reaction was carried out
with Tf2NH (20 mol%) for 48 h. h In the reaction, quinoline 7b, which possesses no substituent on the C(4), was obtained in 54% yield.
TABLE 3. Catalytic Activity in the Reaction of 1a with 2aa
TABLE 4. One-Pot Synthesis of Quinolines 4 by a Sequential
Procedure
% yield
entry
1 (R1, R2)
% yield of 4
entry
catalyst
3aa (trans/cis)c
4aa
totalb
1
2
1a (p-CF3, H)
1c (p-NO2, H)
1e (p-Br, H)
84
83
60
72
87
68
66
1
2
3
4
5
6
7
8d
BF3 ·OEt2
Sc(OTf)3
SnCl4
Yb(OTf)3
HCl
CSA
TfOH
TfOH
37 (74:26)
20 (85:15)
30 (88:12)
23 (80:20)
0 (-)
42
37
38
37
0
0
56
69
79
57
68
60
0
0
80
83
3a
4b
5c
6d
7e
1f (o-Br, H)
1i (p-CF3, o-NO2)
1j (p-Br, o-NO2)
1k (o-Br, o-NO2)
0 (-)
24 (90:10)
14 (100:0)
a Reaction conditions: 1 (1.25 equiv), 2a (1.0 equiv), Tf2NH (15 mol
%), DCE, 60 °C, 3 h; then DDQ (2.0 equiv), ambient temperature, 10
min. b Povarov reaction for 24 h, DDQ oxidation for 10 min. c Povarov
reaction for 1 h, DDQ oxidation for 10 min. d Povarov reaction for 45
min, DDQ oxidation for 1 h. e Povarov reaction for 1 h, DDQ oxidation
for 1 h.
a Reaction conditions: 1a (3.0 equiv), 2a (1.0 equiv), catalyst (10 mol
%), toluene, 60 °C, 24 h. b Isolated yields. All chemical yields are
calculated on the basis of 2a. c The diastereomeric ratios were
determined by 1H NMR. d Sum of the % yields of 3 and 4. e Catalyst
(20 mol %), 144 h.
the mixtures at ambient temperature and stirred for 10 min to
furnish 4aa in 84% yield (Table 4, entry 1). The one-pot reaction
would be an alternative method to provide quinolines against
the above auto-tandem catalysis procedure. We examined the
possibility that the oxidation of 3 with DDQ would be activated
by Tf2NH, but only a slight rate enhancement (ca. 1.1 times)
was observed. With the alternative conditions in hand, we tested
the sequential Povarov reaction and successive oxidation
reaction. Substituted quinolines 4 were obtained in good yield
in one pot (Table 4, entries 2-7).
Three-Component Reactions Affording Quinolines. It is
sometimes difficult to isolate and handle alkyl aldimines
prepared from aliphatic aldehydes, owing to their instability.
To avoid these problems, we envisaged elaboration of the
cascade reaction to the multicomponent variant. When a mixture
of 2a (1.0 equiv), aniline 8 (3.0 equiv), and isobutylaldehyde
SCHEME 2
temperature for 5 min (84% yield; Scheme 2). Further study
indicates that Tf2NH is compatible with DDQ-oxidation. We
envisaged that quinoline 4aa would be obtained in good yield
by a one-pot sequence. Thus, a mixture of 1a (1.25 equiv) with
2a (1.0 equiv) in DCE was treated with a catalytic amount of
Tf2NH at 60 °C for 3 h. After completion of the Povarov
reaction (monitored by TLC), DDQ (2.0 equiv) was added to
7454 J. Org. Chem. Vol. 73, No. 19, 2008

Cascade PoVaroV-Hydrogen-Transfer Reaction
SCHEME 3
SCHEME 4
(9a) (3.0 equiv) in the presence of Tf2NH (10 mol%) in toluene
was stirred at 60 °C, only tetrahydroquinoline 3la was obtained
in 60% yield as a 1:1 diastereomeric mixture (Scheme 3a).
However, no formation of 4 was observed, although the excess
amount of imine was employed. On the other hand, quinoline
4la could be synthesized under one-pot synthesis conditions
using DDQ. Thus, heating a mixture of 2a (1.0 equiv), 8 (1.25
equiv), and 9a (1.25 equiv) in DCE at 60 °C, followed by the
addition of DDQ (2.0 equiv) at ambient temperature, success-
fully furnished 4la in 52% yield (Scheme 3b). In the process,
completion of the Povarov reaction was monitored by TLC. The
method is applicable in the reaction with aromatic aldehyde 9b
to furnish quinoline 4ma in 86% yield (Scheme 3c).
Synthetic Application of Substituted Quinolines. To dem-
onstrate the synthetic utility of the products in the above
quinoline synthesis, transformation reactions of 4 were sum-
marized in Scheme 4. Protodesilylation of 4aa can be ac-
complished by the treatment of tetrabutylammonium fluoride
(TBAF) in the presence of H2O to give methylquinoline 7a in
quantitative yield (Scheme 4a). In the presence of aldehydes 9,
instead of H2O as an electrophile, the corresponding alcohols
10 were obtained in 53-92% yield from 4aa with the formation
of a new C-C bond (Scheme 4b). Obtained alcohol 10b can
be transformed into tetracyclic heteroaromatic compound 11 by
means of radical cyclization-dehydration. Namely, treatment
of 10b with tris(trimethylsilyl)silane and AIBN in refluxed
benzene,16 followed by treatment with hydrochloric acid,
furnished benzo[i]phenanthridine 11 in 40% yield (Scheme 4c).
Moreover, the reaction of 4aa with CsF in the presence of
hexachloroethane as an electrophile17 afforded 12, whose
chloromethyl moiety would be a trigger of further chemical
transformation (Scheme 4d). Suzuki-Miyaura coupling of
bromoquinoline 4fa with boronic acid successfully gave dia-
rylquinoline 4na (Scheme 4e). Recently, its structurally related
diarylquinolines have been reported to be potential drug
candidates for rheumatoid arthritis.18
Cadogan and co-workers reported the synthesis of carbazoles
from 2-nitrobiphenyls by treatment with phosphite or phosphine
via the formation of nitrenes.19 We were intrigued that the
application of Cadogan’s method to synthesized 2-(o-nitrophe-
nyl)quinolines 4ia-ka gave tetracyclic heterocycles. According
to the literature, two groups individually reported the reaction
of 2-(o-nitrophenyl)quinoline with excess amounts of P(OEt)3.20
Although the reaction was carried out under nearly identical
conditions, Ray’s group and Reddy’s group reported the
production of different products, benzo-δ-carboline19a and
indazolo[2,3-a]quinoline,20b respectively, in good yield. Our
interest is directed toward which heterocycles would be obtained
(17) Smith, A. P.; Lamba, J. J. S.; Fraser, C. L. Org. Synth. 2002, 78, 82–
90.
(18) Kaila, N.; Janz, K.; DeBernardo, S.; Bedard, P. W.; Camphausen, R. T.;
Tam, S.; Tsao, D. H. H.; Keith, Jr., J. C.; Nickerson-Nutter, C.; Shilling, A.;
Young-Sciame, R.; Wang, Q. J. Med. Chem. 2007, 50, 21–39.
(19) (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G.
J. Chem. Soc. 1965, 4831–4837. (b) Bouchard, J.; Wakim, S.; Leclerc, M. J.
Org. Chem. 2004, 69, 5705–5711. (c) Freeman, A. W.; Urvoy, M.; Criswell,
M. E. J. Org. Chem. 2005, 70, 5014–5019.
(16) Harrowven, D. C.; Woodcock, T.; Howes, P. D. Angew. Chem., Int.
Ed. 2005, 44, 3899–3901.
(20) (a) Dutta, B.; Some, S.; Ray, J. K. Tetrahedron Lett. 2006, 47, 377–
379. (b) Reddy, Y. P.; Reddy, K. K. Indian J. Chem. 1988, 27B, 563–564.
J. Org. Chem. Vol. 73, No. 19, 2008 7455

Shindoh et al.
SCHEME 5
(2R*,4S*)-6-Trifluoromethyl-4-(triisopropylsilyl)methyl-2-
phenyl-1,2,3,4-tetrahydroquinoline (trans-3aa). colorless viscous
1
oil; IR (neat) 1618, 1329, 1271, 1109, 1070 cm-1; H NMR (400
MHz, CDCl3) δ 7.38-7.22 (m, 7H), 6.53 (d, J ) 8.5 Hz, 1H),
4.62 (t, J ) 7.0 Hz, 1H), 4.38 (bs, 1H), 3.13-3.08 (m, 1H), 1.97
(dd, J ) 7.0, 4.1 Hz, 2H), 1.11-1.04 (m, 23H); 13C NMR (100
MHz, CDCl3) δ 146.0, 144.0, 128.8, 127.8, 127.6, 126.6, 125.7
(q, 3J(C,F) ) 3.3 Hz), 125.0 (q, 1J(C,F) ) 271.2 Hz), 124.1 (q, 3J(C,F)
2
) 4.1 Hz), 118.4 (q, J(C,F) ) 31.1 Hz), 113.2, 52.1, 37.4, 31.7,
19.1, 19.0, 18.9, 11.8; LRMS (APCI) m/z 448 (M+ + 1). Anal.
Calcd for C26H36F3NSi: C, 69.76; H, 8.11; N, 3.13. Found: C, 69.52;
H, 8.03; N, 3.00.
6-Trifluoromethyl-4-(triisopropylsilyl)methyl-2-phenylquino-
line (4aa). colorless plates; mp 104-106 °C; IR (KBr) 1591, 1470,
1
1312, 1119 cm-1; H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H),
8.22 (d, J ) 8.8 Hz, 1H), 8.14 (d, J ) 7.1 Hz, 2H), 7.85 (d, J )
8.8 Hz, 1H), 7.75 (s, 1H), 7.56-7.46 (m, 3H), 2.75 (s, 2H),
1.19-1.12 (m, 3H), 1.10 (d, J ) 7.2 Hz, 18H); 13C NMR (100
MHz, CDCl3) δ 158.3, 150.8, 149.6, 139.4, 131.6, 129.7, 128.9,
127.6, 127.1 (q, J(C,F) ) 32.0 Hz), 125.9, 124.9 (q, J(C,F) ) 3.3
Hz), 124.4 (q, 1J(C,F) ) 272.8 Hz), 122.2 (q, 3J(C,F) ) 4.1 Hz), 119.5,
18.5, 16.5, 11.5; LRMS (APCI) m/z 444 (M+ + 1). Anal. Calcd
for C26H32F3NSi: C, 70.39; H, 7.27; N, 3.16. Found: C, 70.48; H,
7.24; N, 3.01.
from our synthesized quinolines 4ia-ka. When 4ia-ka were
reacted with 2.5 equiv of triphenylphosphine in refluxing
o-dichlorobenzene, indazolo[2,3-a]quinolines 13ia-ka were
obtained in 68-98% yield but no formation of benzo-δ-
carbolines 14 was observed (Scheme 5). The structure of 13
was fully assigned by DEPT techniques. In our case, steric
hindrance of the silylmethyl moiety of the C(4) position of 4
would suppress the approach of the nitrene group at the C(3)
position, leading to N-N bond formation preferred to result in
the production of indazolo[2,3-a]quinolines 13. Indazolo[2,3-
a]quinolines have been reported to show inhibitory effects on
reverse transcriptase.21
2
3
Typical Procedure for One-Pot Reaction of Tf2NH-Catalyzed
Povarov Reaction and DDQ-Mediated Oxidation (Table 4,
Entry 1). To a stirred solution of 2a (40.8 mg, 0.21 mmol) and 1a
(64.6 mg, 0.26 mmol) in 1,2-dichloroethane (0.2 mL) was added
Tf2NH (0.4 M solution in toluene, 77 µL, 31 µmol, 15 mol%) at
ambient temperature. The reaction mixture was stirred at 60 °C
for 3 h and then cooled to ambient temperature followed by addition
of 2,3-dichloro-5,6-dicyano-1,2-benzoquinone (DDQ, 94.0 mg, 0.41
mmol) in one portion. The brown reaction mixture was stirred at
the same temperature for 10 min (exothermic), diluted with CHCl3,
and filtered through pad of Celite. The organic layer was added
saturated aqueous solution of NaHCO3, and the aqueous phase was
extracted twice with CHCl3. Combined organic layers were washed
with saturated aqueous solution of NaHCO3, dried over MgSO4,
filtered, and concentrated in vacuo. The crude mixture was purified
by silica gel flash column chromatography (3: 2 CHCl3-hexane
with 0.5% NEt3) to afford 4aa (76.3 mg, 84%).
3-Bromo-5-(triisopropylsilyl)methylindazolo[2,3-a]quinolo-
ne (13ja). Quinoline 4ja (2.00 g, 4.00 mmol) and PPh3 (2.66 g,
10.1 mmol) were dissolved in 10 mL of o-dichlorobenzene and
heated to reflux for 10 h. The solvent was removed under high
vacuum, and the crude product was purified by silica gel column
chromatography (3:1 CHCl--hexane with 0.25% NEt3) to afford
13ja (1.83 g, 98%) as yellow solids: mp 149-151 °C; IR (KBr)
2941, 1632, 1545, 1356 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.81
(d, J ) 8.0 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J ) 8.0 Hz, 1H), 7.87
(d, J ) 8.0 Hz, 1H), 7.82 (d, J ) 8.0 Hz, 1H), 7.64 (s, 1H), 7.52
(t, J ) 8.0 Hz, 1H), 7.19 (t, J ) 8.0 Hz, 1H), 2.53 (s, 2H),
1.16-1.11 (m, 3H), 1.01 (d, J ) 6.8 Hz, 18H); 13C NMR (100
MHz, CDCl3) δ 149.3, 133.4, 132.5, 132.1, 128.2, 126.5, 120.2,
119.8, 119.3 × 2, 116.2, 115.8, 114.4, 18.7, 15.7, 11.6; LRMS
(EI) m/z 466, 468 (M+, M+ + 2). Anal. Calcd for C25H31BrN2Si:
C, 64.23; H, 6.68; N, 5.99. Found: C, 63.89; H, 6.67; N, 5.98.
Conclusions
In summary, we have found that several acid catalysts, such
as Tf2NH, TfOH, and Lewis acids, activate two mechanistically
distinct reactions, such as the inverse-electron-demand hetero-
Diels-Alder reaction (Povarov reaction) and oxidative aroma-
tization, in a cascade reaction process. As a result, the reaction
of benzaldimines 1 and electron-rich olefins 2 in the presence
of the catalyst could afford substituted quinolines 4. As an
alternative way to access substituted quinolines, we found that
a one-pot reaction with the addition of DDQ as an oxidant would
be effective. The described approach in this paper would suggest
a rapid entry to synthesize substituted quinolines.
Experimental Section
Typical Procedure for Tf2NH-Catalyzed Cascade Povarov-
Hydrogen-Transfer Reaction (Table 1, Entry 5). To a stirred
solution of allyltriisopropylsilane (2a) (41.7 mg, 0.21 mmol) and
aldimine 1a (160 mg, 0.64 mmol) in 1,2-dichloroethane (0.9 mL)
was added Tf2NH (0.4 M solution in toluene, 52 µL, 21 µmol, 10
mol%) at ambient temperature. The reaction mixture was stirred at
60 °C for 24 h, diluted with CHCl3, and cooled to ambient
temperature. The mixture was quenched with satd NaHCO3, and
the aqueous phase was extracted twice with CHCl3. The combined
organic layers were dried over MgSO4, filtered, and concentrated
in vacuo. The crude mixture was purified by flash column
chromatography (2: 3 CHCl3-hexane with 0.5% NEt3, then CHCl3
with 0.5% NEt3) to afford 1,2,3,4-tetrahydroquinoline 3aa (46.4
mg, 49%, trans/cis ) 76:24) and quinoline 4aa (34.1 mg, 37%),
which was further purified by silica gel flash column chromatog-
raphy (1:8 AcOEt-hexane).
Acknowledgment. This work was financially supported by
a Grant-in-Aid for Scientific Research and Targeted Proteins
Research Program from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Supporting Information Available: Experimental proce-
dures, full spectral data for all new compounds, and copies of
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Sharples, D.; Hajo´s, G.; Riedl, Z.; Csa´nyi, D.; Molna´r, J.; Szabo´, D.
Arch. Pharm. 2001, 334, 269–274.
JO8009243
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