Cascade and one-pot processes providing substituted quinolines from aldimines and allylsilanes: auto-tandem catalysis of triflic imide

Article abstract of DOI:10.1016/j.tetlet.2007.05.032

We have demonstrated cascade and one-pot reactions, which constitute inverse electron demand hetero-Diels-Alder reaction and oxidative aromatization, to provide substituted quinolines to form aryl aldimines and allylsilanes. The cascade process involves a

Full text of DOI:10.1016/j.tetlet.2007.05.032

Tetrahedron Letters 48 (2007) 4749–4753
Cascade and one-pot processes providing substituted
quinolines from aldimines and allylsilanes: auto-tandem
catalysis of triflic imide
Naoya Shindoh, Hidetoshi Tokuyama* and Kiyosei Takasu*,
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Sendai 980-8578, Japan
Received 5 April 2007; revised 26 April 2007; accepted 1 May 2007
Available online 22 May 2007
Abstract—We have demonstrated cascade and one-pot reactions, which constitute inverse electron demand hetero-Diels–Alder reac-
tion and oxidative aromatization, to provide substituted quinolines to form aryl aldimines and allylsilanes. The cascade process
involves an auto-tandem catalysis; Tf2NH activates these mechanistically distinct reactions. We have found that a multicomponent
process starting from aniline, aldehyde, and allylsilane is also available.
Ó 2007 Elsevier Ltd. All rights reserved.
Classes of cascade and one-pot reactions, which include
multiple bond formation and/or transformation of func-
tional groups, provide powerful and useful methods for
the synthesis of structurally complex molecules.1 Cas-
cade and one-pot reactions, if possible, the catalytic
variants, would give a number of opportunities to
improve chemical transformations, such as reduction
of the number of reaction operations, saving reagents,
energy, time and labor, and minimum generation of
waste. Therefore, development of efficient cascade pro-
cesses would lead to significant economical and ecolog-
ical impact.
we have recently reported Tf2NH-catalyzed imino
Diels–Alder reaction of imines with 2-siloxydienes or
its analogous three-component reaction to provide
multi-substituted piperidin-4-ones.6e As a part of our
continuous efforts, we were intrigued that Tf2NH would
display good catalytic activity in an inverse electron
demand hetero-Diels–Alder reaction of 2-azadienes with
electron-rich olefins.8 In the reaction, we have also
found that the same catalyst, Tf2NH, activates dehydro-
genation of tetrahydroquinolines in the presence of
imine. We wish to report herein a cascade hetero-
Diels–Alder reaction and oxidative aromatization, cata-
lyzed by Tf2NH, to construct substituted quinolines. In
addition, we wish to describe a one-pot process that pro-
vides quinolines by the assistance of DDQ.
Several groups depicted the significant utility of triflic
imide (Tf2NH) in the catalytic carbon–carbon (C–C)
bond formation reactions, such as aldol reactions,2
Mannich reactions,3 Diels–Alder reactions,4 and so
on.5 Recently, we have independently reported Tf2NH
shows good catalytic performance in several cycloaddi-
tion and cascade reactions.6 In the processes, Tf2NH
acts as a strong Brønsted acid, as well as a precursor
of the strong Lewis acidic silyl triflic imide,7 which is
generated in situ by reaction with silylated substrates,
such as silyl enol ethers and allylsilanes. For instance,
Benzylideneaniline 1a (1.0 equiv) was treated with allyl-
triisopropylsilane (2a, 1.0 equiv) in the presence of
Tf2NH (10 mol %) in CH2Cl2 (DCM) at 60 °C for
24 h. Tetrahydroquinoline 3aa was obtained in 51%
yield as a mixture of two diastereomers (trans:
cis = 10:9), together with quinoline 4aa (12% yield),
which resulted from oxidation of 3aa (Table 1, run 1).
The stereochemistry of both diastereomers of 3aa was
1
determined by the coupling constants of H NMR. At
the same time, production of amine 5 was observed.
We believed that hydrogen transfer between the yielded
tetrahydroquinoline 3aa and imine 1a would take place
in this reaction. Thus, when the reaction of 2a
(1.0 equiv) with an excess amount of 1a (3.0 equiv) in
*
Corresponding authors. E-mail addresses: kay-t@mail.pharm.tohoku.
ac.jp; kay-t@pharm.kyoto-u.ac.jp
Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University, Japan.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.032

4750
N. Shindoh et al. / Tetrahedron Letters 48 (2007) 4749–4753
Table 1. Reaction of aldimine 1a and allylsilanes 2 in the presence of Tf2NHa
Tf2NH (10 mol%)
F3C
Si
+
N
Ph
1a (3 eq)
2 (1 eq)
Si
Si
F3C
F3C
+
N
H
Ph
N
Ph
3
4
Run
2 (Si)
Solvent
Yieldb (%)
3 (trans:cis)c
4
Total (3 + 4)
1d
2
2a (TIPS)
2a
DCM
DCM
DCM
DCE
Toluene
Toluene
Toluene
51 (53:47)
48 (74:26)
36 (100:0)
49 (76:24)
32 (71:29)
10 (73:27)g
32 (66:34)
12
31
48
37
44
Trace
39
63
79
84
86
66
10
71
3e
4
2a
2a
5
2a
2b (TMS)
2c (TBS)
6f
7
a Reaction conditions: 1a (3.0 equiv), 2 (1.0 equiv), Tf2NH (10 mol %), 12 h.
b Isolated yields. All chemical yields are calculated based on 2.
c The diastereomeric ratios were determined by 1H NMR.
d Reaction conditions: 1a (1.0 equiv), 2 (1.0 equiv), Tf2NH (10 mol %), 12 h.
e Reaction conditions: 1a (3.0 equiv), 2 (1.0 equiv), Tf2NH (15 mol %), 6 days.
f Compound 5 was obtained in 22% yield as a byproduct.
g The yield has ꢀ10% error owing to contamination of inseparable impurities.
F3C
F3C
N
H
Ph
N
H
Ph
5
6
the presence of Tf2NH was carried out, the chemical
yield of 4aa increased to 31%, whereas production of
3aa decreased to 48% and its trans/cis ratio was changed
to 3:1 (run 2). When the reaction time was prolonged to
six days using 15 mol % of Tf2NH, trans-3aa as a single
diastereomer and 4aa were obtained in 36% and 48%
yield, respectively (run 3). These results indicate kinetic
resolution of two diastereomers of 3aa proceeds in the
oxidation process, and the reaction rate of cis-3aa is
much faster than that of trans-3aa. In fact, no reaction
occurred when the isolated trans-3aa was exposed to a
similar reaction conditions (with 2.0 equiv of 1a in the
presence of 10 mol % of Tf2NH in DCM). Next, the
solvent effect was examined. Production of 4aa slightly
increased in 1,2-dichloroethane (DCE) and toluene
(runs 4 and 5). Notably, we found the rate of the
hetero-Diels–Alder reaction of 1a with 2a in DCE was
faster than that in toluene, but, in contrast, oxidation
of 3aa smoothly proceeded in toluene rather than in
DCE. Reaction in polar solvents, such as THF, CH3CN
and AcOEt, resulted in no formation of 4aa and poor
production of 3aa, but generation of homoallylamine 6
was observed. When allyltrimethylsilane (2b) was
employed, both 3ab and 4ab were obtained in low yield,9
but the Hosomi–Sakurai type adduct 6 was obtained
(run 6). In contrast, allyl-tert-butyldimethylsilane (2c)
bearing a sterically demanding silyl group suppressed
formation of 6 and thereby furnished heterocyclic
compounds 3ac and 4ac (run 7).
We have considered that the cascade process involves
an auto-tandem catalysis, in which Tf2NH activates
both hetero-Diels–Alder reaction of 1 with 2 and
oxidation of 3. The term ‘auto-tandem catalysis’ is
defined as one catalyst which promotes two or more
mechanistically distinct reactions in a cascade reaction
process.10 Recently, an auto-tandem catalysis received
significant attention in its synthetic efficiency.6d,11,12 It
was also made clear that the oxidative aromatization
was promoted by the assistance of both imine 1 and
Tf2NH. In the absence of either 1 or Tf2NH, no for-
mation of the dehydrogenated product from tetra-
hydroquinoline 3aa (as a 1:1 diastereomeric mixture)
was observed. The inverse electron demand hetero-
Diels–Alder reaction of aryl aldimines with allylsilanes
was reported by Akiyama and his co-workers as a rare
example.13 In the literature, stoichiometric amounts
of SnCl4 promoted the reaction to give tetrahydro-
quinolines. Moreover, to the best of our knowledge,
no example for successive dehydrogenation to fur-
nish quinolines from tetrahydroquinolines has been
reported.14

N. Shindoh et al. / Tetrahedron Letters 48 (2007) 4749–4753
4751
For the practical synthesis of quinoline derivatives,
we established an alternative oxidative conversion of
trans-3aa into 4aa using 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ). Thus, treatment of trans-3aa
with two equivalents of DDQ in DCE at ambient tem-
perature for 1 h, 78% yield of qinoline 4aa was obtained
in the presence of 10 mol % of Tf2NH.15 Since Tf2NH
was compatible to these oxidative conditions, we
extended the reaction sequence to a one-pot quinoline
synthesis with DDQ. After treatment of a mixture of
imine 1a (1.25 equiv) and allylsilane 2a (1.0 equiv) with
a catalytic amount of Tf2NH (10 mol %) in DCE,
DDQ (2.0 equiv) was added to the reaction mixture to
furnish quinoline 4aa in 84% yield (Scheme 1). The
one-pot reaction would be an alternative method to pro-
vide quinolines against the above auto-tandem catalysis
procedure.
an auto-tandem catalyst to give quinoline 4. In method
A (in the presence of an excess amount of imine), the
chemical yield of 4 resulted in low to moderate yield,
and tetrahydroquinoline 3, in which the trans diastereo-
mer was enriched, was obtained (runs 1, 2, 4, 5, 7, 9, and
10). Imine 1h, which was prepared from electron-donat-
ing p-anisidine and electron-withdrawing p-nitrobenzal-
dehyde, afforded quinoline 4ha in 47% yield by method
A (run 10). In method B (consequent addition of
2.0 equiv DDQ), quinoline 4 was obtained in good yield
(runs 3, 6, 8, 11, and 12). It should be noted that the
reaction of substrates containing halogen or nitro
groups, which make possible further derivatization,
occurred smoothly.
It is sometimes difficult to isolate and handle an alkyl
aldimine prepared from an aliphatic aldehyde, owing
to its instability. To avoid these problems, we envisaged
to elaborate the cascade reaction to the multicomponent
variant. When a mixture of 2a (1.0 equiv), aniline 7
(3.0 equiv), and isobutylaldehyde (8) (3.0 equiv) in the
presence of Tf2NH (10 mol %) in toluene was stirred
at 60 °C (under method A-like conditions), only tetra-
hydroquinoline 3ka was obtained in 60% yield as a 1:1
diastereomeric mixture (Scheme 2a). However, no
formation of 4 was observed, despite the excess amount
of imine that would be formed in the reaction. On the
other hand, quinoline 4ka could be synthesized under
method B-like conditions. Thus, heating a mixture of
2a (1.0 equiv), 7 (1.25 equiv) and 8 (1.25 equiv) in
DCE at 60 °C, followed by addition of DDQ (2.0 equiv)
With two standard conditions in hand, we investigated
the scope of the hetero-Diels–Alder reaction and succes-
sive oxidation reaction. Some of the typical results are
summarized in Table 2. In all the cases, Tf2NH acts as
Tf2NH (10 mol%)
DCE, 60 °C, 3 h;
1a
4aa
+
2a
DDQ (2 eq)
rt, 10 min
84% yield
Scheme 1.
Table 2. Scope of the auto-tandem catalysis procedurea
TIPS
TIPS
method A or B
+
TIPS
R
R
R
+
N
H
Ar
N
Ar
N
Ar
2
1
3
4
Run
1 (R, Ar)
Method
Products
Yieldb (%)
3 (trans:cis)c
4
Total (3 + 4)
1
2
3
4
5
6
7
8
9
1b (H, Ph)
1c (p-NO2, Ph)
1c
A
A
B
3ba, 4ba
3ca, 4ca
4ca
11 (72:28)
28
28d
83
39
41
60
19
72
34
47
68
66
39
88
83
55
66
60
66
72
39
74
68
66
60 (60:40)d
0
1d (p-Cl, Ph)
1e (p-Br, Ph)
1e
A
A
Be
A
Be
A
A
Bf
Bg
3da, 4da
3ea, 4ea
4ea
16 (84:16)
15 (79:21)
0
47 (60:40)
0
5 (91:9)
27 (62:38)
1f (o-Br, Ph)
1f
3fa, 4fa
4fa
1g (p-MeO, Ph)
3ga, 4ga
3ha, 4ha
4ia
10
11
12
1h (p-MeO, p-NO2C6H4)
1i (p-Br, o-NO2C6H4)
1j (o-Br, o-NO2C6H4)
0
0
4ja
a Reaction conditions: method A; 1 (3.0 equiv), 2a (1.0 equiv), Tf2NH (10 mol %), toluene, 60 °C, 24 h. method B; 1 (1.25 equiv), 2a (1.0 equiv),
Tf2NH (15 mol %), DCE, 60 °C, 3 h; then DDQ (2.0 equiv), rt, 10 min.
b Isolated yields. All chemical yields are calculated based on 2.
c The diastereomeric ratios were determined by 1H NMR.
d The yield has ꢀ10% error owing to contamination of inseparable impurities.
e Hetero-Diels–Alder reaction was carried out for 24 h.
f Hetero-Diels–Alder reaction was carried out for 1 h.
g Hetero-Diels–Alder reaction and DDQ-oxidation were carried out for 45 min and 1 h, respectively.

4752
N. Shindoh et al. / Tetrahedron Letters 48 (2007) 4749–4753
In summary, we have found Tf2NH acts as an auto-
F3C
OHC
tandem catalyst, which activates an inverse electron
demand hetero-Diels–Alder reaction and successive
oxidative aromatization, to give substituted quinolines
4 from aldimines 1 with allylsilanes 2. Notably, a multi-
component strategy is also available. In the course of
this study, we made clear two new catalytic aspects of
Tf2NH. To the best of our knowledge, Tf2NH is the first
example of a catalyst for inverse electron demand het-
ero-Diels–Alder reactions of aryl aldimines with allylsil-
anes. Second, tetrahydroquinoline 3 can be oxidized into
4 by the assistance of imine as an oxidant in the presence
of catalytic amounts of Tf2NH. As an alternative way to
access substituted quinolines, we found a one-pot reac-
tion adding DDQ as an oxidant would be effective. Fur-
ther extension of the auto-tandem catalysis procedure
into rapid synthesis of biologically active compounds
is in progress.
(a)
2a
+
+
NH2
(1 eq)
7 (3 eq)
8 (3 eq)
TIPS
F3C
Tf2NH (10 mol%)
toluene, 60 °C
24 h
60% (dr = 1 : 1)
N
H
3ka
2a
(1 eq)
7
8
+
+
(b)
(1.25 eq) (1.25 eq)
TIPS
Tf2NH (10 mol%)
DCE, 60 °C, 24 h;
F3C
DDQ (2.0 eq)
rt, 15 min
52%
N
4ka
Scheme 2. Multicomponent reaction.
Acknowledgments
This work was financially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
at rt, successfully furnished 4ka in 52% yield (Scheme
2b).
Quinolines are important ring systems present in a vari-
ety of natural products, pharmaceuticals, and agro-
chemicals. To demonstrate the synthetic utility of the
products in the above cascade process, transformation
reactions of 4 were summarized in Scheme 3. Protodesi-
lylation of 4aa can be accomplished by the treatment of
tetrabutylammonium fluoride (TBAF) in the presence of
H2O to give methylquinoline 9 in quantitative yield. In
the presence of an aldehyde, instead of H2O as an elec-
trophile, alcohol 10 was obtained in 53% yield from 4aa
with formation of a new C–C bond. Moreover, the
reaction of 4aa with CsF in the presence of hexachloro-
ethane as an electrophile16 afforded 11, whose chloro-
methyl moiety would be a trigger for further chemical
transformation.
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TIPS
Ph
TBAF (1 eq)
H2O (2 eq)
Me
N
F3C
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98%
Ph
N
4aa
9
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see: (a) Field, L. D.; Messerle, B. A.; Wren, S. L.
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Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004, 126, 1352–
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OH
TBAF (1 eq)
i-PrCHO (3 eq)
F3C
4aa
THF, rt, 12 h
53%
N
N
Ph
10
11
Cl
C2Cl6 (2 eq)
CsF (2 eq)
F3C
4aa
MeCN, 70 °C, 24 h
Ph
66%
Scheme 3. Desilylative transformation of 4.

N. Shindoh et al. / Tetrahedron Letters 48 (2007) 4749–4753
4753
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